Cyclic amine derivative, its composition and its use.

Abstract

The present invention relates to a cyclic amine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the cyclic amine derivative or the pharmaceutically acceptable salt thereof, and the use of the cyclic amine derivative or the pharmaceutically acceptable salt thereof or the composition thereof. The cyclic amine derivative of the present invention has a relatively strong capacity of binding to apo(a), can effectively reduce the level of Lp(a), and has low toxic side effects.

Description

/ 47 CYCLIC AMINE DERIVATIVE, ITS COMPOSITION AND USE

[001] This application claims priority to the patent application filed with the China Patent Office on March 24, 2023, under application number 202310301299.3 and application name “A cyclic amine derivative, and composition and use thereof”, the full content of which is incorporated herein by reference. TECHNICAL FIELD

[002] The present invention relates to a cyclic amine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the cyclic amine derivative or the pharmaceutically acceptable salt thereof, and the use of the cyclic amine derivative or the pharmaceutically acceptable salt thereof or the composition thereof. FUNDAMENTALS

[003] Hyperlipidemia is a major risk factor for atherosclerosis and is closely associated with cardiovascular disease, representing a serious threat to human health.

[004] In the human body, blood lipids must combine with apolipoproteins to form lipoproteins in order to be soluble in the blood and transported to the tissues for metabolism.

[005] Lipoproteins include chylomicrons (CM), very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), low-density lipoproteins (LDL), high-density lipoproteins (HDL), and lipoproteins (Lp(a)).

[006] Lp(a) is readily deposited in the vascular wall and can lead to the formation of atherosclerotic lesions through multiple mechanisms; its atherogenic potential is no less than that of LDC-C. In addition, Lp(a) also exhibits prothrombotic properties.

[007] After being synthesized in the liver, Lp(a) is secreted into Petition 870250110916, dated 03 / 12 / 2025, page 7 / 100 / 47 blood circulation and deposited predominantly in vascular tissues and in the leaflets of the aortic valve.

[008] The lipid composition of Lp(a) is similar to that of LDL, the difference being that Lp(a) contains a unique apolipoprotein, apo(a), which is combined with apoB100 by a disulfide bond. Apo(a) is a highly glycosylated hydrophilic protein with structural polymorphism, representing 25% to 40% of the total protein content of Lp(a), which is key to the specific role of Lp(a) in causing atherosclerotic cardiovascular disease (ACVD).

[009] Patent WO2020 / 247429A1 describes a series of pharmaceutically acceptable compounds for reducing plasma levels of Lp(a), which can be used in the preparation of drugs for cardiovascular diseases.

[0010] Although there has been some progress in the development of drugs to treat cardiovascular diseases in this field, more cardiovascular drugs are still needed to meet clinical needs. SUMMARY OF THE INVENTION

[0011] The present invention provides a cyclic amine derivative that exhibits strong binding affinity for apo(a), effectively reduces Lp(a) levels, and exhibits low toxicity and side effects.

[0012] Specifically, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof: in which, Petition 870250110916, dated 03 / 12 / 2025, p. 8 / 100 / 47 R is selected from aryl or heteroaryl, which may be further substituted; R1, R2, R3 and R4 are each independently selected from H and alkyl, the alkyl may be further substituted; x is 1 or 2, preferably 1; y is either 0 or 1.

[0013] In some embodiments, R is selected from aryl C6-C20, preferably aryl C6-C14, more preferably aryl C6-C12, which may be additionally substituted.

[0014] In some embodiments, R1, R2, R3, and R4 are each independently selected from H and C1-6 alkyl.

[0015] In some embodiments, R1, R2, R3, and R4 are each independently selected from H and methyl, preferably H.

[0016] In some embodiments, R is selected from phenyl, benzo[d][1,3]dioxol, tetrahydroquinoline, tetrahydroisoquinoline, pyridine, quinoline, or isoquinoline, which may be further substituted.

[0017] In some modalities, R is selected from the following groups: ,,,,, Petition 870250110916, dated 03 / 12 / 2025, p. 9 / 100 / 47 where n is 0, 1, 2 or 3; R5 is each independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylcarbonylamino, halogen, hydroxyl, nitro, cyano, cycloalkyl, aryl or heteroaryl; preferably alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylcarbonylamino or halogen; R5 can be located in one, two, or three selected positions among the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, and 8th positions of the aforementioned aryl or heteroaryl.

[0018] In some embodiments, R5 is each independently selected from C1-6 alkyl, C3-6 cycloalkyl, C1-6 haloalkyl, OH \ R4 alkoxy C1-6, haloalkoxy C1-6, alkylcarbonylamino C1-6, halogen or ; wherein x, y and R4 are as defined above.

[0019] In some embodiments, R5 is each selected independently from trifluoromethyl, preferably , preferably or ; in which,

[0020] In some modalities, R is selected from the following groups: or

[0021] In the present invention, the carbon in * can be in the R or S configuration, preferably in the R configuration. Petition 870250110916, dated 03 / 12 / 2025, p. 10 / 100 / 47

[0022] In the present invention, the carbon atom that is bonded to the cyclic amine and the carboxyl group can be in the R or S configuration, preferably in the S configuration.

[0023] Specifically, the present invention also provides a compound of formula II or formula III or a pharmaceutically acceptable salt thereof: in what R, R2, R3, R4, x and y are as defined above; R6 is each selected independently from C1-6 alkyl groups; preferably methyl. \

[0024] In the present invention, the carbon in * can be in the R or S configuration, preferably in the R configuration.

[0025] In the present invention, the carbon atom that is bonded to the cyclic amine and the carboxyl group can be in the R or S configuration, preferably in the S configuration.

[0026] Specifically, the present invention also provides a compound of formula IV or a pharmaceutically acceptable salt thereof: Petition 870250110916, dated 03 / 12 / 2025, p. 11 / 100 / 47 in what Y is a trivalent group; the trivalent group is selected from ? ,3 , ^, , > ,\· or^ ; R, R3, R4, x and y are as defined above.

[0027] In some embodiments, the compound of formula IV or its pharmaceutically acceptable salt may be a compound of formula IV-1, formula IV-2, formula IV-3 or formula IV-4, or a pharmaceutically acceptable salt thereof: Petition 870250110916, dated 03 / 12 / 2025, p. 12 / 100 / 47 or R, R3, R4, x and y are as defined above. (^i. \

[0028] In the present invention, the carbon in * can be in the R or S configuration, preferably in the R configuration.

[0029] In the present invention, the carbon atom bonded to the cyclic amine and the carboxyl group may be in the R or S configuration, preferably in the S configuration.

[0030] In some embodiments, the compound of the present invention is selected from: Petition 870250110916, dated 03 / 12 / 2025, p. 13 / 100 / 47

[0031] The present invention also relates to a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the pharmaceutical composition optionally includes a pharmaceutically acceptable excipient.

[0033] The present invention also relates to a method for treating cardiovascular diseases, comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to a patient.

[0034] The present invention also relates to a method for treating a patient requiring treatment for elevated plasma levels of Lp(a), comprising administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof to Petition 870250110916, dated 03 / 12 / 2025, p. 14 / 100 / 47 patients.

[0035] The present invention also relates to a method for inhibiting the clustering of LDL particles with apo(a), comprising linking the compound of the present invention or a pharmaceutically acceptable salt thereof to apo(a).

[0036] The present invention also relates to the compound of the present invention, or to a pharmaceutically acceptable salt thereof, or to the aforementioned composition, for use in the preparation of a binder for apo(a).

[0037] In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or the aforementioned composition, is used to prepare an inhibitor of LDL particle clustering with apo(a).

[0038] In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or the aforementioned composition, is used to prepare an agent to reduce Lp(a) levels.

[0039] In some embodiments, the compound of the present invention, or a pharmaceutically acceptable salt thereof, or the aforementioned composition, is used to prepare a drug for cardiovascular treatment. DETAILED DESCRIPTION OF THE INVENTION

[0040] Before describing the present invention in more detail, it should be understood that it is not limited to the embodiments described, and may, of course, vary.

[0041] It should also be understood that the terminology used in this document is intended to describe embodiments only and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0042] Unless otherwise indicated, all technical terms and Petition 870250110916, dated 03 / 12 / 2025, p. 15 / 100 / 47 The scientific terms used in this document have the same meaning as is commonly understood by those skilled in the art to which this invention pertains.

[0043] All patents, applications, published applications and other publications mentioned in this document are incorporated by reference in their entirety.

[0044] If the definition in this section is contrary to or inconsistent with the definition in patents, applications, or other publications incorporated herein by reference, the definition in this section shall prevail over the definition incorporated herein by reference.

[0045] In the present invention, “alkyl” refers to a saturated aliphatic hydrocarbon group, which may be a C1-20 alkyl group, preferably a C1-8 alkyl group, more preferably a C1-6 alkyl group, and most preferably a C1-3 alkyl group.

[0046] Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, nheptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched isomers thereof, etc.,

[0047] In the present invention, “haloalkyl” refers to a group Petition 870250110916, dated 03 / 12 / 2025, p. 16 / 100 / 47 alkyl substituted by one or more (preferably 1, 2, 3, 4, 5 or 6) halogen atoms, wherein the alkyl group is as defined above, which may be a C1-20 haloalkyl group, preferably a C1-8 haloalkyl group, more preferably a C1-6 haloalkyl group, and most preferably a C1-3 haloalkyl group.

[0048] Non-limiting examples include trifluoromethyl, monofluoromethyl, difluoromethyl, trichloromethyl, pentafluoroethyl, etc.

[0049] In the present invention, “alkoxy” refers to alkyl-O-, wherein the alkyl is as defined above.

[0050] In the present invention, “haloalkoxy” refers to haloalkyl-O-, wherein haloalkyl is as defined above.

[0051] In the present invention, “alkylamino” refers to alkyl-NH-, wherein the alkyl is as defined above.

[0052] In the present invention, “alkylcarbonylamino” refers to alkylC(O)-NH-, wherein the alkyl group is as defined above.

[0053] In the present invention, "halogen" refers to fluorine, chlorine, bromine or iodine.

[0054] In the present invention, “cycloalkyl” refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, and more preferably from 3 to 6 carbon atoms.

[0055] Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.

[0056] In the present invention, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylcarbonylamino, cycloalkyl, etc., may be substituted or unsubstituted and, when substituted, the substituent may be substituted at any accessible point of attachment. The substituent is Petition 870250110916, dated 03 / 12 / 2025, p. 17 / 100 / 47 preferably one or more of the following groups, independently selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, alkylcarbonylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0057] In the present invention, “aryl” refers to an optionally substituted fused monocyclic, biaryl, bicyclic or polycyclic ring system, which has the well-known characteristics of aromaticity, wherein at least one ring contains a fully conjugated π-electron system.

[0058] Typically, aryl groups contain 6 to 20 carbon atoms (“aryl C6-C20”) as ring members, preferably 6 to 14 carbon atoms (“aryl C6-C14”), or more preferably 6 to 12 carbon atoms (“aryl C6-C12”).

[0059] Fused aryl groups may include an aryl ring (e.g., a phenyl ring) fused to another aryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring.

[0060] The point of attachment to the base molecule in these fused aryl ring systems can be a C atom of the aromatic portion or a C or N atom of the non-aromatic portion of the ring system.

[0061] Examples, without limitation, of aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, benzo[d][1,3]dioxol and tetrahydronaphthyl.

[0062] In the present invention, “heteroaryl” refers to fused monocyclic, heterobiaryl, bicyclic, or polycyclic ring systems possessing the well-known characteristics of aromaticity, containing the specified number of ring atoms, and including at least one heteroatom selected from N, O, and S as a ring member in a Petition 870250110916, dated 03 / 12 / 2025, page 18 / 100 / 47 aromatic ring.

[0063] The inclusion of a heteroatom allows aromaticity in 5-membered rings as well as in 6-membered rings.

[0064] Typically, heteroaryl groups contain 5 to 20 atoms in the ring (“5 to 20 membered heteroaryl”), preferably 5 to 14 atoms in the ring (“5 to 14 membered heteroaryl”), and most preferably 5 to 12 atoms in the ring (“5 to 12 membered heteroaryl”).

[0065] The heteroaryl rings are linked to the base molecule by an atom from the heteroaromatic ring, so that aromaticity is maintained.

[0066] Thus, 6-membered heteroaryl rings can be linked to the base molecule via a C atom of the ring, while 5-membered heteroaryl rings can be linked to the base molecule via a C or N atom of the ring.

[0067] Examples of unsubstituted heteroaryl groups often include, but are not limited to, pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, triazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, indole, benzimidazole, indazole, quinoline, isoquinoline, purine, triazine, naphthyridine, and carbazole.

[0068] In the present invention, “aryl” or “heteroaryl” may be optionally substituted or unsubstituted; when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, alkylthio, alkylamino, alkylcarbonylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxy or carboxylate.

[0069] In the present invention, “elevated plasma Lp(a) levels” means a plasma Lp(a) level that is equal to or greater than about 50 Petition 870250110916, dated 03 / 12 / 2025, p. 19 / 100 / 47 mg / dL.

[0070] In the present invention, any isotopically labeled derivative of the compound or pharmaceutically acceptable salt thereof described in this document is covered by the present invention.

[0071] Atoms that can be isotopically labeled include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine, etc. They can be separately replaced by the isotopes 2H(D), 3H,nC,13C,14C,15N,18F,31P,32P,35S,36Cl and125I, etc. Unless otherwise indicated, when a position is specifically designated as deuterium (D), that position should be understood as deuterium with an abundance that is at least 3,000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., incorporating at least 45% deuterium).

[0072] In the present invention, “more” means at least two, for example, 2, 3, 4, 5 or 6, etc.

[0073] In the present invention, “optional” or “optionally” means that the event or circumstance described below may occur, but does not necessarily occur, and this description includes cases where the event or circumstance either occurs or does not occur.

[0074] For example, “heterocyclic group that is optionally replaced by an alkyl” means that the alkyl may be present, but not necessarily present, and this description includes the case where the heterocyclic group is replaced by an alkyl and the case where the heterocyclic group is not replaced by an alkyl.

[0075] In the present invention, “each independently” or “independently” means that substituents with the same selection range may be the same or different groups in each occurrence, and the group selection of the substituent in each occurrence is not affected by the selection of the substituent (or substituents with the same selection range) in other occurrences. Petition 870250110916, dated 03 / 12 / 2025, p. 20 / 100 / 47 positions.

[0076] In the present invention, “pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals and exhibits the desired biological activity.

[0077] In the present invention, the following abbreviations / terms are used: Apo(a): apolipoprotein(a) Lp(a): lipoprotein(a) TEA: triethylamine THF: tetrahydrofuran LiHMDS: lithium hexamethyldisylazide PE: petroleum ether EtOAc: ethyl acetate MTBE: methyl tert-butyl ether 2-MeTHF: 2-methyltetrahydrofuran DMAP: 4-dimethylaminopyridine Boc2O: di-tert-butyl carbonate HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate DIEA: N,N-diisopropylethylamine NMP: N-methylpyrrolidone SPR: surface plasmonic resonance EDC: 1-Ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride NHS: N-hydroxysuccinimide NaAc: sodium acetate; RU: response unit; BLI: biolayer interferometry; PBS: phosphate-buffered saline solution Petition 870250110916, dated 03 / 12 / 2025, page 21 / 100 16 / 47 BSA: bovine serum albumin HEC: hydroxyethylcellulose EDTAK2: dipotassium salt of ethylenediaminetetraacetic acid EXAMPLE EXAMPLE 1 Step 1:

[0078] Compound la (53.8 g, 249.94 mmol) was dissolved in THF (300 mL), TEA (63.23 g, 624.855 mmol) was added under ice bath conditions, pivaloyl chloride (37.67 g, 312.43 mmol) was added Petition 870250110916, dated 03 / 12 / 2025, page 22 / 100 / 47 after agitation for 5 minutes under ice bath conditions and agitation for 15 minutes under ice bath conditions.

[0079] LiCl (13.24 g, 312.427 mmol) and (4S)-4-benzyl-1,3-oxazol-2-one (44.29 g, 249.94 mmol) were previously dissolved in THF (400 mL) and stirred until dissolved.

[0080] The LiCl / (4S)-4-benzyl-1,3-oxazol-2-one solution was added to the reaction solution of compound 1a and the mixture was stirred at room temperature for 24 hours.

[0081] The white solid was formed in the reaction solution.

[0082] 1 M HCl was added until the solid disappeared, the organic phase was separated, washed once with 1 M aqueous NaOH solution (350 mL) and then washed once with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to yield a yellow oily product.

[0083] MeOH:H2O (1:2) (600 mL) was added and left in suspension overnight, the suspension was filtered, the filter cake was dried to obtain the white solid 1b (68 g, yield of 72.66%). MS m / z(ESI):319.2[M-56]+. Step 2:

[0084] Compound 1b (11 g, 29.38 mmol) was dissolved in THF (100 mL) and LiHMDS (1 M in hexane, 41.13 mL) was added at -10°C. After holding the temperature for 15 minutes, a solution (25 mL) of m-bromobenzyl bromide (8.08 g, 32.32 mmol) in THF was added and slowly heated to room temperature, reacted overnight.

[0085] Rapidly cooled with saturated ammonium chloride solution (20 mL), water was added and the mixture was extracted twice with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by reversed-phase column chromatography (acetonitrile / water = 30% to 100%) to obtain compound 1c (8 g, yield of 50.11%). Petition 870250110916, dated 03 / 12 / 2025, page 23 / 100 / 47 MS m / z(ESI):487.1[M-56]+. Step 3:

[0086] Compound 1c (8000 mg, 14.72 mmol) was dissolved in THF (100 mL), H2O2 (30% aqueous solution, 25.09 mL, 248 mmol) and an aqueous solution (20 mL) of lithium hydroxide monohydrate (926.51 mg, 22.08 mmol) was added and reacted at room temperature for 2.5 hours.

[0087] An aqueous solution (100 mL) of sodium bisulfite (2.09 g, 29.74 mmol) was added.

[0088] Aqueous 2N NaOH solution was added to adjust the pH to 10 and washed twice with TMBE, 6M HCl was added to the aqueous phase to adjust the pH to 2-3 and extracted three times with TMBE, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by reverse phase preparation (acetonitrile / water = 20% to 100%) to obtain compound 1d (5650 mg, 99.88% yield). MS m / z (ESI):384.1 [MH]-. Step 4:

[0089] Compound 1d (5650 mg, 14.70 mmol) was dissolved in TMBE (100 mL), NH3 / MeOH (7 M) (6 mL) was added, stirred at room temperature overnight and concentrated to obtain a white solid (5900 mg).

[0090] The solid was dissolved in 2-MeTHF (100 mL), O-tert-butylN,N'-diisopropylisourea (11781.18 mg, 58.81 mmol) was added and reacted at 65°C overnight.

[0091] Water was added, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EtOAc / PE = 0 to 20%) to obtain compound 1e (5070 mg, yield of 78.31%) as a colorless oil. MS m / z(ESI):328.1[M-112]+. Petition 870250110916, dated 03 / 12 / 2025, page 24 / 100 / 47 Step 5:

[0092] Compound 1e (5070 mg, 11.51 mmol) was dissolved in THF (50 mL) and Pd(dppf)CUCH2Cl2 (940.18 mg, 1.15 mmol), Cs2CO3 (11253.29 mg, 34.54 mmol) and potassium vinyltrifluoroborate (97% purity, 4626.41 mg, 33.50 mmol) were added.

[0093] After protection with nitrogen, the tube was sealed and reacted at 80°C overnight, water was added, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EtOAc / PE=0 to 20%) to obtain compound 1f (3960 mg, yield of 88.76%) as a colorless oil. MS m / z(ESI):276.1[M-112]+. Step 6:

[0094] Compound 1f (3960 mg, 10.22 mmol) was dissolved in THF (60 mL), an aqueous solution (30 mL) of sodium periodate (4360.37 mg, 20.44 mmol) was added, OsO4 (4% in water, 4 mL) was added and reacted at room temperature overnight.

[0095] The solid was filtered, water was added and extracted with EtOAc, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (EtOAc / PE=0 to 30%) to obtain 1g of compound (1140 mg, yield of 28.64%) as a colorless oil. MS m / z(ESI):234.1[M-156]+. Step 7:

[0096] Compound 1 g (145 mg, 0.37 mmol) and 3-aminomethylpyridine (20 mg, 0.185 mmol) were dissolved in 5 mL of MeOH, acetic acid (11.11 mg, 0.185 mmol) and molecular sieve 4A (20 mg) were added and reacted at room temperature for 3 hours.

[0097] Sodium cyanoborohydride (34.87 mg, 0.555 mmol) was added and stirred at room temperature overnight. Petition 870250110916, dated 03 / 12 / 2025, page 25 / 100 / 47

[0098] Filtered aqueous solution of 2N sodium hydroxide was added to adjust the pH to 8-9, the solvent was removed by rotary evaporation, purified by preparative high-performance liquid chromatography (MeOH / H2O) to obtain compound 1h (19 mg, 12% yield) as a colorless oil. MS m / z(ESI):855.5[M+H]+. Step 8:

[0099] Compound 1h (19.0 mg, 0.022 mmol) was dissolved in HCl / EtOAc (4M, 2 mL) and reacted at room temperature overnight.

[00100] The reaction system was cooled using a dry ice and ethanol bath, purified water (5 mL) was slowly added to the reaction system, the system was further cooled until freezing and then lyophilized directly to obtain the hydrochloride of compound 1 (11.2 mg, 78.1% yield) as a white solid. MS m / z(ESI):543.3[M+H]+. EXAMPLE 2 Step 1:

[00101] Compound 1g (100 mg, 0.26 mmol) was dissolved in methanol (5 mL), 3-aminomethylquinoline (20.33 mg, 0.13 mmol) was added, five pellets of 4A molecular sieve were added, after stirring at room temperature for 1 hour, glacial acetic acid (46.25 mg, 0.77 mmol) and sodium cyanoborohydride (48.4 mg, 0.77 mmol) were added, stirred at room temperature overnight.

[00102] Then, the reaction solution was filtered and purified by Petition 870250110916, dated 03 / 12 / 2025, page 26 / 100 / 47 reverse phase preparation (methanol / water = 80% to 100%) to obtain compound 2a as a white solid. Step 2:

[00103] Compound 2a (70 mg, 0.077 mmol) was dissolved in HCl / EtOAc (4 M, 5 mL) and reacted at 40°C overnight.

[00104] Water (10 mL) was added, washed twice with EtOAc, and the aqueous phase was lyophilized to obtain the hydrochloride of compound 2 (53.29 mg, 98.15%). MS m / z(ESI):593.4[M+H]+. EXAMPLE 3 Step 1:

[00105] Compound 1 g (100 mg, 0.26 mmol) and propylfluoromethylbenzylamine (22.48 mg, 0.13 mmol) were dissolved in 5 mL of MeOH, acetic acid (7.71 mg, 0.13 mmol) and 4A molecular sieves (20 mg) were added and reacted at room temperature for 3 hours.

[00106] Sodium cyanoborohydride (24.2 mg, 0.385 mmol) was added and reacted at room temperature overnight.

[00107] Filtered aqueous solution of 2N sodium hydroxide was added to adjust the pH to 8-9, the solvent was removed by rotary evaporation, purified by preparative high-performance liquid chromatography (methanol / H2O) to obtain compound 3a (35 mg, yield: 29.5%) as a colorless oil. Step 2: Petition 870250110916, dated 03 / 12 / 2025, page 27 / 100 22 / 47

[00108] Compound 3a (35 mg, 0.038 mmol) was dissolved in HCl / EtOAc (4M, 2 mL) and reacted at room temperature overnight.

[00109] The reaction system was cooled using a dry ice and ethanol bath, purified water (5 mL) was slowly added to the reaction system and cooling continued until the system was frozen, then lyophilized directly three times, obtaining the hydrochloride of compound 3 (27 mg, yield: 98.9%) as a white solid. MS m / z(ESI):610.3[M+H]+. EXAMPLE 4 Boc NalO41OsO4 THF / H2O Petition 870250110916, dated 03 / 12 / 2025, page 28 / 100 / 47 Step 1:

[00110] Compound 4a (22.81 g, 105.00 mmol) was dissolved in anhydrous tetrahydrofuran (240 mL) under nitrogen protection and an ice bath, triethylamine (25.30 g, 250.00 mmol) was added and, after stirring for 5 minutes, pivaloyl chloride (15.07 g, 125.00 mmol) was added slowly drop by drop.

[00111] After stirring at 10°C for 30 minutes, anhydrous lithium chloride (5.30 g, 125 mmol) and a solution of compound 4r (17.72 g, 100.00 mmol) in anhydrous tetrahydrofuran (240 mL) were added and returned to room temperature and stirred overnight.

[00112] A 1 M aqueous HCl solution (300 mL) was added to a water bath, after stirring for 1 minute and then left to stand to separate into layers. The upper organic phase was separated and washed with a 1 M aqueous NaOH solution (300 mL), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered and concentrated, purified by silica gel column (A / EtOAc=100 / 0 to 80 / 20, A:PE / DCM=1 / 1) to generate a colorless oily liquid.

[00113] The colorless oily liquid was dissolved in anhydrous tetrahydrofuran (50 mL) and concentrated to obtain compound 4b (26.00 g, 65.7% yield) as a colorless oily liquid. Step 2:

[00114] Compound 4b (26.00 g, 69.07 mmol) was dissolved in DMF (200 mL), triethylamine (20.97 g, 207.20 mmol) and DMAP (0.84 g, 6.91 mmol) were added in a water bath, and Boc2O (22.61 g, 103.60 mmol) was added slowly, sealed with a nitrogen flask, after stirring in Petition 870250110916, dated 03 / 12 / 2025, page 29 / 100 / 47 at room temperature overnight, the reaction was monitored by TLC, which showed the formation of half of the product and leaving the other half of the starting material unreacted.

[00115] Triethylamine (13.97 g, 138.13 mmol) and Boc2O (15.07 g, 40.03 mmol) were added and stirred overnight.

[00116] Dilute with ethyl acetate (600 mL), wash with water (200 mL ^ 3), concentrate and purify by silica gel column (PE / EtOAc=100 / 0 to 84 / 16) to obtain compound 4c (24.00 g, yield of 72.9%) as a light yellow oily liquid, dissolved in anhydrous THF and concentrated twice, the product was used directly in the next step. Step 3:

[00117] Under nitrogen protection, compound 4c (9.70 g, 20.354 mmol) was added to anhydrous THF (80 mL), cooled to approximately -70°C, a LiHMDS / THF solution (1 M, 24.43 mL) was added dropwise, stirred for 1 hour, and a solution (40 mL) of compound 4q (6.10 g, 24.43 mmol) in anhydrous THF was added dropwise, heated to 0°C and stirred for 3 hours. After the reaction was monitored to completion by TLC, a saturated aqueous solution of ammonium chloride (200 mL) was added at 0°C to rapidly cool the reaction. The organic phase was separated and washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and suspended with petroleum ether to obtain a white solid (8.60 g). The filtrate was purified by silica gel column to obtain a white solid (2.00 g), combined with two batches of the compound from product 4d, producing a total of (10.60 g, 80% yield). Step 4:

[00118] Compound 4d (10.20 g, 15.80 mmol) was dissolved in THF (60 mL), hydrogen peroxide (2.687 mL, 23.70 mmol), LiOH (0.99 g, 23.70 mmol) aqueous solution (24 mL) were added to an ice bath and stirred for 3 hours in an ice bath, the reaction was monitored until Petition 870250110916, dated 03 / 12 / 2025, page 30 / 100 / 47 conclusion by TLC.

[00119] A saturated aqueous solution of NaHSO3 (5 mL) was added dropwise in an ice bath, returned to room temperature and stirred for 5 minutes, and the pH was adjusted to 2-3 using 1M HCl, extracted with ethyl acetate (100 mL x 2), washed with saturated aqueous sodium chloride solution, concentrated, reversed (water / acetonitrile, 62% peak), concentrated, extracted with ethyl acetate (100 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 4e (6.00 g, 78% yield) as a colorless oily liquid. Step 5:

[00120] Compound 4e (6.00 g, 12.34 mmol) was dissolved in 2-methyltetrahydrofuran (50 mL), triethylamine (2.50 g, 24.67 mmol) was added, after stirring at room temperature for 5 minutes, O-tert-butyl-N,N'-diisopropylisourea (8.65 g, 43.17 mmol) was added, stirred at 65°C overnight under the protection of a nitrogen flask and cooled to room temperature, filtered and the filtrate was concentrated, purified by silica gel column (PE / EtOAc = 10 / 1) to obtain compound 4f (5.80 g, yield of 86.67%) as a colorless oily liquid. Step 6:

[00121] Compound 4f (5.80 g, 10.69 mmol) was dissolved in a dioxane / water mixture (30 / 10 mL) and potassium vinyl trifluoroborate (4.30 g, 32.07 mmol), CS2CO3 (10.45 g, 32.07 mmol) and Pd(dppf)CUCH2Cl2 (0.44 g, 0.535 mmol) were added in a water bath.

[00122] The system was replaced with argon three times, stirred at 90°C overnight under argon protection, cooled, concentrated to remove most of the dioxane by rotary evaporation, diluted with ethyl acetate (100 mL), washed with water (50 mL), concentrated and purified by silica gel column (PE / EtOAc=5 / 1) to obtain the compound 4g (4.80 g, 91.67% yield) as a colorless oily liquid. Petition 870250110916, dated 03 / 12 / 2025, page 31 / 100 / 47 Step 7:

[00123] Compound 4g (4.80 g, 9.80 mmol) was dissolved in a THF / water mixture (60 / 30 mL), and aqueous OsO4 solution (0.98 mmol, 6.24 mL) was added in a water bath, after stirring for 15 minutes, sodium periodate (6.29 g, 29.41 mmol) was added in a water bath and stirred at 35°C overnight.

[00124] The reaction was monitored to completion by TLC, a saturated aqueous solution of sodium thiosulfate (50 mL) was added in a water bath, after stirring for 5 minutes, concentrated to remove most of the THF and diluted with ethyl acetate (150 mL), washed with water (50 mL x 2), concentrated and purified by silica gel column (PE / EtOAc=100 / 0~86 / 14) to obtain compound 4h (3.6 g, 75% yield) as a colorless oily liquid. Step 8:

[00125] Compound 4h (100 mg, 0.20 mmol) was dissolved in methanol (10 mL), p-trifluoromethylbenzylamine (35.63 mg, 0.20 mmol) was added, molecular sieves 4A (20 mg, approximately 5 pellets) were added and stirred for 2 hours, acetic acid (20 µL) was added, and then sodium cyanoborohydride (63.91 mg, 1.02 mmol) was added and stirred at 70°C under sealed conditions overnight.

[00126] The solvent was removed by rotary evaporation, H2O (5 mL) was added and 2N aqueous NaOH solution was added to adjust the pH to 8-9, and the organic phase was extracted with ethyl acetate (5 mL x 3), the organic phases were combined and concentrated by rotary evaporation and purified by reverse phase preparation (methanol / H2O) to obtain compound 4i (40 mg, yield: 30.22%) as a white solid and compound 4j (50 mg, yield: 21.82%) as a white solid. Step 9:

[00127] Compound 4j (38 mg) was added to a reaction flask, and Petition 870250110916, dated 03 / 12 / 2025, page 32 / 100 27 / 47 EtOAc (2 mL) and 4N HCl / EtOAc (2 mL) were added, stirred for 2 hours, and the reaction system was cooled using a dry ice and ethanol bath. Purified water (5 mL) was added slowly until frozen to ice. After extraction with EtOAc (3 mL), it was subjected to lyophilization using a freeze dryer to obtain the hydrochloride of compound 4 (24.2 mg, yield: 97.89%) as a white flocculant solid. MS m / z(ESI):614.3[M+H]+. Step 1:

[00128] Reagent 5a (5 g, 12.39 mmol) was added to tert-butyl alcohol (50 mL), water (50 mL) and NaClO2 (11.21 g, 123.91 mmol) and stirred to dissolve.

[00129] NaEEPCL (8.92 g, 74.35 mmol) and 2-methyl-2-butene (10 mL) Petition 870250110916, dated 03 / 12 / 2025, page 33 / 100 / 47 were added and stirred at 25°C overnight.

[00130] The solvent was removed from the system by rotary evaporation, EtOAc (80 mL) was added, the liquid was separated and the aqueous phase was extracted once with EtOAc (40 mL), the organic phases were combined, washed with saturated sodium chloride solution (40 mL), separated and the organic phase was dried.

[00131] The filtrate was concentrated by rotary evaporation, mixed with silica gel and purified by column chromatography (EtOAc / PE 0 to 50%), and compound 5b (4.3 g, yield of 82.72%) was obtained by rotary evaporation. MS m / z(ESI):320.3[M-100+H]+. Step 2:

[00132] Reagent 5b (700 mg, 1.67 mmol) was dissolved in DMF (5 mL), and HATU (1008 mg, 2.65 mmol) and DIEA (685 mg, 5.3 mmol) were added. After stirring at room temperature for 15 minutes, a DMF solution (5 mL) of B31 (1400 mg, 1.77 mmol) was added and reacted at 30°C overnight.

[00133] Water was added, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated and purified by reverse phase preparation (methanol / water) to obtain compound 5c (1.5 g, 75.32% yield) as a solid. MS m / z(ESI):497.4[M / 2-100]+. Step 3:

[00134] Compound 5c (770 mg, 0.645 mmol) was dissolved in 4M HCl / EtOAc and reacted at 40°C overnight.

[00135] Water was added, washed twice with EtOAc, the aqueous phase was lyophilized to obtain the hydrochloride of compound 5 (510 mg, yield of 94.76%). MS m / z(ESI):726.5[M+H]+. Petition 870250110916, dated 03 / 12 / 2025, page 34 / 100 / 47 EXAMPLE 6 Step 1:

[00136] Compound 5a (2000 mg, 4.96 mmol) was dissolved in methanol (100 mL) and NaBH4 (335.1 mg, 9.91 mmol) was added at -20°C, and the mixture was reacted at room temperature overnight.

[00137] After concentration, a saturated aqueous solution of sodium bicarbonate was added, and the mixture was extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 6a (2000 mg, 99.5% yield) as a colorless oil. MS m / z(ESI):306.2[M+H-100]+. Step 2:

[00138] Compound 6a (1800 mg, 4.44 mmol) was dissolved in THF (100 mL), and PPh3 (2310 mg, 8.81 mmol) and NBS (900 mg, 5.06 mmol) were added at -20°C and reacted for 3 hours.

[00139] After filtration, water (10 mL) was added to the filtrate, and the mixture was extracted three times with EtOAc, the organic phases were combined, washed with saturated brine, filtered, concentrated and Petition 870250110916, dated 03 / 12 / 2025, page 35 / 100 / 47 purified by column chromatography (EtOAc / PE=0 at 20%) to obtain compound 6b (1300 mg, yield of 62.53%) as a colorless oil. MS m / z(ESI):356.1[M-112]+. Step 3:

[00140] Compound 6b (620.27 mg, 1.32 mmol) and 1,3,5-cyclohexanetriol (50 mg, 0.38 mmol) were dissolved in N-methylpyrrolidone (5 mL), sodium hydride (90.80 mg, 3.78 mmol) was added, replaced with nitrogen three times, and reacted at room temperature for 16 hours.

[00141] Water (2 mL x 3) was added for washing, the organic phase was extracted with ethyl acetate (3 mL x 3), the organic phases were combined, dried by rotary evaporation and purified by reverse phase preparation (methanol / H2O) to obtain compound 6c (90 mg, yield: 18.3%) as a light yellow solid. MS m / z(ESI):520.0[(M-256) / 2+H]+. Step 4:

[00142] Compound 6c (50 mg, 0.03 mmol) was dissolved in HCl / EtOAc (4 M, 3 mL) and reacted at room temperature for 16 hours.

[00143] Water (3 mL) was added to the reaction solution, and the liquid was separated, and the aqueous phase was washed with ethyl acetate (3 mL x 3), and the aqueous phase was lyophilized to obtain the hydrochloride of compound 6 (19.75 mg, yield: 54.68%) as a light yellow solid. MS m / z(ESI):827.1[M+H]+. EXAMPLE 7 Petition 870250110916, dated 03 / 12 / 2025, page 36 / 100 31 / 47 Step 1:

[00144] Compound 7a (3.00 g, 6.60 mmol) was dissolved in dioxane (26 mL) and pinacol borate (2.51 g, 9.90 mmol), potassium acetate (1.29 g, 13.20 mmol) and Pd(dppf)C12CH2C12 (0.27 g, 0.33 mmol) were added.

[00145] The mixture was replaced with argon three times and stirred at 90°C overnight under argon protection.

[00146] The disappearance of the starting material and the formation of new points were monitored by TLC.

[00147] After cooling, concentrated, diluted with ethyl acetate (50 mL), washed with water (50 mL) and concentrated to obtain compound 7b (3.31 g, 100% yield) as a red liquid. Step 2:

[00148] Compound 7b (3.31 g, 6.60 mmol) was dissolved in THF (50 mL) and a solution of NaOH (0.79 g, 19.80 mmol) in water (10 mL) was added.

[00149] H2O2 (7.50 mL, 66.00 mmol) was added slowly drop by drop in an ice bath.

[00150] After the addition was completed, the mixture was stirred at 25°C overnight.

[00151] Saturated aqueous solution of sodium thiosulfate (20 mL) was Petition 870250110916, dated 03 / 12 / 2025, page 37 / 100 / 47 added in a water bath to rapidly cool the hydrogen peroxide, the pH was adjusted to 3 with 1 M hydrochloric acid, concentrated by rotary evaporation and most of the THF was removed, ethyl acetate (50 mL x 2) was added for extraction, the organic phases were combined, washed with water (50 mL), concentrated and passed through a silica gel column (PE / EtOAc=1 / 0 to 3 / 1) to obtain compound 7c (2.08 g, 80% yield) as a white solid. Step 3:

[00152] Compound 7c (400 mg, 1.02 mmol) was dissolved in anhydrous THF (10 mL), and molecular sieves 4A (50 mg) were added under the protection of an argon flask, stirred at room temperature for 10 minutes and then placed in an ice bath, and sodium hydride (40.88 mg, 1.02 mmol) was added, returned to room temperature and stirred for 20 minutes, compound 7r (47.10 mg, 0.255 mmol) was added in an ice bath, stirred at 40°C overnight.

[00153] The formation of new hotspots was monitored by TLC.

[00154] Saturated aqueous solution of ammonium chloride (20 mL) was added to an ice bath and extracted with ethyl acetate (20 mL x 2), the organic phases were combined, washed with water (50 mL x 1), concentrated and passed through a silica gel column (PE / EtOAc=3 / 1) to obtain compound 7d (200.00 mg, yield of 15.66%) as a white solid. Step 4:

[00155] Compound 7d (40.00 mg, 0.03 mmol) was added to a single-necked flask, ethyl chloride / acetate (5 mL) was added and stirred at room temperature overnight, deionized water (10 mL) was added at -20°C, the aqueous phase was separated and the aqueous phase was back-extracted with ethyl acetate (10 mL x 3), the aqueous phase was lyophilized, deionized water (10 mL) was added to dissolve and then lyophilized to obtain Petition 870250110916, dated 03 / 12 / 2025, page 38 / 100 / 47 the hydrochloride of compound 7 (27.03 mg, yield of 94.88%) as a yellow solid. EXAMPLE 8 Step 1:

[00156] Compound 5b (94.67 mg, 0.23 mmol) was dissolved in DMF (5 mL), and HATU (104 mg, 0.27 mmol) and DIEA (53.03 mg, 0.41 mmol) were added. After reacting at room temperature for 15 minutes, compound 8r (10 mg, 0.068 mmol) was added and reacted at room temperature overnight.

[00157] Water was added, extracted with EtOAc, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated.

[00158] After preparation (methanol / water), compound 8a (87.75 mg, 95%) was obtained. MS m / z(ESI):474.4[M / 2-200]+. Step 2:

[00159] Compound 8a (87.75 mg, 0.065 mmol) was dissolved in 4M HCl / EtOAc (5 mL) and reacted at 40°C overnight.

[00160] Water (10 mL) was added, washed twice with EtOAc, and the aqueous phase was lyophilized to obtain the hydrochloride of compound 8 (58.48 mg, yield of 87.57%). Petition 870250110916, dated 03 / 12 / 2025, page 39 / 100 / 47 MS m / z(ESI):883.5[M+H]+. EXAMPLE 9 Step 1:

[00161] Reagent 7a (1.2 g, 2.64 mmol) was added to the reaction flask, NMP (2 mL) was added and stirred.

[00162] Water with ammonia (5 mL) was added and stirred.

[00163] Cuprous oxide (0.38 g, 2.65 mmol) and water (2 mL) were added and stirring continued.

[00164] Heat to 80°C and stir overnight.

[00165] Water (20 mL) was added and stirred, extracted with EtOAc (20 mL), and the phases were separated, the organic phase was dried by rotary evaporation, mixed with silica gel.

[00166] Purified by PE / EtOAc (80:20) column chromatography to obtain the product, the product was dried by rotary evaporation to obtain compound 9a (726 mg, 70.4% yield) as a solid. Step 2:

[00167] Compound 6b (200 mg, 0.51 mmol) was dissolved in DMF. Petition 870250110916, dated 03 / 12 / 2025, page 40 / 100 35 / 47 (7 mL), K2CO3 (212.35 mg, 1.54 mmol) and compound 9a (263.89 mg, 0.56 mmol) were added and reacted at 60°C overnight.

[00168] Compound 9b (135 mg, 22.62% yield) was obtained by preparative high-performance liquid chromatography (MeOH / H2O). Step 3:

[00169] Compound 9b (120 mg, 0.10 mmol) was dissolved in 4M HCl / EtOAc (7 mL) and reacted at 40°C for 4 hours.

[00170] Water was added, washed twice with EtOAc, the aqueous phase was lyophilized to obtain the hydrochloride of compound 9 (64 mg, yield of 73.77%). MS m / z(ESI):698.4[M+H]+. EXAMPLE 10 Step 1:

[00171] l,3,5-tri(bromomethyl)benzene (37 mg, 0.10 mmol) and compound 10a (162 mg, 0.41 mmol) were dissolved in DMF (3 mL), potassium carbonate (201 mg, 0.61 mmol) was added, and stirred at 60°C. Petition 870250110916, dated 03 / 12 / 2025, page 41 / 100 / 47 during the night, filtered, and the filtrate was purified by preparative reversed-phase chromatography (MeOH / H2O) to obtain compound 10b (70 mg, 52% yield) as a white solid. Step 2:

[00172] Compound 10b (70 mg, 0.054 mmol) was dissolved in ethyl acetate (1 mL), triethylsilane (0.1 mL) and HCl / EtOAc (4 mol / L, 3 mL) were added, stirred at room temperature for 2 hours and concentrated to obtain the solid which was washed with ethyl acetate three times, pure water (10 mL) was added for dissolution and lyophilized to obtain the hydrochloride of compound 10 (36.18 mg, 72% yield) as a white solid. EXAMPLE 11 Step 1:

[00173] Compound 1g (60 mg, 0.154 mmol) was dissolved in methanol (5 mL), 11b (110 mg, 0.139 mmol) and AcOH (37 mg, 0.616 mmol) were added, 5 pellets of molecular sieves to 4A were added to remove water and reacted at room temperature for 1 hour, then AcOH (37 mg, 0.616 mmol) and NaBH3CN (21 mg, 0.621 mmol) were Petition 870250110916, dated 03 / 12 / 2025, page 42 / 100 37 / 47 added and reacted at 70°C overnight.

[00174] After filtering the solid, the filtrate was concentrated.

[00175] Compound 11c (70 mg, 39% yield) was obtained as a colorless oil by high-performance preparative liquid chromatography (MeOH / H2O). MS m / z(ESI):533.5[M / 2-50]+. Step 2:

[00176] Compound 11c (70 mg, 0.26 mmol) was dissolved in 4M HCl / EtOAc (5 mL) and reacted at room temperature overnight.

[00177] The solid was produced, water was added, washed twice with EtOAc, and the aqueous phase was lyophilized twice to obtain the hydrochloride of compound 11 (48 mg, 95% yield). MS m / z(ESI):697.2[M+H]+. COMPARATIVE EXAMPLE 1 Comparative example 1

[00178] Comparative compound 1 can be synthesized with reference to patent WO2020 / 247429A1. BIOLOGICAL TEST EVALUATION Example Test 1: Using SPR to detect the affinity of the compounds of the present invention to Apo(a) 1. Experimental purpose:

[00179] The purpose of the test is to test the affinity of the compounds of the present invention to Apo(a). 2. Experimental instruments and reagents: Petition 870250110916, dated 03 / 12 / 2025, page 43 / 100 / 47 Biomolecular interaction analyzer (Biacore 8K)

[00180] Apolipoprotein (a) was synthesized by Hangzhou Haoyang Biotechnology Co., Ltd.

[00181] The NHS was bought from Cytiva. 3. Experimental methods:

[00182] Apolipoprotein(a) was covalently linked to a CM5 S-series sensor chip in a Biacore 8K instrument.

[00183] The activator was prepared by mixing 400 mM of EDC and 100 mM of NHS before injection.

[00184] The CM5 sensor chip was activated with the activator for 420 seconds at a flow rate of 10 μL / minute.

[00185] 60 pg / mL of apolipoprotein(a) were dissolved in 10 mM NaAc solution (pH 4.5) and injected into the Fc2 sample channel at a flow rate of 10 pL / minute to achieve an immobilization level of approximately 10,000 RU.

[00186] It was inactivated for 420 seconds with 1 M ethanolamine hydrochloride-sodium hydroxide at a flow rate of 10 pL / minute.

[00187] The Fc1 reference channel was blocked using the same procedure used for Fc2, but without performing the protein injection step.

[00188] The compound was diluted to 100 nM with running buffer (1 x PBS containing 0.005% Tween-20, pH 7.4), injected into the Fc1-Fc2 channel at a flow rate of 30 pL / minute, turned on for 90 seconds and dissociated for 210 seconds.

[00189] Both the binding and dissociation processes were carried out in the running buffer.

[00190] 3M magnesium chloride was injected at a flow rate of 20 pL / minute into the race buffer for 30 seconds to regenerate the chip.

[00191] The affinity constant KD reflects the size of the binding capacity of the interaction; when the concentration of the compound is in KD, the Petition 870250110916, dated 03 / 12 / 2025, page 44 / 100 / 47 equilibrium sign Req is half of Rmax.

[00192] The results show that the compounds of the present invention exhibit a strong binding capacity with the human Apo(a) protein. Example Test 2: Using BLI to detect the affinity of the compounds of the present invention to Apo(a) 1. Experimental purpose:

[00193] The purpose of this test is to test the affinity of the compounds of the present invention to Apo(a). 2. Experimental instruments and reagents: Molecular interaction analyzer (ForteBio Octet red 96e) Sensor SA (ForteBio)

[00194] Plates from 96 wells were acquired from Greine. 3. Experimental methods:

[00195] Two 96-well plates were prepared, one as a sample plate and the other as a pre-wetted plate, curing buffer was added to a 200 μL well of the pre-wetted plate, and the SA sensor was pre-wetted for at least ten minutes.

[00196] All reagents and samples were added to another black sample plate. After the sample addition was complete, the sensor plate and the sample plate were placed in the ForteBio Octet red 96e instrument.

[00197] The program was configured sequentially for detection.

[00198] The experimental temperature was set at 30°C and the acquisition frequency was set at 5.0 Hz.

[00199] The biosensor was run in 1 x PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA in the first column for 60 seconds, which was the baseline step.

[00200] Biotinylated apolipoprotein (a) was diluted to 40 μg / ml with 1 x PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA and added to the second column, where it was run for a period of time until the Petition 870250110916, dated 03 / 12 / 2025, page 45 / 100 / 47 quantity of cure in the sensor reached 2.0 nm.

[00201] The biosensor was run in 1 x PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA in the first column for 60 seconds, which was the baseline step.

[00202] The compound was diluted to 100 nM with 1 x PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA and added to the fourth column, where the sensor was run for 60 seconds.

[00203] The sensor was run in 1 x PBS, pH 7.4, 0.02% Tween-20, 0.1% BSA in the third column for 120 seconds, during this process, the compound dissociated from the sensor.

[00204] The affinity constant KD reflects the size of the binding capacity of the interaction. When the analyte concentration is at KD, the equilibrium signal Req is half of Rmax.

[00205] The results show that the compounds of the present invention exhibit a strong binding force with the human Apo(a) protein. Table 1: Example KD (nM) Example 5 10.9 Example 6 19.9 Example 7 8.06 Example 8 18.7 Example 10 25.3 Example 11 14.2 Example Test 3: Pharmacokinetics in mice 1. Experimental purpose:

[00206] The objective of this test is to test the pharmacokinetics of the compounds of the present invention in mice. 2. Experimental animals: Mouse (C57BL-6J) 3. Experimental methods:

[00207] C57BL-6J mice were housed with a standard light cycle (12 hours of light / 12 hours of darkness), at an ambient temperature of 18 to 26°C and relative humidity of 40 to 70%, with free access to water and food. Petition 870250110916, dated 03 / 12 / 2025, p. 46 / 100 / 47 normal.

[00208] Five days before the study, the mice were randomly divided into groups (n=3 per group) based on body weight for the study.

[00209] The administration volume was calculated according to the animals' body weight on the day of administration, with an administration volume of 10 mL / kg, a single oral administration was performed at a dose of 10 mg / kg, and the solvent was 1% HEC and 0.25% Tween 80 in water.

[00210] Blood was collected from the submandibular vein or other suitable veins at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after administration.

[00211] Each sample was collected at approximately 0.03 mL per time point.

[00212] After the blood sample was collected, it was placed on ice and centrifuged at 4°C, 6800g, for 10 minutes, within 1 hour, to separate the plasma and detect the concentration of drugs in the blood. Example Test 4: Inhibition of Lp(a) in vivo in cynomolgus monkeys 1. Experimental purpose:

[00213] The purpose of this test is to test the inhibitory effect of the compounds of the present invention on Lp(a) in cynomolgus monkeys. 2. Experimental instruments and reagents: Fully automated biochemical analyzer (Hitachi 7600 model) 3. Experimental methods:

[00214] Cynomolgus monkeys were housed with a standard light cycle (12 hours of light / 12 hours of darkness), at an ambient temperature of 18 to 26°C and a relative humidity of 40 to 70%, with drinking water provided continuously for 24 hours, and food was provided to the animals twice a day, in the morning (around 10:30) and in the afternoon (around 15:00). Petition 870250110916, dated 03 / 12 / 2025, page 47 / 100 / 47

[00215] Five days prior to the study, cynomolgus monkeys were randomly assigned to groups (n=3 / group) based on body weight and baseline serum Lp(a) concentration for the study.

[00216] The administration volume was calculated according to the animals' body weight on the first day of administration, with an administration volume of 5 mL / kg, administered once daily by oral gavage for 5 consecutive days, the dosage was 3 mg / kg and the solvent was 1% HEC and 0.25% Tween 80.

[00217] Adaptation period (after overnight fasting), before administration on Day 1 and 8 hours after administration on Day 5.

[00218] 1 mL of whole blood was collected from the cephalic vein or saphenous vein of the animal, placed at room temperature for 30 minutes, and then centrifuged at 4°C, 3500 rpm, for 10 minutes to separate the serum.

[00219] Serum Lp(a) levels were detected using a fully automated biochemical analyzer.

[00220] Defining the average Lp(a) level before administration as 0% inhibition, the percentage reduction in Lp(a) in each group was determined.

[00221] The results confirmed that the compounds of the present invention have a good effect on reducing plasma Lp(a) levels in vivo.

[00222] The in vivo Lp(a) inhibition rate of the compounds of the present invention in cynomolgus monkeys is shown in Table 2 below: Table 2: Example: Lp(a) Inhibition Rate (%) Example Comparative 1: 32.87±17.30 Example 5: 50.23±20.41 Example Test 5: Determination of exposure in beagle dogs 1. Experimental purpose:

[00223] The objective of this test is to test the exposure of the compound in Petition 870250110916, dated 03 / 12 / 2025, p. 48 / 100 / 47 beagle dogs. 2. Experimental methods:

[00224] Beagle dogs were housed with a standard light cycle (12 hours of light / 12 hours of darkness), at an ambient temperature of 18 to 26°C and relative humidity of 40 to 70%, with free access to water and a normal diet.

[00225] Five days prior to the study, beagle dogs were randomly assigned to groups based on body weight for the study, including an oral administration group (n = 3 / group). The administration volume was calculated according to the animals' weight on the day of administration, and the administration volume was 5 mL / kg, single oral administration was performed at a dose of 4.5 mg / kg, and the solvent was 1% HEC and 0.25% Tween 80 in water.

[00226] Blood was collected from a forelimb vein or other suitable veins at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, 72h and 96h after administration.

[00227] Approximately 1 mL of each sample was collected, anticoagulated with K2-EDTA, placed on ice after collection and, after 1 hour, centrifuged to separate the plasma (centrifugation conditions: 2200g, 10 minutes, 2 to 8°C) for detection of drug concentration in the blood.

[00228] Beagle dog exhibitions were calculated as shown in Table 3 below: Table 3: Example AUC(0-®) (h*ng / mL) Comparative Example 1 37435.29 Example 5 118713.17 Example Test 6: Determination of bioavailability in cynomolgus monkeys 1. Experimental purpose:

[00229] The purpose of this test is to test the bioavailability of the compound in cynomolgus monkeys. 2. Experimental methods: Petition 870250110916, dated 03 / 12 / 2025, page 49 / 100 / 47

[00230] Cynomolgus monkeys were housed with a standard light cycle (12 hours of light / 12 hours of darkness), at an ambient temperature of 18 to 26°C and a relative humidity of 40 to 70%, with free access to water and a normal diet.

[00231] Five days prior to the study, cynomolgus monkeys were randomly assigned to an intravenous administration group and an oral administration group (n = 2 / group) based on study body weight. The administration volume was calculated according to the animals' body weight on the day of administration, and the administration volume was 2 mL / kg, single intravenous administration was performed at a dose of 1 mg / kg, and the solvent was 5% DMSO, 5% Solutol, and 90% saline solution.

[00232] Blood was collected from a forelimb vein or other suitable veins at 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h, and 72h after administration.

[00233] The administration volume was calculated according to the weight of the animals on the day of administration, with an administration volume of 5 mL / kg, a single oral administration was performed at a dose of 7.5 mg / kg, and the solvent was 1% HEC and 0.25% Tween 80 in water.

[00234] Blood was collected from a vein in the forelimb or other suitable veins at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h, 24h, 48h and 72h after administration.

[00235] Approximately 1 mL of each sample was collected, anticoagulated with K2-EDTA, placed on ice after collection and, after 1 hour, centrifuged to separate the plasma (centrifugation conditions: 2200g, 10 minutes, 2 to 8°C) for detection of drug concentration in the blood.

[00236] Bioavailability F was calculated as shown in Table 4 below: Table 4: Example Bioavailability F (%) Example Comparative 1 10.20 Example 5 16.77 Petition 870250110916, dated 03 / 12 / 2025, p. 50 / 100 / 47 Example test 7: hERG experiment 1. Experimental purpose:

[00237] The aim of this test is to test the inhibition rate of compounds on the hERG potassium channel. 2. Experimental methods:

[00238] The hERG current was recorded using the whole-cell patch clamp technique.

[00239] A suspension of HEK-293-hERG cells was added to a small culture plate and placed on an inverted microscope stage.

[00240] After the cells adhered to the plate, extracellular fluid was perfused at a rate of 1 to 2 mL / minute.

[00241] The glass microelectrode was pulled out in two stages by a microelectrode extractor, after the electrode was filled with internal fluid, its resistance to water was 2 to 5 MO.

[00242] After establishing the whole-cell recording mode, the holding potential was maintained at -80 mV.

[00243] A depolarizing voltage of +60 mV was applied for 850 ms, followed by repolarization of -50 mV for 1275 ms to induce the hERG tail current.

[00244] This set of pulse programs was repeated every 15 seconds throughout the experiment.

[00245] After the current stabilized, the test compound was administered via continuous extracellular infusion, from low to high concentration.

[00246] Starting from a low concentration, the infusion was continued until the drug effect stabilized, and then the next concentration was infused.

[00247] The rate of inhibition of the compound on the hERG potassium channel Petition 870250110916, dated 03 / 12 / 2025, page 51 / 100 / 47 was calculated as shown in Table 5 below: Table 5: Example Inhibition Rate (%) 0.3 μM 1 μM 3 μM Comparative Example 1 7.37 24.62 29.16 Example 5 -0.06 3.47 3.67 Example Test 8: Salmonella typhimurium reverse mutation test

[00248] Revived strains or a single colony from the master plate were inoculated into the broth and cultured in a thermostatic gas bath shaker at 100 to 120 rpm and 37±1°C for 10 to 16 hours, labeled and stored for later use.

[00249] The agar stock medium (containing an appropriate amount of agar, Vogel-Bonner buffer, 20% glucose solution, and 20% magnesium sulfate solution) was poured into a six-well plate, approximately 20 mL to 25 mL into each well, and allowed to cool and solidify naturally, each well labeled, and stored for later use.

[00250] Three wells were set up in each group for parallel experiments.

[00251] The surface agar medium was sterilized under high pressure and kept warm at approximately 65°C.

[00252] In each test tube, 0.1 mL of negative control (DMSO) or positive control or test sample, 0.1 mL of bacterial solution suspension, 0.5 mL of phosphate buffer (0.2 M PBS) (-S9) or 0.5 mL of mixed S9 solution (+S9) and 2.5 mL of surface culture medium were added, after vortexing, and then spread rapidly and evenly on the culture plate that was already spread with the background agar medium.

[00253] After natural cooling and solidification, the culture plate was inverted and placed in an incubator at 37°C for 48 to 72 hours.

[00254] After cultivation for 48 to 72 hours, the culture plate was removed and the number of reverting colonies in each well was counted, the history of Petition 870250110916, dated 03 / 12 / 2025, page 52 / 100 / 47 growth was observed under a microscope to determine if there was antibacterial or bactericidal activity, and the experimental results were recorded.

[00255] The mutagenicity of the compounds of the present invention in various strains is shown in Table 6 below: Table 6: Example Strain Metabolic Activation Mutagenicity 62μg / plate 185μg / plate 556μg / plate 1667μg / plate 5000μg / plate Example Comparative 1 TA98 + - - + + + - - + + + + TA1537 + - - - - - - - - - - - TA100 + - - - - - - - - - - - TA102 + - - - - - - - - - - - TA1535 + - - - - - - - - - - - Example 5 TA98 + ^B ^B ^B ^B ^B ^B ^B ^B ^B ^B TA1537 + ^B ^B ^B ^B ^B ^B ^B ^B ^B ^B TA100 + ^B ^B ^B ^B ^B ^B ^B ^B ^B ^B ^B TA102 + ^B ^B ^B ^B ^B ^B ^B ^B ^B ^B ^B TA1535 + ^B ^B ^B ^B ^B ^B ^B ^B ^B ^B ^B Observation: In the "Metabolic Activation" column: + indicates the addition of mixture S9; - indicates no addition of mixture S9. In the "Mutagenicity" column: + indicates a positive mutagenic result; - indicates a negative mutagenic result. Petition 870250110916, dated 03 / 12 / 2025, p. 53 / 100

Claims

1 / 6 CLAIMS 1. A compound of formula I, formula II, formula III or formula IV, or a pharmaceutically acceptable salt thereof, characterized in that the structure of the compound of formula I, formula II, formula III or formula IV is as shown below: wherein R is selected from aryl or heteroaryl, which may be further substituted; R1, R2, R3 and R4 are each independently selected from H and alkyl, wherein the alkyl may be further substituted; R6 is each independently selected from C1-6 alkyl; preferably methyl; Y is a trivalent group, wherein the trivalent group is Petition 870250084769, dated 19 / 09 / 2025, p. 61 / 116 2 / 6 or selected from x is 1 or 2, preferably 1; and y is 0 or 1.

2. A pharmaceutically acceptable compound or salt thereof according to claim 1, characterized in that the compound of formula IV is a compound of formula IV-1, formula IV-2, formula IV-3 or formula IV-4; or 3. A pharmaceutically acceptable compound or salt thereof according to claim 1 or 2, characterized in that R is selected from aryl C6-20, preferably aryl C6-14, more preferably aryl C6-12, which may be further substituted. Petition 870250084769, dated 09 / 19 / 2025, p. 62 / 116 3 / 6 4. A pharmaceutically acceptable compound or salt thereof according to claim 1 or 2, characterized in that R1, R2, R3 and R4 are each independently selected from H and C1-6 alkyl, preferably H or methyl.

5. A pharmaceutically acceptable compound or salt thereof according to claim 3, characterized in that R is selected from phenyl, benzo[d][1,3]dioxol, tetrahydroquinoline, tetrahydroisoquinoline, pyridine, quinoline or isoquinoline, which may be further substituted.

6. A pharmaceutically acceptable compound or salt thereof according to claim 5, characterized in that R is selected from the following groups: or ; where n is 0, 1, 2 or 3; R5 is each independently selected from hydrogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylcarbonylamino, halogen, hydroxyl, nitro, cyano, cycloalkyl, aryl or heteroaryl; preferably alkyl, haloalkyl, alkoxy, haloalkoxy, alkylamino, alkylcarbonylamino or halogen; and Petition 870250084769, dated 19 / 09 / 2025, p. 63 / 116 4 / 6 R5 may be located in one, two, or three selected positions among the 1st, 2nd, 3rd, 4th, 5th, 6th, 7th, and 8th positions of the aforementioned aryl or heteroaryl.

7. A pharmaceutically acceptable compound or salt thereof according to claim 6, characterized in that it is independently selected from C1-6 alkyl haloalkyl, C1-6 alkoxy, or C1-6 haloalkoxy, wherein R5 is each C1-6 cycloalkyl alkylcarbonylamino, C3-6, C1-6, halogen or 8. A pharmaceutically acceptable compound or salt thereof according to claim 7, characterized in that R5 is each independently selected from trifluoromethyl, or wherein, preferably, preferably 9. A pharmaceutically acceptable compound or salt thereof according to claim 6, characterized in that R is selected from the following groups: , 10. A pharmaceutically acceptable compound or salt thereof according to claim 1, characterized in that the compound is selected from among the following compounds: Petition 870250084769, dated 09 / 19 / 2025, page 64 / 116 5 / 6 O — HO HNNH or 11. Pharmaceutical composition, characterized in that it comprises the pharmaceutically acceptable compound or salt thereof as defined in any one of claims 1 to 10. Petition 870250084769, dated 19 / 09 / 2025, page 65 / 116 6 / 6 12. Use of the compound or its salt, pharmaceutically acceptable as defined in any one of claims 1 to 10, characterized in that it is for preparing an agent to reduce Lp(a) levels.

13. Use according to claim 12, characterized in that the compound or its pharmaceutically acceptable salt is used to prepare a drug for cardiovascular treatment. Petition 870250084769, dated 09 / 19 / 2025, pp. 66 / 116

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