CN112010846A - Pyridine derivative and preparation method and application thereof - Google Patents

Pyridine derivative and preparation method and application thereof Download PDF

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CN112010846A
CN112010846A CN202010450404.6A CN202010450404A CN112010846A CN 112010846 A CN112010846 A CN 112010846A CN 202010450404 A CN202010450404 A CN 202010450404A CN 112010846 A CN112010846 A CN 112010846A
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compound
ring
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况伟宏
李进
谢永美
田蓉
吴小艾
张霓
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West China Hospital of Sichuan University
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    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
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Abstract

The invention relates to a pyridine derivative and a preparation method and application thereof. In particular to a compound shown in formula I, or pharmaceutically acceptable salt, hydrate, solvate, conformational isomer, crystal form or isotope substitution form thereof, and a preparation method and application thereof. Experimental results show that the pyridine compounds provided by the inventionThe substance can be used as a Tau protein tracer agent after being labeled by radionuclide, is used for identifying neurofibrillary tangles (NFTs) formed by abnormal aggregation of hyperphosphorylated Tau protein in brain, can be used for diagnosing diseases related to the neurofibrillary tangles, can also be used for monitoring the progress of the diseases in the treatment process, provides higher and more accurate diagnosis and tracking for patients or potential patients with the diseases related to the neurofibrillary tangles, and has good application prospect in clinical diagnosis.
Figure DDA0002507481830000011

Description

Pyridine derivative and preparation method and application thereof
Technical Field
The invention belongs to the field of material processing, and particularly relates to a pyridine derivative, and a preparation method and application thereof.
Background
Alzheimer's Disease (AD), also known as senile dementia, is a chronic neurodegenerative disease most common in the elderly causing dementia. The number of AD patients in China reaches 600 ten thousands, and the morbidity of the AD patients is on a remarkable rising trend along with the aggravation of the aging of the global population. Therefore, the pathogenesis of AD is clarified, and effective treatment means are found to prevent and delay the occurrence and development of AD, so that the method not only becomes a key subject of medical research at home and abroad, but also has strategic significance on long-term economic development of various countries. The current targets for the study of alzheimer's disease focus mainly on the aggregation of beta amyloid and neurofibrillary tangles (NFTs) formed by abnormal aggregation of hyperphosphorylated Tau protein.
Tau protein is a member of a microtubule binding protein family, and is mainly concentrated around neuron axons in normal neurons, and has the main functions of regulating microtubule assembly and disassembly and maintaining microtubule stability, and meanwhile, Tau protein also has the function of assisting the neuron axons in transporting goods and the like. Hyperphosphorylated Tau protein has reduced binding to microtubules and tends to accumulate into abnormal ultrastructural double filaments (PHF) and bundled filaments. The oligomeric Tau protein diffuses in a prion-like manner. In AD and neurodegenerative diseases (generally called Tau protein disease), Tau protein is over-phosphorylated and abnormally aggregated and then dissociated from microtubules, so that axonal transport disorder is caused, and the form and the function of neurons are influenced. Tau proteinopathies associated therewith include Progressive Supranuclear Palsy (PSP), corticoid encephalitis (CBS), Down Syndrome (DS), Parkinson (PD) and dementia with Lewy bodies (DLB).
Recently, Tau-specific ligands for Positron Emission Tomography (PET) have emerged, including the first generation compounds (e.g., [ solution ] ])18F]THK5317，[18F]THK5351，[18F]AV1451, and11C]PBB3) and a second-generation compound [ e.g., [ 2 ]18F]MK-6240，[18F]RO-948 (formerly referred to as [, ])18F]RO69558948)，[18F]PI-2620，[18F]GTP1，[18F]PM-PBB3, and18F]JNJ64349311，[18F]JNJ311 and derivative thereof, [ 2 ]18F]JNJ-067. The specific ligands can be used as Tau protein tracers, can mark and display the deposition and distribution conditions of Tau protein in the brain of a subject during PET imaging, and are expected to bring breakthrough progress in the aspects of accurate pathological diagnosis, treatment, drug effect tracking and the like of AD.
However, the currently known Tau protein tracers are difficult to synthesize and have insufficient clinical effects. It is therefore essential to find new, simple, easily synthesized, highly specific Tau tracer molecules.
Disclosure of Invention
The invention aims to provide a Tau protein tracer agent which has a novel structure, high specificity and is easy to obtain.
The invention provides a compound shown as a formula I, or a pharmaceutically acceptable salt, a hydrate, a solvate, a conformational isomer, a crystal form or an isotope substitution form thereof:
Figure BDA0002507481810000021
wherein R is1、R2、R3、R4、R5Each independently selected from H, deuterium,18F、19F、123I、125I、127I、-NO2、-OH、-OCD3、-O11CH3、-O11CD3、-NH2、-NHCH3、-NHCD3、-NH11CH3、-NH11CD3、-N(CH3)2、-N(CD3)2、-N(11CH3)2、-N(11CD3)2、-O(CH2)m 18F、-O(CH2)m 19F、
Figure BDA0002507481810000022
Halogen, cyano, carboxyl, C1～10Alkyl radical, C1～10Alkoxy radical, C2～10Alkenyl radical, C2～10Alkynyl, radionuclides; wherein R is selected from-OH,18F、19F and m are integers from 1 to 6;
R6selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, each of said substituents on heteroaryl or aryl being independently selected from: deuterium,18F、19F、123I、125I、127I、-OH、-OCD3、-O11CH3、-O11CD3、-NHCD3、-NH11CH3、-NH11CD3、-N(CD3)2、-N(11CH3)2、-N(11CD3)2、-O(CH2)m 18F、-O(CH2)m 19F、
Figure BDA0002507481810000023
-NRn1Rn2Halogen, cyano, carboxyl, C1～10Alkyl radical, C1～10Alkoxy radical, C2～10Alkenyl radical, C2～10An alkynyl group; wherein R is selected from-OH,18F、19F, m is an integer of 1 to 6, Rn1、Rn2Each independently selected from H, deuterium, halogen, C1～10Alkyl radical, C1～10Alkoxy radical, C2～10Alkenyl radical, C2～10Alkynyl, or Rn1、Rn2Together with the nitrogen atom to which they are both attached form a ring selected from a saturated heterocyclic ring, an unsaturated heterocyclic ring, a saturated carbocyclic ring or an unsaturated carbocyclic ring.
Further, the structure of the compound is shown as formula II:
Figure BDA0002507481810000024
wherein R is2Selected from H, deuterium,18F、19F、123I、125I、127I、-NO2、-OH、-OCD3、-O11CH3、-O11CD3、-NH2、-NHCH3、-NHCD3、-NH11CH3、-NH11CD3、-N(CH3)2、-N(CD3)2、-N(11CH3)2、-N(11CD3)2、-O(CH2)18F、-O(CH2)19F. Halogen, cyano, carboxyl, C1～3Alkyl radical, C1～3An alkoxy group;
R6selected from substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered arylAnd the substituents on the heteroaryl or aryl are each independently selected from: -NRn1Rn2Halogen, cyano, carboxyl, C1～8Alkyl radical, C1～8Alkoxy radical, C2～8Alkenyl radical, C2～8Alkynyl, deuterium,18F、19F、123I、125I、127I、-OH、-OCD3、-O11CH3、-O11CD3、-NHCD3、-NH11CH3、-NH11CD3、-N(CD3)2、-N(11CH3)2、-N(11CD3)2、-O(CH2)m 18F、-O(CH2)m 19F、
Figure BDA0002507481810000025
Figure BDA0002507481810000026
Wherein R is selected from-OH,18F、19F, m is an integer of 1 to 6, Rn1、Rn2Each independently selected from H, halogen, C1～5Alkyl radical, C1～5Alkoxy, or Rn1、Rn2And a nitrogen atom which is connected with the heterocyclic ring together forms a ring, and the ring is selected from a 3-8 membered saturated heterocyclic ring, a 3-8 membered unsaturated heterocyclic ring, a 3-8 membered saturated carbocyclic ring and a 3-8 membered unsaturated carbocyclic ring.
Further, R2Is selected from-NO2Or18F；
R6Substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered aryl, each of the substituents on the heteroaryl or aryl being independently selected from: -NRn1Rn2Halogen, cyano, carboxyl, C1～3Alkyl radical, C1～3Alkoxy, deuterium,18F. -OH; wherein R isn1、Rn2Each independently selected from H, halogen, C1～5Alkyl radical, C1～5Alkoxy, or Rn1、Rn2Together with the nitrogen atom to which they are both attached form a ring selected from the group consisting of 3E toA 6-membered saturated heterocyclic ring, a 3-6-membered unsaturated heterocyclic ring, a 3-8-membered saturated carbocyclic ring, and a 3-8-membered unsaturated carbocyclic ring.
Further, the structure of the compound is shown as a formula III-1 or a formula III-2:
Figure BDA0002507481810000031
wherein R is2Is selected from-NO2Or18F；
M1Is selected from N or CH; m2Selected from S or O;
Rn1、Rn2each independently selected from C1～2Alkyl, or Rn1、Rn2Form a ring together with the nitrogen atom to which they are both attached, said ring being a 5-to 6-membered saturated heterocyclic ring, preferably said ring is
Figure BDA0002507481810000032
Figure BDA0002507481810000033
Further, the compound is selected from the following structures:
Figure BDA0002507481810000041
。
further, the compound is selected from the following structures:
Figure BDA0002507481810000042
。
the invention also provides a preparation method of the compound, or pharmaceutically acceptable salt, hydrate, solvate, conformational isomer, crystal form or isotopic substitution form of the compound, wherein the method comprises the following steps:
(1) reacting compound 1a with compound 2a to give compound 3 a;
(2) reacting compound 3a with compound 4a to give compound 5 a;
alternatively, the method further comprises the steps of: (3) reacting compound 5a with a radionuclide-containing compound to give compound 6 a;
wherein the compound 1a has the structure
Figure BDA0002507481810000051
The compound 2a has the structure
Figure BDA0002507481810000052
The compound 3a has the structure
Figure BDA0002507481810000053
The compound 4a has the structure
Figure BDA0002507481810000054
The compound 5a has the structure
Figure BDA0002507481810000055
The compound 6a has the structure
Figure BDA0002507481810000056
X is a radionuclide; r2、R6As described above;
preferably, the radionuclide-containing compound is [ 2 ]18F]Fluoride, compound 6a having the structure
Figure BDA0002507481810000057
The invention also provides the application of the compound or the pharmaceutically acceptable salt, the hydrate, the solvate, the conformational isomer, the crystal form or the isotopic substitution form of the compound in the preparation of a Tau protein tracer agent, preferably, the Tau protein tracer agent can target hyperphosphorylated Tau protein.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof, or the hydrate thereof, or the solvate thereof, or the conformational isomer thereof, or the crystal form thereof, or the isotopic substitution form thereof in preparation of nuclear medicine imaging agents, optical imaging agents or PET imaging agents.
Further, the nuclear medicine imaging agent, the optical imaging agent or the PET imaging agent is capable of diagnosing a disease associated with neurofibrillary tangles; preferably, the neurofibrillary tangles are those formed by abnormal aggregation of hyperphosphorylated Tau protein, more preferably, the disease is selected from the group consisting of alzheimer's disease, frontotemporal dementia, corticobasal degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, pick's disease, cortico-encephalitis, down's syndrome, parkinson's disease or dementia with lewy bodies.
The experimental result shows that the pyridine compound provided by the invention is irradiated by radionuclide18After F labeling, the protein can be used as a Tau protein tracer for identifying neurofibrillary tangles (NFTs) formed by abnormal aggregation of hyperphosphorylated Tau protein in brain, can be used for diagnosing diseases related to the neurofibrillary tangles, can also be used for monitoring the progress of the diseases in the treatment process, provides higher and more accurate diagnosis and tracking for patients or potential patients with the diseases related to the neurofibrillary tangles, and has good application prospect in clinical diagnosis.
In the present invention, hyperphosphorylated Tau protein means that a large amount of Tau protein is phosphorylated and loses the effect of maintaining microtubule stability.
A nuclide refers to an atom having a number of protons and a number of neutrons. Nuclei of the same isotope with different nuclear properties have the same proton number and different neutron number, and have different structural modes, thereby showing different nuclear properties.
Radionuclides, also called unstable nuclides, are referred to as stable nuclides. It refers to an unstable nucleus that spontaneously emits radiation (e.g., alpha, beta, etc.) to decay to form a stable species.
A radionuclide-containing compound means that at least one atom of the compound is a radionuclide.
"substituted" means that 1, 2 or more hydrogen atoms in a molecule are replaced by a different atom or molecule, including 1, 2 or more substitutions on the same or different atoms in the molecule.
The minimum and maximum values of the carbon atom content in the hydrocarbon groups are indicated by the prefix, Ca～bAlkyl means all radicals or molecules containing a to b carbon atoms, where C1～10The alkyl group means all of linear or branched alkyl groups having 1 to 10 carbon atoms.
C1～10The alkoxy group means all straight chain or branched chain alkoxy groups having 1 to 10 carbon atoms.
Isotopically-substituted forms refer to compounds wherein one or more atoms in the compound are replaced by their corresponding isotopes. Such as compounds obtained by replacing one or more hydrogens (H) in the compound with deuterium (D) or tritium (T); such as one or more than two carbons in a compound12Quilt carbon11Or carbon13The compound obtained after replacement.
"saturated heterocycle" refers to a saturated heterocycle, and "unsaturated heterocycle" refers to a heterocycle containing at least one unsaturated bond.
"saturated carbocycle" refers to a saturated cycloalkane. "unsaturated carbocyclic ring" refers to cycloalkanes containing at least one unsaturated bond.
By "pharmaceutically acceptable" is meant that the carrier, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and physiologically compatible with the recipient.
"salts" are acid and/or base salts of a compound or a stereoisomer thereof with inorganic and/or organic acids and/or bases, and also include zwitterionic (inner) salts, as well as quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly in the final isolation and purification of the compounds. The compound, or a stereoisomer thereof, may be obtained by appropriately (e.g., equivalentlymixing) a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
"aryl" refers to all-carbon monocyclic or fused polycyclic groups having a conjugated pi-electron system, such as phenyl and naphthyl. The aryl ring may be fused to other cyclic groups (including saturated and unsaturated rings) but must not contain heteroatoms such as nitrogen, oxygen, or sulfur, while the point of attachment to the parent must be at a carbon atom on the ring with the conjugated pi-electron system. The aryl group may be substituted or unsubstituted.
The "5-to 6-membered aryl group" means an aryl group having 5 to 6 ring-constituting atoms.
"heteroaryl" refers to a monocyclic or fused polycyclic group containing one to more heteroatoms having a conjugated pi-electron system, containing at least one ring heteroatom (e.g., N, O or S), the remaining ring atoms being C, and additionally having a fully conjugated pi-electron system. Heteroaryl groups may be optionally substituted or unsubstituted.
The "5-to 6-membered heteroaryl group" means a heteroaryl group having 5 to 6 ring-constituting atoms.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 shows autoradiographs of brain tissue sections of AD patients with Compound 6 (A, C, E), confirmed by thioflavin-S staining (B, D, F); wherein C and D are enlarged views.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Compounds of general formula 5a and 6a of the present invention were synthesized according to the following synthetic routes:
Figure BDA0002507481810000071
first, specific compounds 5 and 6 of the present invention were prepared according to the following synthetic routes.
Figure BDA0002507481810000072
EXAMPLE 1 Synthesis of Compound 5 of the present invention
(1) Synthesis of compound 3:
Figure BDA0002507481810000081
dissolving compound 1(22.0g, 143.66mmol) and compound 2(10.35g, 143.66mmol) in glacial acetic acid, refluxing for 5 hours, after TLC monitoring reaction is complete, spin-drying solvent, washing with water, EA (ethyl acetate) extracting, drying organic phase with anhydrous sodium sulfate, filtering, concentrating, and then performing silica gel column chromatography to obtain compound 3(23g, yield 85%). MS (ESI) M/z 190.1[ M + H ]]+。
(2) Synthesis of compound 5:
Figure BDA0002507481810000082
dissolving methyltrioctylammonium chloride (Aliquat336, 64mg,0.159mmol) in 5M sodium hydroxide solution, adding compound 3(150.00mg, 0.797mmol), 5-dimethylaminothiophene-2-carbaldehyde (compound 4, 123mg,0.797mmol), refluxing at 110 deg.C, TLC monitoring reaction completion, adjusting pH to 7, washing with water, DCM extracting, collecting organic phase, drying with anhydrous sodium sulfate, filtering, concentrating, and passing through silica gel column layerThis was isolated to give Compound 5(200mg, yield 77%). MS (ESI) M/z 327.10[ M + H ]]+。
Example 2 Synthesis of Compound 6 of the present invention
Figure BDA0002507481810000083
A solution of Compound 5(30mg) and a phase transfer catalyst kryptofix (5mg) in DMF (1.5mL) was added to the solution containing dried [ alpha ], [ solution ] in DMF (1.5mL)18F]Fluoride (in this example, K218F]) And the reaction mixture was heated at 140 deg.c (65W) for 4 minutes. After cooling below 50 ℃, the reaction mixture is washed with H20(1mL), mixed and injected into a semi-preparative HPLC column. The resulting product was purified using a Zorbax Eclipse XDB-C-18 liquid chromatography column and the product was purified at 5 μm, 9.4X 250mm (Agilent) flow rate of 5 mL/min. The mobile phase used is a 50% to 80% acetonitrile solution in 10mM NaH2P04Aqueous solution for 15 minutes. The resulting radioactive fractions were collected, concentrated under reduced pressure, diluted with 0.9% saline solution (3mL) and transferred to a sterile container to give Compound 6, MS (ESI) M/z 298.10[ M + H ]]+。
The final product was then tested for chemical and radiochemical purity using an analytical HPLC system (Waters) on an Onix Monoolithic C-18100X 3.0mm column (Phenomenex) at a flow rate of lmL/min. The mobile phase used was acetonitrile: aqueous solution containing 0.1% trifluoroacetic acid 30: 70, compound 6 has a retention time of 7.4 minutes. The concentration of compound 6 was determined using an ultraviolet detector (254 nm). The product was characterized by co-injecting a sample of compound 5 and the radiochemical purity of compound 6 was determined to be 98.6% using a sodium iodide detector (Bioscan).
Example 3 Synthesis of Compounds 7 to 11 of the present invention
Following the above synthetic route for compound 5a of the general formula, the same procedure as in example 1 was used to synthesize compound 4
Figure BDA0002507481810000091
Is replaced by a corresponding R6The compounds 7-11 of the invention are prepared, and the structure and the representation are shown in table 1.
TABLE 1 Structure and characterization data for Compounds 7-11 of the invention
Figure BDA0002507481810000092
Example 4 Synthesis of Compounds 12 to 16 of the present invention
According to the synthetic route of the compound 6a with the general formula, the compound 5 is replaced by the compounds 7 to 11 by the same method as that in the embodiment 2, so as to prepare the compounds 12 to 16 of the invention, and the structures are shown in the table 2:
TABLE 2 structures of the compounds 12 to 16 of the present invention
Figure BDA0002507481810000093
Figure BDA0002507481810000101
The beneficial effects of the present invention are demonstrated by the following experimental examples.
Experimental example 1 imaging test of Tau protein by the Compound of the present invention
1. Experimental methods
Using autoradiography experiments, each was used separately18The F-labeled compound (i.e., Compound 6 of the present invention) binds to plaques in brain sections of Alzheimer's Disease (AD) patients, and after exposure through a phosphorimager screen, the images are analyzed using a phosphorimager screen storage system. The specific experimental steps are as follows:
(1) pretreating AD human brain tissue slices;
(2) covering the AD human brain tissue section with 20 mu Ci18F labeled compound solution 100 u L, room temperature incubation for 40 minutes;
(3) washing with 20% ethanol solution for 1 min;
(4) after drying, the slices are coated with a preservative film, exposed for 40 minutes under a phosphorus screen, and the images are analyzed by a phosphorus screen storage system.
2. Results of the experiment
The results are shown in FIG. 1. The experimental results show that the compound 5 of the invention is irradiated by radionuclide18After F labeling, obtained18The F-labeled derivative (compound 6) can be used as a tracer of Tau protein in the brain of an AD patient, can be combined with the Tau protein in the brain tissue section of the AD patient in a targeted manner, and has an excellent imaging effect on neurofibrillary tangles in the brain tissue section of the AD patient.
In conclusion, the invention provides a pyridine compound with a novel structure. The pyridine compound is radionuclide18After F labeling, the protein can be used as a Tau protein tracer for identifying neurofibrillary tangles (NFTs) formed by abnormal aggregation of hyperphosphorylated Tau protein in brain, can be used for diagnosing diseases related to the neurofibrillary tangles, can also be used for monitoring the progress of the diseases in the treatment process, provides higher and more accurate diagnosis and tracking for patients or potential patients with the diseases related to the neurofibrillary tangles, and has good application prospect in clinical diagnosis.

Claims (10)

1. A compound represented by formula I, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof:
Figure FDA0002507481800000011
wherein R is1、R2、R3、R4、R5Each independently selected from H, deuterium,18F、19F、123I、125I、127I、-NO2、-OH、-OCD3、-O11CH3、-O11CD3、-NH2、-NHCH3、-NHCD3、-NH11CH3、-NH11CD3、-N(CH3)2、-N(CD3)2、-N(11CH3)2、-N(11CD3)2、-O(CH2)m 18F、-O(CH2)m 19F、
Figure FDA0002507481800000012
Halogen, cyano, carboxyl, C1～10Alkyl radical, C1～10Alkoxy radical, C2～10Alkenyl radical, C2～10Alkynyl, radionuclides; wherein R is selected from-OH,18F、19F and m are integers from 1 to 6;
R6selected from substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, each of said substituents on heteroaryl or aryl being independently selected from: deuterium,18F、19F、123I、125I、127I、-OH、-OCD3、-O11CH3、-O11CD3、-NHCD3、-NH11CH3、-NH11CD3、-N(CD3)2、-N(11CH3)2、-N(11CD3)2、-O(CH2)m 18F、-O(CH2)m 19F、
Figure FDA0002507481800000013
-NRn1Rn2Halogen, cyano, carboxyl, C1～10Alkyl radical, C1～10Alkoxy radical, C2～10Alkenyl radical, C2～10An alkynyl group; wherein R is selected from-OH,18F、19F, m is an integer of 1 to 6, Rn1、Rn2Each independently selected from H, deuterium, halogen, C1～10Alkyl radical, C1～10Alkoxy radical, C2～10Alkenyl radical, C2～10Alkynyl, or Rn1、Rn2Together with the nitrogen atom to which they are both attached form a ring selected from a saturated heterocyclic ring, an unsaturated heterocyclic ring, a saturated carbocyclic ring or an unsaturated carbocyclic ring.
2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof, wherein: the structure of the compound is shown as formula II:
Figure FDA0002507481800000014
wherein R is2Selected from H, deuterium,18F、19F、123I、125I、127I、-NO2、-OH、-OCD3、-O11CH3、-O11CD3、-NH2、-NHCH3、-NHCD3、-NH11CH3、-NH11CD3、-N(CH3)2、-N(CD3)2、-N(11CH3)2、-N(11CD3)2、-O(CH2)18F、-O(CH2)19F. Halogen, cyano, carboxyl, C1～3Alkyl radical, C1～3An alkoxy group;
R6selected from substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered aryl, each of the substituents on the heteroaryl or aryl being independently selected from: -NRn1Rn2Halogen, cyano, carboxyl, C1～8Alkyl radical, C1～8Alkoxy radical, C2～8Alkenyl radical, C2～8Alkynyl, deuterium,18F、19F、123I、125I、127I、-OH、-OCD3、-O11CH3、-O11CD3、-NHCD3、-NH11CH3、-NH11CD3、-N(CD3)2、-N(11CH3)2、-N(11CD3)2、-O(CH2)m 18F、-O(CH2)m 19F、
Figure FDA0002507481800000021
Figure FDA0002507481800000022
Wherein R is selected from-OH,18F、19F, m is an integer of 1 to 6, Rn1、Rn2Each independently selected from H, halogen, C1～5Alkyl radical, C1～5Alkoxy, or Rn1、Rn2And a nitrogen atom which is connected with the heterocyclic ring together forms a ring, and the ring is selected from a 3-8 membered saturated heterocyclic ring, a 3-8 membered unsaturated heterocyclic ring, a 3-8 membered saturated carbocyclic ring and a 3-8 membered unsaturated carbocyclic ring.
3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof, wherein:
R2is selected from-NO2Or18F；
R6Substituted or unsubstituted 5-6 membered heteroaryl, substituted or unsubstituted 5-6 membered aryl, each of the substituents on the heteroaryl or aryl being independently selected from: -NRn1Rn2Halogen, cyano, carboxyl, C1～3Alkyl radical, C1～3Alkoxy, deuterium,18F. -OH; wherein R isn1、Rn2Each independently selected from H, halogen, C1～5Alkyl radical, C1～5Alkoxy, or Rn1、Rn2And a nitrogen atom which is connected with the heterocyclic ring together forms a ring, and the ring is selected from a 3-6-membered saturated heterocyclic ring, a 3-6-membered unsaturated heterocyclic ring, a 3-8-membered saturated carbocyclic ring and a 3-8-membered unsaturated carbocyclic ring.
4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof, wherein: the structure of the compound is shown as a formula III-1 or a formula III-2:
Figure FDA0002507481800000023
wherein R is2Is selected from-NO2Or18F；
M1Is selected from N or CH; m2Selected from S or O;
Rn1、Rn2each independently selected from C1～2Alkyl, or Rn1、Rn2Form a ring together with the nitrogen atom to which they are both attached, said ring being a 5-to 6-membered saturated heterocyclic ring, preferably said ring is
Figure FDA0002507481800000024
Figure FDA0002507481800000025
5. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof, wherein: the compound is selected from the following structures:
Figure FDA0002507481800000031
。
6. the compound according to claim 4, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof, wherein: the compound is selected from the following structures:
Figure FDA0002507481800000032
。
7. a process for the preparation of a compound according to any one of claims 3 to 6, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof, characterized in that: the method comprises the following steps:
(1) reacting compound 1a with compound 2a to give compound 3 a;
(2) reacting compound 3a with compound 4a to give compound 5 a;
alternatively, the method further comprises the steps of: (3) reacting compound 5a with a radionuclide-containing compound to give compound 6 a;
wherein the compound 1a has the structure
Figure FDA0002507481800000041
The compound 2a has the structure
Figure FDA0002507481800000042
The compound 3a has the structure
Figure FDA0002507481800000043
The compound 4a has the structure
Figure FDA0002507481800000044
The compound 5a has the structure
Figure FDA0002507481800000045
The compound 6a has the structure
Figure FDA0002507481800000046
X is a radionuclide; r2、R6As claimed in any one of claims 3 to 6;
preferably, the radionuclide-containing compound is [ 2 ]18F]Fluoride, compound 6a having the structure
Figure FDA0002507481800000047
8. Use of a compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof, for the preparation of a Tau protein tracer, preferably one which is capable of targeting hyperphosphorylated Tau protein.
9. Use of a compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or a hydrate thereof, or a solvate thereof, or a conformational isomer thereof, or a crystalline form thereof, or an isotopically substituted form thereof, for the preparation of a nuclear medicine imaging agent, an optical imaging agent, or a PET imaging agent.
10. Use according to claim 9, characterized in that: the nuclear medicine imaging agent, optical imaging agent or PET imaging agent is capable of diagnosing a disease associated with neurofibrillary tangles; preferably, the neurofibrillary tangles are those formed by abnormal aggregation of hyperphosphorylated Tau protein, more preferably, the disease is selected from the group consisting of alzheimer's disease, frontotemporal dementia, corticobasal degeneration, chronic traumatic encephalopathy, progressive supranuclear palsy, pick's disease, cortico-encephalitis, down's syndrome, parkinson's disease or dementia with lewy bodies.
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