PCSK9 micromolecule autophagy degradation agent as well as preparation method and application thereof

Abstract

The invention provides a PCSK9 micromolecule autophagy degradation agent as well as a preparation method and application thereof. The PCSK9 micromolecule autophagy degradation agent is a tetrahydroisoquinoline compound as shown in a chemical structural general formula I or a pharmaceutically acceptable salt or solvate of the tetrahydroisoquinoline compound. The compounds have the effect of degrading PCSK9 and can be used for preparing drugs for preventing and / or treating diseases related to inhibition of PCSK9 activity.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a PCSK9 small molecule autophagy degrader, its preparation method, and its application. Background Technology

[0002] Proprotein convertase subtilisin 9 (PCSK9) is a serine protease primarily expressed in the liver, discovered in 2003 by Nabil Seidah et al. Under normal physiological conditions, low-density lipoprotein cholesterol (LDL-C) in the blood mainly enters cells by forming a complex with low-density lipoprotein receptors (LDLRs) on the cell surface. The low pH conditions in the endosome cause LDL to separate from its receptors, leading to LDL degradation in lysosomes, while LDLRs cycle back to the cell surface to participate in the next round of LDL-C clearance. PCSK9, by binding to LDLRs, causes LDLRs and LDL-C to degrade simultaneously intracellularly, thereby inhibiting the ability of LDLRs to clear LDL-C from the blood. Generally, inhibiting the production or secretion of PCSK9 can lower blood cholesterol levels, and autophagic degraders of PCSK9 can be used to treat hypercholesterolemia.

[0003] Generally, PCSK9 inhibitors or degraders exhibit good lipid-lowering activity. For example, alirocumab, evolocumab, and tafolecimab, three monoclonal antibodies, and the small interfering RNA inclisiran are four examples of PCSK9 inhibitors already in clinical use for the treatment of cardiovascular and cerebrovascular diseases. According to CN113876955A, WO2022002160A1, WO2021052472A1, CN113332423A, CN113663075A, WO2021243002A1, WO2021207712A1, WO2021154947A1, WO2021143762A1, CN112083163A, WO2020229718A1, CN113412258A, CN111154760A, WO2020252383A1, WO2018057409 Patents such as A1 have disclosed various PCSK9 drugs for the treatment or prevention of cardiovascular and cerebrovascular diseases, hair loss, vitiligo, keratosis, scars, pulmonary fibrosis, metabolic syndrome, obesity, diabetes, Alzheimer's disease, anti-rejection reactions, non-alcoholic hepatitis, and malignant tumors.

[0004] The three currently approved clinical drugs mentioned above—alirocumab, evolocumab, and tafolecimab—are all biologics, which have high treatment costs, inconvenient administration routes, and poor patient compliance. Currently, there are no small-molecule PCSK9 drugs available for clinical use. Therefore, developing small-molecule PCSK9 drugs for the treatment or prevention of cardiovascular and cerebrovascular diseases, alopecia, vitiligo, keratosis disorders, scars, pulmonary fibrosis, metabolic syndrome, obesity, diabetes, Alzheimer's disease, rejection reactions, non-alcoholic hepatitis, and malignant tumors is of great significance.

[0005] Autophagy has long been associated with various aspects of regulating immune responses, including pathogen capture, metabolic regulation, and cellular homeostasis. Current research indicates that autophagy is linked to the development of metabolic diseases, malignancies, immune dysregulation, and neurodegenerative diseases. Macroautophagy (hereinafter referred to as autophagy) is responsible for degrading cytotoxic misfolded proteins, which are recognized and classified by various selective autophagy receptors. P62 / SQSTM1 / Sequestosome_1 is the main selective autophagy receptor that binds to misfolded proteins, causing them to co-aggregate and be delivered to autophagosomes. P62-mediated transport of misfolded proteins to autophagosomes requires the oligomerization capacity of P62. Through oligomerization, P62 not only packages its cargo but also delivers it to the autophagosome formation site for co-degradation. At this point, the unfolded proteins aggregate, reducing their volume and making them more readily degraded via autophagy. The P62 PB1 domain mediates the self-oligomerization of P62. When autophagosomes bind to lysosomes, the unfolded protein-P62 complex delivered to the autophagosomes can be degraded by lysosomal enzymes. Therefore, designing a P62-mediated degradation mechanism holds promise for effectively reducing the content of target proteins. Summary of the Invention

[0006] To address the aforementioned problems, this invention provides a novel small-molecule autophagy degrader of PCSK9, which is a tetrahydroisoquinoline compound or its pharmaceutically acceptable salt or solvate. These compounds degrade PCSK9, reducing PCSK9 levels and hold promise for use in the preparation of drugs for the prevention and / or treatment of diseases related to the inhibition of PCSK9 activity. This invention can be achieved through the following technical means:

[0007] In a first aspect, the present invention provides a PCSK9 small molecule autophagy degrader, which is a tetrahydroisoquinoline compound of general chemical formula I or a pharmaceutically acceptable salt or solvate thereof: in, X is -CH2- or -C(=O)-; that is, X is methylene or carbonyl. R1 is hydrogen or C1-C 20 The alkyl group; preferably, R1 is hydrogen or a C1-C6 alkyl group; Linking group A is selected from: C1-C 20 Alkyl chains, ether chains, oxygen heterochains, sulfur heterochains, nitrogen heterochains, C2-C 20 Alkenyl chain, C2-C 20 Alkyne chain, -C(=O)NH(C1-C 19 Alkyl chains, ether chains, oxygen heterochains, sulfur heterochains, nitrogen heterochains, C2-C 19 alkenyl, C2-C 19 (Alynyl group), or any substituent on linking group A, is linked to R1 and / or any substituent on linking group A is linked to each other to form a linking fragment. Forming connecting segments with single-ring, multi-ring, helical, or bridged ring structures; R2 and R3 are independently hydrogen or R8, R9 and R 10 Independently selected from hydrogen, halogen (e.g., fluorine, chlorine), hydroxyl, nitro, C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy (e.g., methoxy), amino, C1-C3 alkylamino (e.g., methylamino, dimethylamino), carboxyl, cyano, ester, halogen-substituted C1-C3 alkyl (e.g., trifluoromethyl), halogen-substituted C1-C3 alkoxy, halogen-substituted C1-C3 alkylamino; R5 is selected from hydrogen, C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy (e.g., methoxy), halogen, hydroxyl, nitro, amino, C1-C3 alkylamino (e.g., methylamino, dimethylamino), carboxyl, cyano, ester; R6 is selected from hydrogen, C1-C3 alkyl (e.g., methyl, ethyl, isopropyl), C1-C3 alkoxy (e.g., methoxy), halogen, hydroxyl, nitro, amino, C1-C3 alkylamino (e.g., methylamino, dimethylamino), carboxyl, cyano, ester. R7 is an aromatic ring group having 0-3 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl, nitro, amino, C1-C3 alkylamino, carboxyl, cyano, and ester groups, or an aromatic heterocyclic group having 0-3 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl, nitro, amino, C1-C3 alkylamino, carboxyl, cyano, and ester groups and having 0-3 heteroatoms. The heteroatoms include, but are not limited to, N, O, and S.

[0008] Preferably, connecting segments Selected from the following structure: Wherein, A1, A2, and A3 are independently selected from methylene, O, S, and NH; a, b, and c are independently selected from integers between 0 and 5 (preferably integers between 1 and 5, such as 1, 2, 3, 4, and 5); or A1, A2, and A3 are not present. In some embodiments, the connecting fragment... Selected from the following structure: Where n and m are independently selected from integers between 1 and 5, for example 1, 2, 3, 4, 5.

[0009] R7 is selected from

[0010] Preferably, R2 is hydrogen,

[0011] Preferably, R6 is methyl.

[0012] Preferably, the tetrahydroisoquinoline compound of general chemical formula I is selected from the following compounds:

[0013] In a second aspect, the present invention provides a pharmaceutical composition comprising a tetrahydroisoquinoline compound as described above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0014] Thirdly, the present invention provides the use of the tetrahydroisoquinoline compound as described above, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the prevention or treatment of diseases related to the inhibition of PCSK9 activity.

[0015] Preferably, the disease is selected from at least one of cardiovascular and cerebrovascular diseases, alopecia, vitiligo, keratosis disorders, scars, pulmonary fibrosis, metabolic syndrome, obesity, diabetes, Alzheimer's disease, anti-rejection reaction, non-alcoholic hepatitis, and malignant tumors.

[0016] Preferably, the cardiovascular and cerebrovascular diseases are selected from at least one of cholesterol-related diseases, hyperlipidemia, and atherosclerosis; the malignant tumors are selected from at least one of leukemia, prostate cancer, thyroid cancer, liver cancer, ovarian cancer, breast cancer, esophageal cancer, adenocarcinoma, gastric cancer, lung cancer, and colorectal cancer. Attached Figure Description

[0017] Figure 1 The Western blot results of compound I-1 prepared according to embodiments of the present invention are shown. Figure 2The Western blot results of compound I-2 prepared according to embodiments of the present invention are shown; Figure 3 The Western blot results of compound I-3 prepared according to embodiments of the present invention are shown; Figure 4 The Western blot results of compound I-10 prepared according to embodiments of the present invention are shown; Figure 5 The Western blot results of compound I-6 prepared according to embodiments of the present invention are shown; Figure 6 The following are Western blot results of compound I-6 prepared according to embodiments of the present invention with PCSK9 ligand P9 and P62 ligand M4; Figure 7 The qPCR experimental results of compound I-6 prepared according to embodiments of the present invention are shown; Figure 8 The results of the MTT toxicity test of compound I-6 prepared according to embodiments of the present invention are shown. Figure 9 The Western blot results of compound I-6 prepared according to embodiments of the present invention in a high-fat model are shown. Figure 10 The results of Western blot experiments demonstrating the binding ability of compound I-6, prepared according to embodiments of the present invention, to PCSK9 and P62 proteins are shown. Figure 11 The results of Western blotting experiments on compound I-6 prepared according to embodiments of the present invention in autophagy and ubiquitination inhibition models are shown. Detailed Implementation

[0018] The present invention will be further described below with reference to the accompanying drawings and the following embodiments. It should be understood that the drawings and the following embodiments are for illustrative purposes only and are not intended to limit the present invention.

[0019] The following example illustrates the preparation process of the compounds provided by this invention.

[0020] As an example, when X is -C(=O)-, R6 is methyl, and R1 is hydrogen, the synthetic route can be as follows:

[0021] Synthesis of intermediate formula II compounds:

[0022] Synthesis of intermediate III-a compounds:

[0023] The target compound Ia was synthesized using intermediate compound of formula II and compound of formula III-a:

[0024] As an example, when X is -CH2-, R6 is methyl, and R1 is hydrogen, the synthetic route can be as follows:

[0025] Synthesis of intermediate formula II compounds:

[0026] Synthesis of intermediate III-b compounds:

[0027] The target compound Ib was synthesized using intermediate compound II and compound III-b:

[0028] R2, R3, R5, R7 and linking group A are as defined above.

[0029] The above synthesis schemes only illustrate some of the preparation methods of the compounds in this invention. Based on the above synthesis schemes, those skilled in the art can use similar methods to synthesize the compounds of this invention, referring to commonly used techniques and existing technologies in the field.

[0030] The expression "mn" used in this paper refers to the range from m to n, the subrange consisting of the individual point values ​​within it, and the individual point values ​​themselves. For example, the expression "C1-C 20 "or "C 1-20 "Covering a range of 1-20 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, etc., and C1, C2, C3, C4, C5, C6, C7, C8, etc. For example, the expression "C3-C..." 10 "or "C 3-10 "It should also be understood in a similar way, for example, it can encompass any subrange and point value contained within it, such as C3-C9, C6-C9, C6-C8, C..." 6- C7, C7-C 10 C7-C9, C7-C8, C8-C9, etc., as well as C3, C4, C5, C6, C7, C8, C9, C 10 Etc. Other similar expressions in this article should also be understood in a similar manner.

[0031] The terms “halogen” or “halogenated” should be understood to refer to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I) atoms.

[0032] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by single bonds. Alkyl groups can have 1-20 carbon atoms, i.e., C1-C2. 20 Alkyl groups, such as C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 1-6 Alkyl, C 3-6 Alkyl. Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl, or their isomers. A "subunit" is a group obtained by removing a hydrogen atom from a carbon atom containing a free valence electron, having two connection sites for attachment to the rest of the molecule. For example, "alkylene" or "alkyl subunit" refers to a saturated straight-chain or branched divalent hydrocarbon group.

[0033] The term "alkylene," when used alone or in combination with other groups herein, refers to a straight-chain or branched saturated divalent hydrocarbon group. For example, the term "C 1-20 "Alkylene" refers to alkylene groups having 1-20 carbon atoms, such as methylene, ethylene, propylene, butylene, pentylene, hexylene, 1-methylethylene, 2-methylethylene, methylpropylene, or ethylpropylene. The term "cycloalkylene" refers to a cyclic, saturated divalent hydrocarbon group. For example, the term "C..." 3-6 "Cycloalkylene" refers to cycloalkyl subunits having 3-6 carbon atoms, such as cyclopropyl subunits, cyclobutyl subunits, cyclopentyl subunits, cyclohexyl subunits, etc. The term "alkoxy subunit" refers to "-O-alkylene" or "alkylene-O-". "C 1-8 Examples of "alkoxy subunits" include, but are not limited to, -O-methylene, -O-ethylene, -O-propylene, -O-butylene, methylene-O-, ethylene-O-, propylene-O-, butylene-O-, etc.

[0034] The term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, with at least one double bond. Alkenyl groups can have 2-20 carbon atoms, i.e., "C6H ... 2-20 "Alkenyl", for example, C 2-4 alkenyl, C 3-4 Alkenyl. Non-limiting examples of alkenyl include, but are not limited to, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, etc.

[0035] The term "alkynyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, with at least one triple bond. Alkynyl groups can have 2-20 carbon atoms, i.e., "C6H2O". 2-8 "Alkyne group", such as C 2-4 alkynyl group, C 3-4 Alkynyl. Non-limiting examples of alkynyl include, but are not limited to, ethynyl, prop-1-alkynyl, prop-2-alkynyl, but-1-alkynyl, but-2-alkynyl, but-3-alkynyl, etc.

[0036] The term "cyclic hydrocarbon group" refers to a saturated or unsaturated non-aromatic cyclic hydrocarbon group composed of carbon and hydrogen atoms, preferably containing one or two rings. The cyclic hydrocarbon group can be a monocyclic, fused polycyclic, bridged, or spirocyclic structure. The cyclic hydrocarbon group can have 3-10 carbon atoms, i.e., "C 3-10 "Cyclic hydrocarbon group", such as C 3-8 Cyclic hydrocarbon group, C 3-6 Cyclic hydrocarbon group, C5 cyclic hydrocarbon group, C6 cyclic hydrocarbon group, C7 cyclic hydrocarbon group. Non-limiting examples of cyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclic [2.2.1]heptyl and spiro[3.3]heptyl. The term also covers cases where the C atom can be substituted with an oxygen (=O).

[0037] The term "cycloalkyl" refers to a saturated cycloalkyl group.

[0038] The term "heterocyclic group" or "heterocyclic hydrocarbon group" refers to a monocyclic or bicyclic ring system (ternary to decacyclic, ternary to octagonal, ternary to heptary, quaternary to hexacyclic) having, for example, 3 to 10 (suitably 3 to 8, more preferably 3 to 7, especially 4 to 6) ring atoms, wherein at least one ring atom (e.g., 1 or 3) is a heteroatom selected from N, O, S, and P, and the remaining ring atoms are C. The ring system can be saturated (or understood as the corresponding "heterocyclic alkyl") or unsaturated (i.e., having one or more double and / or triple bonds within the ring). "Heterocyclic group" or "heterocyclic hydrocarbon group" is not aromatic. The term also covers cases where the C atom can be substituted with an oxo (=O) and / or the S atom on the ring can be substituted with one or two oxo (=O) atoms and / or the P atom on the ring can be substituted with one or two oxo (=O) atoms.

[0039] The heterocyclic group can be, for example, a four-membered ring, such as aza-butyl or oxa-butyl; or a five-membered ring, such as tetrahydrofuranyl, dioxyl, pyrrolyl, imidazoyl, pyrazolyl, pyrrolinyl, oxopyrrolyl, 2-oxoimidazolidin-1-yl; or a six-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazine, 1,1-dioxo-1,2-thiazin-2-yl or trithiaalkyl; or a seven-membered ring, such as diaza-butyl. The heterocyclic group may optionally be benzofused.

[0040] Heterocyclic groups can be bicyclic, without restriction, such as five-membered fused five-membered rings, such as hexahydrocyclopentane[C]pyrrole-2(1H)-yl ring; or five-membered fused six-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazine-2(1H)-yl ring.

[0041] As mentioned above, heterocycles can be unsaturated, meaning they can contain one or more double bonds without limitation. For example, unsaturated heterocycles containing nitrogen atoms can be 1,6-dihydropyrimidine, 1,2-dihydropyrimidine, 1,4-dihydropyrimidine, 1,6-dihydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridine, 2,3-dihydro-IH-pyrrole, 3,4-dihydro-IH-pyrrole, 2,5-dihydro-IH-pyrroleyl, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl rings. Unsaturated heterocycles containing oxygen atoms can be 2H-pyran, 4H-pyran, or 2,3-dihydrofuran. Unsaturated heterocycles containing sulfur atoms can be 2H-thiaran or 4H-thiaran. Heterocycles can be benzofused without limitation, such as dihydroisoquinoline rings.

[0042] The term "hydrocarbon chain" refers to a chain-like group composed of carbon and hydrogen atoms, which can be straight or branched. The hydrocarbon chain can be saturated (i.e., alkylene) or unsaturated, meaning it can contain one or more carbon-carbon double or triple bonds. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2-), 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and 1,7-heptene (-CH2CH2CH2CH2CH2CH2-).

[0043] The "compound" described in this invention includes all stereoisomers, geometric isomers, tautomers, and isotopes.

[0044] The "compound" described in this invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all isomers include, such as enantiomers and diastereomers. Compounds containing asymmetric carbon atoms in this invention may be isolated in optically active pure form or in racemic form; the optically active pure form may be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0045] The "compound" described in this invention also includes geometric isomers; the geometric isomers may exist as mixtures or as separate E or Z structural forms.

[0046] The "compound" described in this invention also includes tautomer forms; the tautomer forms originate from the exchange of a single bond with an adjacent double bond and are accompanied by the migration of a proton.

[0047] The "compound" described in this invention also includes atoms of all isotopes, whether intermediates or final compounds; isotopic atoms include those having the same number of protons but different mass numbers, for example, hydrogen isotopes include deuterium and tritium. If desired, for example for specific therapeutic or diagnostic purposes, the compounds of this invention may incorporate isotopes or radioactive isotopes known in the art, such as... 3 H, 15 O、 13 C or 15 Nitrogen isotopes.

[0048] "Pharmaceutically acceptable salts" refer to salts that are pharmaceutically acceptable in that they retain the pharmacological activity of their parent compound while improving their physicochemical or metabolic properties. These salts include acid addition salts or base addition salts, or mixtures thereof, prepared from pharmaceutically acceptable acids or bases (including organic acids, inorganic acids, organic bases, and inorganic bases). In this invention, suitable inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or similar acids; suitable organic acids include fumaric acid, tartaric acid, lactic acid, acetic acid, citric acid, trifluoromethanesulfonic acid, mandelic acid, salicylic acid, or their analogues.

[0049] The compounds according to the invention can also exist in the form of solvates, such as hydrates (hemihydrates, monohydrates, dihydrates, trihydrates, etc.).

[0050] Dosage

[0051] Generally, the compounds of the present invention can be administered in an effective amount via any acceptable route of administration for other similar uses. For example, the compounds of the present invention can be administered orally, parenterally, transdermally, topically, rectally, intraperitoneally, or intranasally.

[0052] Pharmaceutical Composition

[0053] The present invention also provides a pharmaceutical composition comprising the aforementioned PCSK9 small molecule autophagy degrader and a pharmaceutically acceptable carrier.

[0054] When used as a pharmaceutical, the compounds of the present invention are typically administered in the form of pharmaceutical compositions. These compositions can be prepared using methods well known in the pharmaceutical field, and these compositions contain at least one active compound. The amount of the active ingredient, i.e., the compound of the present invention, in the pharmaceutical composition and unit dosage form can be varied or significantly adjusted depending on the specific application, the activity of the particular compound, and the expected concentration.

[0055] In formulating the compositions provided by this invention, the active ingredient is typically mixed with an excipient (carrier), diluted by the excipient, or encapsulated in a container of capsules, sachets, paper, or other forms. When the excipient acts as a diluent, it can be a solid, semi-solid, or liquid substance, serving as a carrier, transporter, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, capsules, elixirs, suspensions, emulsions, solutions, syrups, sprays (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0056] Some typical excipients include lactose, glucose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate, sterile water, syrup, and methylcellulose. Other excipients may include lubricants (such as talc, magnesium stearate, and mineral oil), wetting agents, emulsifiers and suspending agents, preservatives (such as methylparaben and propylparaben), sweeteners, and flavor enhancers. The pharmaceutical compositions of the present invention can achieve rapid, sustained, or delayed release of the active pharmaceutical ingredient after administration to a patient via specific excipient methods, which is a widely used approach in the art.

[0057] The present invention also provides the use of the PCSK9 small molecule autophagy degrader or pharmaceutical composition described herein in the preparation of medicaments for the prevention and / or treatment of diseases related to the inhibition of PCSK9 activity.

[0058] “Treatment” means any treatment of disease in a mammal, including: (1) preventing disease, i.e. causing the symptoms of clinical disease to not develop; (2) suppressing disease, i.e. preventing the development of clinical symptoms; and (3) alleviating disease, i.e. causing the clinical symptoms to subside.

[0059] The disease is selected from at least one of the following: cardiovascular and cerebrovascular diseases, hair loss diseases, vitiligo, keratosis disorders, scars, pulmonary fibrosis, metabolic syndrome, obesity, diabetes, Alzheimer's disease, anti-rejection reaction, non-alcoholic hepatitis, and malignant tumors.

[0060] Preferably, the cardiovascular and cerebrovascular diseases are selected from at least one of cholesterol-related diseases, hyperlipidemia, and atherosclerosis; the malignant tumors are selected from at least one of leukemia, prostate cancer, thyroid cancer, liver cancer, ovarian cancer, breast cancer, esophageal cancer, adenocarcinoma, gastric cancer, lung cancer, and colorectal cancer.

[0061] The present invention will be further described in detail below with reference to specific embodiments. It should also be understood that the following embodiments are only for further illustration of the present invention and should not be construed as limiting the scope of protection of the present invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of the present invention are within the scope of protection of the present invention. The specific process parameters, etc., in the following examples are merely examples within a suitable range; that is, those skilled in the art can make appropriate selections within the appropriate range based on the description herein, and are not intended to be limited to the specific values ​​in the examples below.

[0062] Unless otherwise specified in this invention, the eluent ratio refers to the volume ratio.

[0063] Example 1: Preparation of Compound I-1

[0064] Synthesis of 3-(benzyloxy)-N-(8-((6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)octyl)benzamide

[0065] Step 1: Synthesis of 2-methoxy-4-(2-nitrovinyl)phenol (P1)

[0066] Ammonium acetate (16.95 g, 0.22 mol) and 1,2-benzopyranone (100 g, 0.66 mol) were added to 350 mL of nitromethane and stirred at room temperature until dissolved. The reaction was then stirred at 100 °C for 1 hour. After the reaction was complete, ice water was added and the mixture was filtered. The yellow filter cake was the crude product P1 (96.5 g, 75.0%). 1 H NMR (400MHz, CDCl3) δ8.22–8.09(m,1H),8.08–7.94(m,1H),7.48(s,1H),7.30(d,J=8.0Hz,1H),6.95–6.77(m,1H),3.82(d,J=1.5Hz,3H). ESI-MS calculated for[M+H] + :196.0, found:196.0.

[0067] Step 2: Synthesis of 2-methoxy-4-(2-nitroethyl)phenol (P2)

[0068] P1 (20 g, 0.10 mol) was added to 150 mL of tetrahydrofuran. Then, under ice bath conditions, sodium borohydride (11.35 g, 0.30 mol) was dissolved in 70 mL of tetrahydrofuran and 100 mL of ethanol. This sodium borohydride solution was then added dropwise to the P1 solution, and the reaction was stirred at 25 °C for 1 hour. The solution was purified by rotary evaporation (petroleum ether:ethyl acetate = 5:1) to give a pale yellow oily compound P2 (9.9 g, 48.9%). ESI-MS calculated for [MH] - :196.0, found:195.9.

[0069] Step 3: Synthesis of 4-(2-aminoethyl)-2-methoxyphenol (P3)

[0070] P2 (5 g, 0.025 mol) was added to 25 mL of anhydrous tetrahydrofuran and stirred until dissolved. Then, 60 mL of lithium aluminum hydride (1 M) was diluted in 50 mL of anhydrous THF. Under ice bath conditions, P2 was added dropwise to the lithium aluminum hydride solution, and the reaction was carried out at 60 °C for 4 hours. The reaction was monitored, and after completion, ice water was slowly added dropwise to the reaction mixture under ice bath conditions. The reaction solution was then filtered, and the filter cake was the crude product P3. ESI-MS calculations for [M+H]... + :168.1, found:168.1.

[0071] Step 4: Synthesis of (E)-3-((4-hydroxy-3-methoxyphenethyl)amino)but-2-enoic acid ethyl ester (P4)

[0072] P3 (5 g, 0.03 mol), ethyl acetoacetate (3.9 g, 0.03 mol), and sodium sulfate were added to anhydrous tetrahydrofuran (50 mL). The reaction was carried out at room temperature for 16 hours. After the reaction was completed, the mixture was filtered and the filter cake was washed with methanol. The solution was evaporated to dryness and purified (petroleum ether:ethyl acetate = 5:1) to give P4 (2.71 g, 32.3%). ESI-MS was calculated for [M+H]. + :280.1, found:280.0.

[0073] Step 5: Synthesis of ethyl 2-(7-hydroxy-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)acetate (P5)

[0074] A mixture of P2O5 (12.38 g, 87.21 mmol) and phosphoric acid (15.19 g, 155 mmol) was added to P4 (2.71 g, 9.69 mmol). The mixture was heated to 120 °C and stirred for 1 hour. After the reaction was complete, the mixture was cooled to 30 °C, adjusted to pH 9-10 with 25% ammonia, and extracted with dichloromethane. The solution was evaporated to dryness to obtain intermediate P5, which was a brownish-yellow oil. ESI-MS calculated for [M+H]+: 280.2, found: 280.2.

[0075] Step 6: Synthesis of 1-(2-ethoxy-2-oxoethyl)-7-hydroxy-6-methoxy-1-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (P6)

[0076] P5 (5.5 g, 19.64 mmol) and (Boc)₂O (4.23 g, 19.64 mmol) were dissolved in DCM (60 mL), followed by the addition of DIPEA (5.08 g, 39.28 mmol). The reaction was carried out at room temperature for 16 hours. After the reaction was completed by TLC monitoring, the reaction solution was evaporated to dryness and purified (petroleum ether: ethyl acetate = 5:1) to give a yellow oily substance P6 (4.95 g, 66.3%). ESI-MS was calculated for [M+H]. + :380.2, found:379.9.

[0077] Step 7: Synthesis of 2-(2-(tert-butoxycarbonyl)-7-hydroxy-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)acetic acid (P7)

[0078] P6 (10 g, 26 mmol) and 1 N lithium hydroxide aqueous solution (66 ml, 1 N) were added to THF (90 ml). The mixture was heated to 90 °C and stirred for 16 hours. After the reaction was complete, the pH was adjusted to 5 with dilute hydrochloric acid. The solution was extracted with EA and then evaporated to dryness to obtain brown solid P7 (8.07 g, 88.2%). 1 H NMR (400MHz, CDCl3) δ6.57(m,1H),6.28(m,1H),3.81(d,J=15.2Hz,1H),3.62(d,J=14.5Hz,4H),3.2 5(s,1H),2.69–2.50(m,2H),2.38(d,J=15.1Hz,1H),1.43(d,J=14.6Hz,3H),1.26(d,J=14.4Hz,8H). ESI-MS calculated for[MH] - :350.2, found:349.8.

[0079] Step 8: Synthesis of tert-butyl 7-hydroxy-6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0080] P7 (8.07 g, 22.9 mmol), HATU (17.42 g, 45.8 mmol), and DIPEA (5.95 g, 45.8 mmol) were dissolved in 120 mL of N-methylpyrrolidone and stirred at room temperature for 0.5 h. Then, 2-aminothiazole (2.75 g, 27.48 mmol) was added. After complete dissolution at room temperature, the mixture was heated at 80 °C overnight. The reaction was monitored by LC-MS until completion. Excess ammonia was neutralized with dilute hydrochloric acid, followed by extraction and purification (petroleum ether: ethyl acetate = 7:3) to obtain P8 (7.49 g, 75.5%). ESI-MS calculated for [M+H] + :434.2, found:433.9.

[0081] Step 9: Synthesis of 3-(benzyloxy)benzoyl chloride (M4-Cl)

[0082] Under nitrogen protection and in an ice bath, oxalyl chloride (4.45 g, 35.1 mmol) was added dropwise to anhydrous DCM (10 mL) solution containing 3-(benzyloxy)benzoic acid (1 g, 4.4 mmol). After the addition was complete, one drop of DMF was added, and the reaction was carried out at room temperature for 0.5 hours. After the reaction was complete, the reaction solution was evaporated to dryness to obtain the crude product acyl chloride, which was not purified and directly proceeded to the next reaction.

[0083] Step 10: Synthesis of 8-(3-(benzyloxy)benzamido)octyl methanesulfonate (L1-S)

[0084] Under nitrogen protection and an ice bath, the above-mentioned acyl chloride was added dropwise to a DCM (10 mL) solution containing Et3N (590 mg, 5.8 mmol) and 8-amino-1-octanol (420 mg, 2.9 mmol), and the reaction was carried out at room temperature for 0.5 hours. After the reaction was complete, the solution was evaporated to dryness to obtain a pale yellow oil. Methanesulfonyl chloride (660 mg, 5.8 mmol) was added dropwise to a DCM (12 mL) solution containing Et3N (590 mg, 5.8 mmol) and the above oil, and the reaction was carried out at room temperature for 0.5 hours. After the reaction was complete, the solution was evaporated to dryness to obtain a yellow crude product. The crude product was purified by silica gel column chromatography (PE:EA = 1:3) to obtain L1-S 564 mg, with a yield of 45.1%.

[0085] Step 11: Synthesis of 7-((8-(3-(benzyloxy)benzamido)octyl)oxy)-6-methoxy-1-methyl-1-(2-oxo-2-(thiazolyl-2-ylamino)ethyl)-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester (L1-P8)

[0086] Under nitrogen protection and at room temperature, P8 (200 mg, 0.46 mmol) was dissolved in anhydrous DMF (5 mL), and Cs₂CO₃ (300 mg, 0.92 mmol) was added. After reacting for 0.5 hours, L₁-S (239 mg, 0.55 mmol) was added, and the mixture was transferred to an oil bath at 60 °C and reacted for 2 hours. After the reaction was complete, the reaction was quenched with ice water, the reaction solution was extracted with EA, and evaporated to dryness to obtain a pale yellow oily crude product. ESI-MS calculated for [M+H] + :771.3, found:771.3.

[0087] Step 12: Synthesis of 3-(benzyloxy)-N-(8-((6-methoxy-1-methyl-1-(2-oxo-2-(thiazo-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)octyl)benzamide (I-1)

[0088] L1-P8 (150 mg, 0.19 mmol) was dissolved in DCM (2 mL), and TFA (216 mg, 1.90 mmol) was added. The mixture was reacted at room temperature for 0.5 hours. The reaction mixture was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 20:1) to obtain the target product I-1 101 mg, with a yield of 78%. 1 H NMR (400MHz, CDCl3) δ7.45-7.27(m,9H),7.08(d,J=7.4Hz,1H),6.89(d,J=3.4Hz,1H),6 .64(s,1H),6.52(s,1H),6.18(s,1H),5.10(s,2H),3.96(s,2H),3.80(s,3H),3.47(d,J =14.6Hz,2H),3.30(d,J=13.2Hz,1H),3.16(s,1H),3.00(m,1H),2.85(d,J=16.4Hz,1H) ,2.76-2.53(m,2H),1.81(d,J=9.5Hz,2H),1.61(s,2H),1.54(s,3H),1.41-1.34(m,8H). 13C NMR (151MHz, CDCl3) δ166.26,157.92,136.45,135.60,135.58,135.30,128.53,127.58,127.05,126.5 3,126.51,118.04,118.01,117.98,117.18,117.16,117.13,112.33,112.07,111.09,111.06,69.11,6 9.09,69.07,68.35,68.28,63.44,59.37,54.85,54.82,54.80,53.79,53.54,45.61,44.85,39.12,39. 09,39.07,39.04,37.78,37.37,28.61,28.57,28.23,28.16,27.51,25.89,25.87,24.94,24.79,24.77. ESI-MScalculated for[M+H] + :671.3,found:671.3.

[0089] Example 2: Preparation of compound I-2

[0090] Synthesis of 3-(benzyloxy)-N-(8-((6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)octyl)benzamide (I-2)

[0091] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3,4-bis(benzyloxy)benzoic acid and 8-amino-1-octanol. The target product I-2 was purified by column chromatography (DCM:MeOH = 20:1) to obtain 42 mg of the target product I-2, with an overall yield of 8% for the multi-step reaction. 1HNMR(600MHz, CDCl3-d)δ7.49(d,J=2.1Hz,1H),7.47-7.40(m,5H),7.36(td,J=7.2,1.0Hz,4H),7.33-7.28(m,2H),7.23(dd, J=8.4,2.1Hz,1H),6.92-6.86(m,2H),6.52(s,1H),6.07(t,J=5.7Hz,1H),5.19(d,J=2.8Hz,4H),3.96(td,J=6.9,3.8Hz,2H), 3.80(s,3H),3.41(td,J=7.2,5.8Hz,2H),3.30(dt,J=13.1,5.3Hz,1H),3.18(td,J=8.0,3.9Hz,1H),3.02(d,J=16.1Hz,1H),2 .86(dt,J=16.2,5.3Hz,1H),2.77-2.63(m,2H),1.81(p,J=7.0Hz,2H),1.58(q,J=6.8Hz,2H),1.55(s,3H),1.48-1.33(m,8H). 13 C NMR (151MHz, CDCl3) δ165.95,150.45,147.74,147.38,146.32,135.89,13 5.71,127.54,127.50,127.02,126.92,126.90,126.43,126.15,118.89,1 13.02,112.70,112.11,111.02,109.48,76.21,76.00,75.79,70.26,69.9 8,68.30,54.88,39.07,37.31,28.68,28.62,28.14,28.04,25.84,24.77. ESI-MS calculated for [M+H] + :777.4,found:777.4.

[0092] Example 3: Preparation of compound I-3

[0093] Synthesis of 3-((4-fluorobenzyl)oxy)-N-(2-(2-((6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)ethoxy)ethoxy)ethyl)benzamide (I-3)

[0094] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3-((4-fluorobenzyl)oxy)benzoic acid and 2-(2-(2-aminoethoxy)ethoxy)-1-ethanol. The target product I-320 mg was purified by column chromatography (DCM:MeOH = 15:1), with an overall yield of 12%. 1 H NMR (400MHz, CDCl3) δ7.49 (d, J = 2.2Hz, 1H), 7.43-7.29 (m, 5H), 7.22 (t, J = 7.9Hz, 1H), 7. 09-6.98(m,3H),6.86(dt,J=3.6,0.7Hz,1H),6.69(s,1H),6.47(s,1H),5.01(s,2H),3.8 2(dd,J=6.0,3.7Hz,2H),3.75-3.56(m,13H),3.26(dt,J=11.8,5.5Hz,1H),3.16(ddd,J= 12.6,7.2,4.9Hz,1H),2.98(m,1H),2.85(m,5.7Hz,1H),2.75-2.58(m,2H),1.50(s,3H). 13 C NMR (151MHz, CDCl3) δ167.68,166.31,162.30,160.67,157.67,156.93,147.32,14 5.76,136.45,135.15,131.46,131.44,130.99,128.44,128.40,128.34,126.20,1 18.41,117.36,114.53,114.39,112.37,112.08,111.07,110.62,69.67,69.23,68 .91,68.71,68.37,67.90,59.38,54.65,53.68,45.68,38.91,37.37,28.38,28.24. ESI-MS calculated for[M+H] + :693.3,found:693.3.

[0095] Example 4: Preparation of compound I-4

[0096] Synthesis of 3-(benzyloxy)-N-(4-((6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)butyl)benzamide (I-4)

[0097] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3-(benzyloxy)benzoic acid and 4-amino-1-butanol. The target product I-4 was purified by column chromatography (DCM:MeOH = 20:1) to obtain 15 mg of the target product, with an overall yield of 7%. 1 H NMR(600MHz, CDCl3)δ7.49(dd,J=2.6,1.6Hz,1H),7.40-7.33(m,6H),7.31-7.27(m,1H),7.14(t,J=5.9Hz,1H) ,7.06(ddd,J=8.2,2.6,1.0Hz,1H),6.86(d,J=3.6Hz,1H),6.66(s,1H),6.48(s,1H),5.05(s,2H),4.03(td,J=6 .0,4.7Hz,2H),3.65(s,3H),3.59-3.44(m,2H),3.30-3.23(m,1H),3.18(ddd,J=12.7,6.7,4.9Hz,1H),3.00(d, J=15.9Hz,1H),2.88(m,1H),2.73-2.63(m,2H),1.88(q,J=6.1Hz,2H),1.81(m,J=6.9,2.2Hz,2H),1.52(s,3H). 13 C NMR (151MHz, CDCl3) δ167.74,166.40,157.86,156.91,147.12,145.72,136.43,135.66,135.42,130.72,128.43,127.59,127.56,127.01, 126.50,125.67,118.26,117.26,112.25,112.09,110.83,109.45,69 .05,67.97,54.52,53.84,45.85,38.32,37.40,28.32,25.37,25.05. ESI-MS calculated for[M+H] + :615.3,found:615.3.

[0098] Example 5: Preparation of compound I-5

[0099] Synthesis of 3-(benzyloxy)-N-(5-((6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)pentyl)benzamide (I-5)

[0100] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3-(benzyloxy)benzoic acid and 5-amino-1-pentanol. The target product I-5 was purified by column chromatography (DCM:MeOH = 20:1) to obtain 25 mg of the target product, with an overall yield of 18%. 1 H NMR(400MHz, CDCl3)δ7.47(t,J=2.1Hz,1H),7.41-7.26(m,7H),7.09-7.02(m,1H),6.85(d,J=3.6Hz,1H), 6.81(t,J=5.6Hz,1H),6.63(s,1H),6.48(s,1H),5.03(s,2H),3.98(td,J=6.5,3.0Hz,2H),3.72(s,3H),3 .56-3.38(m,2H),3.25(ddd,J=12.0,6.8,4.8Hz,1H),3.19-3.08(m,1H),2.98(d,J=16.0Hz,1H),2.86(dt ,J=16.3,5.8Hz,1H),2.77-2.53(m,2H),1.92-1.75(m,2H),1.67(q,J=7.2Hz,2H),1.51(d,J=14.2Hz,5H). 13 C NMR (151MHz, CDCl3) δ167.78,166.38,157.87,156.88,147.27,145.96,136.46,135.62,135.34,130.73,128.49,127.57,127.03,126.55,12 5.59,118.22,117.16,112.30,112.07,111.07,109.75,69.05,68.08, 54.74,53.73,45.86,38.92,37.40,28.33,28.32,28.08,27.62,22.47. ESI-MS calculated for [M+H] + :629.3,found:629.3.

[0101] Example 6: Preparation of Compound I-6

[0102] Synthesis of 3-(benzyloxy)-N-(2-(2-((6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)ethoxy)ethoxy)ethyl)benzamide (I-6)

[0103] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3-(benzyloxy)benzoic acid and 2-(2-(2-aminoethoxy)ethoxy)-1-ethanol. The target product I-6 was purified by column chromatography (DCM:MeOH = 15:1) to obtain 48 mg of the target product, with an overall yield of 15%. 1 H NMR (400MHz, CDCl3) δ7.49 (dd, J=2.6, 1.6Hz, 1H), 7.43-7.30 (m, 6H), 7.22 (d, J=7.8Hz, 1H), 7.16 (d ,J=5.7Hz,1H),7.03(m,1H),6.86(d,J=3.5Hz,1H),6.70(s,1H),6.48(s,1H),5.05(s,2H),4.10(dd, J=5.6,4.1Hz,2H),3.90-3.77(m,2H),3.76-3.61(m,11H),3.32-3.21(m,1H),3.16(ddd,J=12.7,7. 2,4.9Hz,1H),3.00(d,J=16.0Hz,1H),2.85(dt,J=16.3,5.6Hz,1H),2.74-2.58(m,2H),1.50(s,3H). 13 C NMR (151MHz, CDCl3) δ167.83,157.02,148.01,147.46,147.30,145.79,136.4 3,136.34,136.29,131.19,127.44,127.40,126.73,126.71,126.40,126.35,1 26.26,120.64,114.45,114.09,112.05,111.24,111.17,70.36,70.15,69.64, 69.29,68.74,68.13,54.76,53.79,51.80,46.94,45.55,37.41,28.42,28.28. ESI-MS calculated for[M+H] + :675.3,found:675.3.

[0104] Example 7: Preparation of Compound I-7

[0105] Synthesis of 3-(benzyloxy)-N-(2-(2-(2-((6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)ethoxy)ethoxy)ethyl)benzamide (I-7)

[0106] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3-(benzyloxy)benzoic acid and 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)-1-ethanol. The target product I-715 mg was purified by column chromatography (DCM:MeOH = 10:1), with an overall yield of 6%. 1 H NMR(600MHz, CDCl3)δ7.42(t,J=2.1Hz,1H),7.34–7.26(m,5H),7.24–7.16(m,2H),7.06(t,J=5.3Hz,1H),6 .96(dd,J=8.2,2.6Hz,1H),6.78(d,J=3.5Hz,1H),6.61(s,1H),6.40(s,1H),4.98(s,2H),3.99(t,J=4.9Hz, 2H),3.71–3.67(m,2H),3.65(s,3H),3.57(t,J=10.6Hz,12H),3.17(dt,J=11.8,5.5Hz,1H),3.07(ddd,J=1 2.7,7.4,4.9Hz,1H),2.91(d,J=16.0Hz,1H),2.76(dt,J=11.2,5.7Hz,1H),2.65–2.53(m,2H),1.42(s,3H). ESI-MS calculated for[M+H] + :719.3,found:719.3.

[0107] Example 8: Preparation of compound I-10

[0108] Synthesis of 3-(benzyloxy)-N-((4-(((6-methoxy-1-methyl-1-(2-oxo-2-(thiazol-2-ylamino)ethyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)oxy)methyl)cyclohexyl)methyl)benzamide (I-10)

[0109] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3-(benzyloxy)benzoic acid and (4-(aminomethyl)cyclohexyl)methanol. The target product I-10 was purified by column chromatography (DCM:MeOH = 20:1) to obtain 43 mg of the target product, with an overall yield of 12%. 1H NMR (400MHz, CDCl3) δ7.47-7.29(m,9H),7.09(dt,J=7.4,2.3Hz,1H),6.89(d,J=3.6Hz,1H),6.64(s, 1H),6.52(s,1H),6.24(s,1H),5.10(s,2H),3.79(s,3H),3.76(t,J=5.6Hz,2H),3.32(t,J=6.4Hz,2H) ,3.20(d,J=7.0Hz,1H),3.06(d,J=16.2Hz,1H),2.97(d,J=14.8Hz,1H),2.87(q,J=7.0Hz,1H),2.73(d d,J=16.6,7.1Hz,2H),1.98(d,J=10.1Hz,2H),1.87(d,J=8.1Hz,5H),1.57(s,3H),1.44-1.17(m,1H). 13 C NMR (151MHz, CDCl3) δ166.39,157.97,147.46,146.56,135.57,135.35,128.62,127.62,127.09,126.55,117.93,117.18 ,112.39,112.10,111.23,109.62,73.61,69.17,54.96,45.15,40.96,37.28,37.08,36.53,29.12,29.10,28.25,28.22. ESI-MS calculated for[M+H] + :669.3,found:669.3.

[0110] Example 9: Preparation of compound I-11

[0111] Synthesis of 2-(7-((7-(3-(benzyloxy)benzoyl)-7-azaspiro[3.5]nonane-2-yl)methoxy)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)-N-(thiazolyl-2-yl)acetamide (I-11)

[0112] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3-(benzyloxy)benzoic acid and (7-azaspiro[3.5]nonane-2-yl)methanol. The target product I-11 was purified by column chromatography (DCM:MeOH = 15:1) to obtain 18 mg of product, with a yield of 8%. 1H NMR (400MHz, CDCl3) δ7.47-7.34(m,5H),7.36-7.27(m,2H),7.00(tdd,J=7.6,6.0,1.9Hz,3H),6.89( d,J=3.6Hz,1H),6.66(s,1H),6.53(s,1H),5.09(s,2H),3.80(s,5H),3.36-3.25(m,1H),3.20(ddd,J= 12.5,6.9,4.8Hz,1H),3.03(d,J=16.0Hz,2H),2.89(dt,J=11.3,5.6Hz,2H),2.80-2.59(m,2H),2.34 (t,J=6.6Hz,1H),2.19-2.08(m,2H),1.97(s,1H),1.92-1.77(m,2H),1.77-1.68(m,1H),1.56(s,3H). 13 C NMR (151MHz, CDCl3) δ169.02,167.64,157.73,156.97,147.45,146.07,136.64,136.40,135.64,130.85,128.65,127.60,127.04 ,126.46,125.89,118.22,115.30,112.07,111.29,69.09,54.88,53.73,45.83,40.96,37.39,35.15,28.34,28.32,25.99,23.97. ESI-MS calculated for[M+H] + :641.3,found:641.3.

[0113] Example 10: Preparation of Compound I-12

[0114] Synthesis of 2-(7-((7-(3-(benzyloxy)benzoyl)-7-azaspiro[3.5]nonane-2-yl)methoxy)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)-N-(thiazolyl-2-yl)acetamide (I-12)

[0115] The synthetic route of I-1 in Example 1 was followed. The starting materials were selected from 3-(benzyloxy)benzoic acid and piperidine-4-methanol. The target product I-11 was purified by column chromatography (DCM:MeOH = 15:1) to obtain 33 mg of product, with a yield of 16%. 1H NMR (400MHz, CDCl3) δ7.47-7.35 (m, 5H), 7.31 (tt, J = 7.2, 2.2Hz, 2H), 7.00 (m 3H),6.88(d,J=3.6Hz,1H),6.65(s,1H),6.53(s,1H),5.08(s,2H),3.7 9(s,5H),3.30(ddd,J=11.7,6.5,4.8Hz,1H),3.19(m,1H),3.02(d,J=16 .1Hz,2H),2.89(m,2H),2.78-2.63(m,2H),2.33(t,J=6.6Hz,1H),2.18 -2.07(m,2H),1.96(s,1H),1.86m,2H),1.77-1.69(m,1H),1.55(s,3H). 13 CNMR(151MHz, CDCl3)δ169.00,167.73,157.71,147.49,146.34,136.72,136.28,135.66,128.62,127.61,127.05,126.46,125.54,11 8.22,115.24,112.09,112.07,111.26,110.09,73.06,69.09,54.91,53.80,45.64,37.35,33.66,33.51,28.68,28.25,28.18,26.82. ESI-MS calculated for[M+H] + :681.3,found:681.3.

[0116] Example 11: Preparation of Compound I-8

[0117] Synthesis of 2-(7-((8-((3-(benzyloxy)benzyl)amino)octyl)oxy)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)-N-(thiazolyl-2-yl)acetamide

[0118] Steps 1-8: Synthesize P8 according to steps 1 to 8 in the synthesis route of Example 1 I-1.

[0119] Step 9: Synthesis of 8-((3-(benzyloxy)benzyl)amino)octyl methanesulfonate (L8-S)

[0120] At room temperature, 3-(benzyloxy)benzaldehyde (500 mg, 2.36 mmol) and 8-aminooctane-1-ol (410 mg, 2.83 mmol) were dissolved in methanol (10 mL) and reacted at 25 °C for 5 hours. NaBH3CN (296 mg, 4.72 mmol) was added, and the reaction was continued overnight at 50 °C. After the reaction was complete, the reaction was quenched with ice water. The reaction mixture was extracted with EA and evaporated to dryness to obtain 598 mg of a pale yellow oil. The oil was dissolved in DCM (5 mL), and Boc2O (420 mg, 1.93 mmol) and DIPEA (453 mg, 3.51 mmol) were added. After stirring at room temperature for 3 hours, the mixture was extracted with DCM and evaporated to dryness. Under ice bath conditions, methanesulfonyl chloride (114 mg, 2.04 mmol) was added dropwise to a DCM (5 mL) solution containing the crude product (300 mg) and Et3N (206 mg, 2.04 mmol), and the reaction was carried out at room temperature for 0.5 h. After the reaction was complete, the solution was evaporated to dryness to obtain a yellow oil. The yellow oil was then purified by column chromatography (DCM:MeOH = 25:1) to give L8-S 197 mg, in 16% yield.

[0121] Step 10: Synthesis of 7-((8-((3-(benzyloxy)benzyl)amino)octyl)oxy)-6-methoxy-1-methyl-1-(2-oxo-2-(thiazo-2-ylamino)ethyl)-3,4-dihydroisoquinoline-2(1H)-formate tert-butyl ester (L8-P8)

[0122] Under nitrogen protection and at room temperature, P8 (150 mg, 0.35 mmol) was dissolved in anhydrous DMF (8 mL), and Cs₂CO₃ (225 mg, 0.69 mmol) was added. After reacting for 0.5 hours, L8-S (218 mg, 0.42 mmol) was added, and the reaction was transferred to an oil bath at 60 °C for 2 hours. After the reaction was complete, the reaction was quenched with ice water, and the reaction solution was extracted with EA and evaporated to dryness to obtain a pale yellow oil. Subsequently, L8-P8 was purified by column chromatography (DCM:MeOH = 50:1) to obtain 75 mg of L8-P8, with a yield of 25%. ESI-MS calculated for [M+H] + :857.4, found:858.0.

[0123] Step 11: Synthesis of 2-(7-((8-((3-(benzyloxy)benzyl)amino)octyl)oxy)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)-N-(thiazolyl-2-yl)acetamide (I-8)

[0124] L8-P8 (75 mg, 0.09 mmol) was dissolved in DCM (1 mL), and TFA (102 mg, 0.9 mmol) was added. The mixture was reacted at room temperature for 0.5 hours. The reaction solution was evaporated to dryness to obtain the crude product. The crude product I-838 mg was purified by column chromatography (DCM:MeOH = 10:1), with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ7.46-7.27(m,6H),7.23(d,J=8.0Hz,1H),7.08-7.02(m,1H),6.96(d,J=7. 5Hz,1H),6.92-6.85(m,2H),6.65(s,1H),6.51(s,1H),5.06(s,2H),3.95(td,J=7.0,2.9Hz,2H) ,3.84(s,2H),3.80(s,3H),3.29(dt,J=13.0,5.3Hz,1H),3.21-3.11(m,1H),3.02(d,J=16.1Hz, 1H), 2.84 (dt, J=16.3, 5.2Hz, 1H), 2.75-2.61 (m, 4H), 1.80 (p, J=7.0Hz, 2H), 1.68-1.15 (m, 13H). 13 C NMR (151MHz, CDCl3) δ167.76,158.02,157.03,147.26,146.28,136.40,135.9 7,131.09,128.60,127.53,126.91,126.52,125.23,120.24,120.19,113.93, 113.89,113.16,112.08,111.03,109.53,68.94,68.28,61.87,54.87,53.62, 52.03,47.49,45.53,37.38,28.39,28.20,28.17,28.16,28.09,26.04,24.78. ESI-MS calculated for[M+H] + :657.3,found:657.3.

[0125] Example 12: Preparation of Compound I-9

[0126] Synthesis of 2-(7-(2-(2-((3-(benzyloxy)benzyl)amino)ethoxy)ethoxy)ethoxy)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)-N-(thiazolyl-2-yl)acetamide (I-9)

[0127] The synthetic route was followed as described in Example 11, I-8. The starting materials were selected from 3-(benzyloxy)benzaldehyde and 2-(2-(2-aminoethoxy)ethoxy)-1-ethanol. Purification by column chromatography (DCM:MeOH = 10:1) yielded 35 mg of the target product I-9, with an overall yield of 19%. 1 H NMR (600MHz, CDCl3) δ7.43(d,J=7.1Hz,2H),7.41-7.36(m,3H),7.34-7.30(m,1H),7.22(t,J=7.8Hz,1H),7.02(t ,J=1.9Hz,1H),6.94(d,J=7.5Hz,1H),6.90-6.86(m,2H),6.79(s,1H),6.51(s,1H),5.05(s,2H),4.22-4.10(m,2H ),3.84(dd,J=9.4,4.4Hz,4H),3.77(s,3H),3.72(dd,J=5.5,3.2Hz,2H),3.67(tt,J=6.7,3.4Hz,4H),3.28(ddd, J=12.9,6.4,4.9Hz,1H),3.18(m,1H),3.04(d,J=16.0Hz,1H),2.90-2.82(m,3H),2.78-2.62(m,2H),1.53(s,3H). 13 C NMR (151MHz, CDCl3) δ167.83,158.00,157.04,147.45,145.83,136.40,136.00,131.12,128.55,127.53,126.90,126.52,126.25,120.10,1 13.87,112.97,112.07,111.17,111.10,69.66,69.29,68.92,68.75,6 8.52,68.08,54.77,53.83,52.10,47.09,45.51,37.40,28.38,28.23. ESI-MS calculated for[M+H] + :661.3,found:661.3.

[0128] Example 13: Preparation of Compound I-13

[0129] Synthesis of 2-(7-(2-(2-((3,4-bis(benzyloxy)benzyl)amino)ethoxy)ethoxy)ethoxy)-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)-N-(thiazolyl-2-yl)acetamide (I-13)

[0130] The synthetic route I-8 in Example 11 was followed. The starting materials were selected from 3,4-bis(benzyloxy)benzaldehyde and 2-(2-(2-aminoethoxy)ethoxy)-1-ethanol. The target product I-1 was purified by column chromatography (DCM:MeOH = 10:1) to obtain 355 mg, with an overall yield of 8%. 1 H NMR (600MHz, CDCl3) δ7.46-7.41(m,4H),7.38(d,J=3.5Hz,1H),7.34(ddt,J=7.8,6.3,1.3Hz,4H),7.31-7.27(m,2H),7.0 4(d,J=1.9Hz,1H),6.89-6.83(m,3H),6.79(s,1H),6.49(s,1H),5.14(s,2H),5.12(s,2H),4.15-4.09(m,2H),3.82(t,J= 5.0Hz,2H),3.78(d,J=1.9Hz,2H),3.74(s,3H),3.70(dd,J=6.1,3.6Hz,2H),3.68-3.63(m,4H),3.26(ddd,J=12.9,6.5,4 .8Hz,1H),3.17(ddd,J=12.6,7.2,4.9Hz,1H),3.03(d,J=15.9Hz,1H),2.89-2.78(m,3H),2.75-2.63(m,2H),1.52(s,3H). 13 C NMR (151MHz, CDCl3) δ167.83,157.02,148.01,147.46,147.30,145.79,136.43,136 .34,136.29,131.19,127.44,127.40,126.73,126.71,126.40,126.35,126.26,120 .64,114.45,114.09,112.05,111.24,111.17,76.22,76.01,75.80,70.36,70.15,6 9.64,69.29,68.74,68.13,54.76,53.79,51.80,46.94,45.55,37.41,28.42,28.28. ESI-MS calculated for[M+H] + :767.3473,found:767.3492.

[0131] Cellular level assay to determine the targeted degradation activity of the compound against PCSK9.

[0132] The compounds of this invention were subjected to Western blotting and immunofluorescence assays to determine their targeted degradation ability against PCSK9. This targeted degradation ability was primarily expressed by two indicators: the maximum degree of PCSK9 protein degradation and the optimal degradation concentration of the compound.

[0133] Cell lines and reagents:

[0134] LDLR and P62 antibodies were purchased from Abcam. PCSK9 and LC3B antibodies were purchased from Cell Signaling Technologies. GAPDH antibody was purchased from Bioworld. All other reagents were purchased from Sigma Aldrich.

[0135] Except for palmitic acid solution, all other drug solutions were stored in DMSO or PBS at 1000 times the actual usage concentration.

[0136] Preparation of connector compounds:

[0137] Synthesis of 3-(benzyloxy)-N-methylbenzamide (M4)

[0138] Under nitrogen protection and in an ice bath, M4-Cl (713 mg, 2.9 mmol) was added dropwise to a 10 mL solution of DCM containing Et3N (590 mg, 5.8 mmol) and methylamine (90 mg, 2.9 mmol), and the reaction was carried out at room temperature for 0.5 hours. After the reaction was complete, the product was evaporated to dryness to obtain a pale yellow oil. The crude product was purified by silica gel column chromatography (PE:EA = 3:1) to obtain M4 mg in 68% yield.

[0139] Synthesis of 2-(7-hydroxy-6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1-yl)-N-(thiazolyl-2-yl)acetamide (P9)

[0140] P8 (150 mg, 0.35 mmol) was dissolved in DCM (2 mL), and TFA (200 mg, 1.75 mmol) was added. The mixture was reacted at room temperature for 0.5 hours. The reaction mixture was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (DCM:MeOH = 30:1) to obtain the target product P991 mg, with a yield of 78%.

[0141] Experimental methods:

[0142] HepG2 cells (ATCC) were cultured in high-glucose DMEM medium (Hyclone) supplemented with 10% fetal bovine serum (BI), 1% penicillin, and 1% streptomycin (Sigma) at 37°C in an incubator with 95% air and 5% carbon dioxide by volume.

[0143] When HepG2 cells reach approximately 70% confluence, administer the drug directly or after model establishment. Hyperlipidemic inflammatory cell model establishment: Once HepG2 cells reach a suitable concentration, treat the cells with 500 μM palmitic acid and 1 μg / mL LPS for 24 hours.

[0144] After drug treatment, HepG2 cells were lysed on ice using RIPA (Beyotime) for 30 minutes. The supernatant was collected by high-speed centrifugation, and protein concentration was determined using the BCA (Beyotime) method. After equilibration to the same concentration, 5× Loading Buffer was added, and the mixture was boiled for 5 minutes to prepare a protein loading solution for Western blotting experiments. The Western blotting experiment mainly involved separating proteins by polyacrylamide gel electrophoresis, transferring the protein onto a PVDF membrane, blocking with TBST solution containing 5% skim milk powder for 30 minutes, incubating overnight at 4°C with primary antibody, incubating with secondary antibody at room temperature for 60 minutes, developing with Millipore, and recording using a gel imaging system. In this experiment, the PCSK9 protein band used PCSK9 primary antibody solution and rabbit anti-secondary antibody solution. The GAPDH protein band used GAPDH primary antibody solution and mouse anti-secondary antibody solution. The LDLR protein band used LDLR primary antibody solution and rabbit anti-secondary antibody solution.

[0145] Figures 1-6 The Western blot results of the compounds prepared according to embodiments of the present invention are shown. It can be seen that compounds I-6 can all reduce PCSK9 activity at the protein level in the HepG2 cell line, and exhibit a significant hook effect. However, Western blot experiments co-incubating with the adaptor compounds demonstrate that the adaptor compounds M4 and P9 did not individually reduce the activity of PCSK9 protein. This indicates that the compounds of the present invention have a good degradation effect on PCSK9 protein.

[0146] Table 1 shows the statistical results of Western Blot experimental data for compounds I-1 to I-13 prepared according to embodiments of the present invention. The degradation rate (%) at the optimal concentration = 1 - gray value of the Western Blot experimental band in the administered group / gray value of the control group. The operation of the control group was basically the same as that of the administered group, the only difference being that the concentration of the test compound in the control group was 0 nM. serial number Degradation rate (%, optimal concentration) I-1 <![CDATA[44.99 *** (200nM)]]> I-2 <![CDATA[62.12 *** (5000nM)]]> I-3 <![CDATA[18.19 ns (500nM)]]> I-4 <![CDATA[13.58 ns (500nM)]]> I-5 <![CDATA[12.02 ** (10nM)]]> I-6 <![CDATA[73.33 **** (10nM)]]> I-7 <![CDATA[16.64 ns (10nM)]]> I-8 <![CDATA[8.97 ns (5000nM)]]> I-9 <![CDATA[24.47 ns (200nM)]]> I-10 <![CDATA[38.47 **** (200nM)]]> I-11 <![CDATA[13.51 ns (5000nM)]]> I-12 <![CDATA[1.12 ns (500nM)]]> I-13 31.00**(50nM)

[0147] Real-time quantitative PCR experiments: Primers for real-time quantitative PCR were synthesized by Sangon Inc., TRIZOL was purchased from TAKARA, and all other real-time quantitative PCR reagents were purchased from Yeason. Real-time quantitative PCR results were homogenized according to GAPDH. Primer sequences are as follows: PCSK9: Forward primer, 5'-AGGGGAGGACATCATTGGTG-3' (SEQ ID NO: 1); Reverse primer, 5'-CAGGTTGGGGGTCAGTACC-3' (SEQ ID NO: 2); GAPDH: Forward primer, 5'-ATGGGGAAGGTGAAGGTCG-3' (SEQ ID NO: 3); Reverse primer, 5'-GGGGTCATTGATGGCAACAATA-3' (SEQ ID NO: 4).

[0148] Figure 7 The qPCR results of compound I-6 prepared according to embodiments of the present invention are shown. It can be seen that compound I-6 has no significant effect on PCSK9 mRNA expression levels, but only affects PCSK9 at the protein level.

[0149] MTT toxicity assay: HepG2 cells were treated with the drug for 24 hours, then the culture medium was discarded, 20 μl of MTT was added to each well and incubated for 4 hours. After that, the supernatant was discarded, 150 μl of DMSO was added, and the cells were shaken for 10 minutes before being tested in a microplate reader (absorbance values ​​were 490 nm and 570 nm).

[0150] Figure 8 The results of the MTT toxicity test of compound I-6 prepared according to embodiments of the present invention are shown. It can be seen that compound I-6 has no significant cytotoxicity.

[0151] High-lipid inflammatory cell experiment: HepG2 cells were incubated with 500μM PA & 1μg / mL LPS (PA: palmitic acid; LPS: lipopolysaccharide) for 24 hours to simulate a high-lipid and inflammatory environment. Then, different concentration gradient groups (10nM, 50nM and 100nM) of I-6 were added and co-incubated with HepG2 cells for 24 hours.

[0152] Figure 9The Western blot results of compound I-6, prepared according to embodiments of the present invention, in a hyperlipidemia model are shown. It can be seen that under the hyperlipidemia inflammatory environment simulated by palmitic acid and LPS, PCSK9 levels are elevated. Compound I-6 can reduce PCSK9 levels and increase LDLR, demonstrating the potential of compound I-6 as a treatment for patients with hyperlipidemia.

[0153] Cell heat transfer assay: This assay investigates changes in protein thermostability during ligand binding. Compared to individual proteins, protein-ligand complexes are less likely to unfold and subsequently aggregate with increasing temperature. First, total cellular protein extracted from HepG2 cells was co-incubated with I-6 and DMSO, respectively. After heating the proteins at different temperatures for a period of time, Western blotting was used to analyze the levels of PCSK9 and P62 proteins, establishing the relationship between protein aggregation levels and temperature in different experimental groups.

[0154] Figure 10 The Western blot results show the binding ability of compound I-6, prepared according to embodiments of the present invention, to PCSK9 and P62 proteins. It can be seen that compound I-6 can target both PCSK9 and P62 proteins and has good affinity for both proteins.

[0155] Chloroquine (Chq), a common autophagy inhibitor, alters the pH of lysosomes, preventing autophagosomes from fusing with lysosomes and hindering the degradation of large amounts of LC3-II. Carfilzomib (Car), a commonly used proteasome inhibitor, irreversibly binds to the proteasome to inhibit ubiquitination degradation. This study investigated the effect of changes in autophagy intensity on I-6 degradation activity using both ubiquitination inhibition and autophagy inhibition protocols. HepG2 cells were pre-incubated with chloroquine or carfilzomib for 4 hours to starve them. Subsequently, 10 nM I-6 was added and the cells were co-incubated for 24 hours. Finally, Western blotting was used to analyze and evaluate PCSK9 levels after drug administration.

[0156] Figure 11 Western blotting results of compound I-6, prepared according to embodiments of the present invention, in autophagy and ubiquitination inhibition models are shown. It can be seen that under the autophagy inhibition environment simulated by chloroquine, the degradation effect of compound I-6 on PCSK9 is inhibited; under the ubiquitination inhibition environment simulated by carfilzomib, compound I-6 still exhibits degradation activity against PCSK9. The experimental results indicate that compound I-6 reduces PCSK9 levels via the autophagy pathway.

[0157] The above detailed embodiments further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above are merely one specific embodiment of the present invention and are not limited to the scope of protection of the present invention. The present invention can be embodied in various forms without departing from its essential characteristics. Therefore, the embodiments described herein are for illustrative purposes only and not for limitation. Since the scope of the present invention is defined by the claims rather than the specification, all changes falling within the scope defined by the claims, or their equivalents, should be understood to be included in the claims. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A PCSK9 small molecule autophagy degrader, which is a tetrahydroisoquinoline compound of general chemical formula I or a pharmaceutically acceptable salt or solvate thereof: in, X is either -CH2- or -C(=O)-; R1 is hydrogen or C1-C 20 alkyl; Linking group A is selected from: C1-C 20 Alkyl chains, ether chains, oxygen heterochains, sulfur heterochains, nitrogen heterochains, C2-C 20 Alkenyl chain, C2-C 20 Alkyne chain, -C(=O)NH(C1-C 19 Alkyl chains, ether chains, oxygen heterochains, sulfur heterochains, nitrogen heterochains, C2-C 19 alkenyl, C2-C 19 (Alynyl group), or any substituent on linking group A, is linked to R1 and / or any substituent on linking group A is linked to each other to form a linking fragment. Forming connecting segments with single-ring, multi-ring, helical, or bridged ring structures; R2 and R3 are independently hydrogen or R8, R9 and R 10 Independently selected from hydrogen, halogen, hydroxyl, nitro, C1-C3 alkyl, C1-C3 alkoxy, amino, C1-C3 alkylamino, carboxyl, cyano, ester, halogen-substituted C1-C3 alkyl, halogen-substituted C1-C3 alkoxy, and halogen-substituted C1-C3 alkylamino. R5 is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl, nitro, amino, C1-C3 alkylamino, carboxyl, cyano, and ester. R6 is selected from hydrogen, C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl, nitro, amino, C1-C3 alkylamino, carboxyl, cyano, and ester. R7 is an aromatic ring group having 0-3 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl, nitro, amino, C1-C3 alkylamino, carboxyl, cyano, and ester groups, or an aromatic heterocyclic group having 0-3 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halogen, hydroxyl, nitro, amino, C1-C3 alkylamino, carboxyl, cyano, and ester groups and having 0-3 heteroatoms.

2. The PCSK9 small molecule autophagy degrader according to claim 1, characterized in that, Connecting fragments Selected from the following structure: Wherein, A1, A2, and A3 are independently selected from methylene, O, S, and NH, and a, b, and c are independently selected from integers between 0 and 5; or A1, A2, and A3 do not exist.

3. The PCSK9 small molecule autophagy degrading agent according to claim 1 or 2, characterized in that, R7 is selected from 4. The PCSK9 small molecule autophagy degrading agent according to any one of claims 1 to 3, characterized in that, R2 is hydrogen, or 5. The PCSK9 small molecule autophagy degrading agent according to any one of claims 1 to 4, characterized in that, R6 is a methyl group.

6. The PCSK9 small molecule autophagy degrading agent according to any one of claims 1 to 5, characterized in that, The tetrahydroisoquinoline compounds of general chemical formula I are selected from the following compounds:

7. A pharmaceutical composition, characterized in that, Includes the PCSK9 small molecule autophagy degrader as described in any one of claims 1 to 6 and a pharmaceutically acceptable carrier.

8. The use of the PCSK9 small molecule autophagy degrader according to any one of claims 1 to 6 or the pharmaceutical composition according to claim 7 in the preparation of a medicament for the prevention and / or treatment of diseases related to the inhibition of PCSK9 activity.

9. The application according to claim 8, characterized in that, The disease is selected from at least one of the following: cardiovascular and cerebrovascular diseases, hair loss diseases, vitiligo, keratosis disorders, scars, pulmonary fibrosis, metabolic syndrome, obesity, diabetes, Alzheimer's disease, anti-rejection reaction, non-alcoholic hepatitis, and malignant tumors.

10. The application according to claim 9, characterized in that, The cardiovascular and cerebrovascular diseases are selected from at least one of cholesterol-related diseases, hyperlipidemia, and atherosclerosis; the malignant tumors are selected from at least one of leukemia, prostate cancer, thyroid cancer, liver cancer, ovarian cancer, breast cancer, esophageal cancer, adenocarcinoma, gastric cancer, lung cancer, and colorectal cancer.

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