WO2024012554A1 - Tpk激动剂及使用其治疗神经退行性疾病的方法 - Google Patents

Tpk激动剂及使用其治疗神经退行性疾病的方法 Download PDF

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WO2024012554A1
WO2024012554A1 PCT/CN2023/107391 CN2023107391W WO2024012554A1 WO 2024012554 A1 WO2024012554 A1 WO 2024012554A1 CN 2023107391 W CN2023107391 W CN 2023107391W WO 2024012554 A1 WO2024012554 A1 WO 2024012554A1
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alkylene
alkyl
compound
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French (fr)
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孟丽娟
景何凤
张寰
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上海日馨医药科技股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/10—1,4-Thiazines; Hydrogenated 1,4-thiazines
    • C07D279/14—1,4-Thiazines; Hydrogenated 1,4-thiazines condensed with carbocyclic rings or ring systems
    • C07D279/18—[b, e]-condensed with two six-membered rings
    • C07D279/32—[b, e]-condensed with two six-membered rings with hetero atoms directly attached to the ring nitrogen atom

Definitions

  • the present invention belongs to the field of biomedicine, and specifically relates to a method for preventing or treating neurodegenerative diseases or alleviating the symptoms of neurodegenerative diseases, which includes administering a preventive or therapeutically effective amount of thiamine pyrophosphate kinase (thiamine pyrophosphate kinase) to an individual in need thereof TPK) agonist.
  • thiamine pyrophosphate kinase thiamine pyrophosphate kinase
  • AD Alzheimer’s disease
  • GDP global gross domestic product
  • AD Alzheimer's disease
  • pathophysiological changes including neuronal loss, glial cell activation, and characteristic senile plaques formed by extracellular amyloid beta (A ⁇ ) deposition, and neurofibrillary tangles caused by hyperphosphorylation of intracellular Tau protein. Knot etc.
  • synapse loss, brain glucose metabolism disorders, oxidative stress, etc. are also constant pathological changes in the AD brain, and decreased brain glucose metabolism in patients is closely related to cognitive dysfunction. Due to unclear pathogenesis, AD still lacks effective treatments.
  • glucose metabolism disorder may be an early preclinical feature of AD.
  • the intracellular metabolism of glucose in AD patients is mainly characterized by three key enzymes (pyruvate dehydrogenase, ⁇ -ketoglutarate dehydrogenase and transketolase) that rely on thiamine diphosphate (TDP) as a coenzyme. ) activity decreased significantly.
  • TDP thiamine diphosphate
  • Multi-center clinical studies have proven that decreased TDP levels in AD patients are a specific and common phenomenon with good diagnostic value, while patients with vascular dementia and frontotemporal dementia do not have abnormal thiamine metabolism.
  • Clinical combined with experimental studies have further shown that decreased TDP is the cause of cerebral glucose metabolism disorders.
  • TPK agonists can be used for the prevention or treatment of neurodegenerative diseases (especially Alzheimer's disease).
  • the present invention provides a method of preventing or treating a neurodegenerative disease or alleviating symptoms of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of thiamine pyrophosphate kinase (TPK) Agonists.
  • TPK thiamine pyrophosphate kinase
  • the invention provides the use of a TPK agonist in the preparation of a medicament for preventing or treating neurodegenerative diseases or alleviating symptoms of neurodegenerative diseases.
  • the present invention provides TPK agonists for preventing or treating neurodegenerative diseases or alleviating symptoms of neurodegenerative diseases.
  • the neurodegenerative disease is preferably Alzheimer's disease; more preferably, the Alzheimer's disease is Alzheimer's disease in which the individual's TPK enzyme activity is reduced, TPK expression level is reduced, and/or TDP level is reduced.
  • the invention relates to TPK agonists with novel structures.
  • the divalent group can be attached to the two groups in any direction. For example, if the other two groups connected by the dimethyl group -CONR- are (group 1) and (group 2), then (group 1)-CONR-(group 2) and (group 2) 2)-CONR- (group 1) are included.
  • alkylene refers to a saturated divalent hydrocarbon radical, preferably having 1, 2, 3, 4, 5 or 6 carbon atoms.
  • a saturated divalent hydrocarbon group such as methylene, ethylene, propylene or butylene.
  • alkyl is defined as a straight or branched chain saturated aliphatic hydrocarbon.
  • an alkyl group has 1 to 12, such as 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl base, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents such as halogen (in which case the group group is called a "haloalkyl”) (eg CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl or -CH 2 CH 2 CF 3 , etc.
  • halogen in which case the group group is called a "haloalkyl
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • alkynyl means a monovalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl, 2-propynyl, 2 -Butynyl, 1,3-butadiynyl, etc.
  • the alkynyl group is optionally substituted with one or more (such as 1 to 3) substituents that may be the same or different.
  • alkynylene refers to the corresponding divalent group, including, for example, “C 2-8 alkynylene", “C 2-6 alkynylene", “C 2-4 alkynylene” and the like. Examples include but are not limited to Etc., the alkynylene group is optionally substituted by one or more (such as 1 to 3) the same or different substituents.
  • ring or “fused ring” refers to a ring system formed by two or more cyclic structures sharing two adjacent atoms with each other.
  • spirocycle refers to a ring system formed by two or more cyclic structures sharing a ring atom with each other.
  • bridged ring refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other.
  • cycloalkylene As used herein, the terms “cycloalkylene”, “cycloalkyl” and “hydrocarbon ring” refer to having, for example, 3 to 10 (suitably 3 to 8, more suitably 3 to 6) ring carbons. Saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings of atoms (including Spiro ring, fused ring (fused ring) or bridged ring system), including but not limited to (ylidene) cyclopropyl (ring), (ylidene) cyclobutyl (ring), (ylidene) cyclopentyl (ring), (Ylidene) cyclohexyl (ring), (ylidene) cycloheptyl (ring), (ylidene) cyclooctyl (ring), (yliden
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cycloctyl, cyclononyl, or bicyclo, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or Bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cycloctyl, cyclononyl, or bicyclo
  • the cycloalkyl group has 3 to 15 carbon atoms .
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl or cyclopropyl) of 3 to 6 ring-forming carbon atoms. hexyl), optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl-substituted cyclopropyl.
  • 3-10 membered heterocyclyl groups are groups with 3-10 carbon atoms and heteroatoms in the ring, such as but not limited to oxiranyl, aziridinyl, azetidinyl ( azetidinyl), oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyridyl pyryl, piperidyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.
  • heterocyclyl encompasses fused ring structures whose point of attachment to other groups can be on any ring in the fused ring structure. Accordingly, heterocyclyl groups of the present invention also include, but are not limited to, heterocyclyl-heterocyclyl, heterocyclyl-cycloalkyl, mono-heterocyclyl-monoheterocyclyl, mono-heterocyclyl-monocycloalkyl, e.g.
  • heterocyclyl encompasses bridged heterocyclyl and spiroheterocyclyl.
  • bridged heterocycle refers to two saturated rings that share two ring atoms that are not directly connected and contain one or more (e.g., 1, 2, 3, or 4) heteroatoms. (such as oxygen atoms, nitrogen atoms and/or sulfur atoms), including but not limited to 7-10-membered bridged heterocycles, 8-10-membered bridged heterocycles, 7-10-membered nitrogen-containing bridged heterocycles, 7- 10-membered oxygen-bridged heterocycles, 7-10-membered sulfur-bridged heterocycles, etc., such as wait.
  • the "nitrogen-containing bridged heterocycle", “oxygen-containing bridged heterocycle” and “sulfur-containing bridged heterocycle” optionally also contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • spiroheterocycle refers to a ring containing one or more (eg, 1, 2, 3, or 4) heteroatoms formed from two or more saturated rings sharing one ring atom. (such as oxygen atoms, nitrogen atoms, sulfur atoms), including but not limited to 5-10-membered spiroheterocycles, 6-10-membered spiroheterocycles, 6-10-membered nitrogen-containing spiroheterocycles, 6-10-membered spiroheterocycles, Oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc., such as
  • the "nitrogen-containing spiroheterocycle", “oxygen-containing spiroheterocycle” and “sulfur-containing spiroheterocycle” optionally also contain one or more other heteroatoms selected from oxygen, nitrogen and sulfur.
  • the terms "(arylene)” and “aromatic ring” refer to monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean aromatic groups containing 6 to 10 carbon atoms, such as ()phenylene (Benzene ring) or (phenylene) naphthyl (naphthalene ring).
  • the ()arylene groups and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • the fused ring may be a hydrocarbon ring, a heterocyclic ring or a heteroaromatic ring.
  • aralkyl preferably means an aryl-substituted alkyl group, wherein said aryl and said alkyl are as defined herein.
  • the aryl group may have 6 to 14 carbon atoms
  • the alkyl group may have 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroarylene and “heteroaryl 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 it contains at least one heteroatom which may be the same or different (the heteroatom is for example oxygen , nitrogen or sulfur), and, additionally in each case may be benzo-fused.
  • (ylidene)heteroaryl or “heteroaryl ring” is selected from (ylidene)thienyl (ring), (ylidene)furyl (ring), (ylidene)pyrrolyl (ring), (ylidene)oxane Azolyl (ring), (ylidene) thiazolyl (ring), (ylidene) imidazolyl (ring), (ylidene) pyrazolyl (ring), (ylidene) isoxazolyl (ring), (ylidene) isothiazole base (ring), (ylidene) oxadiazolyl (ring), (ylidene) triazolyl (ring), (ylidene) thiadiazolyl (ring), etc., and their benzo derivatives; or (ylidene) Pyridyl (ring), (ylidene) pyridazinyl (ring), (ylidene) pyrimidinyl (ring
  • halo or halogen group is defined to include F, Cl, Br or I.
  • alkylthio means an alkyl group as defined above attached to the parent molecular moiety through a sulfur atom.
  • Representative examples of C 1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • the nitrogen-containing heterocycle is preferably a saturated nitrogen-containing monocyclic ring.
  • 3- to 14-membered nitrogen-containing heterocycles are groups having 3-14 carbon atoms and heteroatoms (at least one of which is a nitrogen atom) in the ring, including but not limited to three-membered nitrogen-containing heterocycles (such as Aziridinyl), four-membered nitrogen-containing heterocycle (such as azetidinyl), five-membered nitrogen-containing heterocycle (such as pyrrolyl, pyrrolidinyl (pyrrolidine ring), pyrrolinyl, pyrrolidonyl, imidazole base, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl), six-membered nitrogen-containing heterocycle (such as piperidinyl (piperidine ring), morpholinyl, thiomorpholinyl, piperazinyl) , seven-membered nitrogen-containing heterocycle, etc.
  • three-membered nitrogen-containing heterocycles such as Azirid
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present in the case of normal valence and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the substituent lists, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Optional substituent substitutions of choice. If the nitrogen of a substituent is described as optionally substituted with one or more of the substituents listed, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected as optional. substitution of substituents.
  • each substituent is selected independently of the other.
  • each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position on the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of the present invention except that one or more atoms are substituted with the same atomic number but an atomic mass or mass number different from the atomic mass that predominates in nature. or atomic substitution of mass number.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium (D, 2 H), tritium (T, 3 H)); isotopes of carbon (e.g., 11 C, 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g.
  • isotopes of iodine e.g. 123 I and 125 I
  • isotopes of nitrogen e.g. 13 N and 15 N
  • isotopes of oxygen such as 15 O, 17 O and 18 O
  • isotopes of phosphorus such as 32 P
  • isotopes of sulfur such as 35 S.
  • Certain isotopically labeled compounds of the invention eg, those incorporating radioactive isotopes
  • the radioactive isotopes tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and detect.
  • positron emitting isotopes eg 11 C, 18 F, 15 O and 13 N
  • PTT positron emission tomography
  • Isotopically labeled compounds of the invention may be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using appropriate isotopically labeled reagents in place of the previously employed non-labeled reagents.
  • Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent may be isotopically substituted, for example, D2O , acetone- d6 or DMSO- d6 .
  • compositions of the present invention may exist in free form for therapeutic use, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs that can be directly administered to a patient in need thereof. Or indirectly provide the compound of the invention or its metabolites or residues. Therefore, when reference is made herein to "a compound of the invention", it is also intended to encompass the various derivative forms of the compound described above.
  • Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids that form pharmaceutically acceptable salts. Examples include aspartate, benzoate, bicarbonate/carbonate, bisulfate/sulfate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluoride Phosphate, hydrobromide/bromide, hydroiodide/iodide, maleate, malonate, methyl sulfate, naphthylate, nicotinate, nitrate , orotate, oxalate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases that 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.
  • esters means esters derived from compounds of each general formula herein, 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 present invention may themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise as structural elements of the crystal lattice of the compounds a polar solvent, in particular such as water, methanol or ethanol.
  • a polar solvent in particular such as water, methanol or ethanol.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention ie substances formed in the body upon administration of the compounds of the invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidation, enzymatic hydrolysis, etc. of the administered compound.
  • the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce metabolites thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which may themselves have little or no pharmacological activity when administered into or onto the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound that are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems," Volume 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 ( Edited by E.B. Roche, American Pharmaceutical Association).
  • prodrugs of the invention may be prepared, for example, by using certain moieties known to those skilled in the art as "pro-moiety” (e.g. described in “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)) Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any relevant molecules, thereby forming chemically protected forms of the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 Protecting Groups, these references are incorporated herein by reference.
  • the protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the term "about” means within ⁇ 10%, preferably ⁇ 5%, and more preferably ⁇ 2% of the stated value.
  • an effective amount refers to an amount of a compound that, when administered, alleviates to a certain extent one or more symptoms of the condition being treated.
  • prevention refers to the prior administration of a drug to avoid or prevent the occurrence of one or more symptoms of a disease or condition.
  • prevention is not an absolute term. In the medical field, it is understood to mean the prophylactic administration of a drug to substantially reduce the likelihood or severity of a condition or the symptoms of a condition, which is the meaning intended in this disclosure.
  • Prevention is divided into primary prevention (to prevent the development of the disease) and secondary prevention (whereby the disease has already developed and the patient is protected against the progression of the process).
  • treating means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Preventing such a disease or condition or one or more symptoms of such a disease or condition.
  • “Individual” as used herein includes humans or non-human animals.
  • Exemplary human subjects include human subjects (referred to as patients) suffering from a disease, such as those described herein, or normal subjects.
  • non-human animals include all vertebrates, such as non-mammals (such as birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals and/or domesticated animals (such as sheep, dogs , cats, cows, pigs, etc.).
  • the term "reduced TPK enzyme activity” means that the TPK enzyme activity in a treated individual is lower than the enzyme activity in a normal individual.
  • the term "reduced TPK expression levels” means that TPK mRNA/DNA levels or protein expression levels in a treated individual are lower than those in normal individuals.
  • the term "reduced TDP level” means that the TDP level in a treated individual is lower than the level in a normal individual.
  • the invention provides a method of preventing or treating a neurodegenerative disease or alleviating symptoms of a neurodegenerative disease, comprising administering to an individual in need thereof a prophylactically or therapeutically effective amount of thiamine pyrophosphate kinase (TPK ) agonist.
  • TPK thiamine pyrophosphate kinase
  • the neurodegenerative disease is Alzheimer's disease.
  • 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.
  • the TPK agonist is a compound of Formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope thereof Labeled compound, metabolite or prodrug:
  • the TPK agonist is a compound of formula (I), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, or isotopically labeled compound thereof. , metabolites or prodrugs:
  • a and B are each independently CR 3 or N;
  • Ring C and Ring D are each independently a C 3-10 hydrocarbon ring (such as a C 3-6 hydrocarbon ring), a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring; preferably, Ring C is a 5-6 membered heteroaromatic ring;
  • R, R a and R b is independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5- 14-membered heteroaryl and C 6-12 aralkyl;
  • n 0, 1, 2, 3 or 4; preferably, n is 0, 1 or 2;
  • Ring C is a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring, or a 5-14 membered heteroaromatic ring.
  • the TPK agonist is a compound of formula (II), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, Isotopically labeled compounds, metabolites or prodrugs:
  • X is -C(R) 2 -, -NR-, -O- or -S-; preferably X is -NR-, -O- or -S-; more preferably X is -NH-, -N( CH 3 )-, -O- or -S-; and
  • each occurrence of R 3 is independently H or C 1-6 alkyl (preferably methyl);
  • a and B are each independently CH, CCH 3 or N; and
  • A is N and B is CH.
  • L 2 is absent or -(3-10 membered heterocyclylene)-;
  • L2 is absent or is piperazinylene or piperidinylene.
  • R 1 at each occurrence is independently selected from halogen, -CN, C 1-6 alkyl, haloC 1-6 alkyl, and C 1-6 alkoxy;
  • R 1 at each occurrence is independently selected from -F, -Cl, -Br, -CN, -CH 3 , -CF 3 and -OCH 3 .
  • R 2 is independently selected from isopropyl
  • the TPK agonist is a compound of formula (III), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, Isotopically labeled compounds, metabolites or prodrugs:
  • the TPK agonist is a compound of Formula (IV), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, isotope thereof Labeled compound, metabolite or prodrug:
  • Ring D does not exist or is a C 3-6 hydrocarbon ring, a 3-10 membered heterocyclic ring, a C 6-10 aromatic ring or a 5-14 membered heteroaromatic ring;
  • R', R e and R f is independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5 -14-membered heteroaryl and C 6-12 aralkyl;
  • p and q are each independently 1, 2, 3 or 4; preferably, p and q are each independently 1 or 2; provided that when ring D does not exist, q is 1;
  • the TPK agonist is a compound of formula (V), or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate, N-oxide, Isotopically labeled compounds, metabolites or prodrugs:
  • the TPK agonist is selected from:
  • the TPK agonist is administered in an amount of about 0.005 mg/day to about 5000 mg/day, such as 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 5000mg /day dosage.
  • the TPK agonist is administered in an amount of about 1 ng/kg to about 200 mg/kg, about 1 ⁇ g/kg to about 100 mg/kg, or about 1 mg/kg to about 50 mg/kg body weight per day. , for example, about 1 ⁇ g/kg, about 10 ⁇ g/kg, about 25 ⁇ g/kg, about 50 ⁇ g/kg, about 75 ⁇ g/kg, about 100 ⁇ g/kg, about 125 ⁇ g/kg, about 150 ⁇ g/kg, about 175 ⁇ g/kg, About 200 ⁇ g/kg, about 225 ⁇ g/kg, about 250 ⁇ g/kg, about 275 ⁇ g/kg, about 300 ⁇ g/kg, about 325 ⁇ g/kg, about 350 ⁇ g/kg, about 375 ⁇ g/kg, about 400 ⁇ g/kg, about 425 ⁇ g/kg, About 450 ⁇ g/kg, about 475 ⁇ g/kg, about 500 ⁇ g/kg, about 525 ⁇ g/kg, about 550 ⁇ g/kg, about 5
  • the daily dose of the TPK agonist is administered in one go or in two, three or four divided doses.
  • 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 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.
  • the TPK agonist is administered for one or more (eg, 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 courses of treatment is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days, two weeks, three weeks, or four weeks.
  • the TPK agonist is administered by injection (eg, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation) or transdermally; or by oral, buccal, or transdermal administration.
  • injection eg, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular injection, including instillation
  • transdermally e.g., oral, buccal, or transdermal administration.
  • the TPK agonist is administered in a form selected from tablets, capsules, lozenges, hard candies, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, It is administered in the form of elixirs, ointments, aqueous suspensions, injectable solutions, elixirs and syrups.
  • the method ameliorates the following pathophysiological manifestations in an individual: cognitive behavioral abnormalities, neurodegenerative changes (e.g., progressive synaptic/neuronal loss and brain atrophy), beta-amyloid deposition, Abnormal phosphorylation of Tau and the resulting neurofibrillary tangles, glial cell activation and inflammation and/or cerebral glucose metabolism disorders.
  • the present disclosure also encompasses the administration of one or more additional therapeutic agents.
  • the present disclosure provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro- Drug, the compound has the structure of formula (III):
  • -L 3 -R 2 is other than H and methyl.
  • the present invention encompasses any combination of the above embodiments.
  • the present disclosure provides compounds, or pharmaceutically acceptable salts, esters, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro- Medicine, wherein said compound is selected from:
  • Example 2 Except that 1b in Example 1 was replaced with 1-(2,5-dichlorophenyl)piperazine hydrochloride (2b) and the reaction solvent was replaced with DMF, the same synthetic route as in Example 1 was used to prepare The title compound 2 (off-white solid) was obtained.
  • Step 1 Add 3a (10g, 75.8mmol, 1.0eq), triethylamine (15.3g, 151.6mmol, 2.0eq), and DCM (100mL) into a 500mL three-necked flask, cool down in an ice bath, and add acetyl chloride (7.1g) dropwise. , 90.96mmol, 1.2eq), stirred at room temperature for 3h, concentrated, and purified by column chromatography to obtain yellow solid intermediate product 3A (8.0g, yield: 60.6%).
  • Step 2 Add 3A (9.0g, 51.7mmol, 1.0eq) and THF (100mL) into a 250mL three-necked flask, cool it in an ice bath, add NaH (3.1g, 77.6mmol, 1.5eq) and ethyl bromoacetate (12.9g) , 0.405mmol, 1.2eq), stir at room temperature for 2 hours, add water to quench, extract with EA, dry the organic phase, concentrate, and obtain white solid intermediate 3B (8.4g, yield: 62.4%) by column chromatography.
  • Step 3 Add 3B (8.4g, 32.3mmol, 1.0eq) and THF (100mL) into a 250mL three-necked flask, cool it in an ice bath, add potassium tert-butoxide (3.84g, 32.3mmol, 1.0eq), and stir at room temperature for 2 hours. , add water to quench, extract with EA, dry the organic phase, and concentrate. Column chromatography yielded white solid intermediate product 3C (4.4g, yield: 62.4%).
  • Step 4 Add 3C (2g, 9.17mmol, 1.0eq), DMF (20mL), and DMF-DMA (4.36g, 36.68mmol, 4.0eq) into a 100mL single-neck bottle, raise the temperature to 70°C, react for 7h, and concentrate to obtain a yellow solid. The 3D crude product is directly used for the next step of reaction.
  • Step 5 Add 3D (crude product, 9.17mmol, 1.0eq), ethanol (20mL) and ⁇ -alanine ethyl ester hydrochloride (2.8g, 18.34mmol, 2.0eq) into a 250mL single-neck bottle, and heat it to 70°C React for 7 hours, cool and crystallize, and filter to obtain white solid intermediate product 3E (1.8g, yield: 65.6%).
  • Step 7 Add 3F (150 mg, 0.55 mmol, 1.0 eq.) to N, N-dimethylformamide (7 mL), add HATU (252 mg, 0.66 mmol, 1.2 eq.), and react at room temperature for 1 h. Add 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.), and react at room temperature overnight. The mixture was concentrated under reduced pressure, and the residue was triturated with methanol to obtain 140 mg of the title compound 3 (light yellow solid), yield: 52%.
  • Example 1 Except that 1b in Example 1 was replaced by 1-(2-trifluoromethylphenyl)piperazine, the title compound 4 (white solid) was obtained using the same synthetic route as in Example 1.
  • Step 1 Add 5a (5g, 28.54mmol) to DCM (100mL), then add dropwise a mixed reagent of 65% HNO 3 (2.77g, 28.54mmol) and AcOH (17.14g, 285.41mmol).
  • Step 2 Add 5A (2.2g, 9.99mmol) to methanol (30mL), then add 10% wt.Pd/C (220mg), and the reaction solution Stir at room temperature for 3 hours under the protection of a hydrogen balloon; filter, and spin the mother liquor to dryness to obtain brown solid intermediate product 5B (1.7g, yield: 89.5%).
  • Step 3 Add 5B (1.7g, 8.94mmol) to DMF (20mL), then add DMF-DMA (4.26g, 35.75mmol); stir the reaction solution at 80°C for 3 hours; add water to dilute, and extract with ethyl acetate. The organic phase was dried, filtered, and spun to dryness to obtain brown solid intermediate product 5C (2g, yield: 91.2%).
  • Step 4 Add 5C (1.8g, 7.34mmol) to MeOH (25mL), then add ⁇ -alanine ethyl ester hydrochloride (2.2g, 14.68mmol), and stir the reaction solution at 70°C for 3 hours; react The liquid was cooled to room temperature, a large amount of solid precipitated, filtered, and the filter cake was spun dry to obtain brown solid intermediate product 5D (1.3g, yield: 62.1%).
  • Step 6 Use the same method as Example 1 except that 1b in Example 1 is replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (5b) and 1a is replaced with 5E. According to the synthetic route, the title compound 5 (white solid) was obtained.
  • Step 1 Dissolve compound 6a (2.0g, 7.35mmol, 1.0eq.) in anhydrous tetrahydrofuran (30mL), add potassium tert-butoxide (824mg, 7.35mmol, 1.0eq.) in batches under ice bath, and react at room temperature. overnight.
  • Step 2-4 Except replacing 3C with 6A in Example 3, the same synthetic route as Step 4 to Step 6 in Example 3 was used to prepare compound 6D.
  • Step 5 Use the same synthetic route as Example 1 except that 1a in Example 1 is replaced with 6D and 1b is replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (5b). , to obtain the title compound 6 (yellow solid).
  • Example 1 Except that 1b in Example 1 was replaced by 1-(2,4-dichlorophenyl)piperazine hydrochloride, the same synthetic route as in Example 1 was used to prepare the title compound 7 (yellow solid).
  • Example 1 Except that 1b in Example 1 was replaced by 1-(2,6-dichlorophenyl)piperazine hydrochloride, the same synthetic route as in Example 1 was used to prepare the title compound 8 (white solid).
  • Example 1 Except that 1b in Example 1 was replaced with 1-(3,4-dichlorophenyl)piperazine hydrochloride, the same synthetic route as in Example 1 was used to prepare the title compound 9 (off-white solid) .
  • Example 1 Except that 1b in Example 1 was replaced by 10b, the title compound 10 (white solid) was obtained using the same synthetic route as in Example 1.
  • Step 2-5 Except replacing 5A with 11A in Example 5, the same synthetic route from step 2 to step 5 in Example 5 was used to prepare compound 11E.
  • Step 6 Except replacing 1b with 5b and 1a with 11E in Example 1, the title compound 11 (white solid) was prepared by using the same synthetic route as in Example 1.
  • Example 1 Except that 1b in Example 1 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (5b) and 1a was replaced with 12a, the same synthetic route as in Example 1 was used to prepare The title compound 12 (white solid) was obtained.
  • Example 1 Except that 1a in Example 1 was replaced by 3F, the same synthetic route as in Example 1 was used to prepare the title compound 13 (light yellow solid).
  • Example 1 Except that 1a in Example 1 was replaced by 3F and 1b was replaced by 1-(2,5-dichlorophenyl)piperazine hydrochloride, the same synthetic route as in Example 1 was used to prepare the title compound 14 (light yellow solid).
  • Step 1 Replace 11a with 15a in Step 1 of Example 11, and use the same synthesis method as Step 1 of Example 11 to prepare compound 15A.
  • Step 2-5 Replace 5A with 15A in Step 2 of Example 5, replace ⁇ -alanine ethyl ester hydrochloride with 15C-1 in Step 4, and prepare by using the same synthesis method as Step 2-5 of Example 5.
  • Compound 15E Replace 5A with 15A in Step 2 of Example 5, replace ⁇ -alanine ethyl ester hydrochloride with 15C-1 in Step 4, and prepare by using the same synthesis method as Step 2-5 of Example 5.
  • Step 6 Except replacing 1a in Example 1 with 15E, the title compound 15 (white solid) was prepared by using the same synthetic route as in Example 1.
  • Example 1 Except that 1b in Example 1 was replaced by 1-(3,5-bis(trifluoromethyl)phenyl)piperazine, the same synthetic route as in Example 1 was used to prepare the title compound 16 (white solid) .
  • the title compound 17 (white solid) was prepared using the same synthetic route as in Example 1, except that 1a was replaced by 15E and 1b was replaced by 5b in Example 1.
  • Example 1 Except that 1b in Example 1 was replaced by 1-(3-bromophenyl)piperazine, the same synthetic method as in Example 1 was used to prepare the title compound 18 (white solid).
  • Example 3 The same synthetic route as in Example 3 was adopted except that 3a in step 1 of Example 3 was replaced by 24a and 1-(2,4-dichlorophenyl)piperazine hydrochloride was replaced by 5b in step 7. The title compound 24 was obtained (white solid).
  • Example 1 Except that 1b in Example 1 was replaced by 1-(3-hydroxyphenyl)piperazine, the same synthetic route as in Example 1 was used to prepare the title compound 25 (white solid).
  • Step 1 Except that 1b in Example 1 is replaced with 1-(3-nitrophenyl)piperazine, the same synthetic route as in Example 1 is used to prepare intermediate product 26A (white solid).
  • Step 1 Except that 1b in Example 1 is replaced by ethyl 3-(piperazin-1-yl)benzoate, the same synthetic route as in Example 1 is used to prepare intermediate product 27A (white solid).
  • Step 2 Except that 1b in Example 1 is replaced by 28A, the title compound 28 (white solid) is prepared using the same synthetic route as Example 1.
  • Step 1 Add 15C (see Example 15 for the synthesis route) (550 mg, 2.06 mmol, 1.0 eq.), 4-aminobutanol (550 mg, 6.18 mmol, 3.0 eq.) and EtOH (8 mL) into the reaction bottle.
  • the reaction liquid was replaced three times under nitrogen and reacted at 85°C for 12 hours. TLC monitoring showed that after the reaction of the raw materials was completed, the reaction mixture was spin-dried and recrystallized with EtOAc (20 mL) to obtain 48A, a white solid.
  • Step 2 Add 48A (270 mg, 1.0 mmol, 1.0 eq.) and toluene (5 mL) to the reaction bottle, and then add sulfoxide dichloride (285 mg, 2.5 mmol, 2.5 eq.) dropwise to the reaction solution.
  • the reaction solution was reacted at 45°C for 3 hours.
  • LCMS monitoring showed that after the reaction of the raw materials was basically completed, the crude product 48B obtained by concentration was directly fed to the next step (280 mg, yield: 90%).
  • Step 3 Add 48B (280mg, 0.9mmol, 1.0eq.), N,N-dimethylformamide (8mL), potassium carbonate (478mg, 3.6mmol, 4.0eq.), potassium iodide (20mg, 0.09 mmol, 0.1 eq) and 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (266 mg, 0.99 mmol, 1.1 eq).
  • the reaction liquid was replaced three times under nitrogen and reacted at 85°C for 4 hours. TLC monitoring shows that after the reaction of the raw materials is completed, filter and spin to dryness.
  • Step 1 Add 48A (270 mg, 1.0 mmol, 1.0 eq.) and DCM (5 mL) to the reaction bottle, and then add Dess-Martin oxidant (510 mg, 1.2 mmol, 1.2 eq.) to the reaction solution in batches.
  • the reaction solution was allowed to react at room temperature for 1 hour.
  • Step 2 Add 50A (250mg, 0.9mmol, 1.0eq.) to the reaction bottle, dissolve it in MeOH (8mL), then add 1-(2,3-dichlorophenyl)piperazine hydrochloride (359mg , 1.35mmol, 1.5eq.), the reaction was stirred at room temperature and under nitrogen for 1 hour, and then sodium triacetoxyborohydride (780mg, 2.70mmol, 3.0eq.) was added in batches, and the reaction was stirred at room temperature and under nitrogen for 12 The reaction was completed after an hour, and the crude product was obtained by spinning to dryness. The crude product was purified using a C18 reverse-phase column. The target components were collected and concentrated to obtain the title compound 50 (white solid).
  • Example 29 Except that 4-aminobutanol in step 1 of Example 29 was replaced with 3-amino-1-propanol, 15C was replaced with 6B, and the same synthetic route as in Example 29 was used to prepare the title compound 51 (light yellow solid) .
  • Example 1 Except that 1a in Example 1 was replaced by 6D and 1b was replaced by 53b, the title compound 53 (light yellow solid) was obtained by using the same synthetic route as in Example 1.
  • Example 6 In addition to replacing 1-(2,4-dichlorophenyl)piperazine hydrochloride in Example 6 with 1-(3,4,5-trifluorobenzyl)piperazine hydrochloride, the same method as Using the same synthetic route as Example 6, the title compound 54 (light yellow solid) was prepared.
  • 57a (3g, 22.6mmol, 1.0eq), methyl bromoacetate (4.14g, 27mmol, 1.2eq), potassium carbonate (6.24g, 45.2mmol, 2.0eq) and DMF (20mL) were heated to 70°C and reacted for 5 hours, cooled, concentrated, added EA for extraction, liquid separation, and the organic phase was dried and concentrated to obtain white solid intermediate 57A (2.5g, yield: 54%).
  • step 7 In addition to replacing 3C with 57A in step 4 of Example 3, 1-(2,4-dichlorophenyl)piperazine hydrochloride in step 7 is replaced with 1-(3-(trifluoromethyl)phenyl) Except for piperazine hydrochloride, the same synthetic route as steps 4-7 in Example 3 was used to prepare the title compound 57 (white solid).
  • Step 4-5 In addition to replacing 3E with 59C in step 6 in Example 3, 1-(2,4-dichlorophenyl)piperazine hydrochloride in step 7 is replaced with 1-(3-(trifluoro Except for methyl)phenyl)piperazine hydrochloride, the title compound 59 (white solid) was obtained by adopting the same synthetic route as steps 6-7 in Example 3.
  • Example 15 In addition to replacing 15C-1 in step 4 of Example 15 with 5-aminovaleric acid ethyl ester hydrochloride, and replacing 1b with m-trifluoromethylbenzylamine in step 6, the same synthetic route as in Example 15 was used to prepare Title compound 65 (pale yellow solid).
  • Example 1 Except that 1b in Example 1 was replaced by 3,5-bis(trifluoromethyl)benzylamine, the title compound 66 (off-white solid) was obtained using the same synthetic route as in Example 1.
  • Example 15 Except that 1-(2,3-dichlorophenyl)piperazine hydrochloride in Example 15 was replaced by m-trifluoromethylbenzylamine, the same synthetic route as in Example 15 was used to prepare the title compound 68 (yellow solid).
  • Example 1 Except that 1b in Example 1 was replaced by 3-(3-(trifluoromethyl)phenyl)propan-1-amine, the same synthetic route as in Example 1 was used to prepare the title compound 69 (off-white solid ).
  • Example 6 The same method as in Example 6 was used except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (5b) in step 5 of Example 6 was replaced with m-trifluoromethylbenzylamine. According to the synthetic route, the title compound 71 (white solid) was obtained.
  • Step 1 Except that 4-aminobutanol in Step 1 of Example 29 is replaced with mono-Boc-ethylenediamine, the same synthetic method as Step 1 of Example 29 is used to prepare intermediate product 72A (white solid).
  • Step 2 Add 72A (410mg, 1.20mmol, 1.0eq.), EtOAc (4mL) and 2M EtOAc/HCl solution (4mL) into the reaction bottle. The reaction solution was reacted at room temperature for 4 hours. After LCMS monitoring, the reaction of the raw materials was completed, and the mixture was spun to dryness to obtain an off-white solid intermediate product 72B (400 mg, yield: 90%).
  • Step 3 Except that 1b in Example 1 was replaced with m-trifluoromethylphenylacetic acid and 1a was replaced with 72B, the title compound 72 (white solid) was obtained by using the same synthetic route as in Example 1.
  • Example 22 The same procedure as in Example 22 was used except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride in the last step of Example 22 was replaced with 3-(trifluoromethyl)benzylamine. According to the synthetic route, the title compound 73 (white solid) was obtained.
  • Example 3 Except that 1-(2,4-dichlorophenyl)piperazine hydrochloride in Example 3 is replaced with 3-(trifluoromethyl)benzylamine, the same synthetic route as in Example 3 is used, The title compound 74 was obtained (white solid).
  • Example 1 Except that 1b in Example 1 was replaced by 76b, the title compound 76 (white solid) was obtained using the same synthetic route as in Example 1.
  • Example 11 The same procedure as in Example 11 was used except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride in the last step of Example 11 was replaced with 3-(trifluoromethyl)benzylamine. According to the synthetic route, the title compound 77 (white solid) was obtained.
  • the title compound 79 (white solid) was prepared using 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.
  • Example 23 Except that compound 5b in Example 23 was replaced by m-trifluoromethylbenzylamine, the same synthetic route as in Example 23 was used to prepare the title compound 80 (light yellow solid).
  • Example 1 Except that 1b in Example 1 was replaced by methyl 3-(aminomethyl)benzoate, the title compound 83 (white solid) was obtained by using the same synthetic route as in Example 1.
  • Step 1 Add compound 85 (380mg, 0.94mmol, 1.0eq.) and dichloromethane (5mL) to the reaction flask, bathe in ice, and then dissolve (COCl) 2 (240mg, 1.88mmol, 2.0eq.) in 5mL Water (2 mL) in dichloromethane was dropped into the reaction solution. After the dripping was completed, stir at room temperature for two hours. The solvent was evaporated to dryness to obtain an orange-yellow solid, which was directly added to the next step of reaction (396 mg, yield: 100%).
  • Example 1 Except that 1b in Example 1 was replaced by m-Boc-aminobenzylamine, the same synthetic route as in Example 1 was used to prepare intermediate product 86A (yellow solid).
  • Dissolve intermediate 86A (200mg, 0.42mmol, 1.0eq.) in 1,4-dioxane (10mL), add hydrogen chloride in dioxane solution (2mL, 8mmol, 20.0eq., 4.0M) at room temperature. React for 2 hours. Filter, wash the filter cake with ethyl acetate (2 ⁇ 10 mL), and dry at 45°C to obtain compound 86 hydrochloride (yellow solid).
  • Example 36 The same procedure as in Example 36 was used except that 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride in the last step of Example 36 was replaced with 3-(trifluoromethyl)benzylamine. According to the synthetic route, the title compound 87 (white solid) was obtained.
  • Example 1 Except that 1b in Example 1 was replaced by 3-aminomethylbenzenesulfonamide, the title compound 88 (white solid) was obtained using the same synthetic route as in Example 1.
  • Example 1 Except that compound 1b in Example 1 was replaced by 89b, the title compound 89 (white solid) was obtained using the same synthetic route as in Example 1.
  • Example 1 Except that 1b in Example 1 was replaced by 90b, the title compound 90 (white solid) was obtained using the same synthetic route as in Example 1.
  • Step 1 Add m-trifluoromethylbromobenzene (1.125g, 5.0mmol, 1.0eq.), compound 91a-1 (1.3g, 7.5mmol, 1.5eq.), Pd 2 (dba) 3 ( 0.915g, 1.0mmol, 0.2eq.), X-phos (0.475g, 1.0mmol, 0.2eq.), potassium phosphate (3.18g, 15mmol, 3.0eq.) and 1,4-dioxane (30mL) , replaced with nitrogen three times, and stirred at 100°C for 12 hours.
  • Step 2 Add 91A (1.0g, 3.1mmol, 1.0eq.), hydrochloric acid (2.0mol/L ethyl acetate solution (12.4mL, 12.4mmol, 4.0eq.) and ethyl acetate (10mL) into the reaction bottle , stir at room temperature for 3 hours. Filter, wash the filter cake with ethyl acetate, and dry to obtain an off-white solid intermediate product 91B (0.8g, yield: 100%).
  • Step 3 Except for replacing 1b with 91B in Example 1, the title compound 91 (white solid) was prepared by using the same synthetic route as in Example 1.
  • Step 1 Except replacing 91a-1 in Example 61 with N,N’-dimethylethylenediamine, the same synthetic method as step 1 in Example 61 was used to prepare compound 92A.
  • Step 2 Except that 1b in Example 1 is replaced by 92A, the title compound 92 (white solid) is prepared using the same synthetic route as in Example 1.
  • Example 61 Except that 91a-1 in Example 61 was replaced with tert-butyl 2-(methylamino)ethylcarbamate, the same synthetic route as in Example 61 was used to prepare the title compound 93 (white solid).
  • Step 1 Except for replacing 4-aminobutanol with 3-amino-1-propanol in step 1 of Example 29, the same synthetic route as in Example 29 was used to prepare intermediate product 94A (yellow solid).
  • Step 2 Use the same method as in Example 31 except that 1-(2,3-dichlorophenyl)piperazine hydrochloride in Example 31 is replaced with 3-(trifluoromethyl)benzylamine. According to the synthetic route, the title compound 94 (white solid) was obtained.
  • Example 1 Except that 1b in Example 1 was replaced by m-trifluoromethylbenzyl alcohol, the title compound 95 (off-white solid) was obtained using the same synthetic route as in Example 1.
  • Step 1 Add 5,6,7,8-tetrahydro-1-naphthylamine (129a) (2g, 0.0136mol, 1.0eq.) and 2-(BOC-amino)bromoethane (3.35) into a 100mL single-neck bottle g, 0.0149 mol, 1.1 eq.), cesium carbonate (8.9 g, 0.0272 mol, 2.0 eq.) and anhydrous DMF (50 mL), under nitrogen protection, heated to 70°C for 1 hour.
  • Step 2 Add 129A (0.15g, 0.000517mol, 1.0eq.) and hydrogen chloride in 1,4-dioxane solution (2mL) into a 50mL single-neck bottle, and react at room temperature for 1 hour. The solvent was spin-dried to obtain crude product 129B, which was directly used in the next step.
  • Step 3 Except for replacing 1b with 129B in Example 1, the title compound 129 (white solid) was prepared using the same synthetic route as in Example 1.
  • the title compound 130 (white solid) was prepared using the same synthetic route as in Example 66, except that the following steps were added between the first and second steps of the synthetic route of Example 66.
  • the EA layer is dried over anhydrous sodium sulfate.
  • Example 66 Except that 129a in Example 66 was replaced by 131a, the title compound 131 (white solid) was prepared using the same synthetic route as in Example 66.
  • Example 66 Except that 129a in Example 66 was replaced by 132a, the title compound 132 (white solid) was obtained using the same synthetic route as in Example 66.
  • Example 66 Except that 129a in Example 66 was replaced by 133a, the title compound 133 (white solid) was obtained using the same synthetic route as in Example 66.
  • Example 1 Except that 1b in Example 1 was replaced by 134a, the title compound 134 (off-white solid) was obtained using the same synthetic route as in Example 1.
  • Example 66 Except that 129a in Example 66 was replaced by 135a, the title compound 135 (white solid) was prepared using the same synthetic route as in Example 66.
  • Step 2 Add methyl bromopyruvate (0.8g, 0.0044mol, 1eq.) and ethanol (20mL) to a 250mL three-neck flask, then add pyridine (0.35g, 0.0044mol, 1eq.), and stir under reflux for 1 hour. Cool to 20°C, add pyridine (1.6g, 0.02mol, 4.6eq.) and 138A (0.6g, 0.0044mol, 1eq.), and continue refluxing for 4 hours.
  • Step 4-6 In addition to replacing 3E in Example 3 with 138D, 1-(2,4-dichlorophenyl)piperazine hydrochloride is replaced with 1-(3-(trifluoromethyl)phenyl) Except for piperazine, the same synthetic route as in Example 3 was used to prepare the title compound 138 (off-white solid).
  • Example 76 Except that 186b in Example 76 was replaced by 189b, the title compound 189 (white solid) was prepared using the same synthetic route as in Example 76.
  • Example 78 Except that 188b in Example 78 was replaced by 190b, the title compound 190 (white solid) was obtained using the same synthetic route as in Example 78.
  • Example 75 Except that 185b in Example 75 was replaced by 191b, the formate salt of the title compound 191 (white solid) was prepared using the same synthetic route as in Example 75.
  • Step 1 Add 193a (600mg, 2.73mmol, 1.0eq.), DMF (10mL), K 2 CO 3 (1.13g, 8.19mmol, 3.0eq.) and 1,6-dibromohexane ( 660mg, 2.73mmol, 1.0eq). Stir overnight at 90°C.
  • the target components were collected and concentrated under reduced pressure to obtain white solid 193A (200 mg, yield: 19%).
  • Step 1 Except for replacing 1,6-dibromohexane with 3-bromopropan-1-ol in Step 1 of Example 83, the same synthetic route as Step 1 of Example 83 was used to prepare compound 194A ( white solid).
  • Step 2 Add 194A (200 mg, 0.72 mmol, 1.0 eq.) and 40% hydrobromic acid aqueous solution to the reaction bottle, and stir under reflux at 100°C overnight. The reaction solution was concentrated under reduced pressure to obtain white solid 194B (150 mg, yield: 62%).
  • Step 3 Except for replacing 193A with 194B in Step 2 of Example 83, the title compound 194 (white solid) was prepared by using the same synthetic route as Step 2 of Example 83.
  • Compound 195 (white solid) was prepared using the same synthetic route as in Example 83, except that 193a in Example 83 was replaced by 195a.
  • Step 1 Use the same synthetic route as in Step 1 of Example 83, except that 1,6-dibromohexane is replaced with 3-bromopropan-1-ol and 193a is replaced with 195a.
  • Compound 196A was prepared.
  • Step 2 Except for replacing 194A with 196A in Step 2 of Example 84, compound 196B was prepared by using the same synthetic route as Step 2 of Example 84.
  • Step 3 Except for replacing 193A with 196B in Step 2 of Example 83, the title compound 196 (white solid) was prepared using the same synthetic route as Step 2 of Example 83.
  • Step 1 Add 144a (5g, 24.13mmol, 1.0eq) to DMF (50mL), then add DMF-DMA (11.5g, 96.50mmol, 4.0eq), and stir at 80°C for 3 hours; the reaction solution is diluted with water. Extract with ethyl acetate, dry the organic phase, filter, spin dry, A brown oily substance 144A (6 g, yield: 94.8%) was obtained.
  • Step 2 Add 144A (6g, 22.87mmol, 1.0eq) to MeOH (100mL), then add 3-aminopropionic acid methyl ester hydrochloride (6.39g, 45.74mmol, 2.0eq), and stir at 70°C for 3 hours; the reaction solution was cooled to room temperature, a large amount of solid precipitated, filtered, and the filter cake was dried to obtain brown solid 144B (4.1g, yield: 62.17%).
  • Step 3 Add 144B (2g, 6.94mmol, 1.0eq) to THF/MeOH/H 2 O (60mL/20mL/20mL), then add LiOH (498mg, 20.81mmol, 3.0eq), and stir at 25°C for 3 hours; the reaction solution was diluted with water, and the pH was adjusted to 6-7 with 1M hydrochloric acid aqueous solution until a large amount of solid precipitated, filtered, and the filter cake was dried to obtain yellow solid 144C (1.2g, yield: 63.0%).
  • Example 91 Except replacing 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in step 4 of Example 91 with 4-(3-(trifluoromethyl)phenyl)piperidine- Except for 4-alcohol (147b), the title compound 147 (off-white solid) was obtained by using the same synthetic route as in Example 91.
  • Step 1 Add 148a (2g, 0.0146mol, 1.0eq.), methyl bromoacetate (2.68g, 0.0175mol, 1.2eq.), potassium carbonate (4g, 0.0292mol, 2.0eq.) and DMF (20mL), react at 60°C for 16h. After the reaction is completed, cool to room temperature, filter, and wash the filter cake with ethyl acetate. Add a large amount of water to the filtrate, extract twice with ethyl acetate, wash the ethyl acetate phase three times with saturated brine, dry, and remove the solvent to obtain brown oil 148A. The crude product was used directly in the next step.
  • Step 2 Add 148A (crude product, 0.0146 mol, 1.0 eq.), DMF-DMA (5.22 g, 0.0438 mol, 3.0 eq.) and DMF (40 mL) into a 100 mL single-neck bottle, and react at 60°C for 3 hours. After the reaction was completed, cooled to room temperature, a large amount of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The ethyl acetate phase was washed three times with saturated brine, dried, and the solvent was removed to obtain brown oil 148B. The crude product was directly used in the next step.
  • Step 3 Add 148B (crude product, 0.0146 mol, 1.0 eq.), 3-aminopropionic acid methyl ester hydrochloride (4.08 g, 0.0292 mol, 2.0 eq.) and acetonitrile (40 mL) into a 100 mL single-neck bottle, and reflux the reaction. 16h. Stir and cool down to room temperature, add an ice bath to cool down, filter, wash the filter cake with methanol, and dry to obtain a white solid 148C (1.43g, yield: 33.7%).
  • Step 4 Add 148C (1.43g, 0.00493mol, 1.0eq.), THF (12mL) and water (3mL) to a 100mL single-neck bottle, cool to 0-5°C in an ice bath, add LiOH (0.236g, 0.00986mol, 2.0eq.), incubate the reaction in an ice bath for 1 hour. After the reaction was completed, the pH was adjusted to 3-4 with dilute hydrochloric acid in an ice bath. A large amount of solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain a white solid 148D (1.12g, yield: 82.2%).
  • Step 5 Add 148D (0.15, 0.000543mol, 1.0eq.), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) (0.22g, 0.000815mol, 1.5eq.), HATU (0.31g, 0.00815mol, 1.5eq.), anhydrous DMF (5mL) and DIPEA (0.35g, 0.00272mol, 5.0eq.), react at room temperature for 1h.
  • Example 95 Except replacing 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in step 5 of Example 95 with 1-(2,3-dichlorophenyl)piperazine hydrochloride. Except for (145b), the title compound 149 (white solid) was obtained by using the same synthetic route as in Example 95.
  • Example 95 In addition to replacing 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in step 5 of Example 95 with 4-(4-fluorobenzyl)piperidine (146b), Using the same synthetic route as Example 95, the title compound 150 (white solid) was obtained.
  • Example 95 Except replacing 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (144b) in Example 95 with 4-(3-(trifluoromethyl)phenyl)piperidine-4- Except for alcohol (147b), the title compound 151 (white solid) was obtained by using the same synthetic route as Example 95.
  • Step 3 Dissolve 152B (2.23g, 10.0mmol, 1.0eq) in DMF (30mL), then add DMF-DMA (5.96g, 50.0mmol, 5.0eq), and stir the mixture at 80°C for 16h. After the reaction is completed, use water (100mL) and dichloromethane (50mL*2) to extract, and spin the organic phase to dryness to obtain red oil 152C (3g).
  • Step 4 Dissolve 152C (3g, 10.83mmol, 1.0eq) in methanol (30mL), and then add 3-aminopropionic acid methyl ester (1.6g, 16.24mmol, 1.5eq). The mixture was stirred at 70 °C for 16 h. After the reaction was completed, the white solid 152D (1 g, yield: 31.9%) was obtained by filtration.
  • Step 5 Add 152D (1g) to THF/H 2 O (10 mL/3 mL), then add 10% sodium hydroxide (3 mL), and stir the mixture at room temperature for 16 h. After the reaction is completed, the mixture is spun dry and the pH of the system is adjusted to 5-6. The mixture is filtered to obtain white solid 152E (0.7g, yield 73.0%).
  • Step 6 Add 152E (200mg, 0.72mmol, 1.0eq), 145b (290mg, 1.08mmol, 1.5eq), HATU (550mg, 1.45mmol, 2.0eq) and DIPEA (233mg, 1.81mmol, 2.5eq) to DCM (5 mL), the mixture was stirred at room temperature for 16 h.
  • Example 100 8-fluoro-3-(3-oxo-3-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)propyl)-3,5-dihydro Synthesis of -4H-pyrimido[5,4-b]indol-4-one
  • Example 99 Except that 145b in step 6 of Example 99 was replaced with 1-(3-(trifluoromethyl)phenyl)piperazine (144b), the same synthetic route as in Example 99 was used to prepare the title compound 153 ( white solid).
  • Example 99 Except that 145b in step 6 of Example 99 was replaced by 146b, the title compound 154 (white solid) was prepared using the same synthetic route as in Example 99.
  • Example 102 In addition to replacing 4-(4-fluorobenzyl)piperidine (146b) with 4-(3-(trifluoromethyl)phenyl)piperidin-4-ol (147b) in Example 102, using Using the same synthetic route as Example 102, the title compound 165 (white solid) was prepared.
  • Example 102 Except replacing 4-(4-fluorobenzyl)piperidine (146b) in Example 102 with N-(2,3-dichlorophenyl)-N-methylpiperidin-4-amine (166b) Except, the title compound 166 (white solid) was obtained using the same synthetic route as Example 102.
  • Example 102 The same synthetic route as in Example 102 was used except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced by 1-(pyridin-3-yl)piperazine (167b). The formate salt of compound 167 was obtained (white solid).
  • Example 106 8-methyl-3-(3-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)-3-oxopropyl)-3,5-di Synthesis of hydrogen-4H-pyrimido[5,4-b]indol-4-one
  • Example 102 The same procedure as Example 102 was used except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced by 1-(4-(methylsulfonyl)phenyl)piperazine (168b). Using the same synthetic route, the title compound 168 (white solid) was obtained.
  • Example 102 In addition to replacing 4-(4-fluorobenzyl)piperidine (146b) with 1-(4-(piperidin-1-ylsulfonyl)phenyl)piperazine (169b) in Example 102, using Using the same synthetic route as Example 102, the title compound 169 (white solid) was obtained.
  • Example 102 Except replacing 4-(4-fluorobenzyl)piperidine (146b) in Example 102 with 1-(3-(piperidin-1-ylsulfonyl)phenyl)piperazine hydrochloride (170b) In addition, the title compound 170 (white solid) was obtained using the same synthetic route as Example 102.
  • Example 102 The same synthetic route as in Example 102 was used except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced by 3-cyanophenylpiperazine hydrochloride (171b). The title compound 171 was obtained (white solid).
  • Example 110 8-methyl-3-(3-(4-(3-nitrophenyl)piperazin-1-yl)-3-oxopropyl)-3,5-dihydro-4H- Synthesis of pyrimido[5,4-b]indol-4-one
  • Example 102 Except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced by 3-nitrophenylpiperazine (172b), the same synthetic route as in Example 102 was used to obtain the title Compound 172 (yellow solid).
  • Example 102 In addition to replacing 4-(4-fluorobenzyl)piperidine (146b) in Example 102 with (3-chlorophenyl)(piperazin-1-yl)methanone hydrochloride (173b), using Using the same synthetic route as Example 102, the title compound 173 (white solid) was obtained.
  • Example 102 Except that 4-(4-fluorobenzyl)piperidine (146b) in Example 102 was replaced by 1-isobutylpiperazine (174b), the same synthetic route as in Example 102 was used to prepare the title compound 174 (white solid).
  • Example 102 In addition to replacing 4-(4-fluorobenzyl)piperidine (146b) with 2-methyl-1-(piperazin-1-yl)propan-1-one (175b) in Example 102, using Using the same synthetic route as Example 102, the title compound 175 (white solid) was obtained.
  • Step 1 Dissolve 176a (5.0g, 32.14mmol, 1.0eq.) in acetonitrile (50mL), add DIPEA (20.8g, 160.71mmol, 5.0eq.) and glycine ethyl ester hydrochloride (6.7g, 48.21mmol ,1.5eq.), raise the temperature to 85°C and react for 3 days (the reaction is still not complete, handle it directly).
  • Step 2 Dissolve 176A (1.6g, 6.70mmol, 1.0eq.) in acetonitrile (20mL), add potassium carbonate (5.6g, 40.22mmol, 6.0eq.), raise the temperature to 85°C and react for 9 days.
  • the reaction solution was filtered, the solid was washed with ethyl acetate (2 ⁇ 20 mL), and the filtrate was concentrated under reduced pressure to dryness to obtain brown solid 176B (1.2 g, yield: 75.00%).
  • Step 3 Dissolve 176B (1.1g, 4.61mmol, 1.0eq.) in N,N-dimethylformamide (5mL), add N,N-dimethylformamide dimethyl acetal (5.5g, 46.09mmol, 10.0eq.), heated to 60°C and reacted overnight. Concentrate to dryness under reduced pressure to obtain brown solid 176C (1.3 g, yield: 96.02%).
  • Step 6 Add 176E (100mg, 0.34mmol, 1.0eq.), HATU (156mg, 0.41mmol, 1.2eq.) and N,N-dimethylformamide (3mL) into the reaction bottle, and react at room temperature for 0.5h. , then add 1-(2,3-dichlorophenyl)piperazine hydrochloride (145b) (110mg, 0.41mmol, 1.2eq.) and DIPEA (164mg, 1.27mmol, 3.7eq.), and react at room temperature overnight. . The reaction solution was filtered, and the filter cake was washed with dichloromethane (2 ⁇ 10 mL) and dried to obtain white solid 176 (60 mg, yield: 34.67%).
  • 1-(2,3-dichlorophenyl)piperazine hydrochloride 145b
  • DIPEA 164mg, 1.27mmol, 3.7eq.
  • Example 114 Except that 145b in step 6 of Example 114 was replaced by 1-(3-trifluoromethylphenyl)piperazine hydrochloride (144b), the same synthetic route as in Example 114 was used to prepare the title compound 177 (white solid).
  • Example 114 Except for replacing 145b in step 6 of Example 114 with 4-(3-trifluoromethyl)phenyl-4-piperidinol (147b), the title compound was obtained by using the same synthetic route as Example 114 178 (yellow solid).
  • Example 114 Except that 145b in step 6 of Example 114 was replaced by 4-(4'-fluorobenzyl)piperidine (146b), the title compound 179 (yellow solid) was prepared using the same synthetic route as in Example 114.
  • Step 2 Add 208A (700mg, 2.04mmol, 1.0eq) to 4M HCl/1,4-dioxane (10mL), then stir at 25°C for 3 hours; the reaction solution is spun to dryness to obtain yellow solid 208B (550mg, yield: 93.9%).
  • Step 2 Add 209A (2.0g, 9.16mmol, 1.0eq) and ammonium acetate (3.5g, 45.82mmol, 5.0eq) into methanol (20 mL), the mixture was stirred at 30°C for 16 hours; after the reaction solution was spun dry, saturated sodium bicarbonate solution (50ml) and ethyl acetate (20ml*2) were added for extraction, and the organic phase was spun dry to obtain white oil 209B (1.8g , Yield: 89.6%).
  • Step 3 Add 209B (1.8g, 8.29mmol, 1.0eq) and DMF-DMA (4.9g, 41.47mmol, 5.0eq) to DMF (20mL); stir at 80°C for 24 hours; add water (100ml) and ethyl acetate (30ml*2), spin the organic phase to dryness to obtain blue oily liquid 209C (2g, yield: 88.6%).
  • Step 4 Add 209C (2g, 7.34mmol, 1.0eq) to formamide (20mL), stir at 200°C for 1 hour; after the reaction is completed, cool to room temperature, add water (100ml) to precipitate the solid, and filter to obtain a brown solid 209D. (0.9g, yield: 57.7%).
  • Step 5 Add 209D (500mg, 2.36mmol, 1.0eq), 209b (724mg, 2.36mmol, 1.0eq) and potassium carbonate (651mg, 4.72mmol, 2.0eq) into acetonitrile (5mL), and the mixture is heated at 70°C Stir for 4 hours; spin the reaction solution to dryness and add water (30 ml) to precipitate the solid. Filter to obtain 200 mg of white solid. The white solid is purified by reversed-phase preparative chromatography (0.1% FA). The resulting preparation is concentrated and freeze-dried to obtain a white solid. 209 (20 mg, yield: 1.75%).
  • Step 1 Add double pinacol borate (2.5g, 0.01mol, 2.0eq.), 201a (1.4g, 0.005mol, 1.0eq.), DMSO (30mL), sodium carbonate ( 1.1g, 0.01mol, 2.0eq.) and tetraphenylphosphorus palladium (0.3g, 0.00026mol, 2.6%), under nitrogen protection, heated to 80°C, and reacted for 6 hours.
  • Step 4 Add 210C (0.21g, 0.001mol, 1.0eq.), acetonitrile (50mL) and potassium carbonate (0.42g, 0.003mol, 3eq.) to a 250mL single-neck bottle, protect with nitrogen, and add 1-chloro-3 bromide.
  • Step 5 Add 210D (0.2g, 0.0007mol, 1.0eq.), acetonitrile (10mL), potassium carbonate (0.28g, 0.002mol, 3eq.) and 3-trifluorophenylpiperazine (144b) into a 250mL single-neck bottle. ) (0.46g, 0.002mol, 3eq.), nitrogen protection, reaction at 80°C for 16h. reaction junction
  • Step 2 Add 211A (15.3g, 79.18mmol, 1.0eq) to MeOH/H 2 O (150mL/50mL), then add NaOH (4.75g, 118.7mmol, 1.5eq), and stir at 25°C for 2 hours;
  • Step 5 Add 211D (6g, 22.96mmol, 1.0eq) to THF (60mL), then add 60% wt.NaH (2.3g, 57.40mmol, 2.5eq, in mineral oil) in portions at 0°C, After stirring at 25°C for 0.5 hours, add dimethyl carbonate (3.1g, 34.4mmol, 1.5eq), and stir at 70°C for 2 hours under nitrogen protection; the reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was dried and filtered.
  • Step 7 Add 211F (2g, 6.28mmol, 1.0eq) to DMF (20mL), then add DMF-DMA (3.74g, 31.41mmol, 5.0eq), and stir at 80°C for 16 hours; the reaction solution is diluted with water. Extract with ethyl acetate, dry the organic phase, filter, and spin dry to obtain black solid 211G (2.1 g, yield: 89.5%).
  • Step 1 Add 213a (4.5g, 27.72mmol, 1.0eq), urea (1.84g, 30.51mmol, 1.1eq) and triethyl orthoformate (4.11g, 27.72mmol, 1.0eq) to MeOH (5mL), Then add methylsulfonic acid (15 drops) and stir at 130°C for 6 hours; the reaction solution is diluted with methanol, filtered, and the filter cake is spin-dried to obtain yellow solid 213A (3.3g, yield: 55.5%).
  • Step 1 Add 209D (0.50g, 2.36mmol, 1.0eq) to anhydrous DMF (30mL), then add potassium carbonate (0.73g, 4.7mmol, 2.0eq) and methyl 3-bromopropionate (1g, 5.62mmol, 2.4eq), the mixture was stirred at 80°C for 4h; after the reaction, the temperature was cooled to room temperature and water (100mL) was added until the system was turbid, filtered to obtain a white filter cake, and dried to obtain 215A (0.48g, yield: 68.2%) .
  • Step 2 Dissolve 215A (0.48g, 1.60mmol, 1.0eq) in THF (3mL), then add water (1mL) and LiOH (116mg, 4.80mmol, 3.0eq) to the system, and stir the mixture at 30°C for 16 hours; after the reaction, spin the system to dryness, add water (10 mL), adjust the pH of the system to 5-6, extract with DCM (5 mL*2), spin the organic phase to dryness to obtain a white solid 215B (0.45 g, yield :98.9%).
  • Step 3 Add 215B (0.40g, 1.40mmol, 1.0eq), DIPEA (0.45g, 3.5mmol, 2.5eq), HATU (1.1g, 2.80mmol) and 144b (0.39g, 1.70mmol, 1.2eq) to DMF (5mL), stir at 30°C for 16 hours; after the reaction is completed, add water (20ml) and ethyl acetate (10ml*2) for extraction, spin the organic phase to dryness, and perform reverse-phase preparative chromatography (0.1% FA) Purified, then concentrated and lyophilized to obtain 215 as a white solid (0.05 g, yield: 7.19%).
  • Step 3 Add 216B (0.5g, 0.0009mol, 1.0eq.), zinc powder (0.6g, 0.009mol, 10.0eq.), saturated NH 4 Cl aqueous solution (0.5mL) and EtOH (5mL) to a 100mL three-necked flask. , stir overnight at 80°C. After the reaction, the product was purified through a reverse-phase column and eluted with methanol/water. After lyophilization, the formate salt of compound 216 was obtained as a yellow solid (0.052 g, yield: 5.91%).
  • Step 1 Add 211H (180mg, 0.574mmol, 1.0eq) to ACN (2mL), then add potassium carbonate (238mg, 1.72mmol, 3.0eq) and tert-butyl 4-bromobutyrate (192mg, 0.862mmol, 1.5 eq), stir at 40°C for 16 hours.
  • Step 2 Add 217A (220mg, 0.483mmol, 1.0eq) to 4M HCl/1,4-dioxane (5mL), stir at 25°C for 1 hour, and spin the reaction solution to dryness to obtain yellow solid 217B ( 140mg, yield: 97.5%).
  • Example 127 Except that 145b in step 3 of Example 127 was replaced by 4-(4-fluorobenzyl)piperidine (146b), the title compound 218 (off-white solid) was obtained by using the same synthetic route as Example 127.
  • Step 2 Add 219A (690mg, 1.94mmol, 1.0eq) to 4M HCl/1,4-dioxane (10mL), stir at 25°C for 2 hours, and spin the reaction liquid to dryness to obtain yellow solid 219B ( 550mg, yield: 94.6%).
  • Example 129 Except that 145b in step 3 of Example 129 was replaced by 4-(4-fluorobenzyl)piperidine (146b), the title compound 220 (off-white solid) was prepared by using the same synthetic route as Example 129.
  • Step 2 Dissolve 222A (3g, 13.74mmol, 1.0eq) and ammonium acetate (4.2g, 54.98mmol) in MeOH (50mL), and stir the mixture at room temperature for 16h. After the reaction was completed, the mixture was spin-dried, and extracted with water (50 mL) and dichloromethane (20 mL*2). The organic phase was spin-dried to obtain white oil 222B (3 g, yield: 99.6%).
  • Step 3 Dissolve 222B (3g, 13.8mmol, 1.0eq) in DMF (30mL), then add DMF-DMA (6.58g, 55.256mmol, 4.0eq), and stir the mixture at 80°C for 16h. After the reaction is completed, use water (100 mL) and dichloromethane (50 mL*2) to extract, and spin dry the organic phase to obtain red oil 222C (3.76 g, crude product yield: 99.2%).
  • Step 3 Add 224B (1.24g, 0.003mol, 1.0eq.), zinc powder (1.95g, 0.03mol, 10.0eq.), saturated NH 4 Cl aqueous solution (1.2mL) and EtOH (10mL) into a 100mL three-necked flask. , stir overnight at 85°C. After the reaction, it was filtered, and the filtrate was spun dry to obtain crude product 224C (0.5g).
  • Step 4 Add 224C (0.5g) and HCl/1,4-dioxane solution (1M, 10mL) into a 50mL three-necked flask, and stir at room temperature overnight. After the reaction, reverse-phase column purification was performed, and MeOH/H 2 O was used to remove the product. The target fraction was collected and spun to dryness to obtain white solid 224D (0.1 g, yield: 27.03%).
  • Step 5 Add 224D (0.1g, 0.35mmol, 1.0eq.), 2,3-dichlorophenylpiperazine hydrochloride (145b) (0.096g, 0.42mmol, 1.2eq.), HATU (0.16g, 0.42mmol, 1.2eq.), DIPEA (0.3mL) and DCM (5mL) were stirred at room temperature overnight. After the reaction, the product was purified by reverse-phase column chromatography, and the product was eluted with MeOH/H 2 O. The target fractions were collected and freeze-dried to obtain white solid 224 (0.014g, yield: 8.05%).
  • Example 125 Except that 144b in step 3 of Example 125 was replaced by 146b, the title compound 225 (white solid) was obtained by using the same synthetic route as Example 125.
  • Example 138 3-(4-oxo-4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-3,5,6,7-tetrahydro Synthesis of -4H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-one
  • Step 2 Add 229A (0.4g, 0.791mmol, 1.0eq.) and HCl 1,4-dioxane solution (5mL, 4mol/L) into a 100mL single-neck bottle, and react at room temperature for 1 hour. After the reaction was completed, it was filtered and the filter cake was washed with 1,4-dioxane to obtain an off-white solid 229B (0.18g, yield 67.1%).
  • Step 3 Add 229B (0.18g, 0.571mmol, 1.0eq.) and 1-(3-trifluoromethylphenyl)piperazine hydrochloride (144b) (0.21g, 0.797mmol, 1.5 eq.), HATU (0.3g, 0.797mmol, 1.5eq.), anhydrous DMF (5mL) and DIPEA (0.34g, 2.66mmol, 5.0eq.), react at room temperature for 1 hour.
  • Step 2 Add 230A (0.33g, 0.665mmol, 1.0eq.) and HCl 1,4-dioxane solution (5mL, 4mol/L) into a 100mL single-neck bottle, and react at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated to obtain crude 230B crude product as a light yellow solid, which was directly used in the next step.
  • Step 3 Add 230B (crude product, 0.831mmol, 1.0eq.) and 1-(2,3-dichlorophenyl)piperazine hydrochloride (145b) (0.33g, 1.25mmol, 1.5eq.) into a 100mL single-neck bottle. .), HATU (0.48g, 1.25mmol, 1.5eq.), anhydrous DMF (5mL) and DIPEA (0.54g, 4.16mmol, 5.0eq.), react at room temperature for 1 hour.
  • Step 3 Add 231B (1.24g, 0.003mol, 1.0eq.), zinc powder (1.95g, 0.03mol, 10.0eq.), saturated NH 4 Cl aqueous solution (1.2mL) and EtOH (10mL) into a 100mL three-necked flask. , stir overnight at 85°C. After the reaction, it was filtered, and the filtrate was spun dry to obtain crude product 231C (0.5g).
  • Step 4 Add 231C (0.5g) and HCl/1,4-dioxane solution (1M, 10mL) to a 50mL three-necked flask, and stir at room temperature overnight. After the reaction, reverse-phase column purification was performed, and MeOH/H 2 O was used to remove the product. The target fraction was collected and spun to dryness to obtain white solid 231D (0.1 g, yield: 27.03%).
  • Step 5 Add 231D (0.1g, 0.35mmol, 1.0eq.), 2,3-dichlorophenylpiperazine hydrochloride (145b) (0.096g, 0.42mmol, 1.2eq.), HATU (0.16g, 0.42mmol, 1.2eq.), DIPEA (0.3mL) and DCM (5mL) were stirred at room temperature overnight. After the reaction, the product was purified by reverse-phase column chromatography, and the product was eluted with MeOH/H 2 O. The target fraction was collected and freeze-dried to obtain white solid 231 (0.008g, yield: 4.44%).
  • Example 142 2-methyl-N-(3-(4-(3-trifluoromethylphenyl)piperazin-1-yl)propyl)-6,6a,7,8,9,10- Synthesis of hexahydrobenzo[b]pyrido[1,2-d][1,4]oxazine-7-carboxamide formate
  • Step 2 Add 233A (7.30g, 27.55mmol, 1.0eq.), acetic acid (100mL), iron powder (9.26g, 165.28mmol, 6.0eq.), potassium carbonate (12.18g, 88.24mmol, 3.0) into the reaction bottle. eq) and potassium iodide (976 mg, 5.88 mmol, 0.2 eq). Stir at 120°C for 30 minutes. After the reaction solution was cooled, it was extracted three times with ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate solution and concentrated to obtain a black oily crude product 233B (10.0g).
  • Step 3 Add 233B (1.26g, 5.36mmol, 1.0eq.), DMF (10mL), DIPEA (2.07g, 16.09mmol, 3.0eq.), 1-bromo-3-chloropropane (1.68g) to the reaction bottle , 10.72mmol, 2.0eq). Stir overnight at 80°C. After the reaction solution was cooled, water was added, and extracted three times with ethyl acetate.
  • Step 4 Add 233C (635mg, 2.042mmol, 1.0eq.) and anhydrous tetrahydrofuran (20mL) to the reaction bottle, replace the nitrogen, cool the system to -78°C, add LiHMDS (1M) (13.2mL, 6.5eq.) dropwise ), react with natural heating for 4 hours.
  • the reaction solution was quenched by adding water dropwise and extracted three times with ethyl acetate.
  • Step 5 Add 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.) into the reaction bottle. Stir at room temperature overnight. After the reaction solution was concentrated, water (5 mL) was added, and 2M HCl was added dropwise until the white solid no longer precipitated. After filtering and drying, white solid 232a (250 mg, yield: 92.77%) was obtained.
  • Example 143 Except that 233b in step 6 of Example 143 was replaced by 234b, the title compound 234 (white solid) was prepared using the same synthetic route as in Example 143.
  • Step 1 Add 235a (2g, 7.17mmol, 1.0eq.), 10% Pd/C (0.3g, 15% w/w) and ethyl acetate (80mL) into a 250mL single-neck bottle, hydrogenate under normal pressure, and room temperature Reaction 16h. At the end of the reaction, filter, wash the filter cake with ethyl acetate, and concentrate the filtrate to obtain 235A. The crude product is directly used in the next step.
  • Step 2 Add 235A (crude product, 7.71mmol, 1.5eq.), 235b (2g, 5.14mmol, 1.0eq.), Pd(dppf)Cl 2 -DCM (0.84g, 1.03mmol, 0.2eq.) into a 250mL single-neck bottle .), sodium carbonate (1.63g, 15.4mmol, 3.0eq.), 1,4-dioxane (100mL) and water (10mL), under nitrogen protection, react at 100°C for 16h.
  • Step 3 Add 235B (0.7g, 2.22mmol, 1.0eq.) and HCl 1,4-dioxane solution (7mL, 4mol/L) into a 100mL single-neck bottle, and react at room temperature for 1 hour. After the reaction was completed, it was filtered, and the filter cake was washed with 1,4-dioxane and dried to obtain a light brown solid 235C (0.45g, yield: 80.2%).
  • Step 4 Add 235C (0.25g, 0.989mmol, 1.0eq.), 1-(3-bromopropyl)-4-(2,3-dichlorophenyl)piperazine (235c)( 0.7g, 1.98mmol, 2.0eq.), triethylamine (0.5g, 4.95mmol, 5.0eq.) and acetonitrile (15mL), react at 60°C for 16h. The reaction was completed, filtered, and the filter cake was washed with acetonitrile. The filter cake was added to DMSO (10 mL), stirred for 30 minutes and filtered. The filter cake was washed with DMSO and methanol in sequence, and dried to obtain an off-white solid 235 (0.12g, yield: 24.9% ).
  • the purpose of this experimental example is to test the compound's promotion effect on TPK enzyme activity and evaluate the compound's in vitro activity based on EC 50 and E max .
  • TPK enzyme solution Tris-HCl buffer, and ATP solution need to be added to each reaction system.
  • the ATP used is 1-500mM. Prepare the above three solutions into a uniform mixture.
  • TPK enzyme activity TDP (nM)/mg protein/min.

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Abstract

本公开属于生物医药领域，并具体涉及预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法，其包括向需要其的个体给药预防或治疗有效量的硫胺素焦磷酸激酶(TPK)激动剂。

Description

TPK激动剂及使用其治疗神经退行性疾病的方法 发明领域
本发明属于生物医药领域，并具体涉及预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法，其包括向需要其的个体给药预防或治疗有效量的硫胺素焦磷酸激酶(TPK)激动剂。
发明背景
阿尔茨海默病(Alzheimer’s disease,AD)是最常见中枢神经系统变性病。由于患者众多、病程迁延、患者丧失生活自理能力生存期长、缺乏有效防治药物，给个人、家庭乃至全社会带来了巨大的经济和精神负担。据报道，中国2015年在AD防治照护等耗费高达1677.4亿美元，预计到2030年耗费将高达5074.9亿美元。2018年全球在以AD为主的痴呆性疾病耗费超过万亿美元，占全球国内生产总值(GDP)超过1％。AD是全球排名前十的重大疾病中唯一缺乏有效防治药物的疾病，已经成为严重影响包括中国在内的全球主要经济体健康保健系统和经济可持续发展的重大疾病。
AD是一种多病理生理改变疾病，包括神经元丢失、胶质细胞活化，以及特征性的细胞外β淀粉样蛋白(Aβ)沉积形成的老年斑，细胞内Tau蛋白过度磷酸化造成的神经纤维缠结等。此外，突触丢失、脑葡萄糖代谢障碍、氧化应激等也是AD脑内恒有的病理改变，并且患者脑葡萄糖代谢下降与认知功能障碍密切相关。由于发病机制不清，AD仍缺乏有效的治疗方法。
发明概述
本申请发明人发现，葡萄糖代谢障碍有可能是AD的一个早期临床前特征。AD患者葡萄糖细胞内代谢过程主要表现为三个依赖二磷酸硫胺素(thiamine diphosphate，TDP)作为辅酶的关键酶(丙酮酸脱氢酶、α-酮戊二酸脱氢酶和转酮醇酶)的活性显著下降。经多中心临床研究证明AD患者TDP水平下降是一个特异且普遍的现象、具有良好的诊断价值，而血管性痴呆和额颞叶痴呆的患者中并没有硫胺素代谢异常。临床结合实验研究进一步表明TDP下降是导致脑葡萄糖代谢障碍的原因。本申请发明人研究发现，在已知的硫胺素代谢相关的4个基因中，仅转换硫胺素为生物活性TDP的关键酶——硫胺素焦磷酸激酶(Thiamine pyrophosphokinse,TPK)表达存在显著抑制，并且TPK表达抑制是AD特异性的。因此TPK激动剂可用于神经退行性疾病(特别是阿尔茨海默病)的预防或治疗。
在一个方面中，本发明提供预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法，其包括向需要其的个体给药预防或治疗有效量的硫胺素焦磷酸激酶(TPK)激动剂。
在另一方面中，本发明提供TPK激动剂在制备用于预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的药物中的用途。
在另一方面中，本发明提供TPK激动剂，其用于预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状。
所述神经退行性疾病优选为阿尔茨海默病；更优选地，所述阿尔茨海默病为个体的TPK酶活性降低、TPK表达水平降低和/或TDP水平降低的阿尔茨海默病。
在另一方面中，本发明涉及具有新颖结构的TPK激动剂。
发明详述
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
如本文中所使用，当描述连接两个其它基团的二价基团时，可以理解的是该二价基团可以任意方向性与两个基团相连。例如，如果由二甲基团-CONR-连接的另两个基团分别是(基团1)和(基团2)，则(基团1)-CONR-(基团2)和(基团2)-CONR-(基团1)都被包括在内。
如本文中所使用，术语“亚烷基”表示饱和二价烃基，优选表示具有1、2、3、4、5或6个碳原 子的饱和二价烃基，例如亚甲基、亚乙基、亚丙基或亚丁基。
如本文中所使用，术语“烷基”定义为直链或支链饱和脂肪族烃。在一些实施方案中，烷基具有1至12个，例如1至6个碳原子。例如，如本文中所使用，术语“C1-6烷基”指1至6个碳原子的线性或支化的基团(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基或正己基)，其任选地被1或多个(诸如1至3个)适合的取代基如卤素取代(此时该基团被称作“卤代烷基”)(例如CF3、C2F5、CHF2、CH2F、CH2CF3、CH2Cl或-CH2CH2CF3等)。术语“C1-4烷基”指1至4个碳原子的线性或支化的脂肪族烃链(即甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基)。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个或多个双键，且具有2-6个碳原子(“C2-6烯基”)。所述烯基为例如-CH＝CH2、-CH2CH＝CH2、-C(CH3)＝CH2、-CH2-CH＝CH-CH3、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。术语“亚烯基”为相应的二价基团，包括例如“C2-6亚烯基”、“C2-4亚烯基”等，其具体实例包括但不限于：-CH＝CH-、-CH2CH＝CH-、-C(CH3)＝CH-、亚丁烯基、亚戊烯基、亚己烯基、亚环戊烯基、亚环己烯基等。
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基、2-丙炔基、2-丁炔基、1,3-丁二炔基等。所述炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。术语“亚炔基”为相应的二价基团，包括例如“C2-8亚炔基”、“C2-6亚炔基”、“C2-4亚炔基”等。其实例包括但不限于等，所述亚炔基任选地被一个或多个(诸如1至3个)相同或不同的取代基取代。
如本文中所使用，术语“并环”或“稠环”指由两个或两个以上环状结构彼此共用两个相邻的原子所形成的环系。
如本文中所使用，术语“螺环”指由两个或两个以上环状结构彼此共用一个环原子所形成的环系。
如本文中所使用，术语“桥环”指由两个或两个以上环状结构彼此共用两个不直接相连的原子所形成的环系。
如本文中所使用，术语“亚环烃基”、“环烃基”和“烃环”是指具有例如3-10个(适合地具有3-8个，更适合地具有3-6个)环碳原子的饱和(即，“亚环烷基”和“环烷基”)或不饱和的(即在环内具有一个或多个双键和/或三键)单环或多环烃环(包括螺环、并环(稠环)或桥环系统)，其包括但不限于(亚)环丙基(环)、(亚)环丁基(环)、(亚)环戊基(环)、(亚)环己基(环)、(亚)环庚基(环)、(亚)环辛基(环)、(亚)环壬基(环)、(亚)环己烯基(环)等。
如本文中所使用，术语“环烷基”指饱和单环或多环(诸如双环)烃环(例如单环，诸如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基，或双环，包括螺环、稠合或桥连系统(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基或双环[5.2.0]壬基、十氢化萘基等)，其任选地被1或多个(诸如1至3个)适合的取代基取代。所述环烷基具有3至15个碳原子。例如，术语“C3-6环烷基”指3至6个成环碳原子的饱和单环或多环(诸如双环)烃环(例如环丙基、环丁基、环戊基或环己基)，其任选地被1或多个(诸如1至3个)适合的取代基取代，例如甲基取代的环丙基。
如本文中所使用，术语“杂环基”指饱和或不饱和的一价单环或双环基团，其在环中具有2、3、4、5、6、7、8或9个碳原子和一个或多个(例如一个、两个、三个或四个)选自O、S、N、S(＝O)、S(＝O)2、S(＝O)(＝NRZ)、NRZ或P(＝O)(RZ)的含杂原子的基团，其中RZ在每次出现时各自独立地表示氢原子或C1-6烷基或卤代-C1-6烷基；所述杂环烷基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地，3-10元杂环基为在环中具有3-10个碳原子及杂原子的基团，例如但不限于环氧乙烷基、氮丙啶基、氮杂环丁烷基(azetidinyl)、氧杂环丁烷基(oxetanyl)、四氢呋喃基、二氧杂环戊烯基(dioxolinyl)、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、吡咯啉基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)。
如本文中所使用，术语“杂环基”涵盖并环结构，所述并环结构与其他基团的连接点可以在并环结构中的任一环上。因此，本发明的杂环基还包括但不限于杂环基并杂环基、杂环基并环烷基、单杂环基并单杂环基、单杂环基并单环烷基，例如3-7元(单)杂环基并3-7元(单)杂环基、3-7元(单)杂环基并(单)环烷基、3-7元(单)杂环基并C4-6(单)环烷基，其实例包括但不限于吡咯烷基并环丙基、环戊基并氮杂环丙基、吡咯烷基并环丁基、吡咯烷基并吡咯烷基、吡咯烷基并哌啶基、吡咯烷基并哌 嗪基、哌啶基并吗啉基、
如本文中所使用，术语“杂环基”涵盖桥杂环基和螺杂环基。
如本文中所使用，术语“桥杂环”是指两个饱和环共用两个不直接相连的环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子和/或硫原子)的环状结构，包括但不限于7-10元桥杂环、8-10元桥杂环、7-10元含氮桥杂环、7-10元含氧桥杂环、7-10元含硫桥杂环等，例如 等。所述“含氮桥杂环”、“含氧桥杂环”、“含硫桥杂环”任选地还含有一个或多个选自氧、氮和硫的其他杂原子。
如本文中所使用，术语“螺杂环”是指由两个或两个以上饱和环共用一个环原子形成的含有一个或多个(例如1个、2个、3个或4个)杂原子(例如氧原子、氮原子、硫原子)的环状结构，包括但不限于5-10元螺杂环、6-10元螺杂环、6-10元含氮螺杂环、6-10元含氧螺杂环、6-10元含硫螺杂环等，例如 所述“含氮螺杂环”、“含氧螺杂环”、“含硫螺杂环”任选地还含有一个或多个选自氧、氮、硫的其他杂原子。术语“6-10元含氮螺杂环基”是指含有共计6-10个环原子并且其中至少一个环原子为氮原子的螺杂环基。
如本文中所使用，术语“(亚)芳基”和“芳环”指具有共轭π电子系统的单环或稠合环多环芳族基团。例如，如本文中所使用，术语“C6-10(亚)芳基”和“C6-10芳环”意指含有6至10个碳原子的芳族基团，诸如(亚)苯基(苯环)或(亚)萘基(萘环)。(亚)芳基和芳环任选地被1或多个(诸如1至3个)适合的取代基(例如卤素、-OH、-CN、-NO2、C1-6烷基等)取代。当(亚)芳基和芳环为稠合环时，所稠合的环可为烃环、杂环或杂芳环。
术语“芳烷基”优选表示芳基取代的烷基，其中所述芳基和所述烷基如本文中所定义。通常，所述芳基可具有6-14个碳原子，并且所述烷基可具有1-6个碳原子。示例性芳烷基包括但不限于苄基、苯基乙基、苯基丙基、苯基丁基。
如本文中所使用，术语“(亚)杂芳基”和“杂芳环”指单环、双环或三环芳族环系，其具有5、6、7、8、9、10、11、12、13或14个环原子，特别是1或2或3或4或5或6或9或10个碳原子，且其包含至少一个可以相同或不同的杂原子(所述杂原子是例如氧、氮或硫)，并且，另外在每一种情况下可为苯并稠合的。特别地，“(亚)杂芳基”或“杂芳环”选自(亚)噻吩基(环)、(亚)呋喃基(环)、(亚)吡咯基(环)、(亚)噁唑基(环)、(亚)噻唑基(环)、(亚)咪唑基(环)、(亚)吡唑基(环)、(亚)异噁唑基(环)、(亚)异噻唑基(环)、(亚)噁二唑基(环)、(亚)三唑基(环)、(亚)噻二唑基(环)等，以及它们的苯并衍生物；或(亚)吡啶基(环)、(亚)哒嗪基(环)、(亚)嘧啶基(环)、(亚)吡嗪基(环)、(亚)三嗪基(环)等，以及它们的苯并衍生物。
如本文中所使用，术语“卤代”或“卤素”基团定义为包括F、Cl、Br或I。
如本文中所使用，术语“烷基硫基”意指通过硫原子连接至母体分子部分的如上文所定义的烷基。C1-6烷基硫基的代表性实例包括但不限于甲硫基、乙硫基、叔丁硫基及己硫基。
如本文中所使用，术语“含氮杂环”指饱和或不饱和的单环或双环基团，其在环中具有2、3、4、5、6、7、8、9、10、11、12或13个碳原子和至少一个氮原子，其还可任选地包含一个或多个(例如一个、两个、三个或四个)选自N、O、C＝O、S、S＝O和S(＝O)2的环成员；所述含氮杂环通过氮原子与分子的其余部分连接。所述含氮杂环优选为饱和含氮单环。特别地，3至14元含氮杂环为在环中具有3-14个碳原子及杂原子(其中至少一个为氮原子)的基团，其包括但不限于三元含氮杂环(如氮丙啶基)、四元含氮杂环(如氮杂环丁烷基)、五元含氮杂环(如吡咯基、吡咯烷基(吡咯烷环)、吡咯啉基、吡咯烷酮基、咪唑基、咪唑烷基、咪唑啉基、吡唑基、吡唑啉基)、六元含氮杂环(如哌啶基(哌啶环)、吗啉基、硫吗啉基、哌嗪基)、七元含氮杂环等。
术语“取代”指所指定的原子上的一个或多个(例如一个、两个、三个或四个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
如果取代基被描述为“任选地被取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
如果取代基被描述为“独立地选自”一组，则各取代基独立于另一者被选择。因此，各取代基可与另一(其他)取代基相同或不同。
如本文中所使用，术语“一个或多个”意指在合理条件下的1个或超过1个，例如2个、3个、4个、5个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
本发明还包括所有药学上可接受的同位素标记的化合物，其与本发明的化合物相同，除了一个或多个原子被具有相同原子序数但原子质量或质量数不同于在自然界中占优势的原子质量或质量数的原子替代。适合包含入本发明的化合物中的同位素的实例包括(但不限于)氢的同位素(例如氘(D，2H)、氚(T，3H))；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36Cl)；氟的同位素(例如18F)；碘的同位素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。某些同位素标记的本发明的化合物(例如掺入放射性同位素的那些)可用于药物和/或底物组织分布研究(例如分析)中。放射性同位素氚(即3H)及碳-14(即14C)因易于掺入且容易检测而特别可用于该目的。用正电子发射同位素(例如11C、18F、15O及13N)进行取代可在正电子发射断层显像术(PET)研究中用于检验底物受体占据情况。被同位素标记的本发明的化合物可通过与描述于随附路线和/或实施例及制备中的那些类似的方法通过使用适当的被同位素标记的试剂代替之前采用的非标记的试剂来制备。本发明的药学上可接受的溶剂合物包括其中结晶溶剂可被同位素取代的那些，例如，D2O、丙酮-d6或DMSO-d6。
还应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本发明中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、酯、溶剂合物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本发明的化合物或其代谢物或残余物。因此，当在本文中提及“本发明的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本发明的化合物的药学上可接受的盐包括其酸加成盐及碱加成盐。
适合的酸加成盐由形成药学可接受盐的酸来形成。实例包括天冬氨酸盐、苯甲酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、延胡索酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、六氟磷酸盐、氢溴酸盐/溴化物、氢碘酸盐/碘化物、顺丁烯二酸盐、丙二酸盐、甲基硫酸盐、萘甲酸盐(naphthylate)、烟酸盐、硝酸盐、乳清酸盐、草酸盐、棕榈酸盐及其它类似的盐。
适合的碱加成盐由形成药学可接受盐的碱来形成。实例包括铝盐、精氨酸盐、胆碱盐、二乙胺盐、赖氨酸盐、镁盐、葡甲胺盐、钾盐及其它类似的盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本发明的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
如本文中所使用，术语“酯”意指衍生自本申请中各个通式化合物的酯，其包括生理上可水解的 酯(可在生理条件下水解以释放游离酸或醇形式的本发明的化合物)。本发明的化合物本身也可以是酯。
本发明的化合物可以溶剂合物(优选水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
在本发明的范围内还包括本发明的化合物的代谢物，即在给药本发明的化合物时体内形成的物质。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢产物的时间的方法制得的化合物。
本发明在其范围内进一步包括本发明的化合物的前药，其为自身可具有较小药理学活性或无药理学活性的本发明的化合物的某些衍生物当被给药至身体中或其上时可通过例如水解裂解转化成具有期望活性的本发明的化合物。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。关于前药的使用的其他信息可参见“Pro-drugs as Novel Delivery Systems”，第14卷，ACS Symposium Series(T.Higuchi及V.Stella)及“Bioreversible Carriers in Drug Design,”Pergamon Press,1987(E.B.Roche编辑，American Pharmaceutical Association)。本发明的前药可例如通过用本领域技术人员已知作为“前-部分(pro-moiety)(例如“Design of Prodrugs”，H.Bundgaard(Elsevier,1985)中所述)”的某些部分替代本发明的化合物中存在的适当官能团来制备。
本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry,ed.J.F.W.McOmie,Plenum Press,1973；和T.W.Greene&P.G.M.Wuts,Protective Groups in Organic Synthesis,John Wiley&Sons,1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以移除保护基。
如本文中所使用，术语“约”是指在所述数值的±10％范围内，优选±5％范围内，更优选±2％范围内。
如本文中所使用的术语“有效量”指被给药后会在一定程度上缓解所治疗病症的一或多种症状的化合物的量。
如本文所用的术语“预防”是指预先施用药物以避免或预防疾病或病症的一种或多种症状的出现。医学领域的普通技术人员认识到术语“预防”不是绝对术语。在医学领域中，应理解为预防性施用药物以基本上减少病症的可能性或严重性或病症的症状，这是本公开内容中意图的意义。预防分为一级预防(以防止疾病的发展)和二级预防(由此疾病已经发展并且患者受到保护以防止该过程的恶化)。
除非另外说明，否则如本文中所使用，术语“治疗(treating)”意指逆转、减轻、抑制这样的术语所应用的病症或病况或者这样的病症或病况的一或多种症状的进展，或预防这样的病症或病况或者这样的病症或病况的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
如本文中所使用，术语“TPK酶活性降低”是指所治疗个体中的TPK酶活性低于正常个体中的酶活性。
如本文中所使用，术语“TPK表达水平降低”是指所治疗个体中的TPK mRNA/DNA水平或者蛋白表达水平低于正常个体中的水平。
如本文中所使用，术语“TDP水平降低”是指所治疗个体中的TDP水平低于正常个体中的水平。
在一些实施方案中，本发明提供预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法，其包括向需要其的个体给药预防或治疗有效量的硫胺素焦磷酸激酶(TPK)激动剂。
在优选的实施方案中，所述神经退行性疾病为阿尔茨海默病。
在更优选的实施方案中，所述阿尔茨海默病为个体的TPK酶活性降低、TPK表达水平降低和/或TDP水平降低的阿尔茨海默病。
在一些实施方案中，所述TPK激动剂为式(I)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
优选地，所述TPK激动剂为式(I)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
其中：
A和B各自独立地为CR3或N；
环C和环D各自独立地为C3-10烃环(例如C3-6烃环)、3-10元杂环、C6-10芳环或5-14元杂芳环；优选地，环C为5-6元杂芳环；
L1、L2和L3各自独立地不存在或者选自-O-、-C(＝O)-、-C(＝O)O-、-NR-、-C(＝O)NR-、-(S＝O)NR-、-S(＝O)2NR-、-S-、-S(＝O)-、-S(＝O)2-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C3-6亚环烃基-、-(3-10元亚杂环基)-、-C6-10亚芳基-、-(5-14元亚杂芳基)-、-W-C1-6亚烷基-、-C1-6亚烷基-W-和-W-C1-6亚烷基-W’-，其中所述亚烷基任选地进一步被一个或多个W间隔；条件是L1、L2和L3中的至少一者存在；
W和W’在每次出现时各自独立地选自-O-、-C(＝O)-、-C(＝O)O-、-NR-、-C(＝O)NR-、-(S＝O)NR-、-S(＝O)2NR-、-S-、-S(＝O)-和-S(＝O)2-；
R1在每次出现时各自独立地选自卤素、-OH、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Ra、-OC(＝O)Ra、-C(＝O)ORa、-ORa、-SRa、-S(＝O)Ra、-S(＝O)2Ra、-S(＝O)2NRaRb、-NRaRb、-C(＝O)NRaRb、-NRa-C(＝O)Rb、-NRa-C(＝O)ORb、-NRa-S(＝O)2-Rb、-NRa-C(＝O)-NRaRb、-C1-6亚烷基-ORa、-C1-6亚烷基-NRaRb和-O-C1-6亚烷基-NRaRb；
R2和R3在每次出现时各自独立地选自H、卤素、-OH、-NH2、-CN、-NO2、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Ra、-OC(＝O)Ra、-C(＝O)ORa、-ORa、-SRa、-S(＝O)Ra、-S(＝O)2Ra、-S(＝O)2NRaRb、-NRaRb、-C(＝O)NRaRb、-NRa-C(＝O)Rb、-NRa-C(＝O)ORb、-NRa-S(＝O)2-Rb、-NRa-C(＝O)-NRaRb、-C1-6亚烷基-ORa、-C1-6亚烷基-NRaRb和-O-C1-6亚烷基-NRaRb；
R、Ra和Rb在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基；
n为0、1、2、3或4；优选地，n为0、1或2；
上述烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、环烃基、亚环烃基、烃环、杂环基、亚杂环基、杂环、芳基、亚芳基、芳环、杂芳基、亚杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Rc、-OC(＝O)Rc、-C(＝O)ORc、-ORc、-SRc、-S(＝O)Rc、-S(＝O)2Rc、-S(＝O)2NRcRd、-NRcRd、-C(＝O)NRcRd、-NRc-C(＝O)Rd、-NRc-C(＝O)ORd、-NRc-S(＝O)2-Rd、-NRc-C(＝O)-NRcRd、-C1-6亚烷基-ORc、-C1-6亚烷基-NRcRd和-O-C1-6亚烷基-NRcRd，所述烷基、亚烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH2、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-O-C1-6烷基和-C1-6亚烷基-O-C1-6烷基；并且
Rc和Rd在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH2、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基和-C1-6亚烷基-O-C1-6烷基。
在一些实施方案中，环C为C3-6烃环、3-10元杂环、C6-10芳环或5-14元杂芳环。
在优选的实施方案中，所述TPK激动剂为式(II)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
其中：
X为-C(R)2-、-NR-、-O-或-S-；优选地X为-NR-、-O-或-S-；更优选地X为-NH-、-N(CH3)-、-O-或-S-；并且
其余各基团如上文中所定义。
在优选的实施方案中，为
在优选的实施方案中，为
在优选的实施方案中，为
在优选的实施方案中，R3在每次出现时各自独立地为H或C1-6烷基(优选甲基)；
优选地，A和B各自独立地为CH、CCH3或N；并且
更优选地，A为N并且B为CH。
在优选的实施方案中，L1和L3各自独立地不存在或者为-C(＝O)-、-N(CH3)-、-C1-6亚烷基-、-W-C1-6亚烷基-或-C1-6亚烷基-W-，所述亚烷基任选地进一步被一个或多个W间隔，并且
W为-O-、-C(＝O)-、-C(＝O)O-、-NH-、-N(CH3)-、-C(＝O)NH-或-C(＝O)N(CH3)-。
在优选的实施方案中，L1和L3各自独立地不存在或者为-C(＝O)-、-N(CH3)-、-C1-6亚烷基-或-C1-6亚烷基-W-，所述亚烷基任选地进一步被一个或多个W间隔，并且
W为-O-、-C(＝O)-、-C(＝O)O-、-NH-、-N(CH3)-、-C(＝O)NH-或-C(＝O)N(CH3)-。
在优选的实施方案中，L2不存在或者为-(3-10元亚杂环基)-；
优选地，L2不存在或者为亚哌嗪基或亚哌啶基。
在优选的实施方案中，为
在优选的实施方案中，为
在优选的实施方案中，R1在每次出现时各自独立地选自卤素、-CN、C1-6烷基、卤代C1-6烷基和C1-6烷氧基；
优选地，R1在每次出现时各自独立地选自-F、-Cl、-Br、-CN、-CH3、-CF3和-OCH3。
在优选的实施方案中，R2独立地选自H、C1-6烷基、C6-10芳基和5-14元杂芳基；所述基团任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、-N(C1-6烷基)2、C1-6烷氧基、卤代C1-6烷氧基、-C(＝O)-C1-6烷基、-C(＝O)OH、-C(＝O)O-C1-6烷基、-S-C1-6烷基、-S(＝O)2-C1-6烷基、-S(＝O)2-(3-10元杂环基)、-S(＝O)2NH2和-C(＝O)NH2；
优选地，R2独立地选自异丙基、
在优选的实施方案中，所述TPK激动剂为式(III)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
其中各基团如上文所定义。
在一些实施方案中，所述TPK激动剂为式(IV)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
其中：
环D不存在或者为C3-6烃环、3-10元杂环、C6-10芳环或5-14元杂芳环；
L4选自-O-、-C(＝O)-、-C(＝O)O-、-NR’-、-C(＝O)NR’-、-(S＝O)NR’-、-S(＝O)2NR’-、-S-、-S(＝O)-、-S(＝O)2-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C3-6亚环烃基-、-(3-10元亚杂环基)-、-C6-10亚芳基-、-(5-14元亚杂芳基)-、-U-C1-6亚烷基-、-C1-6亚烷基-U-、-U-C1-6亚烷基-U’-和-C1-6亚烷基-U-C1-6亚烷基-，其中所述亚烷基任选地进一步被一个或多个U间隔；
U和U’在每次出现时各自独立地选自-O-、-C(＝O)-、-C(＝O)O-、-NR’-、-C(＝O)NR’-、-(S＝O)NR’-、-S(＝O)2NR’-、-S-、-S(＝O)-和-S(＝O)2-；
R4、R4’、R5、R5’、R6和R7在每次出现时各自独立地选自H、卤素、-OH、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Re、-OC(＝O)Re、-C(＝O)ORe、-ORe、-SRe、-S(＝O)Re、-S(＝O)2Re、-S(＝O)2NReRf、-NReRf、-C(＝O)NReRf、-NRe-C(＝O)Rf、-NRe-C(＝O)ORf、-NRe-S(＝O)2-Rf、-NRe-C(＝O)-NReRf、-C1-6亚烷基-ORe、-C1-6亚烷基-NReRf、-O-C1-6亚烷基-NReRf和-C1-6亚烷基-OC(＝O)-C1-6亚烷基-C(＝O)ORe；或者，R4与R4’或R5与R5’共同构成＝O；或者，R4、R4’、R5、R5’连同其所连接的基团共同沟通C3-6烃环、3-10元杂环、C6-10芳环或5-14元杂芳环；
R’、Re和Rf在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基；
p和q各自独立地为1、2、3或4；优选地，p和q各自独立地为1或2；条件是当环D不存在时，q为1；
上述烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、环烃基、亚环烃基、烃环、杂环基、亚杂环基、杂环、芳基、亚芳基、芳环、杂芳基、亚杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Rg、-OC(＝O)Rg、-C(＝O)ORg、-ORg、-SRg、-S(＝O)Rg、-S(＝O)2Rg、-S(＝O)2NRgRh、-NRgRh、-C(＝O)NRgRh、-NRg-C(＝O)Rh、-NRg-C(＝O)ORh、-NRg-S(＝O)2-Rh、-NRg-C(＝O)-NRgRh、-C1-6亚烷基-ORg、-C1-6亚烷基-NRgRh和-O-C1-6亚烷基-NRgRh，所述烷基、亚烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH2、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-O-C1-6烷基和-C1-6亚烷基-O-C1-6烷基；并且
Rg和Rh在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH2、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基和-C1-6亚烷基-O-C1-6烷基。
在优选的实施方案中，所述TPK激动剂为式(V)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
其中各基团如上文所定义。
在优选的实施方案中，所述L4选自-(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-和-CH2-CH(OH)-CH2-NH-。
在优选的实施方案中，为-CN、-NH2、
在一些的实施方案中，所述TPK激动剂选自：










在优选的实施方案中，将所述TPK激动剂以约0.005mg/日至约5000mg/日的量，例如约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或5000mg/日的量给药。
在优选的实施方案中，将所述TPK激动剂以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg/kg、约225μg/kg、约250μg/kg、约275μg/kg、约300μg/kg、约325μg/kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg/kg、约550μg/kg、约575μg/kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg或约300mg/kg体重的量给药。
在优选的实施方案中，将所述TPK激动剂的每日剂量一次性给予或分两次、三次或四次给予。
在优选的实施方案中，将所述TPK激动剂连续给药至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天。
在优选的实施方案中，将所述TPK激动剂给药一个或多个(例如1、2、3、4、5、6、7、8、9或10个)疗程，其中每个疗程持续至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；并且每两个疗程之间间隔0、1、2、3、4、5、6、7、8、9、10天、两周、三周或四周。
在优选的实施方案中，将所述TPK激动剂通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
在优选的实施方案中，将所述TPK激动剂以选自片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂和糖浆剂的剂型给药。
在优选的实施方案中，所述方法改善了个体的以下病理生理学表现：认知行为学异常、神经变性改变(例如进行性突触/神经元丢失和脑萎缩)、β-淀粉样蛋白沉积、Tau异常磷酸化及其所造成的神经纤维缠结、胶质细胞激活和炎症和/或脑葡萄糖代谢障碍。
在优选的实施方案中，本公开还包括给药一种或多种其它的治疗剂。
在一些实施方案中，本公开提供化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，所述化合物具有式(III)的结构：
其中各基团如上文所定义；
条件是-L3-R2不是H和甲基。
本发明涵盖以上实施方案的任意组合。
在一些实施方案中，本公开提供化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：







实施例
以下结合实施例进一步描述本发明，但提供这些实施例并非意在限制本发明的范围。
本发明中的缩写具有以下含义：
实施例1：3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物1)的合成
向反应瓶中加入1a(100mg,0.37mmol,1.0eq.)、1-(2,3-二氯苯基)哌嗪盐酸盐(1b)(118mg,0.44mmol,1.2eq.)、HATU(280mg,0.74mmol,2.0eq.)和二氯甲烷(3mL)，再加入DIPEA(0.2mL,1.11mmol,3.0eq.)，室温下反应过夜。减压浓缩，剩余物采用18C反相过柱(洗脱剂：0.1％甲酸水溶液：MeOH＝10％～70％)纯化，收集目标组分，浓缩得标题化合物1(白色固体)。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例2：3-(3-(4-(2,5-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物2)的合成
除了将实施例1中的1b替换成1-(2,5-二氯苯基)哌嗪盐酸盐(2b)，反应溶剂替换为DMF之外，采用与实施例1相同的合成路线，制得标题化合物2(类白色固体)。
LCMS：484[M+1]+
1H NMR(400MHz,DMSO-d6):δ11.97(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).
实施例3：3-(3-(4-(2,4-二氯苯基)哌嗪-1-基)-3-氧代丙基)-7-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物3)的合成
步骤1：将3a(10g，75.8mmol，1.0eq)、三乙胺(15.3g，151.6mmol，2.0eq)、DCM(100mL)加入500mL三口瓶中，冰浴降温，滴加乙酰氯(7.1g，90.96mmol，1.2eq)，室温搅拌3h，浓缩，柱层析纯化得黄色固体中间产物3A(8.0g，收率：60.6％)。
步骤2：将3A(9.0g，51.7mmol，1.0eq)、THF(100mL)加入250mL三口瓶中，冰浴降温，加入NaH(3.1g，77.6mmol，1.5eq)和溴乙酸乙酯(12.9g，0.405mmol，1.2eq)，室温搅拌2小时，加水淬灭，EA萃取，有机相干燥，浓缩，柱层析得白色固体中间产物3B(8.4g，收率：62.4％)。
步骤3：将3B(8.4g，32.3mmol，1.0eq)和THF(100mL)加入250mL三口瓶中，冰浴降温，加入叔丁醇钾(3.84g，32.3mmol，1.0eq)，室温搅拌2小时，加水淬灭，EA萃取，有机相干燥，浓缩， 柱层析得白色固体中间产物3C(4.4g，收率：62.4％)。
步骤4：将3C(2g，9.17mmol，1.0eq)、DMF(20mL)、DMF-DMA(4.36g，36.68mmol，4.0eq)加入100mL单口瓶中，升温至70℃反应7h，浓缩得黄色固体3D粗品直接做下一步反应。
步骤5：将3D(粗品，9.17mmol，1.0eq)、乙醇(20mL)和β-丙氨酸乙酯盐酸盐(2.8g，18.34mmol，2.0eq)加入250mL单口瓶中，升温至70℃反应7h，冷却结晶，过滤得白色固体中间产物3E(1.8g，收率：65.6％)。
步骤6：将3E(1.8g，6.02mmol，1.0eq)、甲醇(20mL)，LiOH(0.433g，18.06mmol，3.0eq)加入100mL单口瓶中，室温搅拌3h，浓缩除去甲醇，稀盐酸调节pH＝4，过滤得白色固体中间产物3F(0.9g，收率：55.3％)。
步骤7：将3F(150mg,0.55mmol,1.0eq.)加入到N,N-二甲基甲酰胺(7mL)中，加入HATU(252mg,0.66mmol,1.2eq.)，室温下反应1h。加入1-(2,4-二氯苯基)哌嗪盐酸盐3b(178mg,0.66mmol,1.2eq.)和DIPEA(264mg,2.05mmol,3.7eq.)，室温下反应过夜。减压浓缩，残留分用甲醇研磨，制得标题化合物3(淡黄色固体)140mg，收率：52％。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例4：8-甲基-3-(3-氧代-3-(4-(2-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物4)的合成
除了将实施例1中的1b替换成1-(2-三氟甲基苯基)哌嗪之外，采用与实施例1相同的合成路线，制得标题化合物4(白色固体)。
LCMS：484[M+1]；
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例5：3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物5)的合成
步骤1：将5a(5g,28.54mmol)加入至DCM(100mL)，然后滴加65％HNO3(2.77g,28.54mmol)与AcOH(17.14g,285.41mmol)的混合试剂，反应液在40℃下搅拌2小时；反应液慢慢倒入饱和碳酸氢钠水溶液中淬灭并调节pH＝8～9，二氯甲烷萃取，有机相干燥，过滤，旋干后正相柱色谱法纯化(洗脱剂:(石油醚:(乙酸乙酯/二氯甲烷(1:1))＝5％～25％))；收集目标产物得到黄色固体中间产物5A(2.2g，收率:35.0％)。
步骤2：将5A(2.2g,9.99mmol)加入至甲醇(30mL)，然后加入10％wt.Pd/C(220mg)，反应液 在氢气球保护下室温搅拌3小时；过滤，母液旋干得到棕色固体中间产物5B(1.7g，收率:89.5％)。
步骤3：将5B(1.7g,8.94mmol)加入至DMF(20mL)，然后加入DMF-DMA(4.26g,35.75mmol)；反应液在80℃下搅拌3小时；加水稀释，乙酸乙酯萃取，有机相干燥，过滤，旋干得到棕色固体中间产物5C(2g，收率:91.2％)。
步骤4：将5C(1.8g,7.34mmol)加入至MeOH(25mL)，然后加入β-丙氨酸乙酯盐酸盐(2.2g,14.68mmol)，反应液在70℃下搅拌3小时；反应液降温至室温，大量固体析出，过滤，滤饼旋干得到棕色固体中间产物5D(1.3g，收率:62.1％)。
步骤5：将5D(500mg,1.75mmol)加入至混合溶剂THF/MeOH/H2O(6mL/2mL/2mL)，然后加入LiOH(126mg,5.26mmol)；反应液室温搅拌2小时；加水稀释，用1M盐酸水溶液调节pH＝5～6直至大量固体析出，过滤，滤饼旋干得到黄色固体中间产物5E(430mg，收率:95.4％)。
步骤6：除了将实施例1中的1b替换成1-(3-(三氟甲基)苯基)哌嗪盐酸盐(5b)，1a替换成5E之外，采用与实施例1相同的合成路线，制得标题化合物5(白色固体)。
LCMS:470[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.11(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).
实施例6：3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-8-(三氟甲基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物6)的合成
步骤1：将化合物6a(2.0g,7.35mmol,1.0eq.)溶于无水四氢呋喃(30mL)，冰浴下分批加入叔丁醇钾(824mg,7.35mmol,1.0eq.)，室温下反应过夜。加水(30mL)稀释，用乙酸乙酯(2×30mL)萃取，合并有机相，用饱和食盐水(20mL)洗涤，干燥过滤，减压浓缩得到粗品，通过硅胶柱分离纯化(洗脱剂：石油醚：乙酸乙酯＝10:1～5:1)，收集目标组分浓缩，得白色固体6A(1.0g，收率：50％)。
步骤2-4：除了将实施例3中3C替换为6A外，采用与实施例3中步骤4至步骤6相同的合成路线，制得化合物6D。
步骤5：除了将实施例1中1a替换为6D，1b替换为1-(3-(三氟甲基)苯基)哌嗪盐酸盐(5b)之外，采用实施例1相同的合成路线，制得标题化合物6(黄色固体)。
LCMS：538[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.61(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).
实施例7：3-(3-(4-(2,4-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物7)的合成
除了将实施例1中的1b替换成1-(2,4-二氯苯基)哌嗪盐酸盐，采用与实施例1相同的合成路线，制得标题化合物7(黄色固体)。
LCMS：484[M+1]+
1H NMR(400MHz,DMSO-d6):δ11.99(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).
实施例8：3-(3-(4-(2,6-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物8)的合成
除了将实施例1中的1b替换成1-(2,6-二氯苯基)哌嗪盐酸盐之外，采用与实施例1相同的合成路线，制得标题化合物8(白色固体)。
LCMS：484[M+1]+
1H NMR(400MHz,DMSO-d6):δ11.97(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).
实施例9：3-(3-(4-(3,4-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物9)的合成
除了将实施例1中的1b替换成1-(3,4-二氯苯基)哌嗪盐酸盐之外，采用与实施例1相同的合成路线，制得标题化合物9(类白色固体)。
LCMS：484[M+1]+
1H NMR(400MHz,DMSO-d6):δ11.96(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).
实施例10：8-甲基-3-(3-氧代-3-(4-(4-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物10)的合成
除了将实施例1中的1b替换成10b之外，采用与实施例1相同的合成路线，制得标题化合物10(白色固体)。
LCMS：484[M+1]；
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例11：9-甲基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物11)的合成
步骤1：将11a(1.0g，5.29mmol，1.0eq)、乙酸(3.17g，52.9mmol，10.0eq)和DCM(20mL)加入100mL单口瓶中，冰浴降温，加入65％硝酸(0.513g，5.29mmol，1.0eq)，室温下搅拌12h，加入饱和碳酸氢钠溶液，分液，有机相干燥浓缩，通过硅胶柱分离纯化(洗脱剂：DCM:MeOH＝30:1～10:1)，得到淡黄色固体11A。
步骤2-5：除了将实施例5中5A替换为11A外，采用实施例5步骤2至步骤5相同的合成路线制得化合物11E。
步骤6：除了将实施例1中的1b替换成5b，1a替换成11E之外，采用与实施例1相同的合成路线，制得标题化合物11(白色固体)。
LCMS：484[M+1]；
1H NMR(400MHz,DMSO-d6)δ12.04(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).
实施例12：8-溴-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物12)的合成
除了将实施例1中的1b替换成1-(3-(三氟甲基)苯基)哌嗪盐酸盐(5b)，1a替换成12a外，采用与实施例1相同的合成路线，制得标题化合物12(白色固体)。
LCMS[M+H]+：548,550
1H NMR(400MHz,CD3OD)δ8.38(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).
实施例13：3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-3-氧代丙基)-7-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物13)的合成
除了将实施例1中1a替换为3F外，采用实施例1相同的合成路线，制得标题化合物13(淡黄色固体)。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例14：3-(3-(4-(2,5-二氯苯基)哌嗪-1-基)-3-氧代丙基)-7-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物14)的合成
除了将实施例1中1a替换为3F，1b替换为1-(2,5-二氯苯基)哌嗪盐酸盐外，采用与实施例1相同的合成路线，制得标题化合物14(淡黄色固体)。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例15：3-(4-(4-(2,3-二氯苯基)哌嗪-1-基)-4-氧代丁基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物15)的合成
步骤1：将实施例11步骤1中11a替换为15a，采用实施例11步骤1相同的合成方法制得化合物15A。
步骤2-5：将实施例5步骤2中5A替换为15A，步骤4中β-丙氨酸乙酯盐酸盐替换为15C-1，采用实施例5步骤2-5相同的合成方法制得化合物15E。
步骤6：除了将实施例1中1a替换成15E之外，采用与实施例1相同的合成路线，制得标题化合物15(白色固体)。
LCMS:498[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例16：3-(3-(4-(3,5-双(三氟甲基)苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物16)的合成
除了将实施例1中的1b替换成1-(3,5-二(三氟甲基)苯基)哌嗪外，采用与实施例1相同的合成路线，制得标题化合物16(白色固体)。
LCMS：552[M+1]；
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例17：8-甲基-3-(4-氧代-4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物17)的合成
除了将实施例1中1a替换为15E，1b替换为5b之外，采用实施例1相同的合成路线，制得标题化合物17(白色固体)。
LCMS:498[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例18：3-(3-(4-(3-溴苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物18)的合成
除了将实施例1中1b替换为1-(3-溴苯基)哌嗪外，采用实施例1相同的合成方法，制得标题化合物18(白色固体)。
LCMS：494，496[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.96(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).
实施例19：3-(3-(4-(3,4-二氯苯基)哌嗪-1-基)-3-氧代丙基)-7-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物19)的合成
除了将实施例3步骤7中的1-(2,4-二氯苯基)哌嗪盐酸盐替换成1-(3,4-二氯苯基)哌嗪盐酸盐外，采用与实施例3相同的合成路线，制得标题化合物19(淡黄色固体)。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例20：3-(3-(4-(2,6-二氯苯基)哌嗪-1-基)-3-氧代丙基)-7-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物20)的合成
除了将实施例3步骤7中的1-(2,4-二氯苯基)哌嗪盐酸盐替换成1-(2,6-二氯苯基)哌嗪盐酸盐外，采用与实施例3相同的合成路线，制得标题化合物20(淡黄色固体)。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例21：7-甲基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物22)的合成
除了将实施例3步骤7中的1-(2,4-二氯苯基)哌嗪盐酸盐替换成1-(3-(三氟甲基)苯基)哌嗪盐酸盐之外，采用与实施例3相同的合成路线，制得标题化合物22(白色固体)。
LCMS：484[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例22：6-甲基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物23)的合成
除了将实施例3步骤1中的3a替换成23a，步骤7中1-(2,4-二氯苯基)哌嗪盐酸盐替换成1-(3-(三氟甲基)苯基)哌嗪盐酸盐之外，采用与实施例3相同的合成路线，制得标题化合物23(白色固体)。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.00(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).
实施例23：8-甲氧基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物24)的合成
除了将实施例3步骤1中的3a替换成24a，步骤7中1-(2,4-二氯苯基)哌嗪盐酸盐替换成5b之外，采用与实施例3相同的合成路线，制得标题化合物24(白色固体)。
LCMS：500[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.96(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).
实施例24：3-(3-(4-(3-羟基苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物25)的合成
除了将实施例1中1b替换为1-(3-羟基苯基)哌嗪之外，采用实施例1相同的合成路线，制得标题化合物25(白色固体)。
LCMS:432[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例25：3-(3-(4-(3-氨基苯基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物26)的合成
步骤1：除了将实施例1中的1b替换成1-(3-硝基苯基)哌嗪之外，采用与实施例1相同的合成路线，制得中间产物26A(白色固体)。
步骤2：将26A(0.09g，0.2mmol，1.0eq)、Pd/C(0.1g)和甲醇(5mL)加入到100mL单口瓶中，氢气置换空气，室温搅拌12小时，过滤，滤液浓缩，通过硅胶柱分离纯化(洗脱剂：DCM:MeOH＝30:1～10:1)，制得标题化合物26(白色固体)。
LCMS：431[M+1]；
1H NMR(400MHz,CD3OD)δ8.33(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).
实施例26：3-(4-(3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰基)哌嗪-1-基)苯甲酸(化合物27)的合成
步骤1：除了将实施例1中的1b替换成3-(哌嗪-1-基)苯甲酸乙酯之外，采用与实施例1相同的合成路线，制得中间产物27A(白色固体)。
步骤2：将27A(100mg，0.206mmol，1.0eq)、LiOH(7.4mg，0.309mmol，1.5eq)和MeOH(20mL)加入到100mL单口瓶中，室温搅拌2小时，浓缩，用稀盐酸调pH＝4，过滤，滤饼烘干，制得标题化合物27(白色固体)。
LCMS：460[M+1]；
1H NMR(400MHz,DMSO-d6)δ12.83(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).
实施例27：3-(4-(3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰基)哌嗪-1-基)苯甲酰胺(化合物28)的合成
步骤1：将28a(200mg,1.07mmol)加入到90％H2SO4(9mL)，室温下反应2天；反应液倒入冰水中淬灭，并用氨水调节pH＝9～10；旋干后用甲醇研磨后过滤得到白色固体中间产物28A(0.1g，收率:45.6％)。
步骤2：除了将实施例1中的1b替换成28A之外，采用与实施例1相同的合成路线，制得标题化合物28(白色固体)。
LCMS:459[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例28：3-(4-(3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰基)哌嗪-1-基)苯磺酰胺(化合物29)的合成
除了将实施例1中的1b替换成29a之外，采用与实施例1相同的合成路线，制得标题化合物29(白色固体)。
LCMS：495[M+1]；
1H NMR(400MHz,DMSO-d6)δ11.95(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).
实施例29：8-甲基-3-(4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物48)甲酸盐的合成
步骤1：向反应瓶中加入15C(合成路线参见实施例15)(550mg,2.06mmol,1.0eq.)、4-氨基丁醇(550mg,6.18mmol,3.0eq)和EtOH(8mL)。反应液于氮气下置换3次且在85℃下反应12小时。TLC监测显示原料反应完后，旋干用EtOAc(20mL)重结晶得到白色固体48A。
步骤2：向反应瓶中加入48A(270mg,1.0mmol,1.0eq.)和甲苯(5mL)，再向反应液中滴加入二氯亚砜(285mg,2.5mmol,2.5eq.)。反应液于45℃下反应3小时。LCMS监测显示原料基本反应完后，浓缩得到的粗品48B直接投往下一步(280mg，收率：90％)。
步骤3：向反应瓶中加入48B(280mg,0.9mmol,1.0eq.)、N,N-二甲基甲酰胺(8mL)、碳酸钾(478mg,3.6mmol,4.0eq)、碘化钾(20mg,0.09mmol,0.1eq)和1-(3-(三氟甲基)苯基)哌嗪盐酸盐(266mg,0.99mmol,1.1eq)。反应液于氮气下置换3次且在85℃下反应4小时。TLC监测显示原料反应完后，过滤旋干，所得粗品用C18反相柱色谱法(洗脱剂：0.1％甲酸水溶液：MeOH＝10％～70％)纯化，收集目标组分浓缩，制得标题化合物48的甲酸盐(白色固体)。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例30：8-甲基-3-(3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物49)的合成
除了将实施例29步骤1中的4-氨基丁醇替换成3-氨基-1-丙醇之外，采用与实施例29相同的合成路线，制得标题化合物49(黄色固体)。
LCMS：470[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.94(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).
实施例31：3-(4-(4-(2,3-二氯苯基)哌嗪-1-基)丁基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物50)的合成
步骤1：向反应瓶中加入48A(270mg,1.0mmol,1.0eq.)和DCM(5mL)，再向反应液中分批加入戴斯-马丁氧化剂(510mg,1.2mmol,1.2eq.)。反应液于常温下反应1小时。LCMS监测显示原料基本反应完后，过滤，用饱和碳酸氢钠水溶液洗涤，DCM萃取，有机相干燥浓缩的粗品，再用正相色谱法分离(洗脱剂PE:EA＝10:1到1:1)，得到淡黄色液体中间产物50A(250mg，收率：90％)。
步骤2：向反应瓶中加入50A(250mg,0.9mmol,1.0eq.)，将其溶于MeOH(8mL)，然后加入1-(2,3-二氯苯基)哌嗪盐酸盐(359mg,1.35mmol,1.5eq.)，反应在室温下及氮气下搅拌1小时后分批加入三乙酰氧基硼氢化钠(780mg,2.70mmol,3.0eq.)，反应在室温下及氮气下搅拌12小时后反应结束，旋干得到粗品，该粗品采用C18反相柱纯化，收集目标组分浓缩，制得标题化合物50(白色固体)。
LCMS：484[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例32：8-(三氟甲基)-3-(3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物51)的合成
除了将实施例29步骤1中的4-氨基丁醇替换成3-氨基-1-丙醇，15C替换成6B，采用与实施例29相同的合成路线，制得标题化合物51(淡黄色固体)。
LCMS：524[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.60(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).
实施例33：3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮 (化合物52)二甲酸盐的合成
除了将实施例29步骤1中的4-氨基丁醇替换成3-氨基-1-丙醇，步骤3中1-(3-(三氟甲基)苯基)哌嗪盐酸盐替换成1-(2,3-二氯苯基)哌嗪盐酸盐之外，采用与实施例29相同的合成路线，制得标题化合物52二甲酸盐(白色固体)。
LCMS：470，472[M+H]+
1H NMR(400MHz,CD3OD)δ8.32(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).
实施例34：3-(3-氧代-3-(4-(3-(三氟甲基)苄基)哌嗪-1-基)丙基)-8-(三氟甲基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物53)的合成
除了将实施例1中的1a替换为6D，1b替换为53b外，采用与实施例1相同的合成路线，制得标题化合物53(淡黄色固体)。
LCMS：552[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.59(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).
实施例35：3-(3-氧代-3-(4-(3,4,5-三氟苄基)哌嗪-1-基)丙基)-8-(三氟甲基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物54)的合成
除了将实施例6中的1-(2,4-二氯苯基)哌嗪盐酸盐替换成1-(3,4,5-三氟苄基)哌嗪盐酸盐之外，采用与实施例6相同的合成路线，制得标题化合物54(淡黄色固体)。
LCMS：538[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.59(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).
实施例36:8-甲基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)苯并呋喃并[3,2-d]嘧啶-4(3H)-酮(化合物57)的合成
将57a(3g，22.6mmol，1.0eq)、溴乙酸甲酯(4.14g，27mmol，1.2eq)、碳酸钾(6.24g，45.2mmol， 2.0eq)和DMF(20mL)升温至70℃反应5h，冷却，浓缩，加入EA萃取，分液，有机相干燥浓缩得白色固体中间产物57A(2.5g，收率：54％)。
除了将实施例3步骤4中的3C替换成57A，步骤7中1-(2,4-二氯苯基)哌嗪盐酸盐替换成1-(3-(三氟甲基)苯基)哌嗪盐酸盐之外，采用与实施例3中步骤4-7相同的合成路线，制得标题化合物57(白色固体)。
LCMS：485[M+1]；
1H NMR(400MHz,DMSO-d6)δ8.59(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).
实施例37：6-甲基-2-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-2,9-二氢-1H-吡啶并[3,4-b]吲哚-1-酮(化合物59)的合成
步骤1：将59a(5g,28.54mmol)、三乙胺(8.66g,85.62mmol)加入至DMF(50mL)，然后加入HATU(16.3g,42.78mmol)，混合液室温搅拌30分钟后加入氨基乙醛缩二甲醇(3.6g,34.25mmol)，反应液在室温条件下反应2小时；反应液加水稀释，乙酸乙酯萃取，有机相干燥，过滤旋干后正相柱色谱法纯化(洗脱剂:(石油醚:乙酸乙酯＝5％～50％))；收集目标产物得到白色固体中间产物59A(5g，收率:66.8％)。
步骤2：将59A(4g,14.2mmol)加入至多聚磷酸(40mL)，反应液在110℃下搅拌1小时；加水稀释并用饱和碳酸氢钠水溶液调节pH＝8～9，乙酸乙酯萃取，有机相干燥，过滤旋干后正相柱色谱法纯化(洗脱剂：二氯甲烷:甲醇＝20:1)；收集目标产物得到黄色固体中间产物59B(1.3g，收率:34.4％)。
步骤3：将59B(1.3g,6.56mmol)和碳酸钾(1.81g,13.12mmol)加入至DMF(20mL)，然后加入3-溴丙酸甲酯(1.2g,7.21mmol)；反应液室温搅拌过夜；加水稀释，乙酸乙酯萃取，有机相干燥，过滤，旋干得到粗品，正相柱色谱法纯化(洗脱剂：二氯甲烷:甲醇＝25:1)；收集目标产物得到黄色固体中间产物59C(1.2g，收率:64.4％)。
步骤4-5：除了将实施例3中的步骤6中3E替换成59C，步骤7中1-(2,4-二氯苯基)哌嗪盐酸盐替换成1-(3-(三氟甲基)苯基)哌嗪盐酸盐之外，采用与实施例3中步骤6-7相同的合成路线，制得标题化合物59(白色固体)。
LCMS:483[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.83(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).
实施例38：5-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苄基)戊酰胺(化合物65)的合成
除了将实施例15步骤4中15C-1替换为5-氨基戊酸乙酯盐酸盐，步骤6中1b替换为间三氟甲基苄胺，采用与实施例15相同的合成路线，制得标题化合物65(淡黄色固体)。
LCMS：457[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.96(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).
实施例39：N-(3,5-双(三氟甲基)苄基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物66)的合成
除了将实施例1中的1b替换成3,5-双(三氟甲基)苄胺外，采用与实施例1相同的合成路线，制得标题化合物66(类白色固体)。
LCMS：497[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.96(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).
实施例40：3-(6-甲基-1-氧代-1,9-二氢-2H-吡啶并[3,4-b]吲哚-2-基)-N-(3-(三氟甲基)苄基)丙酰胺(化合物67)的合成
除了将实施例37步骤5中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐替换成间三氟甲基苄胺之外，采用与实施例37相同的合成路线，制得标题化合物67(黄色固体)。
LCMS:428[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.82(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).
实施例41：4-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苄基)丁酰胺(化合物68)的合成
除了将实施例15中的1-(2,3-二氯苯基)哌嗪盐酸盐替换成间三氟甲基苄胺外，采用与实施例15相同的合成路线，制得标题化合物68(黄色固体)。
LCMS：443[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例42：3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(3-(三氟甲基)苯基)丙基) 丙酰胺(化合物69)的合成
除了将实施例1中的1b替换成3-(3-(三氟甲基)苯基)丙-1-胺外，采用与实施例1相同的合成路线，制得标题化合物69(类白色固体)。
LCMS：457[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例43：3-(4-氧代-8-(三氟甲基)-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苄基)丙酰胺(化合物71)的合成
除了将实施例6步骤5中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐(5b)替换成间三氟甲基苄胺之外，采用与实施例6相同的合成路线，制得标题化合物71(白色固体)。
LCMS：483[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.62(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).
实施例44：N-(2-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)乙基)-2-(3-(三氟甲基)苯基)乙酰胺(化合物72)的合成
步骤1：除了将实施例29步骤1中的4-氨基丁醇替换成单Boc-乙二胺之外，采用与实施例29步骤1相同的合成方法，制得中间产物72A(白色固体)。
步骤2：向反应瓶中加入72A(410mg,1.20mmol,1.0eq.)、EtOAc(4mL)和2M EtOAc/HCl溶液(4mL)。反应液于常温下反应4小时。LCMS监测后原料反应完，旋干用得到类白色固体中间产物72B(400mg，收率：90％)。
步骤3：除了将实施例1中的1b替换成间三氟甲基苯乙酸，1a替换成72B外，采用与实施例1相同的合成路线，制得标题化合物72(白色固体)。
LCMS：429[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例45：3-(6-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苄基)丙酰胺 (化合物73)的合成
除了将实施例22最后一步中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐替换成3-(三氟甲基)苯甲胺之外，采用与实施例22相同的合成路线，制得标题化合物73(白色固体)。
LCMS：429[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.02(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).
实施例46：3-(7-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苄基)丙酰胺(化合物74)的合成
除了将实施例3中的1-(2,4-二氯苯基)哌嗪盐酸盐替换成3-(三氟甲基)苯甲胺之外，采用与实施例3相同的合成路线，制得标题化合物74(白色固体)。
LCMS：429[M+1]；
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例47：N-(3-溴苄基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物75)的合成
除了将实施例1中的1b替换成3-溴苄胺之外，采用与实施例1相同的合成路线，制得标题化合物75(白色固体)。
LCMS：439，441[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例48：3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苯乙基)丙酰胺(化合物76)的合成
除了将实施例1中的1b替换成76b之外，采用与实施例1相同的合成路线，制得标题化合物76(白色固体)。
LCMS：443[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例49：3-(9-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苄基)丙酰胺(化合物77)的合成
除了将实施例11最后一步中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐替换成3-(三氟甲基)苯甲胺之外，采用与实施例11相同的合成路线，制得标题化合物77(白色固体)。
LCMS：429[M+1]；
1H NMR(400MHz,DMSO-d6)δ12.07(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).
实施例50：3-(8-溴-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苄基)丙酰胺(化合物79)的合成
除了将实施例1中的1b替换成间三氟甲基苄胺，1a替换成12a外，采用与实施例1相同的合成路线，制得标题化合物79(白色固体)。
LCMS[M+H]+：493,495
1H NMR(400MHz,DMSO-d6)δ12.35(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).
实施例51：3-(8-甲氧基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-(三氟甲基)苄基)丙酰胺(化合物80)的合成
除了将实施例23中化合物5b替换为间三氟甲基苄胺外，采用实施例23相同的合成路线，制得标题化合物80(淡黄色固体)。
LCMS：445[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例52：N-(3-羟基苄基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物82)的合成
将81(200mg,0.52mmol,1.0eq.)溶于二氯甲烷(2mL)，冰浴下滴加入三溴化硼二氯甲烷溶液(2.3g,1.54mmol,3.0eq.,17％)，室温下反应过夜。过滤，滤饼用二氯甲烷(2×10mL)洗涤，滤饼溶于乙酸乙酯(10mL)和饱和碳酸氢钠溶液(10mL)，分液，水相用乙酸乙酯(2×20mL)萃取，合并有机相，用饱和食盐水(20mL)洗涤，干燥过滤，减压浓缩，制得标题化合物82(白色固体)。
LCMS：377[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.00(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).
实施例53：3-((3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺基)甲基)苯甲酸甲酯(化合物83)的合成
除了将实施例1中的1b替换成3-(氨甲基)苯甲酸甲酯之外，采用与实施例1相同的合成路线，制得标题化合物83(白色固体)。
LCMS：419[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例54：3-((3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺基)甲基)苯甲酰胺(化合物84)的合成
步骤1：向反应瓶中加入化合物85(380mg,0.94mmol,1.0eq.)和二氯甲烷(5mL)，冰浴，再把(COCl)2(240mg,1.88mmol,2.0eq.)溶于5mL二氯甲烷中水(2mL)，滴入反应液中，滴毕，室温下搅拌两个小时。将溶剂蒸干后得橙黄色固体，直接投下一步反应(396mg，收率：100％)。
步骤2：向反应瓶中加入84A(396mg,0.94mmol,1.0eq.)和四氢呋喃(5mL)，冰浴，再把氨水(5mL,40％)滴入反应液中，滴毕，室温下搅拌半小时。有机相浓缩得粗品，该粗品采用C18反相柱(洗脱剂：0.5％甲酸水溶液:MeOH＝10％～80％)纯化，收集目标组分浓缩，制得标题化合物84(白色固体)。
LCMS：404[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例55：3-((3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺基)甲基)苯甲酸(化合物85)的合成
向反应瓶中加入化合物83(150mg,0.358mmol,1.0eq.)、LiOH(34mg,1.43mmol,4.0eq.)、乙醇(10mL)和水(2mL)，室温下搅拌过夜。加1.0mol/L盐酸调节pH＝5～6，过滤，滤饼用水洗涤至中性，烘干制得标题化合物85(白色固体)。
LCMS：405[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例56：N-(3-氨基苄基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物86)盐酸盐的合成
除了将实施例1中的1b替换成间Boc-氨基苄胺之外，采用与实施例1相同的合成路线，制得中间产物86A(黄色固体)。
将中间体86A(200mg,0.42mmol,1.0eq.)溶于1,4-二氧六环(10mL)，加入氯化氢的二氧六环溶液(2mL,8mmol,20.0eq.,4.0M)，室温下反应2小时。过滤，滤饼用乙酸乙酯(2×10mL)洗涤，45℃烘干，制得化合物86盐酸盐(黄色固体)。
LCMS：376[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.04(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).
实施例57：3-(8-甲基-4-氧代苯并呋喃并[3,2-d]嘧啶-3(4H)-基)-N-(3-(三氟甲基)苄基)丙酰胺(化合物87)的合成
除了将实施例36最后一步中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐替换成3-(三氟甲基)苯甲胺之外，采用与实施例36相同的合成路线，制得标题化合物87(白色固体)。
LCMS：430[M+1]；
1H NMR(400MHz,DMSO-d6)δ8.58(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).
实施例58：3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(3-磺酰胺苄基)丙酰胺(化合物88)的合成
除了将实施例1中的1b替换成3-氨甲基苯磺酰胺之外，采用与实施例1相同的合成路线，制得标题化合物88(白色固体)。
LCMS：440[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.00(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).
实施例59：3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(2-((3-(三氟甲基)苯基)氨基)乙基)丙酰胺(化合物89)的合成
除了将实施例1中的化合物1b替换成89b之外，采用与实施例1相同的合成路线，制得标题化合物89(白色固体)。
LCMS：458[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例60：3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(2-(3-(三氟甲基)苯氧基)乙基)丙酰胺(化合物90)的合成
除了将实施例1中的1b替换成90b外，采用与实施例1相同的合成路线，制得标题化合物90(白色固体)。
LCMS：459[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.96(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).
实施例61：N-甲基-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(2-((3-(三氟甲基)苯基)氨基)乙基)丙酰胺(化合物91)的合成
步骤1：向反应瓶中加入间三氟甲基溴苯(1.125g,5.0mmol,1.0eq.)、化合物91a-1(1.3g,7.5mmol,1.5eq.)、Pd2(dba)3(0.915g,1.0mmol,0.2eq.)、X-phos(0.475g,1.0mmol,0.2eq.)、磷酸钾(3.18g,15mmol,3.0eq.)和1,4-二氧六环(30mL)，氮气置换三次，于100℃下搅拌12小时。过滤，滤饼用乙酸乙酯洗涤，浓缩，通过硅胶柱分离纯化(洗脱剂：PE:EtOAc＝100:1～90:10)，收集目标组分，浓缩得到酒红色油状液体中间产物91A(1.0g，收率：62.9％)。
步骤2：向反应瓶中加入91A(1.0g,3.1mmol,1.0eq.)、盐酸(2.0mol/L的乙酸乙酯溶液(12.4mL,12.4mmol,4.0eq.)和乙酸乙酯(10mL)，室温搅拌3小时。过滤，滤饼用乙酸乙酯洗涤，烘干，得类白色固体中间产物91B(0.8g，收率：100％)。
步骤3：除了将实施例1中的1b替换成91B之外，采用与实施例1相同的合成路线，制得标题化合物91(白色固体)。
LCMS：472[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97-11.94(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).备注：受手性氮的影响，大部分氢呈现为两组峰。
实施例62：N-甲基-N-(2-(甲基(3-(三氟甲基)苯基)氨基)乙基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物92)的合成
步骤1：除了将实施例61中的91a-1替换成N,N’-二甲基乙二胺外，采用实施例61步骤1相同的合成方法，制得化合物92A。
步骤2：除了将实施例1中的1b替换成92A之外，采用与实施例1相同的合成路线，制得标题化合物92(白色固体)。
LCMS：486[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.96-11.93(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).备注：受手性氮的影响，大部分氢呈现两组峰。
实施例63：N-(2-(甲基(3-(三氟甲基)苯基)氨基)乙基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物93)的合成
除了将实施例61中的91a-1替换成2-(甲基氨基)乙基氨基甲酸叔丁酯之外，采用与实施例61相同的合成路线，制得标题化合物93(白色固体)。
LCMS：472[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例64：8-甲基-3-(3-((3-(三氟甲基)苄基)氨基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮(化合物94)的合成
步骤1：除了将实施例29步骤1中4-氨基丁醇替换成3-氨基-1-丙醇之外，采用与实施例29相同的合成路线，制得中间产物94A(黄色固体)。
步骤2：除了将实施例31中的1-(2,3-二氯苯基)哌嗪盐酸盐替换成3-(三氟甲基)苯甲胺之外，采用与实施例31相同的合成路线，制得标题化合物94(白色固体)。
LCMS：415[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例65：3-(三氟甲基)苄基3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酸酯(化合物95)的合成
除了将实施例1中的1b替换成间三氟甲基苄醇之外，采用与实施例1相同的合成路线，制得标题化合物95(类白色固体)。
LCMS：430[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例66：3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(2-((5,6,7,8-四氢萘-1-基)氨基)乙基)丙酰胺(化合物129)的合成
步骤1：向100mL单口瓶中加入5,6,7,8-四氢-1-萘胺(129a)(2g,0.0136mol,1.0eq.)、2-(BOC-氨基)溴乙烷(3.35g,0.0149mol,1.1eq.)、碳酸铯(8.9g,0.0272mol,2.0eq.)和无水DMF(50mL)，氮气保护，加热至70℃反应1h。反应结束，冷却至室温，加入大量水稀释，DCM萃取两次，DCM层用饱和食盐水洗涤三次，分液，DCM层无水硫酸钠干燥。有机相除去溶剂，粗品通过柱层析(洗脱剂：DCM:MeOH＝100:1～10:1)纯化，得到淡黄色油状物中间产物129A(0.45g,收率：11.4％)。
步骤2：向50mL单口瓶中加入129A(0.15g,0.000517mol,1.0eq.)和氯化氢的1,4-二氧六环溶液(2mL)，室温反应1h。旋干溶剂，得到129B粗品，直接用于下一步。
步骤3：除了将实施例1中的1b替换成129B之外，采用与实施例1相同的合成路线，制得标题化合物129(白色固体)。
LCMS：444[M+1]+
1H NMR(400MHz,DMSO-d6):δ12.00(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).
实施例67：N-(2-(甲基(5,6,7,8-四氢萘-1-基)氨基)乙基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物130)的合成
除了将实施例66的合成路线的第一步和第二步之间加入以下步骤，采用与实施例66相同的合成路线，制得标题化合物130(白色固体)。
向100mL三口瓶中加入130A(0.15g,0.000517mol,1.0eq.)和无水DMF(3mL)，氮气保护，冰浴降温。降至0-5℃时，加入NaH(0.025g,0.00062mol,1.2eq.,60％)。保温反应1h，加入碘甲烷(0.088g,0.00062mol,1.2eq.)的无水DMF(1mL)溶液，室温反应1h。反应结束，加入大量水稀释，EA萃取，EA层用饱和食盐水洗涤三次，分液，EA层无水硫酸钠干燥。有机相除去溶剂，粗品柱层析(洗脱剂：DCM:MeOH＝100:1～10:1)，得到淡黄色油状物中间产物130B(0.13g,收率：82.8％)。
LCMS：458[M+1]+
1H NMR(400MHz,DMSO-d6):δ11.98(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).
实施例68：3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(2-((5,6,7,8-四氢萘-2-基)氨基)乙基)丙酰胺(化合物131)的合成
除了将实施例66中的129a替换成131a之外，采用与实施例66相同的合成路线，制得标题化合物131(白色固体)。
LCMS：444[M+1]+
1H NMR(400MHz,DMSO-d6):δ12.00(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).
实施例69：3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)-N-(2-(萘-2-基氨基)乙基)丙酰胺(化合物132)的合成
除了将实施例66中的129a替换成132a之外，采用与实施例66相同的合成路线，制得标题化合物132(白色固体)。
LCMS：440[M+1]+
1H NMR(400MHz,DMSO-d6):δ12.00(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).
实施例70：N-(2-(6-氯-1H-吡咯并[3,2-c]吡啶-1-基)乙基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物133)的合成
除了将实施例66中的129a替换成133a之外，采用与实施例66相同的合成路线，制得标题化合物133(白色固体)。
LCMS：449[M+1]；
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例71：N-(咪唑并[1,2-a]吡啶-2-基甲基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物134)的合成
除了将实施例1中的1b替换成134a之外，采用与实施例1相同的合成路线，制得标题化合物134(类白色固体)。
LCMS：401[M+1]；
1H NMR(400MHz,DMSO-d6)δ12.00(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).
实施例72：N-(2-(6-氯-1H-吡咯并[3,2-b]吡啶-1-基)乙基)-3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰胺(化合物135)的合成
除了将实施例66中的129a替换成135a之外，采用与实施例66相同的合成路线，制得标题化合物135(白色固体)。
LCMS：449[M+1]；
1H NMR(400MHz,DMSO-d6)δ12.00(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).
实施例73：8-甲基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)嘧啶并[5,4-b]喹啉-4(3H)-酮(化合物138)的合成
步骤1：向250mL三口瓶中加入2-氨基-5-甲基苯甲醇(5g,0.0365mol,1eq.)(138a)、二氧化锰(3.2g,0.0365mol,1.0eq.)和二氯甲烷(100mL)，氮气保护条件下升温50℃搅拌3小时。反应结束，硅胶柱色谱法(二氯甲烷:甲醇＝10:1)纯化，减压浓缩，得到黄色固体中间产物138A(4.5g,收率：91.3％)。
步骤2：向250mL三口瓶中加入溴代丙酮酸甲酯(0.8g,0.0044mol,1eq.)和乙醇(20mL)，然后加入吡啶(0.35g，0.0044mol，1eq.)，回流搅拌1小时，冷却到20℃，加入吡啶(1.6g，0.02mol，4.6eq.)和138A(0.6g，0.0044mol，1eq)，继续回流4小时。然后加入四氢吡咯(0.94g，0.0132mol，3.0eq)，加热到90℃，回流1小时，冷却到20℃，然后硅胶柱色谱法(乙酸乙酯:石油醚＝1:5)纯化，减压浓缩，得到黄色液体中间产物138B(0.86g,收率：85％)。
步骤3：向250mL三口瓶中加入138B(0.9g,0.0039mol,1eq.)/DMF-DMA(1.8mL)和DMF(10mL)，加热到90℃搅拌2小时。然后加入3-氨基丙酸乙酯(1.3g,0.008mol,2eq.)，乙醇(10mL)，继续回流3小时，反应结束，硅胶柱色谱法(二氯甲烷:甲醇＝20:1)纯化，减压浓缩干，得到黄色固体中间产物138C(0.95g,收率：76.9％)。
步骤4-6：除了将实施例3中的3E替换成138D，1-(2,4-二氯苯基)哌嗪盐酸盐替换成1-(3-(三氟甲基)苯基)哌嗪之外，采用与实施例3相同的合成路线，制得标题化合物138(类白色固体)。
LCMS：496[M+1]+
1H NMR(400MHz,DMSO-d6):δ8.59(s,1H),δ8.44(s,1H),δ8.09(d,1H),δ7.90(s,1H),7.71(d,1H),δ7.38(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).
实施例74:(2-(4-(3-(2-(三氟甲基)-10H-吩噻嗪-10-基)丙基)哌嗪-1-基)乙基)琥珀酸甲酯(化合物184)的合成
向反应瓶中加入184a(100mg,0.23mmol,1.0eq.)和二氯甲烷(4mL)，再加入三乙胺(70mg,0.69mmol,3.0eq)，然后在冰水浴下滴加丁二酸单甲酯酰氯(52mg,0.34mmol,1.5eq)，反应液升温至室温下反应4小时。LCMS监测显示原料反应完后，将反应液过滤，浓缩，用C18反相柱分离得到标题化合物184(白色固体)(84mg，收率：66％)。
LCMS：552[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.24-7.14(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).
实施例75:1-(3-(10H-吩噻嗪-10-基)丙基)哌啶-2-甲酰胺(化合物185)的甲酸盐的合成
向反应瓶中加入185a(100mg,0.31mmol,1.0eq.)和N,N-二甲基甲酰胺(4mL)，再加入碳酸钾(130mg,0.93mmol,3.0eq)、2-哌啶甲酰胺(185b)(54mg,0.37mmol,1.2eq)和碘化钾(10mg,0.038mmol,0.1eq)，反应液于95℃下反应4小时。LCMS监测显示原料反应完后，将反应液过滤，用C18反相柱分离纯化得到标题化合物185的甲酸盐(白色固体)(60mg，收率：52％)。
LCMS：368[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.16(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).
实施例76:1-(3-(10H-吩噻嗪-10-基)丙基)哌啶-2-酮(化合物186)的合成
向反应瓶中加入185a(100mg,0.31mmol,1.0eq.)和N,N-二甲基甲酰胺(4mL)，再加入氢化钠(20mg,0.48mmol,1.5eq)以及哌啶酮(118b)(50mg,0.48mmol,1.5eq)，反应液于室温下反应4小时。
LCMS监测显示原料反应完后，将反应加入冰水淬灭，乙酸乙酯萃取，干燥，浓缩，通过硅胶柱层析(DCM:MeOH＝20:1)纯化，得到标题化合物186(灰色液体)(100mg，收率：94％)。
LCMS：339[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.23-7.11(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).
实施例77:1-(6-(2-(三氟甲基)-10H-吩噻嗪-10-基)己基)哌啶-2-酮(化合物187)的合成
将2-哌啶酮(186b)(86g,0.87mmol,1.25eq.)溶于N,N-二甲基甲酰胺(3mL)，冰浴下慢慢加入氢化钠(45mg,1.12mmol,1.6eq.)，反应0.5h。再滴加入187a(300mg,0.70mmol,1.0eq.)的N,N-二甲基甲酰胺溶液，室温下反应4h。加水(20mL)淬灭，用乙酸乙酯(3×20mL)萃取，合并有机相，用饱和食盐水(20mL)洗涤，干燥浓缩得到粗品，反相柱色谱法(洗脱剂：0.1％甲酸水溶液:MeOH＝9:1～2:8)纯化，收集目标组分浓缩得标题化合物187(棕色油状液体)(200mg，收率：64％)。
LCMS：448[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.33(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).
实施例78:N-(3-(10H-吩噻嗪-10-基)丙基)咪唑并[1,2-a]吡啶-3-胺(化合物188)甲酸盐的合成
向反应瓶中加入185a(383mg,1.2mmol,1.2eq.)和乙腈(6mL)，再加入碳酸钾(415mg,3.0mmol,3.0eq)、咪唑并[1,2-a]吡啶-3-胺(188b)(133mg,1.0mmol,1.0eq)和碘化钾(20mg,0.12mmol,0.1eq)，反应液于60℃下反应4小时。LCMS监测显示原料反应完后，将反应液过滤，旋干，用C18反相柱分离纯化得到标题化合物188的甲酸盐(白色固体)(160mg，收率：36％)。
LCMS：373[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.48(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).
实施例79:2-(3-(10H-吩噻嗪-10-基)丙基)异吲哚啉-1-酮(化合物189)的合成
除了将实施例76中的186b替换成189b之外，采用与实施例76相同的合成路线，制得标题化合物189(白色固体)。
LCMS：373[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.63(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).
实施例80:6-(3-(10H-吩噻嗪-10-基)丙氧基)吲哚啉-2-酮(化合物190)的合成
除了将实施例78中的188b替换成190b之外，采用与实施例78相同的合成路线，制得标题化合物190(白色固体)。
LCMS：389[M+H]+
1H NMR(400MHz,DMSO-d6)δ10.27(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).
实施例81:1-(3-(10H-吩噻嗪-10-基)丙基)哌啶-2-羧酸甲酯(化合物191)甲酸盐的合成
除了将实施例75中的185b替换成191b之外，采用与实施例75相同的合成路线，制得标题化合物191的甲酸盐(白色固体)。
LCMS：383[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.13(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).
实施例82:1-(3-(10H-吩噻嗪-10-基)丙基)哌啶-2-羧酸(化合物192)的合成
向反应瓶中加入191(100mg,0.26mmol,1.0eq.)和甲醇(3mL)/水(1mL)，再加入氢氧化锂(60mg,1.3mmol,5.0eq)，反应液于45℃下反应12小时。LCMS监测显示原料反应完后，将反应液旋干，调节浓缩液pH值至3-5，旋干，再用C18反相柱分离纯化得到标题化合物192(灰色固体)(40mg，收率：42％)。
LCMS：369[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.30(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).
实施例83:1-(6-(6-(三氟甲基)-2,3-二氢-4H-苯并[b][1,4]噻唑-4-基)己基)哌啶-2-酮(化合物193)的合成
步骤1：向反应瓶中加入193a(600mg,2.73mmol,1.0eq.)、DMF(10mL)、K2CO3(1.13g,8.19mmol,3.0eq.)以及1,6-二溴己烷(660mg，2.73mmol,1.0eq)。90℃下搅拌过夜。反应液过滤后通过柱色谱法纯化(洗脱剂：0.1％甲酸水溶液:MeOH＝4:6)，收集目标组分，减压浓缩得白色固体193A(200mg，收率：19％)。
步骤2：向反应瓶中加入193A(200mg,0.53mmol,1.0eq.)和DMF(2mL)，降温至0℃，置换氮气后加入氢化钠(38mg,1.59mmol,3.0eq.)，常温搅拌30min后加入哌啶-2-酮(186b)(79mg，0.80mmol,1..5eq)。室温下搅拌2小时。向反应液滴加水来淬灭反应，用乙酸乙酯萃取后，有机相浓缩后通过柱色谱法纯化(洗脱剂：0.1％甲酸水溶液：MeOH＝55:45)，收集目标组分，减压浓缩得标题化合物193(白色固体)(64mg，收率：30％)。
LCMS：401[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.15(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).
实施例84:1-(3-(6-(三氟甲基)-2,3-二氢-4H-苯并[b][1,4]噻嗪-4-基)丙基)哌啶-2-酮(化合物194)的合成
步骤1：除了将实施例83步骤1中的1,6-二溴己烷替换成3-溴丙烷-1-醇之外，采用与实施例83步骤1相同的合成路线，制得化合物194A(白色固体)。
步骤2：向反应瓶中加入194A(200mg,0.72mmol,1.0eq.)和40％的氢溴酸水溶液，于100℃下回流搅拌过夜。反应液减压浓缩得白色固体194B(150mg，收率：62％)。
步骤3：除了将实施例83步骤2中的193A替换成194B之外，采用与实施例83步骤2相同的合成路线，制得标题化合物194(白色固体)。
LCMS：359[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.16(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).
实施例85:4-(6-(2-氧代哌啶-1-基)己基)-6-(三氟甲基)-2H-苯并[b][1,4]噻嗪-3(4H)-酮(化合物195)的合成
除了将实施例83中的193a替换成195a之外，采用与实施例83相同的合成路线，制得化合物195(白色固体)。
LCMS：415[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.69(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).
实施例86:4-(3-(2-氧代哌啶-1-基)丙基)-6-(三氟甲基)-2H-苯并[b][1,4]噻嗪-3(4H)-酮(化合物196)的合成
步骤1：除了将实施例83步骤1中的1,6-二溴己烷替换成3-溴丙烷-1-醇，193a替换成195a之外，采用与实施例83步骤1相同的合成路线，制得化合物196A。
步骤2：除了将实施例84步骤2中的194A替换成196A之外，采用与实施例84步骤2相同的合成路线，制得化合物196B。
步骤3：除了将实施例83步骤2中的193A替换成196B之外，采用与实施例83步骤2相同的合成路线，制得标题化合物196(白色固体)。
LCMS：373[M+H]+
1H NMR(400MHz,CD3OD)δ7.64(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).
实施例87:2-(3-(6-(三氟甲基)-2,3-二氢-4H-苯并[b][1,4]噻嗪-4-基)丙基)异吲哚啉-1-酮(化合物197)的合成
除了将实施例83步骤2中的193A替换成194B，186b替换成197a之外，采用与实施例83步骤2相同的合成路线，制得标题化合物197(白色固体)。
LCMS：393[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.71(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).
实施例88：7-(4-(2-(三氟甲基)-10H-吩噻嗪-10-基)丁氧基)-3,4-二氢喹啉-2(1H)-酮(化合物205)的合成
向反应瓶中加入205a(200mg,0.75mmol,1.0eq.)和N,N-二甲基甲酰胺(4mL)，再加入钠氢(60mg,1.50mmol,2.0eq)，反应液于室温下反应30分钟后加入205b(268mg,0.90mmol,1.2eq.)。反应液于室温下反应4小时。LCMS监测原料基本反应完后，将反应通过加入冰水淬灭，乙酸乙酯萃取，干燥，浓缩。剩余物采用硅胶柱层析(DCM:MeOH＝20:1)纯化，收集目标组分，将其减压浓缩得到标题化合物(类白色固体)(250mg，收率：69％)。
LCMS：485[M+H]+
1H NMR(400MHz,CDCl3)δ7.93(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).
实施例89：7-((5-(2-(三氟甲基)-10H-吩噻嗪-10-基)戊基)氧基)-3,4-二氢喹啉-2(1H)-酮(化合物206)的合成
向反应瓶中加入205a(0.294g,1.1mmol,1.1eq.)和DMF(10mL)，冰浴下分批加入NaH(52mg,1.3mmol,1.3eq.)，加毕，搅拌15分钟后加入206b(0.312g,1.0mmol,1.0eq.)，搅拌3小时。冰浴下加水淬灭反应，浓缩得到粗品，该粗品通过硅胶柱分离纯化(洗脱剂：PE:EtOAc＝1:1)，收集目标组分，浓缩旋干得到标题化合物206(白色固体)(85mg，收率：57.8％)。
LCMS：499[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.93(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).
实施例90：7-((6-(2-(三氟甲基)-10H-吩噻嗪-10-基)己基)氧)-3,4-二氢喹啉-2(1H)-酮(化合物207)的合成
将化合物187a(100mg,0.23mmol,1.0eq.)溶于N,N-二甲基甲酰胺(1mL)和水(0.1mL)中，加入无水碳酸钾(42mg,0.30mmol,1.3eq.)和7-羟基-3,4-二氢喹啉-2(1H)-酮(207b)(46mg,0.28mmol,1.2eq.)，升温至35℃反应过夜。加水(20mL)稀释，用乙酸乙酯(2×20mL)萃取，将合并有机相用饱和食盐水(20mL)洗涤，干燥浓缩得到粗品。所得粗品采用C18反相柱色谱法(洗脱剂：0.1％甲酸水溶液:MeOH＝1:9～9:1)纯化，收集目标组分浓缩得白色固体形式的标题化合物(60mg，收率：50％)。
LCMS：513[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.94(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).
实施例91:3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)苯并[4,5]噻吩并[3,2-d]嘧啶-4(3H)-酮的合成
步骤1：将144a(5g,24.13mmol,1.0eq)加入至DMF(50mL)，然后加入DMF-DMA(11.5g,96.50mmol,4.0eq)，在80℃下搅拌3小时；反应液加水稀释，乙酸乙酯萃取，有机相干燥，过滤，旋干， 得到棕色油状物144A(6g，收率:94.8％)。
步骤2：将144A(6g,22.87mmol,1.0eq)加入至MeOH(100mL)，然后加入3-氨基丙酸甲酯盐酸盐(6.39g,45.74mmol,2.0eq)，在70℃下搅拌3小时；反应液降温至室温，大量固体析出，过滤，滤饼干燥得到棕色固体144B(4.1g，收率:62.17％)。
步骤3：将144B(2g,6.94mmol,1.0eq)加入至THF/MeOH/H2O(60mL/20mL/20mL)，然后加入LiOH(498mg,20.81mmol,3.0eq)，在25℃下搅拌3小时；反应液加水稀释，用1M盐酸水溶液调节pH＝6～7直至有大量固体析出，过滤，滤饼干燥得到黄色固体144C(1.2g，收率:63.0％)。
步骤4：将144C(150mg,0.547mmol,1.0eq)、1-(3-(三氟甲基)苯基)哌嗪盐酸盐(144b)(175mg,0.656mmol,1.2eq)和DIPEA(353mg,2.73mmol,5.0eq)加入至DMF(3mL)，然后加入HATU(312mg,0.821mmol,1.5eq)，在25℃下搅拌2小时；反应液用C18反相色谱柱纯化(洗脱剂：0.1％甲酸水溶液:MeOH＝1:20～9:1)，收集目标馏分冻干得到类白色固体144(37mg，收率:13.9％)。
LCMS:487[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.72(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).
实施例92:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-3-氧代丙基)苯并[4,5]噻吩并[3,2-d]嘧啶-4(3H)-酮的合成
除了将实施例91步骤4中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐(144b)替换成1-(2,3-二氯苯基)哌嗪盐酸盐(145b)之外，采用与实施例91相同的合成路线，制得标题化合物145(类白色固体)。
LCMS:487[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.72(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).
实施例93:3-(3-(4-(4-氟苄基)哌啶-1-基)-3-氧代丙基)苯并[4,5]噻吩并[3,2-d]嘧啶-4(3H)-酮的合成
除了将实施例91步骤4中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐(144b)替换成4-(4-氟苄基)哌啶(146b)之外，采用与实施例91相同的合成路线，制得标题化合物146(类白色固体)。
LCMS:450[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.67(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).
实施例94:3-(3-(4-羟基-4-(3-(三氟甲基)苯基)哌啶-1-基)-3-氧代丙基)苯并[4,5]噻吩并[3,2-d]嘧啶-4(3H)-酮的合成
除了将实施例91步骤4中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐(144b)替换成4-(3-(三氟甲基)苯基)哌啶-4-醇(147b)之外，采用与实施例91相同的合成路线，制得标题化合物147(类白色固体)。
LCMS:502[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.72(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).
实施例95:8-氟-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)苯并呋喃并[3,2-d]嘧啶-4(3H)-酮的合成
步骤1：向100mL单口瓶中加入148a(2g,0.0146mol,1.0eq.)、溴乙酸甲酯(2.68g,0.0175mol,1.2eq.)、碳酸钾(4g,0.0292mol,2.0eq.)和DMF(20mL)，60℃反应16h。反应结束，冷却至室温，过滤，滤饼乙酸乙酯洗涤，滤液中加入大量水，乙酸乙酯萃取两次，乙酸乙酯相用饱和食盐水洗涤三次，干燥，除去溶剂得到棕色油状物148A，粗品直接用于下一步。
步骤2：向100mL单口瓶中加入148A(粗品,0.0146mol,1.0eq.)、DMF-DMA(5.22g,0.0438mol,3.0eq.)和DMF(40mL)，60℃反应3h。反应结束，冷却至室温，反应液中加入大量水，乙酸乙酯萃取两次，乙酸乙酯相用饱和食盐水洗涤三次，干燥，除去溶剂得到棕色油状物148B，粗品直接用于下一步。
步骤3：向100mL单口瓶中加入148B(粗品,0.0146mol,1.0eq.)、3-氨基丙酸甲酯盐酸盐(4.08g,0.0292mol,2.0eq.)和乙腈(40mL)，回流反应16h。搅拌降温，降至室温后加冰浴降温，过滤，滤饼用甲醇洗涤，烘干得到白色固体148C(1.43g,收率：33.7％)。
步骤4：向100mL单口瓶中加入148C(1.43g,0.00493mol,1.0eq.)、THF(12mL)和水(3mL)，冰浴降温至0-5℃，加入LiOH(0.236g,0.00986mol,2.0eq.)，冰浴保温反应1h。反应结束，冰浴下用稀盐酸调节pH＝3～4，大量固体析出，过滤，滤饼水洗，烘干得到白色固体148D(1.12g,收率：82.2％)。
步骤5：向100mL单口瓶中加入148D(0.15,0.000543mol,1.0eq.)、1-(3-(三氟甲基)苯基)哌嗪盐酸盐(144b)(0.22g,0.000815mol,1.5eq.)、HATU(0.31g,0.00815mol,1.5eq.)、无水DMF(5mL)和DIPEA(0.35g,0.00272mol,5.0eq.)，室温反应1h。反应液通过反相柱层析(洗脱剂：0.5‰甲酸水:甲醇＝100:0～10:90)收集产物组分，蒸干甲醇，冻干得到淡黄色固体148(0.16g,收率：21.4％)。
LCMS：489[M+1]+
1H NMR(400MHz,DMSO-d6):δ8.63(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).
实施例96:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-氟苯并呋喃并[3,2-d]嘧啶-4(3H)-酮的合成
除了将实施例95步骤5中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐(144b)替换成1-(2,3-二氯苯基)哌嗪盐酸盐(145b)之外，采用与实施例95相同的合成路线，制得标题化合物149(白色固体)。
LCMS：489[M+1]+
1H NMR(400MHz,DMSO-d6):δ8.64(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).
实施例97:8-氟-3-(3-(4-(4-氟苄基)哌啶-1-基)-3-氧代丙基)苯并呋喃并[3,2-d]嘧啶-4(3H)-酮的合成
除了将实施例95步骤5中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐(144b)替换成4-(4-氟苄基)哌啶(146b)之外，采用与实施例95相同的合成路线，制得标题化合物150(白色固体)。
LCMS：452[M+1]+
1H NMR(400MHz,DMSO-d6):δ8.60(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).
实施例98:8-氟-3-(3-(4-羟基-4-(3-(三氟甲基)苯基)哌啶-1-基)-3-氧代丙基)苯并呋喃并[3,2-d]嘧啶-4(3H)-酮的合成
除了将实施例95中的1-(3-(三氟甲基)苯基)哌嗪盐酸盐(144b)替换成4-(3-(三氟甲基)苯基)哌啶-4-醇(147b)之外，采用与实施例95相同的合成路线，制得标题化合物151(白色固体)。
LCMS：504[M+1]+
1H NMR(400MHz,DMSO-d6):δ8.64(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).
实施例99:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-氟-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮甲酸盐的合成
步骤1：将152a(5g,24.1mmol,1.0eq)溶解于DCM(30mL)中，然后往体系中缓慢滴加65％HNO3与醋酸的混合溶液(2.34g 65％HNO3/15g醋酸)，滴加完毕后将混合液在40℃搅拌16h。反应完成后在0℃下使用饱和碳酸氢钠溶液调整体系pH＝8～9，然后使用水(100mL)和二氯甲烷(50mL*2)萃取，将有机相旋干并通过快速柱色谱法(PE:EA＝1:1)制得黄色固体152A(3g,收率:49.3％)。
步骤2：将152A(3g)溶解于MeOH(50mL)中，然后加入Pd/C(300mg,0.1w/w)，混合物在氢气氛围下常温搅拌16h。反应完成后，将混合物过滤，将滤液旋干并通过快速柱色谱法(PE:EA＝1:1)制得黄色固体152B(2.23g,收率:84.3％)。
步骤3：将152B(2.23g,10.0mmol,1.0eq)溶解于DMF(30mL)中，然后加入DMF-DMA(5.96g,50.0mmol,5.0eq)，混合物在80℃搅拌16h。反应完成后使用水(100mL)和二氯甲烷(50mL*2)萃取,将有机相旋干制得红色油状物152C(3g)。
步骤4：将152C(3g,10.83mmol,1.0eq)溶解于甲醇中(30mL)中，然后加入3-氨基丙酸甲酯(1.6g,16.24mmol,1.5eq)。混合物在70℃搅拌16h。反应完成后过滤得到白色固体152D(1g,收率:31.9％)。
步骤5：将152D(1g)加入至THF/H2O(10mL/3mL)中，然后加入10％氢氧化钠(3mL)，混合液在常温下搅拌16h。反应完成后，将混合液旋干并调整体系pH＝5～6，混合物过滤得白色固体152E(0.7g,收率73.0％)。
步骤6：将152E(200mg,0.72mmol,1.0eq)、145b(290mg,1.08mmol,1.5eq)、HATU(550mg,1.45mmol,2.0eq)和DIPEA(233mg,1.81mmol,2.5eq)加入至DCM(5mL)中，混合液在常温下搅拌16h。反应完成后，将混合物于水(20mL)和二氯甲烷(10mL*2)萃取，将有机相旋干并通过反相柱(0.1％FA/H2O:MeOH＝30:70)纯化，将所得制备液冻干得到黄色固体形式的化合物152的甲酸盐(40mg,收率11.3％)。
LCMS:488[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.19(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).
实施例100:8-氟-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例99步骤6中的145b替换成1-(3-(三氟甲基)苯基)哌嗪(144b)之外，采用与实施例99相同的合成路线，制得标题化合物153(白色固体)。
LCMS:488[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.20(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).
实施例101:8-氟-3-(3-(4-(4-氟苄基)哌啶-1-基)-3-氧代丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮 的合成
除了将实施例99步骤6中的145b替换成146b之外，采用与实施例99相同的合成路线，制得标题化合物154(白色固体)。
LCMS:451[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.22(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).
实施例102:3-(4-氟苄基)哌啶-1-基)-3-氧代丙基-8-甲基-3,5-二氢-4H-嘧啶并[5，4-b]吲哚-4-酮的合成
向反应瓶中加入165a(100mg,0.37mmol,1.0eq.)、DMF(2mL)和HATU(169mg,0.44mmol,1.2eq.)，常温搅拌30min。然后加入4-(4-氟苄基)哌啶(146b)(79mg，0.41mmol，1.1eq)以及DIPEA(143mg，1.11mmol，3.0eq)。常温下搅拌过夜。反应液通过柱色谱法纯化(洗脱剂：0.1％甲酸水溶液：MeOH＝44％)，收集目标组分，减压浓缩得白色固体164(49mg，收率：29.70％)。
LCMS：447[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例103:3-(3-(4-羟基-4-(3-(三氟甲基)苯基)哌啶-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成4-(3-(三氟甲基)苯基)哌啶-4-醇(147b)之外，采用与实施例102相同的合成路线，制得标题化合物165(白色固体)。
LCMS：499[M+H]
1H NMR(400MHz,DMSO-d6)δ11.98(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).
实施例104:3-(3-(4-((2,3-二氯苯基)(甲基)氨基)哌啶-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成N-(2,3-二氯苯基)-N-甲基哌啶-4-胺(166b)之外，采用与实施例102相同的合成路线，制得标题化合物166(白色固体)。
LCMS：513[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.99(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).
实施例105:8-甲基-3-(3-氧代-3-(4-(吡啶-3-基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮甲酸盐的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成1-(吡啶-3-基)哌嗪(167b)之外，采用与实施例102相同的合成路线，制得化合物167的甲酸盐(白色固体)。
LCMS：417[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例106:8-甲基-3-(3-(4-(4-(甲基磺酰基)苯基)哌嗪-1-基)-3-氧代丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成1-(4-(甲基磺酰基)苯基)哌嗪(168b)之外，采用与实施例102相同的合成路线，制得标题化合物168(白色固体)。
LCMS：494[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.96(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).
实施例107:8-甲基-3-(3-氧代-3-(4-(4-(哌啶-1-基磺酰基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成1-(4-(哌啶-1-基磺酰基)苯基)哌嗪(169b)之外，采用与实施例102相同的合成路线，制得标题化合物169(白色固体)。
LCMS：563[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例108:8-甲基-3-(3-氧代-3-(4-(3-(哌啶-1-基磺酰基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成1-(3-(哌啶-1-基磺酰基)苯基)哌嗪盐酸盐(170b)之外，采用与实施例102相同的合成路线，制得标题化合物170(白色固体)。
LCMS：563[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例109:3-(4-(3-(8-甲基-4-氧代-4,5-二氢-3H-嘧啶并[5,4-b]吲哚-3-基)丙酰基)哌嗪-1-基)苯甲腈的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成3-氰基苯基哌嗪盐酸盐(171b)之外，采用与实施例102相同的合成路线，制得标题化合物171(白色固体)。
LCMS：441[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例110:8-甲基-3-(3-(4-(3-硝基苯基)哌嗪-1-基)-3-氧代丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成3-硝基苯基哌嗪(172b)之外，采用与实施例102相同的合成路线，制得标题化合物172(黄色固体)。
LCMS：461[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.96(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).
实施例111:3-(3-(4-(3-氯苯甲酰基)哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成(3-氯苯基)(哌嗪-1-基)甲酮盐酸盐(173b)之外，采用与实施例102相同的合成路线，制得标题化合物173(白色固体)。
LCMS：478[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.97(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).
实施例112:3-(3-(4-异丁基哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成1-异丁基哌嗪(174b)之外，采用与实施例102相同的合成路线，制得标题化合物174(白色固体)。
LCMS:396[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.94(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).
实施例113:3-(3-(4-异丁酰基哌嗪-1-基)-3-氧代丙基)-8-甲基-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例102中的4-(4-氟苄基)哌啶(146b)替换成2-甲基-1-(哌嗪-1-基)丙-1-酮(175b)之外，采用与实施例102相同的合成路线，制得标题化合物175(白色固体)。
LCMS:410[M+H]+
1H NMR(400MHz,DMSO-d6)δ11.94(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).
实施例114:8-氯-3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-3-氧代丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
步骤1：将176a(5.0g,32.14mmol,1.0eq.)溶于乙腈(50mL)中，加入DIPEA(20.8g,160.71mmol,5.0eq.)和甘氨酸乙酯盐酸盐(6.7g,48.21mmol,1.5eq.)，升温至85℃反应3天(仍未反应完全，直接处理)。将反应液过滤，固体用乙腈(2×20mL)洗涤，滤液减压浓缩，残留分通过硅胶柱正相色谱法分离纯化(洗脱剂：石油醚:乙酸乙酯＝67:33)得黄色固体176A(2.1g，收率：27.37％)。
步骤2：将176A(1.6g,6.70mmol,1.0eq.)溶于乙腈(20mL)，加入碳酸钾(5.6g,40.22mmol,6.0eq.)，升温至85℃反应9天。将反应液过滤，固体用乙酸乙酯(2×20mL)洗涤，滤液减压浓缩至干得棕色固体176B(1.2g，收率：75.00％)。
步骤3：将176B(1.1g,4.61mmol,1.0eq.)溶于N,N-二甲基甲酰胺(5mL)，加入N,N-二甲基甲酰胺二甲基缩醛(5.5g,46.09mmol,10.0eq.)，升温至60℃反应过夜。减压浓缩至干得棕色固体176C(1.3g，收率：96.02％)。
步骤4：将176C(1.3g,4.43mmol,1.0eq.)溶于甲醇(20mL)，加入3-氨基丙酸甲酯盐酸盐(2.5g,17.70mmol,4.0eq.)，升温至70℃反应过夜。减压浓缩，残留分通过硅胶柱正相色谱法分离纯化(洗脱剂：二氯甲烷:甲醇＝90:10)得淡黄色固体176D(670mg，收率：47.69％)。
步骤5：将176D(670mg,2.19mmol,1.0eq.)溶于甲醇(10mL)，加入氢氧化锂(210mg,8.77mmol,4.0eq.)和水(2mL)，室温下反应过夜。减压浓缩除去溶剂，残留分加水(10mL)溶解，用稀盐酸调节 pH＝5，过滤，滤饼用水(2×10mL)洗涤，烘干得淡黄色固体176E(580mg，收率：90.73％)。
步骤6：向反应瓶中加入176E(100mg,0.34mmol,1.0eq.)、HATU(156mg,0.41mmol,1.2eq.)和N,N-二甲基甲酰胺(3mL)，室温下反应0.5h，再加入1-(2,3-二氯苯基)哌嗪盐酸盐(145b)(110mg,0.41mmol,1.2eq.)和DIPEA(164mg,1.27mmol,3.7eq.)，室温下反应过夜。将反应液过滤，滤饼用二氯甲烷(2×10mL)洗涤，烘干得白色固体176(60mg，收率：34.67％)。
LCMS：504[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.37(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).
实施例115:8-氯-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例114步骤6中的145b替换成1-(3-三氟甲基苯基)哌嗪盐酸盐(144b)之外，采用与实施例114相同的合成路线，制得标题化合物177(白色固体)。
LCMS：504[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.37(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).
实施例116:8-氯-3-(3-(4-羟基-4-(3-(三氟甲基)苯基)哌啶-1-基)-3-氧代丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例114步骤6中的145b替换成4-(3-三氟甲基)苯基-4-哌啶醇(147b)之外，采用与实施例114相同的合成路线，制得标题化合物178(黄色固体)。
LCMS：519[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.35(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).
实施例117:8-氯-3-(3-(4-(4-氟苄基)哌啶-1-基)-3-氧代丙基)-3,5-二氢-4H-嘧啶并[5,4-b]吲哚-4-酮的合成
除了将实施例114步骤6中的145b替换成4-(4'-氟苄基)哌啶(146b)之外，采用与实施例114相同的合成路线，制得标题化合物179(黄色固体)。
LCMS：467[M+H]+
1H NMR(400MHz,DMSO-d6)δ12.37(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).
实施例118:9-甲基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-2H-色烯并[4,3-d]嘧啶-2-酮的合成
步骤1：将208a(500mg,2.33mmol,1.0eq)和碳酸钾(968g,7.00mmol,3.0eq)加入至DMF(5mL)，然后加入溴丙酸叔丁酯(976mg,4.67mmol,2.0eq)，在40℃下反应16小时；加水稀释，乙酸乙酯萃取，有机相干燥，过滤，旋干得到粗品，用正相柱纯化(石油醚:乙酸乙酯＝5％～60％))；收集目标馏分冻干得到白色固体208A(700mg，收率:87.5％)。
步骤2：将208A(700mg,2.04mmol,1.0eq)加入至4M HCl/1,4-二氧杂环己烷(10mL)，然后在25℃下搅拌3小时；反应液旋干得到黄色固体208B(550mg，收率:93.9％)。
步骤3：将208B(200mg,0.699mmol,1.0eq)、144b(279mg,1.05mmol,1.5eq)和DIPEA(451mg,3.49mmol,5.0eq)加入至DMF(3mL)，然后加入HATU(399mg,1.05mmol,1.5eq)，在25℃下搅拌16小时；反应液用C18反相柱纯化(洗脱剂：0.1％甲酸水溶液:MeOH＝1:20～9:1)，收集目标馏分冻干得到白色固体208(77mg，收率:22.1％)。
LCMS:499[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.22(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).
实施例119:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-9-甲基-5,6-二氢苯并[h]喹唑啉-4(3H)-酮的合成
步骤1：将209a(3.2g,20.0mmol,1.0eq)加入至无水THF(30ml)中，然后加入60％NaH(2.0g,50.0mmol,2.5eq)，在氮气保护下0℃下搅拌0.5小时，用注射器将DMC(20ml)加入体系中，然后在70℃搅拌16h；反应完成后加入甲醇淬灭，混合液旋干后正相柱纯化(洗脱剂:(石油醚:乙酸乙酯＝1％～10％))，所得有机相旋干得无色油状液体209A(3.0g，收率:68.8％)。
步骤2：将209A(2.0g,9.16mmol,1.0eq)和乙酸铵(3.5g,45.82mmol,5.0eq)加入至甲醇中(20 mL)，混合液在30℃搅拌16小时；反应液旋干后加入饱和碳酸氢钠溶液(50ml)和乙酸乙酯(20ml*2)萃取，将有机相旋干得到白色油状物209B(1.8g，收率:89.6％)。
步骤3：将209B(1.8g,8.29mmol,1.0eq)和DMF-DMA(4.9g,41.47mmol,5.0eq)加入至DMF(20mL)中；在80℃下搅拌24小时；加入水(100ml)和乙酸乙酯(30ml*2)，将有机相旋干得到蓝色油状液体209C(2g,收率:88.6％)。
步骤4：将209C(2g,7.34mmol,1.0eq)加入至甲酰胺(20mL)中，200℃搅拌1小时；反应结束后冷却至室温，加入水(100ml)使固体析出，过滤得棕色固体209D(0.9g，收率:57.7％)。
步骤5：将209D(500mg,2.36mmol,1.0eq)、209b(724mg,2.36mmol,1.0eq)和碳酸钾(651mg,4.72mmol,2.0eq)加入至乙腈(5mL)中，混合液在70℃搅拌4小时；反应液旋干后加入水(30ml)析出固体，过滤得白色固体200mg，将白色固体通过反相制备色谱法(0.1％FA)纯化，将所得制备液浓缩并冻干得到白色固体209(20mg，收率:1.75％)。
LCMS:483[M+H]+
1H NMR(400MHz,CDCl3)δ8.23(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).
实施例120:8-甲氧基-3-(3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5-二氢-4H-吡咯并[2,3-c]喹啉-4-酮的合成
步骤1：向250mL单口瓶中加入双联频哪醇硼酸酯(2.5g,0.01mol,2.0eq.)、201a(1.4g,0.005mol,1.0eq.)、DMSO(30mL)、碳酸钠(1.1g,0.01mol,2.0eq.)和四三苯基磷钯(0.3g,0.00026mol,2.6％)，氮气保护，升温到80℃，反应6h。反应液浓缩，然后硅胶柱色谱法纯化，乙酸乙酯:石油醚＝1:2洗脱产品，浓缩得到淡白色液体210A(1.8g,收率：64.5％)。
步骤2：向250mL单口瓶中加入3-溴吡咯-2-甲酸甲酯(1.62g,0.0064mol,1.0eq.)、210A(1.8g,0.0064mol,1.0eq.)、碳酸钾(4.2g,0.03mol,5.0eq.)、Pd(dppf)2Cl2(0.6g,0.00074mol,11.6％)、二氧六环(60mL)和水(10mL)，氮气保护，升温到100℃，反应3h。反应结束，硅胶柱色谱法纯化，石油醚:乙酸乙酯＝2:1洗脱产品，浓缩得到黄色固体210B(2.1g,收率：100％)。
步骤3：向250mL单口瓶中加入210B(2.1g,0.0064mol,1.0eq.)、Pd/C(0.5g,25％wt.)和甲醇(50mL)，氢气保护，室温反应6h。反应结束，过滤，有机相硅胶柱色谱法纯化，二氯甲烷:甲醇＝10:1洗脱产品，浓缩得到淡白色液体210C(0.21g,收率：15.3％)。
步骤4：向250mL单口瓶中加入210C(0.21g,0.001mol,1.0eq.)、乙腈(50mL)和碳酸钾(0.42g,0.003mol,3eq.)，氮气保护，加入1-氯-3溴丙烷(0.45g,0.003mol,3.0eq.)，60℃反应3h。反应结束，硅胶柱色谱法纯化，二氯甲烷:甲醇＝10:1洗脱产品，浓缩得到类白色固体210D(0.2g,收率：68.8％)。
步骤5：向250mL单口瓶中加入210D(0.2g,0.0007mol,1.0eq.)、乙腈(10mL)、碳酸钾(0.28g,0.002mol,3eq.)和3-三氟苯基哌嗪(144b)(0.46g,0.002mol,3eq.)，氮气保护，80℃反应16h。反应结 束，硅胶柱色谱法纯化，二氯甲烷:甲醇＝10:1洗脱产品，浓缩得到粗品，然后制备液相色谱法纯化，浓缩得到类白色固体210(0.02g,收率：6％)。
LCMS：485[M+1]+
1H NMR(400MHz,CD3OD):δ7.54-7.49(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).
实施例121:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-9-甲基嘧啶并[5,4-c]喹啉-4(3H)-酮甲酸盐的合成
步骤1：将211a(10g,93.32mmol,1.0eq)加入至AcOH(20mL)，然后加入3-溴丙酸甲酯(8.03g,93.32mmol,1.0eq)，在70℃下搅拌4小时；反应液加水稀释，二氯甲烷萃取，有机相干燥，过滤，旋干得到粗品，用正相柱纯化(石油醚:乙酸乙酯＝5％～10％))；收集目标馏分旋干得到黄色固体211A(15.3g，收率:84.8％)。
步骤2：将211A(15.3g,79.18mmol,1.0eq)加入至MeOH/H2O(150mL/50mL)，然后加入NaOH(4.75g,118.7mmol,1.5eq)，在25℃下搅拌2小时；反应液加水稀释，乙酸乙酯洗涤；水相用饱和柠檬酸水溶液调节pH＝5～6，乙酸乙酯萃取，有机相干燥，过滤，旋干得到黄色油状物211B(14.1g，收率:99.3％)。
步骤3：将211B(14.1g,78.68mmol,1.0eq)加入至PPA(50mL)，在130℃下搅拌3小时；反应液倒入饱和碳酸钠水溶液中，调节pH＝7～8，乙酸乙酯萃取，有机相干燥，过滤，旋干得到粗品，用正相柱纯化(石油醚:乙酸乙酯＝5％～50％))；收集目标馏分旋干得到黄色固体211C(4.2g，收率:33.1％)。
步骤4：将211C(4.2g,26.05mmol,1.0eq)和DMAP(4.77g,39.08mmol,1.5eq)加入至DCM(50mL)，然后加入Boc2O(11.37g,52.11mmol,2.0eq)，在25℃下搅拌16小时；反应液旋干得到粗品，用正相柱纯化(石油醚:乙酸乙酯＝1％～20％))；收集目标馏分旋干得到白色固体211D(6g，收率:88.1％)。
步骤5：将211D(6g,22.96mmol,1.0eq)加入至THF(60mL)，然后在0℃下分批加入60％wt.NaH(2.3g,57.40mmol,2.5eq，在矿物油中)，在25℃下搅拌0.5小时后加入碳酸二甲酯(3.1g,34.4mmol,1.5eq)，在氮气保护下70℃搅拌2小时；反应液加水稀释，乙酸乙酯萃取，有机相干燥，过滤，旋干得到粗品，用正相柱纯化(石油醚:乙酸乙酯＝1％～10％)；收集目标馏分旋干得到黄色固体211E(6 g，收率:81.8％)。
步骤6：将211E(2.5g,7.83mmol,1.0eq)加入至MeOH(30mL)，然后加入NH4OAc(3.02g,39.14mmol,5.0eq)，在80℃下搅拌16小时；反应液旋干得到粗品，用正相柱纯化(石油醚:乙酸乙酯＝1％～15％))；收集目标馏分旋干得到白色固体211F(2g，收率:80.2％)。
步骤7：将211F(2g,6.28mmol,1.0eq)加入至DMF(20mL)，然后加入DMF-DMA(3.74g,31.41mmol,5.0eq)，在80℃下搅拌16小时；反应液加水稀释，乙酸乙酯萃取，有机相干燥，过滤，旋干得到黑色固体211G(2.1g，收率:89.5％)。
步骤8：将211G(700mg,1.88mmol,1.0eq)加入至MeOH(10mL)，然后加入NH4OAc(1.44g,18.8mmol,10.0eq)，在80℃下搅拌16小时；反应液旋干得到粗品，用正相柱纯化(二氯甲烷:甲醇＝1％～10％))；收集目标馏分旋干得到白色固体211H(580mg，收率:98.7％)。
步骤9：将211H(300mg,0.957mmol,1.0eq)和碳酸钾(265mg,1.91mmol,2.0eq)加入至ACN(5mL)，然后加入209b(442mg,1.44mmol,1.5eq)，在50℃下搅拌16小时；反应液旋干得到粗品，用正相柱纯化(石油醚:乙酸乙酯＝5％～100％))；收集目标馏分旋干得到白色固体211I(440mg，收率:78.6％)。
步骤10：将211I(440mg,0.75mmol,1.0eq)加入至DCM(6mL)，然后加入TFA(3mL)，在25℃下搅拌1小时；反应液旋干得到粗品，用C18反相柱纯化(洗脱剂：0.1％甲酸水溶液:MeOH＝1:20～9:1)；收集目标馏分冻干得到白色固体形式的化合物211的甲酸盐(85mg，收率:23.4％)。
LCMS:482[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.40(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).
实施例122:9-甲基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)嘧啶并[5,4-c]喹啉-4(3H)-酮的合成
步骤1：将211G(500mg,1.34mmol,1.0eq)加入至MeOH(10mL)，然后加入3-氨基丙酸甲酯盐酸盐(374mg,2.68mmol,2.0eq)，在70℃下搅拌16小时；反应液旋干得到粗品，用正相柱纯化(石油醚:乙酸乙酯＝5％～50％))；收集目标馏分旋干得到黄色固体212A(200mg，收率:37.4％)。
步骤2：将212A(200mg,0.5mmol,1.0eq)加入至THF/H2O(8mL/2mL)，然后加入LiOH(30mg,1.25mmol,2.5eq)，在0℃下搅拌2小时；反应液加水稀释，用1M盐酸水溶液调节pH＝5～6，乙酸乙酯萃取，有机相干燥，过滤，旋干得到白色固体212B(190mg，收率:98.4％)。
步骤3：将212B(190mg,0.493mmol,1.0eq)、144b(197mg,0.739mmol,1.5eq)和DIPEA(319mg,2.46mmol,5.0eq)加入至DMF(2mL)，然后加入HATU(281mg,0.739mmol,1.5eq)，在25℃下搅拌16小时；反应液加水稀释，乙酸乙酯萃取，有机相干燥，过滤，旋干得到粗品，用正相柱纯化(二氯甲烷:甲醇＝1％～5％)；收集目标馏分旋干得到黄色固体212D(200mg，收率:67.8％)。
步骤4：将212D(200mg,0.335mmol,1.0eq)加入至4M HCl/1,4-二氧杂环己烷(3mL)，在25℃下搅拌2小时；反应液旋干得到粗品，用C18反相柱纯化(洗脱剂：0.1％甲酸水溶液:MeOH＝1:20～9:1)；收集目标馏分冻干得到白色固体212(28mg，收率:16.8％)。
LCMS:496[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.40(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).
实施例123:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-9-甲基-3,5-二氢-2H-色烯并[4,3-d]嘧啶-2-酮的合成
步骤1：将213a(4.5g,27.72mmol,1.0eq)、尿素(1.84g,30.51mmol,1.1eq)和原甲酸三乙酯(4.11g,27.72mmol,1.0eq)加入至MeOH(5mL)，然后加入甲基磺酸(15滴)，在130℃下搅拌6小时；反应液加甲醇稀释，过滤，滤饼旋干得到黄色固体213A(3.3g，收率:55.5％)。
步骤2：将213A(500mg,2.33mmol,1.0eq)和碳酸钾(968mg,7.00mmol,3.0eq)加入至DMF(5mL)，然后加入209b(862mg,2.80mmol,1.2eq)，在50℃下搅拌24小时；加水稀释，乙酸乙酯萃取，有机相干燥，过滤，旋干得到粗品，用正相柱纯化(二氯甲烷:甲醇＝1％～10％))，然后用C18反相柱纯化(洗脱剂：0.1％甲酸水溶液:MeOH＝1:20～9:1)；收集目标馏分冻干得到白色固体213(155mg，收率:13.6％)。
LCMS:485[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.20(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).
实施例125:9-甲基-3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-5,6-二氢苯并[h]喹唑啉-4(3H)-酮的合成
步骤1：将209D(0.50g,2.36mmol,1.0eq)加入至无水DMF(30mL)中，然后加入碳酸钾(0.73g,4.7mmol,2.0eq)和3-溴丙酸甲酯(1g,5.62mmol,2.4eq)，混合液在80℃搅拌4h；反应结束后降温至室温并加入水(100mL)至体系混浊，过滤得白色滤饼，干燥得215A(0.48g,收率:68.2％)。
步骤2：将215A(0.48g,1.60mmol,1.0eq)溶解于THF(3mL)，然后往体系中加入水(1mL)和LiOH(116mg,4.80mmol,3.0eq)，混合液在30℃搅拌16小时；反应结束后将体系旋干，加入水(10mL)，并将体系调pH＝5-6，用DCM(5mL*2)萃取，将有机相旋干得到白色固体215B(0.45g,收率:98.9％)。
步骤3：将215B(0.40g,1.40mmol,1.0eq)、DIPEA(0.45g,3.5mmol,2.5eq)、HATU(1.1g,2.80mmol)和144b(0.39g,1.70mmol,1.2eq)加入至DMF(5mL)中，在30℃下搅拌16小时；反应完成后加入水(20ml)和乙酸乙酯(10ml*2)萃取，将有机相旋干，经反相制备色谱法(0.1％FA)纯化，然后浓缩及冻干得到白色固体215(0.05g,收率:7.19％)。
LCMS:497[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.52(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).
实施例126:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-8-甲氧基-3,5-二氢-4H-咪唑并[4,5-c]喹啉-4-酮甲酸盐的合成
步骤1：向100mL三口瓶中加入216a(0.8g,0.0039mol,1.5eq.)、209b(0.8g,0.0026mol,1.0eq.)、碳酸铯(1.7g,0.0052mol,2.0eq.)和DMF(10mL)，80℃搅拌过夜。反应结束，硅胶柱色谱法纯化，MeOH:DCM＝10％洗脱产品，液相浓缩后得到黄色油状物216A(1.2g，收率79.56％)。
步骤2：向250mL三口瓶中加入216A(1.14g,0.0024mol,1.0eq.)、210A(1.0g,0.0036mol,1.5eq.)、Pd-118(0.15g,0.00024mol,0.1eq.)、碳酸钾(0.66g,0.0048mol,2.0eq.)、1,4-二氧杂环己烷(20mL)和H2O(5mL)，氮气保护下100℃搅拌过夜。反应结束后柱色谱法纯化，MeOH:DCM＝7％洗脱产品。减压浓缩后得到棕色油状物216B(1.14g，收率:86.83％)。
步骤3：向100mL三口瓶中加入216B(0.5g,0.0009mol,1.0eq.)、锌粉(0.6g,0.009mol,10.0eq.)、饱和NH4Cl水溶液(0.5mL)和EtOH(5mL)，80℃下搅拌过夜。反应结束后通过反相柱纯化，甲醇/水洗脱产品。冻干后得到黄色固体形式的化合物216的甲酸盐(0.052g，产率：5.91％)。
LCMS：486[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.55(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).
实施例127:3-(4-(4-(2,3-二氯苯基)哌嗪-1-基)-4-氧代丁基)-9-甲基嘧啶并[5,4-c]喹啉-4(3H)-酮的合成
步骤1：将211H(180mg,0.574mmol,1.0eq)加入至ACN(2mL)，然后加入碳酸钾(238mg,1.72mmol,3.0eq)和4-溴丁酸叔丁酯(192mg,0.862mmol,1.5eq)，在40℃下搅拌16小时。然后将反应液旋干得到粗品，用正相柱纯化(洗脱剂:(石油醚:乙酸乙酯＝5％～40％))；收集目标馏分旋干得到黄色 油状物217A(220mg，收率:84.0％)。
步骤2：将217A(220mg,0.483mmol,1.0eq)加入至4M HCl/1,4-二氧杂环己烷(5mL)，在25℃下搅拌1小时，反应液旋干得到黄色固体217B(140mg，收率:97.5％)。
步骤3：将217B(70mg,0.236mmol,1.0eq)、145b(82mg,0.305mmol,1.3eq)和DIPEA(152mg,1.18mmol,5.0eq)加入至DMF(2mL)，然后加入HATU(135mg,0.354mmol,1.5eq)，在25℃下搅拌2小时；反应液用C18反相柱纯化(洗脱剂：0.1％甲酸水溶液:MeOH＝1:20～9:1)，收集目标馏分冻干得到类白色固体217(14mg，收率:11.6％)。
LCMS:510[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.38(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).
实施例128:3-(4-(4-(4-氟苄基)哌啶-1-基)-4-氧代丁基)-9-甲基嘧啶并[5,4-c]喹啉-4(3H)-酮的合成
除了将实施例127步骤3中的145b替换成4-(4-氟苄基)哌啶(146b)之外，采用与实施例127相同的合成路线，制得标题化合物218(类白色固体)。
LCMS:473[M+H]+
1H NMR(400MHz,DMSO-d6)δ9.44(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).
实施例129:3-(4-(4-(2,3-二氯苯基)哌嗪-1-基)-4-氧代丁基)-9-甲基-3,5-二氢-2H-色烯并[4,3-d]嘧啶-2-酮的合成
步骤1：将213A(600mg,2.80mmol,1.0eq)加入至DMF(10mL)，然后加入碳酸钾(1.16g,8.40mmol,3.0eq)和4-溴丁酸叔丁酯(937mg,4.20mmol,1.5eq)，在40℃下搅拌16小时后；反应液加水稀释，乙酸乙酯萃取，有机相旋干得到粗品，用正相柱纯化(洗脱剂:(石油醚:乙酸乙酯＝5％～80％))；收集目标馏分旋干得到黄色固体219A(690mg，收率:69.1％)。
步骤2：将219A(690mg,1.94mmol,1.0eq)加入至4M HCl/1,4-二氧杂环己烷(10mL)，在25℃下搅拌2小时，反应液旋干得到黄色固体219B(550mg，收率:94.6％)。
步骤3：将219B(150mg,0.499mmol,1.0eq)、145b(160mg,0.599mmol,1.2eq)和DIPEA(323mg,2.50mmol,5.0eq)加入至DMF(3mL)，然后加入HATU(285mg,0.749mmol,1.5eq)，在25℃下搅拌2小时；反应液用C18反相柱纯化(洗脱剂：0.1％甲酸水溶液:MeOH＝1:20～9:1)，收集目标馏分冻干得到类白色固体219(169mg，收率:65.9％)。
LCMS:513[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.17(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).
实施例130:3-(4-(4-(4-氟苄基)哌啶-1-基)-4-氧代丁基)-9-甲基-3,5-二氢-2H-色烯并[4,3-d]嘧啶-2-酮的合成
除了将实施例129步骤3中的145b替换成4-(4-氟苄基)哌啶(146b)之外，采用与实施例129相同的合成路线，制的标题化合物220(类白色固体)。
LCMS:476[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.12(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).
实施例131:3-(3-氧代-3-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丙基)-3,5,6,7-四氢-4H-苯并[6,7]环庚并[1,2-d]嘧啶-4-酮的合成
步骤1：将220D(200mg,0.94mmol,1.0eq)、3-溴丙酸甲酯(224mg,1.13mmol,1.2eq)和碳酸钾(325mg,2.36mmol,2.5eq)溶解于ACN(10mL)中，混合物在70℃搅拌16h。反应完成后将反应液旋干并通过快速柱色谱法(PE:EA＝1:1)制得白色油状物221A(250mg,收率:89.1％)。
步骤2：将221A(250mg)溶解于THF/H2O(5mL/2mL)中，然后加入LiOH(50mg,0.2w/w)，混合物在常温搅拌16h。反应完成后将混合物过滤，将滤液旋干并通过快速柱色谱法(PE:EA＝1:1)制得白色固体221B(150mg,收率:62.9％)。
步骤3：将221B(150mg,0.52mmol,1.0eq)、144b(181mg,0.79mmol,1.5eq)、HATU(400mg,1.05mmol,2.0eq)和DIPEA(169mg,1.31mmol,2.5eq)溶解于DCM(5mL)中，混合物在常温搅拌16h。反应完成后使用水(20mL)和二氯甲烷(5mL*2)萃取，将有机相旋干并通过反相柱(0.1％FA/H2O:MeOH＝30:70)纯化，将所得制备液冻干得到白色固体221(100mg,收率38.7％)。
LCMS:497[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.50(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).
实施例132:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-3,5,6,7-四氢-4H-苯并[6,7]环庚并[1,2-d]嘧啶-4-酮甲酸盐的合成
步骤1：将222a(10g,62.4mmol,1.0eq)溶解于THF(100mL)中，将体系降温至0℃后加入60％NaH，混合液在氮气保护下，常温下搅拌30分钟，最后加入DMC(30mL)，体系在常温下搅拌16h。反应完成后使用MeOH(100mL)淬灭，将混合液旋干，并通过快速柱色谱法(PE:EA＝1:1)制得黄色油状物222A(13g,收率:95.4％)。
步骤2：将222A(3g,13.74mmol,1.0eq)和醋酸铵(4.2g,54.98mmol)溶解于MeOH(50mL)中，混合物在常温下搅拌16h。反应完成后将混合液旋干，并使用水(50mL)和二氯甲烷(20mL*2)萃取，将有机相旋干制得白色油状物222B(3g,收率:99.6％)。
步骤3：将222B(3g,13.8mmol,1.0eq)溶解于DMF(30mL)中,然后加入DMF-DMA(6.58g,55.256mmol,4.0eq)，混合物在80℃搅拌16h。反应完成后使用水(100mL)和二氯甲烷(50mL*2)萃取，将有机相旋干制得红色油状物222C(3.76g，粗品收率:99.2％)。
步骤4：将222C(3.76g)溶解于甲酰胺(20mL)中，混合液在200℃下搅拌1h。反应完成后使用水(50mL)和二氯甲烷(20mL*2)萃取，将有机相旋干，并通过快速柱色谱法(DCM:MeOH＝20:1)制得黄色固体222D(1.2g,收率:41.2％)。
步骤5：将222D(200mg,0.94mmol,1.0eq)、209b(347mg,1.13mmol,1.2eq)和碳酸钾(325mg,2.36mmol,2.5eq)加入至乙腈(5mL)中，混合液在70℃下搅拌16h。反应完成后将混合液旋干并使用水(20mL)和二氯甲烷(10mL*2)萃取，将有机相旋干，并通过反相柱色谱法(0.05％FA/H2O:MeOH＝30:70)纯化，冻干制得白色固体形式的化合物222的甲酸盐(90mg,收率19.8％)。
LCMS:483[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.47(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).
实施例133:3-(4-(3-(4-氟苄基)哌啶-1-基)-4-氧代丁基)-9-甲基-5,6-二氢苯并[h]喹唑啉-4(3H)-酮的合成
步骤1：将215B(500mg,2.35mmol,1.0eq)、4-溴丁酸甲酯(639mg,3.53mmol,1.5eq)和碳酸钾(813mg,5.89mmol,2.5eq)溶解于ACN(10mL)中，混合物在70℃搅拌16h。反应完成后将反应液旋干并通过快速柱色谱法(PE:EA＝1:1)纯化，制得黄色油状物223A(600mg，收率:81.7％)。
步骤2：将223A(600mg)溶解于THF/H2O(10mL/3mL)中，然后加入LiOH(120mg,0.2w/w)，混合物在常温下搅拌16h。反应完成后将混合物过滤，将滤液旋干并通过快速柱色谱法(PE:EA＝1:1)制得白色固体223B(500mg,收率:87.2％)。
步骤3：将223B(200mg,0.67mmol,1.0eq)、146b(194mg,1.00mmol,1.5eq)、HATU(510mg,1.34mmol,2.0eq)和DIPEA(216mg,1.67mmol,2.5eq)溶解于DCM(5mL)中，混合物在常温搅拌16h。反应完成后使用水(20mL)和二氯甲烷(5mL*2)萃取，将有机相旋干并通过反相柱(0.1％FA/H2O:MeOH＝30:70)纯化，将所得制备液冻干得到黄色固体223(50mg,收率15.7％)。
LCMS:474[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.39(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).
实施例134:3-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-甲氧基-3,5-二氢-4H-咪唑并[4,5-c]喹啉-4-酮的合成
步骤1：向250mL三口瓶中加入224a(1.11g,0.0054mol,1.0eq.)、4-溴丙酸叔丁酯(1.7g,0.0108mol,2.0eq.)、碳酸铯(3.53g,0.0108mol,2.0eq.)、DIPEA(1mL)和DMF(20mL)，80℃下搅拌过夜。反应结束后柱色谱法纯化，EtOAc:PE＝20:80洗脱产品。减压浓缩后得到黄色油状物224A(1.1g，收率:61.45％)。
步骤2：向250mL三口瓶中加入224A(1.1g,0.0033mol,1.0eq.)、210A(1.38g,0.0049mol,1.5eq.)、Pd-118(0.2g,0.00033mol,0.1eq.)、碳酸钾(0.91g,0.0066mol,2.0eq.)、二氧六环(20mL)和水(5mL)，氮气保护下100℃搅拌过夜。反应结束，硅胶柱色谱法纯化，EtOAc:PE＝20:80洗脱产品，液相浓缩后得到黄色油状物224B(1.24g，收率93.23％)。
步骤3：向100mL三口瓶中加入224B(1.24g,0.003mol,1.0eq.)、锌粉(1.95g,0.03mol,10.0eq.)、饱和NH4Cl水溶液(1.2mL)和EtOH(10mL)，85℃下搅拌过夜。反应结束后过滤，滤液旋干后得到粗品224C(0.5g)。
步骤4：向50mL三口瓶中加入224C(0.5g)、HCl/1,4-二氧杂环己烷溶液(1M,10mL)，室温下搅拌过夜。反应结束后反相柱纯化，MeOH/H2O脱产品，收集目标馏分旋干得到白色固体224D(0.1g，产率：27.03％)。
步骤5：向100mL三口瓶中加入224D(0.1g,0.35mmol,1.0eq.)、2,3-二氯苯基哌嗪盐酸盐(145b)(0.096g,0.42mmol,1.2eq.)、HATU(0.16g,0.42mmol,1.2eq.)、DIPEA(0.3mL)和DCM(5mL)，室温下搅拌过夜。反应结束后反相柱色谱法纯化，MeOH/H2O洗脱产品。收集目标馏分冻干后得白色固体224(0.014g，产率：8.05％)。
LCMS：500[M+1]+
1H NMR(400MHz,DMSO-d6)δ11.58(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).
实施例135:3-(3-(4-(4-氟苄基)哌啶-1-基)-3-氧代丙基)-9-甲基-5,6-二氢苯并[h]喹唑啉-4(3H)-酮的合成
除了将实施例中125步骤3的144b替换成146b之外，采用与实施例125相同的合成路线，制得标题化合物225(白色固体)。
LCMS:460[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.45(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).
实施例136:3-(8-甲基-4-氧代嘧啶并[5,4-b]喹啉-3(4H)-基)-N-(3-(三氟甲基)苄基)丙酰胺的合成
向250mL三口瓶中加入226a(0.28g,0.001mol,1eq.)、3-(三氟甲基)苯甲胺(226b)(0.17g,0.001mol,1eq.)、HATU(0.76g,0.002mol,2eq.)、DIPEA(0.26g,0.002mol,2eq.)和二氯甲烷(50mL)，降温至0℃，反应2小时。反应结束后，用饱和碳酸氢钠溶液淬灭反应，二氯甲烷萃取两次，有机相用无水硫酸钠干燥，浓缩，然后制备液相色谱法纯化，甲醇/水洗脱产品，减压浓缩然后冻干，得到类白色固体226(0.06g,收率：13.6％)。
LCMS：441[M+1]+
1H NMR(400MHz,DMSO-d6):δ8.59(t,2H),δ8.30(s,1H),δ8.12(d,1H),δ7.92(s,1H),7.72(d,1H),δ7.50(s,2H),7.43-7.38(m,2H),4.41(d,2H),4.26(t,2H),2.75(t,2H),2.54(s,3H).
实施例137:3-(4-(4-(2,3-二氯苯基)哌嗪-1-基)-4-氧代丁基)-8-甲氧基-3,5-二氢-4H-咪唑并[4,5-c]喹啉-4-酮的合成
向100mL单口瓶中加入227a(0.23g,0.681mmol,1.0eq.)、1-(2,3-二氯苯基)哌嗪盐酸盐(145b)(0.27g,1.02mmol,1.5eq.)、HATU(0.39g,1.02mmol,1.5eq.)、无水DMF(5mL)和DIPEA(0.44g,3.41mmol,5.0eq.)，室温反应1h。反应液通过反相柱层析(洗脱剂：0.5‰甲酸水:甲醇＝10:90)收集产物组分，蒸干甲醇，有固体析出，过滤，滤饼水洗，减压烘干得到浅棕色固体227(0.21g,收率：59.9％)。
LCMS：514[M+1]+
1H 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).
实施例138:3-(4-氧代-4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁基)-3,5,6,7-四氢-4H-苯并[6,7]环庚并[1,2-d]嘧啶-4-酮的合成
步骤1：将222D(200mg,0.94mmol,1.0eq)、4-溴丁酸甲酯(240mg,1.13mmol,1.2eq)和碳酸钾(325mg,2.36mmol,2.5eq)溶解于ACN(10mL)中，混合物在70℃搅拌16h。反应完成后将反应液旋干并通过快速柱色谱法(PE:EA＝1:1)制得白色油状物228A(150mg,收率:51.1％)。
步骤2：将228A(150mg)溶解于THF/H2O(5mL/2mL)中，然后加入LiOH(50mg,0.2w/w)，混合物在常温搅拌16h。反应完成后将混合物过滤，将滤液旋干并通过快速柱色谱法(PE:EA＝1:1)制得白色固体228B(120mg,收率:83.3％)。
步骤3：将228B(120mg,0.40mmol,1.0eq)、1-(3-(三氟甲基)苯基)哌嗪(144b)(138mg,0.60mmol,1.5eq)、HATU(305mg,0.80mmol,2.0eq)和DIPEA(129mg,1.00mmol,2.5eq)溶解于DCM(5mL)中，混合物在常温搅拌16h。反应完成后使用水(20mL)和二氯甲烷(5mL*2)萃取，将有机相旋干并通过反相柱(0.1％FA/H2O:MeOH＝30:70)纯化，将所得制备液冻干得到白色固体228(40mg,收率19.6％)。
LCMS:511[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.43(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).
实施例139:8-甲氧基-2-(4-氧代-4-(4-(3-(三氟甲基)苯基)哌嗪-1-基)丁基)-1,2,3,5-四氢-4H-吡咯并[3,4-c]喹啉-4-酮的合成
步骤1：向100mL单口瓶中加入229a(0.2g,0.791mmol,1.0eq.)、4-溴丁酸叔丁酯(0.26g,1.19mmol,1.5eq.)、三乙胺(0.4g,3.96mmol,5.0eq.)和乙腈(15mL)，60℃反应24h。反应结束，粗品柱层析(洗脱剂：DCM:MeOH＝96:4)纯化，收集产物组分，浓缩，得到浅棕色固体229A(0.4g，初步纯化粗品，直接用于下一步)。
步骤2：向100mL单口瓶中加入229A(0.4g,0.791mmol,1.0eq.)和HCl的1,4-二氧六环溶液(5mL,4mol/L)，室温反应1h。反应结束，过滤，滤饼用1,4-二氧六环洗涤，得到类白色固体229B(0.18g，收率67.1％)。
步骤3：向100mL单口瓶中加入229B(0.18g,0.571mmol,1.0eq.)、1-(3-三氟甲基苯基)哌嗪盐酸盐(144b)(0.21g,0.797mmol,1.5eq.)、HATU(0.3g,0.797mmol,1.5eq.)、无水DMF(5mL)和DIPEA(0.34g,2.66mmol,5.0eq.)，室温反应1h。反应液通过反相柱层析(洗脱剂：0.5‰甲酸水:甲醇＝51:49)初步纯化，将所得粗品通过制备色谱法(洗脱剂：0.5‰甲酸水:甲醇＝44:56)纯化，收集产物组分，蒸干甲醇，冻干得到类白色固体229(0.08g,收率：27.1％)。
LCMS：515[M+1]+
1H 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).
实施例140:2-(3-(4-(2,3-二氯苯基)哌嗪-1-基)-3-氧代丙基)-8-甲氧基-1,2,3,5-四氢-4H-吡咯并[3,4-c]喹啉-4-酮的合成
步骤1：向100mL单口瓶中加入229a(粗品,0.665mmol,1.0eq.)、3-溴丙酸叔丁酯(0.21g,0.998mmol,1.5eq.)、三乙胺(0.27g,2.66mmol,4.0eq.)和乙腈(15mL)，60℃反应24h。反应结束，粗品柱层析(洗脱剂：DCM:MeOH＝95:5)纯化，收集产物组分，浓缩，得到浅棕色固体230A(0.33g，初步纯化粗品，直接用于下一步)。
步骤2：向100mL单口瓶中加入230A(0.33g,0.665mmol,1.0eq.)和HCl的1,4-二氧六环溶液(5mL,4mol/L)，室温反应1h。反应结束，浓缩，得到浅黄色固体230B粗品，直接用于下一步。
步骤3：向100mL单口瓶中加入230B(粗品,0.831mmol,1.0eq.)、1-(2,3-二氯苯基)哌嗪盐酸盐(145b)(0.33g,1.25mmol,1.5eq.)、HATU(0.48g,1.25mmol,1.5eq.)、无水DMF(5mL)和DIPEA(0.54g,4.16mmol,5.0eq.)，室温反应1h。反应液通过反相柱层析(洗脱剂：0.5‰甲酸水:甲醇＝55:45)初步纯化，将所得粗品通过制备色谱法(洗脱剂：1‰甲酸水:甲醇＝43:57)纯化，收集产物组分，蒸干甲醇，冻干得到浅黄色固体230(0.05g,收率：11.9％)。
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).
实施例141:3-(4-(4-(2,3-二氯苯基)哌嗪-1-基)-4-氧代丁基)-8-甲氧基-3,5-二氢-4H-咪唑并[4,5-c]喹啉-4-酮的合成
步骤1：向250mL三口瓶中加入216a(1.11g,0.0054mol,1.0eq.)、4-溴丁酸叔丁酯(1.7g,0.0108mol,2.0eq.)、碳酸铯(3.53g,0.0108mol,2.0eq.)、DIPEA(1mL)和DMF(20mL)，80℃下搅拌过夜。反应结束后柱色谱法纯化，EtOAc:PE＝20:80洗脱产品。减压浓缩后得到黄色油状物231A(1.1g，收率:61.45％)。
步骤2：向250mL三口瓶中加入231A(1.1g,0.0033mol,1.0eq.)、201A(1.38g,0.0049mol,1.5eq.)、Pd-118(0.2g,0.00033mol,0.1eq.)、碳酸钾(0.91g,0.0066mol,2.0eq.)、二氧六环(20mL)和水(5mL)，氮气保护下100℃搅拌过夜。反应结束，硅胶柱色谱法纯化，EtOAc:PE＝20:80洗脱产品，液相浓缩后得到黄色油状物231B(1.24g，收率93.23％)。
步骤3：向100mL三口瓶中加入231B(1.24g,0.003mol,1.0eq.)、锌粉(1.95g,0.03mol,10.0eq.)、饱和NH4Cl水溶液(1.2mL)和EtOH(10mL)，85℃下搅拌过夜。反应结束后过滤，滤液旋干后得到粗品231C(0.5g)。
步骤4：向50mL三口瓶中加入231C(0.5g)和HCl/1,4-二氧杂环己烷溶液(1M,10mL)，室温下搅拌过夜。反应结束后反相柱纯化，MeOH/H2O脱产品，收集目标馏分旋干得到白色固体231D(0.1g，产率：27.03％)。
步骤5：向100mL三口瓶中加入231D(0.1g,0.35mmol,1.0eq.)、2,3-二氯苯基哌嗪盐酸盐(145b)(0.096g,0.42mmol,1.2eq.)、HATU(0.16g,0.42mmol,1.2eq.)、DIPEA(0.3mL)和DCM(5mL)，室温下搅拌过夜。反应结束后反相柱色谱法纯化，MeOH/H2O洗脱产品。收集目标馏分冻干后得白色固体231(0.008g，产率：4.44％)。
LCMS：514[M+1]+
1H NMR(500MHz,DMSO-d6)δ11.57(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).
实施例142:2-甲基-N-(3-(4-(3-三氟甲基苯基)哌嗪-1-基)丙基)-6,6a,7,8,9,10-六氢苯并[b]吡啶并[1,2-d][1,4]噁嗪-7-甲酰胺甲酸盐的合成
向反应瓶中加入232a(50mg,0.20mmol,1.0eq.)、DMF(2mL)和HATU(93mg,0.24mmol,1.2eq.)常温搅拌30min。然后加入3-(4-(3-三氟甲基苯基)哌嗪-1-基丙胺(232b)(72mg，0.22mmol，1.1eq)以及DIPEA(78mg，0.61mmol，3.0eq)。常温下搅拌过夜。反应液通过柱色谱法纯化(洗脱剂：0.1％甲酸水溶液：MeOH＝46％)，收集目标组分，减压浓缩得白色固体232(40mg，收率：38.31％)。
LCMS：517[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.16(s,1H),8.03(t,0.73H),7.77(t,0.23H),7.41(t,1H),7.26-7.11(m,2H),7.06(d,1H),6.81(s,0.25H),6.71(s,0.76H),6.56(t,1H),6.47(d,0.25H),6.38(d,0.77H),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).
实施例143:N-(2-4-(2,3-二氯苯基)哌嗪-1-基)乙基)-2-甲基-6,6a,7,8,9,10-六氢苯并[b]吡啶并[1,2-d][1,4]噁嗪-7-甲酰胺的合成
步骤1：向反应瓶中加入233a(4.50g,29.41mmol,1.0eq.)、MeCN(100mL)，4-溴丁-2-烯酸甲酯(11.35g,58.82mmol,2.0eq.)、碳酸钾(12.18g，88.24mmol，3.0eq)以及碘化钾(976mg，5.88mmol，0.2eq)。85℃下搅拌过夜。反应液过滤后滤饼用乙酸乙酯洗涤，滤液加入硅胶，浓缩后通过柱色谱法纯化(洗脱剂：乙酸乙酯：石油醚＝45％)，收集目标组分，减压浓缩得白色固体233A(7.3g，收率：93.66％)。
步骤2：向反应瓶中加入233A(7.30g,27.55mmol,1.0eq.)、醋酸(100mL)、铁粉(9.26g,165.28mmol,6.0eq.)、碳酸钾(12.18g，88.24mmol，3.0eq)以及碘化钾(976mg，5.88mmol，0.2eq)。120℃下搅拌30分钟。反应液冷却后用乙酸乙酯萃取三遍，有机相用碳酸氢钠水溶液洗涤后浓缩得黑色油状粗品233B(10.0g)。
步骤3：向反应瓶中加入233B(1.26g,5.36mmol,1.0eq.)、DMF(10mL)、DIPEA(2.07g,16.09mmol,3.0eq.)、1-溴-3-氯丙烷(1.68g，10.72mmol，2.0eq)。80℃下搅拌过夜。反应液冷却后加水，用乙酸乙酯萃取三遍，有机相用饱和氯化钠洗涤，无水硫酸钠干燥后，加入硅胶，浓缩后通过柱色谱法纯化(洗脱剂：乙酸乙酯:石油醚＝12％)，收集目标组分，减压浓缩得白色固体233C(635mg，收率：39.87％)。
步骤4：向反应瓶中加入233C(635mg,2.042mmol,1.0eq.)、无水四氢呋喃(20mL)，置换氮气，体系降温至-78℃后，滴加LiHMDS(1M)(13.2mL,6.5eq)，自然升温反应4h。反应液滴加水淬灭后用乙酸乙酯萃取三遍，有机相用饱和氯化钠洗涤，无水硫酸钠干燥后加入硅胶，浓缩后通过柱色谱 法纯化(洗脱剂：乙酸乙酯：石油醚＝20％)，收集目标组分，减压浓缩得白色固体233D(300mg，收率：47.24％)。
步骤5：向反应瓶中加入233D(300mg,1.09mmol,1.0eq.)、四氢呋喃(3mL)、水(1mL)和氢氧化锂(79mg,3.27mmol,3.0eq.)。室温搅拌过夜。反应液浓缩后加水(5mL)，滴加2M HCl至白色固体不再析出，过滤烘干后得白色固体232a(250mg，收率：92.77％)。
步骤6：向反应瓶中加入232a(50mg,0.20mmol,1.0eq.)、DMF(2mL)和HATU(93mg,0.24mmol,1.2eq.)，常温搅拌30min。然后加入2-(4-(2,3-二氯苯基)哌嗪-1-基)乙烷-1-胺(233b)(123mg，0.44mmol，1.2eq)以及DIPEA(78mg，0.61mmol，3.0eq)。常温下搅拌过夜。反应液通过柱色谱法纯化(洗脱剂：0.1％甲酸水溶液：MeOH＝46％)，收集目标组分，减压浓缩得白色固体233(30mg，收率：29.58％)。
LCMS：503[M+H]+
1H NMR(400MHz,DMSO-d6)δ7.97(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).
实施例144:N-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-2-甲基-6,6a,7,8,9,10-六氢苯并[b]吡啶并[1,2-d][1,4]噁嗪-7-甲酰胺甲酸盐的合成
除了将实施例中143步骤6中的233b替换成234b之外，采用与实施例143相同的合成路线，制得标题化合物234(白色固体)。
LCMS：517[M+H]+
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),8.05(t,1H),7.31(d,2H),7.17-7.11(m,1H),6.81(s,0.23H),6.72(s,0.74H),6.58(d,1H),6.55(d,0.24H),6.39(d,0.75H),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).
实施例145:2-(3-(4-(2,3-二氯苯基)哌嗪-1-基)丙基)-8-甲氧基-1,2,3,5-四氢-4H-吡咯并[3,4-c]喹啉-4-酮的合成
步骤1：向250mL单口瓶中加入235a(2g,7.17mmol,1.0eq.)、10％Pd/C(0.3g,15％w/w)和乙酸乙酯(80mL)，常压加氢，室温反应16h。反应结束，过滤，滤饼用乙酸乙酯洗涤，滤液浓缩，得到235A，粗品直接用于下一步。
步骤2：向250mL单口瓶中加入235A(粗品,7.71mmol,1.5eq.)、235b(2g,5.14mmol,1.0eq.)，Pd(dppf)Cl2-DCM(0.84g,1.03mmol,0.2eq.)、碳酸钠(1.63g,15.4mmol,3.0eq.)、1,4-二氧六环(100mL)和水(10mL)，氮气保护，100℃反应16h。反应结束，过滤，滤饼用DCM洗涤，滤液浓缩，粗品硅胶柱层析(洗脱剂：DCM:MeOH＝97:3)，收集产物组分，蒸干溶剂，得到棕色固体235B(0.7g,收率：43.0％)。
步骤3：向100mL单口瓶中加入235B(0.7g,2.22mmol,1.0eq.)、HCl的1,4-二氧六环溶液(7mL,4mol/L)，室温反应1h。反应结束，过滤，滤饼用1,4-二氧六环洗涤，烘干得到浅棕黄色固体235C(0.45g,收率：80.2％)。
步骤4：向100mL单口瓶中加入235C(0.25g,0.989mmol,1.0eq.)、1-(3-溴丙基)-4-(2,3-二氯苯基)哌嗪(235c)(0.7g,1.98mmol,2.0eq.)、三乙胺(0.5g,4.95mmol,5.0eq.)和乙腈(15mL)，60℃反应16h。反应结束，过滤，滤饼乙腈洗涤，将滤饼加入DMSO(10mL)中，搅拌30min并过滤，滤饼依次用DMSO、甲醇洗涤，烘干得到类白色固体235(0.12g,收率：24.9％)。
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).
实验例
实验例1.药效学实验(TPK酶活性测试)
1.1实验目的
本实验例的目的是为了测试化合物对TPK酶活性的促进作用，根据EC50和Emax评价化合物的体外活性作用。
1.2实验方法
1.2.1实验材料
1.2.2实验步骤
1.1).提前半小时将恒温水浴摇床预热，预热温度37℃。
1.2).将待测试的化合物储存液取出，放置室温融解，并将其稀释至所需浓度。
1.3).将所需试剂置于冰上融解。
2.1).每个反应体系需加入TPK酶溶液、Tris-HCl缓冲液、ATP溶液，所使用的ATP为1-500mM，将上述三种溶液配制成均匀的混合液。
2.2).将上述三种溶液的混合液分装至离心管中，然后向每个离心管中加入所需浓度的化合物，最后向其中加入硫胺素溶液(1-100μM)。上述体系加入完成后，将离心管盖子封紧，插入浮漂板内，放置在已经预热至37℃恒温水浴摇床中，孵育0.5-2.0小时。
2.3).孵育结束后，加入高氯酸终止液混匀，取样至1.5mL离心管中，置于-20℃保存。
3.1).将-20℃保存的样品取出，室温融解，然后进行衍生化处理，将样品置于离心管中，向其加入铁氰化钾衍生化试剂，最后加入磷酸终止液停止反应。
3.2).将衍生化处理后的样品置于液相色谱分析样品瓶中，通过高效液相色谱法检测TDP/硫胺素的含量。TPK酶活性＝TDP(nM)/mg蛋白/min。
1.3实验结果
按以上操作测定本发明化合物在不同浓度下对于TPK酶活性的作用，测得Emax(以DMSO对TPK酶活性的影响效应为100％计算)和EC50数据如下表中所示。




除本文中描述的那些外，根据前述描述，本发明的各种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (26)

  1. 预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法，其包括向需要其的个体给药预防或治疗有效量的硫胺素焦磷酸激酶(TPK)激动剂；
    优选地，所述神经退行性疾病为阿尔茨海默病；
    更优选地，所述阿尔茨海默病为个体的TPK酶活性降低、TPK表达水平降低和/或TDP水平降低的阿尔茨海默病；
    其中所述TPK激动剂为式(I)-I的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    优选地，所述TPK激动剂为式(I)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    其中：
    A和B各自独立地为CR3或N；
    环C和环D各自独立地为C3-10烃环(例如C3-6烃环)、3-10元杂环、C6-10芳环或5-14元杂芳环；优选地，环C为5-6元杂芳环；
    L1、L2和L3各自独立地不存在或者选自-O-、-C(＝O)-、-C(＝O)O-、-NR-、-C(＝O)NR-、-(S＝O)NR-、-S(＝O)2NR-、-S-、-S(＝O)-、-S(＝O)2-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C3-6亚环烃基-、-(3-10元亚杂环基)-、-C6-10亚芳基-、-(5-14元亚杂芳基)-、-W-C1-6亚烷基-、-C1-6亚烷基-W-和-W-C1-6亚烷基-W’-，其中所述亚烷基任选地进一步被一个或多个W间隔；条件是L1、L2和L3中的至少一者存在；
    W和W’在每次出现时各自独立地选自-O-、-C(＝O)-、-C(＝O)O-、-NR-、-C(＝O)NR-、-(S＝O)NR-、-S(＝O)2NR-、-S-、-S(＝O)-和-S(＝O)2-；
    R1在每次出现时各自独立地选自卤素、-OH、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Ra、-OC(＝O)Ra、-C(＝O)ORa、-ORa、-SRa、-S(＝O)Ra、-S(＝O)2Ra、-S(＝O)2NRaRb、-NRaRb、-C(＝O)NRaRb、-NRa-C(＝O)Rb、-NRa-C(＝O)ORb、-NRa-S(＝O)2-Rb、-NRa-C(＝O)-NRaRb、-C1-6亚烷基-ORa、-C1-6亚烷基-NRaRb和-O-C1-6亚烷基-NRaRb；
    R2和R3在每次出现时各自独立地选自H、卤素、-OH、-NH2、-CN、-NO2、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Ra、-OC(＝O)Ra、-C(＝O)ORa、-ORa、-SRa、-S(＝O)Ra、-S(＝O)2Ra、-S(＝O)2NRaRb、-NRaRb、-C(＝O)NRaRb、-NRa-C(＝O)Rb、-NRa-C(＝O)ORb、-NRa-S(＝O)2-Rb、-NRa-C(＝O)-NRaRb、-C1-6亚烷基-ORa、-C1-6亚烷基-NRaRb和-O-C1-6亚烷基-NRaRb；
    R、Ra和Rb在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基；
    n为0、1、2、3或4；优选地，n为0、1或2；
    上述烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、环烃基、亚环烃基、烃环、杂环基、亚杂环基、杂环、芳基、亚芳基、芳环、杂芳基、亚杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Rc、-OC(＝O)Rc、-C(＝O)ORc、-ORc、-SRc、-S(＝O)Rc、-S(＝O)2Rc、-S(＝O)2NRcRd、-NRcRd、-C(＝O)NRcRd、-NRc-C(＝O)Rd、 -NRc-C(＝O)ORd、-NRc-S(＝O)2-Rd、-NRc-C(＝O)-NRcRd、-C1-6亚烷基-ORc、-C1-6亚烷基-NRcRd和-O-C1-6亚烷基-NRcRd，所述烷基、亚烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH2、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-O-C1-6烷基和-C1-6亚烷基-O-C1-6烷基；并且
    Rc和Rd在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH2、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基和-C1-6亚烷基-O-C1-6烷基。
  2. 权利要求1的方法，其中所述TPK激动剂为式(II)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    其中：
    X为-C(R)2-、-NR-、-O-或-S-；优选地X为-NR-、-O-或-S-；更优选地X为-NH-、-N(CH3)-、-O-或-S-；并且
    其余各基团如权利要求1中所定义。
  3. 权利要求1的方法，其中为
  4. 权利要求1至3中任一项的方法，其中R3在每次出现时各自独立地为H或C1-6烷基(优选甲 基)；
    优选地，A和B各自独立地为CH、CCH3或N；并且
    更优选地，A为N并且B为CH。
  5. 权利要求1至4中任一项的方法，其中L1和L3各自独立地不存在或者为-C(＝O)-、-N(CH3)-、-C1-6亚烷基-、-W-C1-6亚烷基-或-C1-6亚烷基-W-，所述亚烷基任选地进一步被一个或多个W间隔，并且
    W为-O-、-C(＝O)-、-C(＝O)O-、-NH-、-N(CH3)-、-C(＝O)NH-或-C(＝O)N(CH3)-。
  6. 权利要求1至5中任一项的方法，其中L2不存在或者为-(3-10元亚杂环基)-；
    优选地，L2不存在或者为亚哌嗪基或亚哌啶基。
  7. 权利要求1至6中任一项的方法，其中为
  8. 权利要求1至7中任一项的方法，其中R1在每次出现时各自独立地选自卤素、-CN、C1-6烷基、卤代C1-6烷基和C1-6烷氧基；
    优选地，R1在每次出现时各自独立地选自-F、-Cl、-Br、-CN、-CH3、-CF3和-OCH3。
  9. 权利要求1至8中任一项的方法，其中R2独立地选自H、C1-6烷基、C6-10芳基和5-14元杂芳基；所述基团任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、-N(C1-6烷基)2、C1-6烷氧基、卤代C1-6烷氧基、-C(＝O)-C1-6烷基、-C(＝O)OH、-C(＝O)O-C1-6烷基、-S-C1-6烷基、-S(＝O)2-C1-6烷基、-S(＝O)2-(3-10元杂环基)、-S(＝O)2NH2和-C(＝O)NH2；
    优选地，R2独立地选自异丙基、
  10. 权利要求1至9中任一项的方法，其中所述TPK激动剂为式(III)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    其中各基团如权利要求1至9中任一项所定义。
  11. 预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法，其包括向需要其的个体给药预防或治疗有效量的硫胺素焦磷酸激酶(TPK)激动剂；
    优选地，所述神经退行性疾病为阿尔茨海默病；
    更优选地，所述阿尔茨海默病为个体的TPK酶活性降低、TPK表达水平降低和/或TDP水平降低的阿尔茨海默病；
    其中所述TPK激动剂为式(IV)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    其中：
    环D不存在或者为C3-6烃环、3-10元杂环、C6-10芳环或5-14元杂芳环；
    L4选自-O-、-C(＝O)-、-C(＝O)O-、-NR’-、-C(＝O)NR’-、-(S＝O)NR’-、-S(＝O)2NR’-、-S-、-S(＝O)-、-S(＝O)2-、-C1-6亚烷基-、-C2-6亚烯基-、-C2-6亚炔基-、-C3-6亚环烃基-、-(3-10元亚杂环基)-、-C6-10亚芳基-、-(5-14元亚杂芳基)-、-U-C1-6亚烷基-、-C1-6亚烷基-U-、-U-C1-6亚烷基-U’-和-C1-6亚烷基-U-C1-6亚烷基-，其中所述亚烷基任选地进一步被一个或多个U间隔；
    U和U’在每次出现时各自独立地选自-O-、-C(＝O)-、-C(＝O)O-、-NR’-、-C(＝O)NR’-、-(S＝O)NR’-、-S(＝O)2NR’-、-S-、-S(＝O)-和-S(＝O)2-；
    R4、R4’、R5、R5’、R6和R7在每次出现时各自独立地选自H、卤素、-OH、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Re、-OC(＝O)Re、-C(＝O)ORe、-ORe、-SRe、-S(＝O)Re、-S(＝O)2Re、-S(＝O)2NReRf、-NReRf、-C(＝O)NReRf、-NRe-C(＝O)Rf、-NRe-C(＝O)ORf、-NRe-S(＝O)2-Rf、-NRe-C(＝O)-NReRf、-C1-6亚烷基-ORe、-C1-6亚烷基-NReRf、-O-C1-6亚烷基-NReRf和-C1-6亚烷基-OC(＝O)-C1-6亚烷基-C(＝O)ORe；或者，R4与R4’或R5与R5’共同构成＝O；或者，R4、R4’、R5、R5’连同其所连接的基团共同沟通C3-6 烃环、3-10元杂环、C6-10芳环或5-14元杂芳环；
    R’、Re和Rf在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基；
    p和q各自独立地为1、2、3或4；优选地，p和q各自独立地为1或2；条件是当环D不存在时，q为1；
    上述烷基、亚烷基、烯基、亚烯基、炔基、亚炔基、环烃基、亚环烃基、烃环、杂环基、亚杂环基、杂环、芳基、亚芳基、芳环、杂芳基、亚杂芳基、杂芳环和芳烷基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-NH2、-CN、-NO2、C1-6烷基、卤代C1-6烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-C(＝O)Rg、-OC(＝O)Rg、-C(＝O)ORg、-ORg、-SRg、-S(＝O)Rg、-S(＝O)2Rg、-S(＝O)2NRgRh、-NRgRh、-C(＝O)NRgRh、-NRg-C(＝O)Rh、-NRg-C(＝O)ORh、-NRg-S(＝O)2-Rh、-NRg-C(＝O)-NRgRh、-C1-6亚烷基-ORg、-C1-6亚烷基-NRgRh和-O-C1-6亚烷基-NRgRh，所述烷基、亚烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH2、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基、-O-C1-6烷基和-C1-6亚烷基-O-C1-6烷基；并且
    Rg和Rh在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基和C6-12芳烷基，所述烷基、环烃基、杂环基、芳基、杂芳基和芳烷基进一步任选地被一个或多个独立地选自下列的取代基取代：卤素、-OH、＝O、-C(＝O)O-叔丁基、-NH2、-CN、-NO2、C1-6烷基、C1-6卤代烷基、C3-6环烃基、3-10元杂环基、C6-10芳基、5-14元杂芳基、C6-12芳烷基和-C1-6亚烷基-O-C1-6烷基。
  12. 权利要求11的方法，其中所述TPK激动剂为式(V)的化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：
    其中各基团如权利要求11中所定义。
  13. 权利要求11或12的方法，其中L4选自-(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-和-CH2-CH(OH)-CH2-NH-。
  14. 权利要求11至13中任一项的方法，其中为-CN、-NH2、
  15. 预防或治疗神经退行性疾病或者减轻神经退行性疾病的症状的方法，其包括向需要其的个体给药预防或治疗有效量的硫胺素焦磷酸激酶(TPK)激动剂；
    优选地，所述神经退行性疾病为阿尔茨海默病；
    更优选地，所述阿尔茨海默病为个体的TPK酶活性降低、TPK表达水平降低和/或TDP水平降低的阿尔茨海默病；
    其中所述TPK激动剂选自以下化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药：









  16. 权利要求1-15中任一项的方法，其中将所述TPK激动剂以约0.005mg/日至约5000mg/日的量，例如约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或5000mg/日的量给药。
  17. 权利要求1-16中任一项的方法，其中将所述TPK激动剂以每日约1ng/kg至约200mg/kg、约1μg/kg至约100mg/kg或者约1mg/kg至约50mg/kg体重的量给药，例如以每日约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg/kg、约225μg/kg、约250μg/kg、约275μg/kg、约300μg/kg、约325μg/kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg/kg、约550μg/kg、约575μg/kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg或约300mg/kg体重的量给药。
  18. 权利要求1-17中任一项的方法，其中将所述TPK激动剂的每日剂量一次性给予或分两次、三次或四次给予。
  19. 权利要求1-18中任一项的方法，其中将所述TPK激动剂连续给药至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至 少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天。
  20. 权利要求1-19中任一项的方法，其中将所述TPK激动剂给药一个或多个(例如1、2、3、4、5、6、7、8、9或10个)疗程，其中每个疗程持续至少3天、至少4天、至少5天、至少6天、至少7天、至少8天、至少9天、至少10天、至少11天、至少12天、至少13天、至少14天、至少15天、至少16天、至少17天、至少18天、至少19天、至少20天、至少21天、至少22天、至少23天、至少24天、至少25天、至少30天、至少35天、至少40天、至少45天或至少50天；并且每两个疗程之间间隔0、1、2、3、4、5、6、7、8、9、10天、两周、三周或四周。
  21. 权利要求1-20中任一项的方法，其中将所述TPK激动剂通过注射(如静脉内、动脉内、皮下、腹膜内、肌内注射，包括滴注)或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
  22. 权利要求1-21中任一项的方法，其中将所述TPK激动剂以选自片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂和糖浆剂的剂型给药。
  23. 权利要求1-22中任一项的方法，其中所述方法改善了个体的以下病理生理学表现：认知行为学异常、神经变性改变(例如进行性突触/神经元丢失和脑萎缩)、β-淀粉样蛋白沉积、Tau异常磷酸化及其所造成的神经纤维缠结、胶质细胞激活和炎症和/或脑葡萄糖代谢障碍。
  24. 权利要求1-23中任一项的方法，其还包括给药一种或多种其它的治疗剂。
  25. 化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，所述化合物具有式(III)的结构：
    其中各基团如权利要求1-9中任一项所定义；
    条件是-L3-R2不是H和甲基。
  26. 化合物，或其药学上可接受的盐、酯、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：






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