Preparation method and application of 3-aryl piperidine-2, 6-diketone VAV1 molecular glue degradation agent

Abstract

The invention discloses a 3-aryl piperidine-2, 6-diketone compound as shown in a general formula I or an enantiomer, a diastereoisomer, a raceme and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the 3-aryl piperidine-2, 6-diketone compound, the compound is used as a VAV1 targeted molecular glue degradation agent, and can degrade VAV1 protein in a targeted manner, so that the VAV1 protein can be degraded in a targeted manner. The invention has the application of preparing medicines for treating and / or preventing inflammatory diseases and autoimmune diseases.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, specifically to a 3-arylpiperidine-2,6-dione compound, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, as well as its preparation method and uses. Background Technology

[0002] Guanine nucleotide exchange factor VAV1 is primarily expressed in human hematopoietic cells, including T and B cells, monocytes, natural killer cells, granulocytes, and dendritic cells. Studies have shown that it plays a crucial role in T / B lymphocyte function and antigen receptor signaling, promoting actin polymerization, immune synapse formation, T cell activation and differentiation, and cytokine production. Particularly in T cells, the 76 kDa leukocyte protein (SLP76) containing a Src-homological SH2 domain is recruited to transmembrane linkers via its SH2 domain to activate and form the LAT / SLP76 complex in T cells. This LAT / SLP76 complex acts as a key scaffold for other proteins, including VAV1, in the proximal signaling complex of the T cell receptor (TCR). VAV1 interacts with other proteins through its SH2 and proline-rich / SH3 domains. As a scaffold protein, VAV1 is highly involved in the activation of multiple pathways in T cells: 1) VAV1 promotes IP3 generation by activating PLCγ1, triggering calcium ion release and activating the transcription factor NFAT; 2) VAV1 connects to components of the Ras-MAPK pathway (such as RasGRP1, MEK, and ERK), regulating the activity of transcription factors such as AP-1; 3) It promotes AKT activation, participating in cell survival and metabolic regulation; 4) As a scaffold, it recruits the WASp and Arp2 / 3 complex, driving actin polymerization. Through these pathways, VAV1 can exert a crucial influence on T cell differentiation (such as Th1, Th2, or Th17) and the secretion of cytokines (such as IL-2, IFN-γ, and IL-4). Furthermore, VAV1 is a key upstream protein for activating Rac / Rho family GTPases. The VAV1-Rac1 pathway significantly influences actin remodeling, F-actin polymerization, TCR aggregation, integrin-mediated cell adhesion activation, immune synapse formation between T cells and antigen-presenting cells, and chemokine-mediated cell migration (Neurath MF, Berg LJ. VAV1 as a putative therapeutic target in autoimmune and chronic inflammatory diseases. Trends Immunol. 2024; 45(8):580-596.). Due to the above mechanisms, the absence / inhibition of VAV1 has a significant effect on regulating autoimmunity and inflammation, which may make it a useful target for certain human immune-mediated diseases, including rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and multiple sclerosis (MS).

[0003] Inflammatory bowel disease (IBD) is a nonspecific chronic inflammatory bowel disease of unknown etiology, mainly including ulcerative colitis (UC) and Crohn's disease (CD). Due to its complex pathological process, the most convincing main pathogenic mechanism has not yet been identified. In recent years, the emergence of targeted therapy has brought breakthroughs in the treatment of IBD, but IBD still has an extremely high relapse rate. 80% of patients will experience chronic relapses, and 20% to 30% of patients have to undergo surgical treatment after multiple relapses, removing part of the intestine, which seriously affects the quality of life of patients (Kaplan GG, Windsor JW. The four epidemiological stages in the globalevolution of inflammatory bowel disease. Nat Rev Gastroenterol Hepatol. 2021; 18(1):56-66.). According to Evaluate Pharma's forecast, the global IBD drug market will reach $28 billion by 2028, and current treatments are far from meeting clinical needs. In 2024, Monte Rosa's first VAV1 molecular glue degrader entered Phase I clinical trials, primarily for autoimmune diseases, rheumatoid arthritis, and ulcerative colitis. The clinical application potential of VAV1 molecular glue degraders has garnered widespread attention from researchers in the field (Patent: WO2024151547 A1, Clinical Trial: NCT06597799). In 2016, studies reported that Rac1 (a downstream of VAV1) inhibitors, thiopurine analogs, could exert inhibitory effects on mucosal immune cells in IBD, potentially contributing positively to IBD treatment. However, the myelotoxicity of these compounds has limited their further development. Due to the specificity of VAV1 expression, VAV1 molecular glue degraders can avoid acting on undifferentiated bone marrow cells, effectively avoiding myelotoxicity (Atreya I, Diall A, Dvorsky R, et al. Designer Thiopurine-analogues for Optimised Immunosuppression in Inflammatory Bowel Diseases. J Crohns Colitis. 2016; 10(10):1132-1143.), demonstrating a significant advantage. In 2025, some clinical data on the VAV1 molecular glue degrader MRT-6160 were released, further demonstrating its development value.Given that VAV1 molecular glue degraders can more effectively and comprehensively inhibit multiple immune pathways against T / B cells and reduce damage to other organs, developing safe and effective VAV1 molecular glue degraders will be an important treatment strategy for IBD in the future (Cartwright A, Desai F, Nguyen S, et al. P164 MRT-6160, a VAV1-directed molecular glue degrader, inhibits disease progression and inflammation in a T-cell transfer model of Colitis. J Crohns Colitis, Volume 18, Issue Supplement 1, January 2024, Page i469). Summary of the Invention

[0004] The purpose of this invention is to provide a 3-arylpiperidine-2,6-dione compound, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, as well as its preparation method and uses. Specifically, it provides a 3-arylpiperidine-2,6-dione VAV1 molecular glue degrading agent, providing its chemical structure, synthesis method, and bioactivity data, offering a new therapeutic approach for treating inflammatory diseases, including inflammatory bowel disease, and autoimmune diseases, thereby addressing the problems mentioned in the background art.

[0005] To achieve the above objectives, the present invention provides the following technical solution:

[0006] The present invention provides a 3-arylpiperidine-2,6-dione compound of Formula I, its enantiomers, its diastereomers, its racemic mixture or a pharmaceutically acceptable salt thereof.

[0007]

[0008] in,

[0009] X1 and X2 are independently selected from nitrogen atoms or carbon atoms. When X2 is a carbon atom, X3 is selected from H or chlorine atoms. When X2 is a nitrogen atom, there is no substitution of X3.

[0010] L is selected from amide bonds, alkynes, alkyne methyl groups, or secondary amines, wherein the amide bonds include -CONH- and -NHCO-;

[0011] Ring A is selected from 5-10 substituted aromatic rings, 5-10 substituted aromatic heterocycles, 5-10 substituted aliphatic heterocycles, or 5-10 fused rings, whether substituted or unsubstituted by R groups.

[0012] R is selected from H, methyl, -NR2R1, -OCH2R3, -CH2R3, -OCH2(C=O)R3, a 5- to 10-membered heterocycle substituted or unsubstituted with R1 or R2, or a 5- to 10-membered aromatic ring substituted or unsubstituted with R1 or R2, where R1 is selected from C. 1-5 Oxyalkyl, R2 is selected from C 1-5 Alkyl group, R3 is selected from 5- to 10-membered aromatic heterocycles or 5- to 10-membered aliphatic heterocycles, and R1 and R2 can be linked together to form a ring;

[0013] n is 0 or 1.

[0014] In one embodiment of the present invention, the L includes, but is not limited to, the following structures:

[0015]

[0016] In one embodiment of the present invention, the A ring includes, but is not limited to, the following structures:

[0017]

[0018] in,

[0019] X4 and X7 can be independently selected from carbon atoms or nitrogen atoms;

[0020] X5 and X6 can be independently selected from carbon atoms, nitrogen atoms, or oxygen atoms;

[0021] n1 is either 0 or 1;

[0022] R4 and R5 are selected from hydrogen or connected to form a benzene ring that is substituted or unsubstituted by R.

[0023] In one embodiment of the present invention, when n is 0, ring A includes, but is not limited to, a benzene ring, a naphthalene ring, a pyridine ring, a benzoxazole ring, or a triazole ring, wherein when X1 or X2 is a nitrogen atom, A is a benzene ring, and when neither X1 nor X2 is a nitrogen atom, A is not a benzene ring; when n is 1 and L is selected from an amide bond or a secondary amine, ring A is a benzene ring; when n is 1 and L is an alkynyl methyl group, ring A is a pyridone ring; when n is 1 and L is selected from an alkynyl group, ring A includes, but is not limited to, pyrimidine-2,4(1H,3H)-dione, a pyridine ring, a pyrazole ring, a benzopyrazole ring, a pyridone ring, a benzofuran ring, or a quinoline ring.

[0024] In one embodiment of the present invention, the 5-10 member aromatic ring or 5-10 member heterocyclic ring in R includes a benzene ring or a tetrahydropyran ring; the C in R1 1-5 The oxoalkyl group is acetyl, and the C in R2 is... 1-5The alkyl group is methyl, and R1 can be connected to R2 to form a pyridone ring; the 5- to 10-membered aromatic heterocycle or 5- to 10-membered aliphatic heterocycle mentioned in R3 includes, but is not limited to, N-methylpyrrole ring, pyridine ring, tetrahydropyran ring, furan ring, tetrahydrofuran ring, oxazole ring, pyrrole ring, and benzoxazole ring.

[0025] In one embodiment of the present invention, the 3-arylpiperidine-2,6-dione compound represented by Formula I includes, but is not limited to, the following structures:

[0026]

[0027] The compounds of general formula I mentioned above in this invention can also exist in the form of their salts, which are converted into compounds of general formula I in vivo. For example, within the scope of this invention, the compounds of this invention are converted into pharmaceutically acceptable salt forms according to processes known in the art, and used in salt form.

[0028] All tautomers of compounds of general formula I of this invention are included within the scope of this invention. The compounds of this invention may exist in specific geometric or stereoisomer forms. Additional asymmetric carbon atoms may be present in alkyl or other substituents; all such isomers and mixtures thereof are included within the scope of this invention.

[0029] In one embodiment of the present invention, the pharmaceutically acceptable salt includes, but is not limited to, acid addition salts formed by the reaction of a 3-arylpiperidine-2,6-dione compound of Formula I with an acid; wherein the acid is selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, fumaric acid, salicylic acid, or phenylacetic acid;

[0030] In other embodiments of the present invention, the pharmaceutically acceptable salt further includes salts formed by a 3-arylpiperidine-2,6-dione compound of Formula I and an inorganic base (weak base), and organic salts formed by a 3-arylpiperidine-2,6-dione compound of Formula I and a basic amine; the inorganic base includes calcium hydroxide, magnesium hydroxide, or zinc hydroxide; the basic amine includes ethylenediamine, dimethylamine, triethanolamine, piperazine, arginine, lysine, or meglumine.

[0031] This invention also provides a method for preparing 3-arylpiperidine-2,6-dione compounds of Formula I as described above, their enantiomers, their diastereomers, their racemic mixtures, or pharmaceutically acceptable salts thereof, wherein the process route of the preparation method is as follows:

[0032]

[0033] Reagents and conditions: (a) N-bromosuccinimide, azobisisobutyronitrile, carbon tetrachloride, 80°C, 2h; (b) trimethylcyanosilane, tetra-n-butylammonium fluoride tetrahydrofuran solution (1M), tetrahydrofuran, room temperature, 3h; (c) sodium methoxide, tert-butyl acrylate, tetrahydrofuran, room temperature, 6h; (d) corresponding borate esters, cesium carbonate, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, dioxane / water = 5 / 1, 100°C, 8h; (e) acetic acid, concentrated sulfuric acid, 90°C, 3h; (f) reduced iron powder, ammonium chloride, ethanol / water = 3 / 1, 80°C, 4h; (g) sodium nitrite, concentrated hydrochloric acid, potassium iodide, 0°C , 12h; (h) corresponding alkyne, cuprous iodide, bis(triphenylphosphine) palladium dichloride, triethylamine, room temperature, 8h; (i) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, N,N-dimethylformamide, 25℃, 8h; (j) tetra(triphenylphosphine) palladium, 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, cesium carbonate, dioxane, 100℃, 6h; (k) tetrahydrofuran, tetra-n-butylammonium fluoride tetrahydrofuran solution (1M), room temperature, 3h; (l) sodium ascorbate, copper sulfate pentahydrate, corresponding azide, tert-butanol, water, room temperature, 12h.

[0034] Unless otherwise specified in the route, X1, X2, X3, and R are defined as in general formula I; ring A in the route represents the other ring system mentioned, excluding triazole, and X8 is bromine or iodine.

[0035] Based on the feasibility of the preparation process and the availability of raw materials, the compound of general formula I of this invention is prepared by the different routes mentioned above. When n = 0 in general formula I and ring A is not triazole, the compound is prepared by route one; when n = 1 in general formula I and L is... or When the compound is prepared via route two; when n = 1 in general formula I and L is... When X3 is a hydrogen atom, it can also be obtained through route one via the intermediate. Preparation is carried out; when n = 1 in general formula I and L is When the compound is prepared via route three; when n = 1 in general formula I and L is... When n = 0 in general formula I and ring A is triazole, the compound is prepared by route four.

[0036] All compounds of general formula I of this invention can be prepared by the methods described above or similarly described, with the appropriate starting materials selected according to the different substituents and their positions. Those skilled in the art should recognize that the above-described route helps in understanding this invention, but does not limit its scope; unless otherwise specified, variables are defined as mentioned in general formula I.

[0037] The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a 3-arylpiperidine-2,6-dione compound of Formula I described above, its enantiomer, its diastereomer, its racemic mixture or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0038] The pharmaceutical compositions of the present invention can be administered in various known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical compositions of the present invention can be administered alone or in combination with other drugs. Oral compositions can be any orally acceptable dosage form, including, but not limited to, tablets, capsules, emulsions, suspensions, dispersions, and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, etc.

[0039] Sterile injectable compositions may be formulated using suitable dispersants or wetting agents and suspending agents in accordance with techniques known in the art. Pharmaceutically acceptable carriers and solvents that may be used include water, mannitol, sodium chloride solution, etc.

[0040] Topical compositions can be formulated as oils, lotions, creams, etc. Carriers used in the compositions include vegetable or mineral oils, animal fats, and high molecular weight alcohols. Pharmaceutically acceptable carriers are those in which the active ingredient is soluble.

[0041] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and route of administration, and is non-toxic to the patient. The selected dosage level depends on a variety of factors, including the activity of the specific compound of the present invention or its salt used, the route of administration, the time of administration, the excretion rate of the specific composition used, the duration of treatment, other drugs, compounds, and / or materials used in combination with the specific composition used, the age, sex, weight, general health condition, and medical history of the patient being treated, and similar factors known in the medical field.

[0042] The present invention also provides the use of a 3-arylpiperidine-2,6-dione compound of formula I as described above, its enantiomers, its diastereomers, its racemic mixtures, or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described above, said use being selected from (1) or (2):

[0043] (1) Preparation of VAV1 protein molecular glue degrading agent;

[0044] (2) Prepare drugs for the prevention and / or treatment of inflammatory diseases and autoimmune diseases related to VAV1 protein function.

[0045] In one embodiment of the present invention, the inflammatory diseases and autoimmune diseases associated with VAV1 protein function include systemic lupus erythematosus (SLE), familial frostbite lupus erythematosus (FCL), amyotrophic lateral sclerosis (ALS), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, nerve damage, rheumatoid arthritis, renal fibrosis, systemic sclerosis, intervertebral disc degeneration, pulmonary fibrosis, psoriasis, inflammatory bowel disease, autoimmune colitis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, uveitis, and mucositis.

[0046] Compared with the prior art, the beneficial effects of the present invention are:

[0047] This invention provides a 3-arylpiperidine-2,6-dione VAV1 molecular gel degrader, including its chemical structure, synthesis method, and bioactivity data, offering a novel therapeutic approach for inflammatory diseases, including inflammatory bowel disease, and autoimmune diseases. This class of compounds can effectively degrade VAV1 protein in Jurkat cells, demonstrating potential for treating inflammatory diseases and autoimmune diseases, including inflammatory bowel disease. Attached Figure Description

[0048] Figure 1 To detect the VAV1 protein degradation activity of representative compound 5 by Western blotting;

[0049] Figure 2 To detect the VAV1 protein degradation activity of the representative compound 12 by Western blotting. Detailed Implementation

[0050] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0051] The starting materials and reaction reagents used in the specific embodiments of this invention are all commercially available. This invention can be prepared into a salt form using methods commonly used in the art, such as: dissolving the compound in hydrochloric acid-ethanol at room temperature to generate hydrochloride; or adding benzenesulfonic acid to generate benzenesulfonate.

[0052] Experimental methods in the embodiments of this invention that do not specify specific conditions are generally performed under conventional conditions or under conditions recommended by the raw material or product manufacturer.

[0053] The structures of all compounds in the examples were determined by proton nuclear magnetic resonance (NMR) spectroscopy. 1¹H NMR was determined using a Bruker Avance 300MHz spectrometer with TMS as an internal standard at a recording temperature of 300K. Compound purity was assessed by reversed-phase HPLC (Agilent 1260, Hanbang C18 4.6×150mm, 5μm) with an elution system of methanol:water = 80:20 (v / v).

[0054] Unless otherwise specified in the examples, all reactions were carried out in an air atmosphere.

[0055] Unless otherwise specified in the examples, "solution" refers to an aqueous solution.

[0056] Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20-30°C.

[0057] Example 1

[0058] Preparation of 3-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)piperidin-2,6-dione (Compound 1)

[0059] Step 1: Preparation of 2-bromo-6-(bromomethyl)pyridine

[0060]

[0061] 2-Bromo-6-methylpyridine (3 g, 7.54 mmol) and azobisisobutyronitrile (287 mg, 0.75 mmol) were dissolved in carbon tetrachloride (40 mL). N-bromosuccinimide (1.33 g, 7.54 mmol) was added under ice bath conditions. The mixture was stirred at room temperature for 10 minutes, then the temperature was increased to 80 °C for 2 h. After the reaction was complete, the solid was filtered off, and the filtrate was evaporated to dryness under vacuum. The filtrate was extracted three times with ethyl acetate (100 mL) and water (100 mL). The combined organic phases were dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under vacuum in silica gel to prepare a sand, which was then purified by rapid silica gel column chromatography with petroleum ether to give 1.27 g of a white oil, with a yield of 67.77%. 1 H NMR (300MHz, Chloroform-d) δ7.56 (t, J = 7.7Hz, 1H), 7.46–7.38 (m, 2H), 4.50 (s, 2H).

[0062] Step 2: Preparation of 2-(6-bromopyridin-2-yl)acetonitrile

[0063]

[0064] 2-Bromo-6-(bromomethyl)pyridine (1.2 g, 4.82 mmol) was dissolved in tetrahydrofuran (20 mL). Trimethylcyanosilane (717 mg, 7.23 mmol) and tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 7 mL) were added under ice bath conditions, and the reaction was carried out at room temperature for 3 h. After the reaction was complete, the reaction solution was evaporated to dryness under vacuum using silica gel to obtain sand. The sand was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to give 705 mg of a white solid, with a yield of 74.62%. 1 H NMR (300MHz, Chloroform-d) δ7.62 (t, J = 7.7 Hz, 1H), 7.47 (t, J = 6.9 Hz, 2H), 3.94 (s, 2H).

[0065] Step 3: Preparation of tert-butyl 4-(6-bromopyridin-2-yl)-4-cyanobutyrate

[0066]

[0067] 2-(6-bromopyridin-2-yl)acetonitrile (705 mg, 3.59 mmol) and sodium methoxide were dissolved in tetrahydrofuran (20 mL), and the mixture was reacted in an ice bath for 10 minutes. Then, a tetrahydrofuran solution (10 mL) of tert-butyl acrylate (717 mg, 7.23 mmol) was slowly added dropwise to the reaction mixture at room temperature, and the reaction was continued for 6 hours. After the reaction was complete, the reaction mixture was evaporated to dryness under vacuum using silica gel to obtain a white oily substance (615 mg, 52.11%). The oil was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (20 / 1) to give 615 mg of the white oily substance. 1 HNMR(300MHz,Chloroform-d)δ7.55(t,J=7.6Hz,1H),7.51–7.45(m,1H),7.24(dd,J=7 .6,1.2Hz,1H),4.40–4.31(m,1H),2.59–2.45(m,2H),2.45–2.28(m,2H),1.42(s,9H).

[0068] Step 4: Preparation of tert-butyl-4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate

[0069]

[0070] tert-butyl 4-(6-bromopyridin-2-yl)-4-cyanobutyrate (600 mg, 1.85 mmol), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)phenyl)pyridin-2(1H)-one (549 mg, 1.85 mmol), and cesium carbonate (1.8 g, 5.55 mmol) were dissolved in dioxane (10 mL) and water (2 mL). Under nitrogen protection, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (67.7 mg, 0.092 mmol) was added. The reaction mixture was reacted at 100 °C for 8 h. After the reaction was complete, the mixture was extracted three times with ethyl acetate (100 mL) and water (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was added to silica gel and dried under vacuum to prepare sand. The sand was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (2 / 1) to obtain 154 mg of yellow oil, with a yield of 20.05%. 1 H NMR(300MHz,Chloroform-d)δ8.11–8.05(m,2H),7.72(dd,J=7.5,1.3Hz,1H),7.65(t,J=7.5Hz,1H),7.59–7.53(m,2H),7.56–7.50(m,2H),7. 34–7.26(m,1H),6.36(t,J=7.5,0.7Hz,1H),6.23(d,J=9.2,0.7Hz,1H) ,4.45–4.39(m,1H),2.59–2.45(m,2H),2.44–2.27(m,2H),1.42(s,9H).

[0071] Step 5: Preparation of 3-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)piperidin-2,6-dione

[0072]

[0073] 150 mg (0.36 mmol) of tert-butyl-4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate was dissolved in glacial acetic acid (2 mL), and concentrated sulfuric acid (0.4 mL) was added. The reaction solution was reacted at 90 °C for 6 h. After the reaction was completed, the reaction solution was poured into ice water (5 mL), and saturated sodium bicarbonate solution (9 mL) was added dropwise. A yellow solid precipitated out. The solid was filtered to give 20 mg, with a yield of 15.47%. 1H NMR (300MHz, DMSO-d6) δ11.01(s,1H),8.19(d,J=8.1Hz,2H),8.08–7.89(m,2H),7.71(d,J=6.9Hz,1H),7.54(d,J=8.0 Hz,3H),7.43(d,J=6.8Hz,1H),6.51(d,J=9.1Hz,1H),6.35(t,J=6.9Hz,1H),3.97(t,J=7.2Hz,1H),2.32–2.11(m,4H).

[0074] Example 2

[0075] Preparation of 3-(5-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-3-yl)piperidin-2,6-dione (Compound 2)

[0076] Step 1: Preparation of 3-bromo-5-(bromomethyl)pyridine

[0077]

[0078] The procedure was the same as step one in Example 1, except that 2-bromo-6-methylpyridine was replaced with 3-bromo-5-methylpyridine (3g, 7.54mmol), and the product was purified by rapid silica gel column chromatography with petroleum ether to obtain 1.46g of white oil, with a yield of 77.90%. 1 HNMR (300MHz, Chloroform-d) δ8.55–8.49 (m, 2H), 7.71 (t, J = 2.0Hz, 1H), 4.49 (s, 2H).

[0079] Step 2: Preparation of 2-(5-bromopyridin-3-yl)acetonitrile

[0080]

[0081] The procedure was the same as step two in Example 1, except that 2-bromo-6-(bromomethyl)pyridine was replaced with 3-bromo-5-(bromomethyl)pyridine (1.4 g, 5.62 mmol). After the reaction was complete, the reaction solution was added to silica gel and evaporated to dryness under vacuum. The resulting solid was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to obtain 814 mg of a white solid, with a yield of 73.89%. 1 H NMR (300MHz, Chloroform-d) δ8.57–8.51 (m, 2H), 7.69 (t, J = 2.0Hz, 1H), 3.90 (s, 2H).

[0082] Step 3: Preparation of tert-butyl 4-(5-bromopyridin-3-yl)-4-cyanobutyrate

[0083]

[0084] The procedure was the same as step three in Example 1, except that 2-(6-bromopyridin-2-yl)acetonitrile was replaced with 2-(5-bromopyridin-3-yl)acetonitrile (800 mg, 4.07 mmol). After the reaction was complete, the reaction solution was dried under vacuum using silica gel to obtain sand, which was then purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (20 / 1) to give 645 mg of a white oil, with a yield of 48.91%. 1 H NMR(300MHz,Chloroform-d)δ8.58(t,J=1.6Hz,1H),8.55–8.50(m,1H),7.87(dd,J=2.1,1 .4Hz,1H),4.37(t,J=7.0,6.1Hz,1H),2.53–2.39(m,2H),2.34–2.22(m,2H),1.42(s,9H).

[0085] Step 4: Preparation of tert-butyl-4-cyano-4-(5-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-3-yl)butyrate

[0086]

[0087] The procedure was the same as step four in Example 1, except that tert-butyl 4-(6-bromopyridin-2-yl)-4-cyanobutyrate was replaced with tert-butyl 4-(5-bromopyridin-3-yl)-4-cyanobutyrate (600 mg, 1.85 mmol). The organic phase was added to silica gel and evaporated under vacuum to obtain sand. The sand was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (2 / 1) to obtain 114 mg of yellow oil, with a yield of 14.84%. 1 H NMR(300MHz,Chloroform-d)δ8.61(t,J=1.6Hz,1H),8.50–8.46(m,1H),7.98( dd,J=2.1,1.4Hz,1H),7.75–7.70(m,1H),7.69–7.63(m,2H),7.55–7.49(m,2H ),7.34–7.26(m,1H),6.36(t,J=7.5,0.7Hz,1H),6.23(d,J=9.2,0.7Hz,1H),4 .38(t,J=6.9,6.2Hz,1H),2.53–2.39(m,2H),2.34–2.22(m,2H),1.42(s,9H).

[0088] Step 5: Preparation of 3-(5-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-3-yl)piperidine-2,6-dione

[0089]

[0090] The procedure was the same as step five in Example 1, except that tert-butyl 4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate was replaced with tert-butyl 4-cyano-4-(5-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-3-yl)butyrate (110 mg, 0.26 mmol). 7 mg of a yellow solid was obtained, with a yield of 7.49%. 1 H NMR(300MHz,Chloroform-d)δ9.63(s,1H),8.61(t,J=1.7Hz,1H),8.31(t,J=1.9Hz,1H),7.79–7.75(m,1H),7.75–7.70(m,1H),7.69–7.63(m,2H),7.55– 7.49(m,2H),7.34–7.26(m,1H),6.36(t,J=7.5,0.7Hz,1H),6.23(d,J=9.2,0 .7Hz,1H),3.65(d,J=6.5,5.7Hz,1H),2.56–2.48(m,2H),2.17–2.02(m,2H).

[0091] Example 3

[0092] Preparation of 3-(4-chloro-5-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-3-yl)piperidin-2,6-dione (Compound 3)

[0093] Step 1: Preparation of 3-bromo-5-(bromomethyl)-4-chloropyridine

[0094]

[0095] The procedure was the same as step one in Example 1, except that 2-bromo-6-methylpyridine was replaced with 3-bromo-4-chloro-5-methylpyridine (912 mg, 4.44 mmol), and the product was purified by rapid silica gel column chromatography with petroleum ether to obtain 900 mg of white oil, with a yield of 71.62%. 1 HNMR(300MHz,Chloroform-d)δ8.49–8.43(m,2H),4.58(s,2H).

[0096] Step 2: Preparation of 2-(5-bromo-4-chloropyridin-3-yl)acetonitrile

[0097]

[0098] The procedure was the same as step two in Example 1, except that 2-bromo-6-(bromomethyl)pyridine was replaced with 3-bromo-5-(bromomethyl)-4-chloropyridine (900 mg, 3.18 mmol). After the reaction was complete, the reaction solution was added to silica gel and evaporated to dryness under vacuum. The resulting solid was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to obtain 387 mg of a white solid, with a yield of 52.90%. 1 H NMR(300MHz,Chloroform-d)δ8.50–8.45(m,2H),4.04(s,2H).

[0099] Step 3: Preparation of tert-butyl 4-(5-bromo-4-chloropyridin-3-yl)-4-cyanobutyrate

[0100]

[0101] The procedure was the same as step three in Example 1, except that 2-(6-bromopyridin-2-yl)acetonitrile was replaced with 2-(5-bromo-4-chloropyridin-3-yl)acetonitrile (380 mg, 1.65 mmol). After the reaction was complete, the reaction solution was dried under vacuum using silica gel to obtain sand, which was then purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (20 / 1) to give 349 mg of a white oil, with a yield of 58.91%. 1 H NMR (300MHz, Chloroform-d) δ8.62(d,J=1.6Hz,1H),8.53(d,J=1.8Hz,1H),4.18(t,J=6.7Hz,1H),2.57–2.43(m,2H),2.40–2.27(m,2H),1.42(s,9H).

[0102] Step 4: Preparation of tert-butyl 4-(4-chloro-5-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-3-yl)-4-cyanobutyrate

[0103]

[0104] The procedure was the same as step four in Example 1, except that tert-butyl 4-(6-bromopyridin-2-yl)-4-cyanobutyrate was replaced with tert-butyl 4-(5-bromo-4-chloropyridin-3-yl)-4-cyanobutyrate (349 mg, 0.97 mmol). The organic phase was added to silica gel and evaporated under vacuum to obtain sand. The sand was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (2 / 1) to obtain 180 mg of yellow solid, with a yield of 41.32%. 1H NMR(300MHz,Chloroform-d)δ8.79(d,J=1.8Hz,1H),8.59(d,J=1.6Hz,1H),7.72(dd,J=7.5,1.3Hz,1H),7.66–7.60(m,2H),7.53–7.47(m,2H),7.3 4–7.26(m,1H),6.36(td,J=7.5,0.7Hz,1H),6.23(dd,J=9.1,0.7Hz,1H), 4.47(t,J=6.7Hz,1H),2.56–2.42(m,2H),2.41–2.30(m,2H),1.42(s,9H).

[0105] Step 5: Preparation of 3-(4-chloro-5-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-3-yl)piperidin-2,6-dione

[0106]

[0107] The procedure was the same as step five in Example 1, except that tert-butyl 4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate was replaced with tert-butyl 4-(4-chloro-5-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-3-yl)-4-cyanobutyrate (180 mg, 0.4 mmol). 8 mg of a yellow solid was obtained, with a yield of 5.09%. 1 H NMR(300MHz,Chloroform-d)δ8.54(s,1H),8.47(s,1H),8.06(s,1H),7.56(q,J=8.3Hz,4H),7.42(d,J=7.3Hz,2H),6.70( d,J=9.1Hz,1H),6.29(d,J=6.9Hz,1H),4.22(d,J=11.7Hz,1H),2.94–2.71(m,2H),2.53–2.39(m,1H),2.36–2.26(m,1H).

[0108] Example 4

[0109] Preparation of 3-(3-(3-(2-oxopyridin-1(2H)-yl)prop-1-yn-1-yl)phenyl)piperidin-2,6-dione (Compound 4)

[0110] Step 1: Preparation of tert-butyl-4-cyano-4-(3-iodophenyl)butyrate

[0111]

[0112] The procedure was the same as step three in Example 1, except that 2-bromo-6-methylpyridine was replaced with 2-(3-iodophenyl)acetonitrile (1 g, 4.11 mmol), and the mixture was purified by rapid silica gel column chromatography with petroleum ether to obtain 700 mg of white solid, with a yield of 54.06%. 1 H NMR(300MHz,Chloroform-d)δ7.73–7.66(m,2H),7.32(d,J=5.2Hz,1H),7.15–7.10( m,1H),3.93(t,J=7.5Hz,1H),2.51–2.30(m,2H),2.14(q,J=7.3Hz,2H),1.46(s,9H).

[0113] Step 2: Preparation of 3-(3-iodophenyl)piperidine-2,6-dione

[0114]

[0115] The procedure was the same as step five in Example 1, except that 2-bromo-6-(bromomethyl)pyridine was replaced with tert-butyl-4-cyano-4-(3-iodophenyl)butyrate (700 mg, 2.22 mmol). After the reaction was complete, the reaction solution was added to silica gel and evaporated to dryness under vacuum. The resulting solid was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (5 / 1) to give 319 mg of a white solid, with a yield of 41.17%. 1 H NMR(300MHz,Chloroform-d)δ9.63(s,1H),7.67(dt,J=7.3,1.5Hz,1H),7.50(td,J=1.9,0.7Hz,1H),7.29–7.23(m,1H),7. 23–7.16(m,1H),3.78(dd,J=6.1,5.4Hz,1H),2.71–2.62(m,1H),2.55–2.46(m,1H),2.09–1.99(m,1H),1.87–1.77(m,1H).

[0116] Step 3: Preparation of 3-(3-(3-(2-oxopyridin-1(2H)-yl)prop-1-yn-1-yl)phenyl)piperidin-2,6-dione

[0117]

[0118] Cuprous iodide (9.3 mg, 0.049 mmol) and palladium dichloride bis(triphenylphosphine) (69 mg, 0.098 mmol) were placed in a reaction flask under nitrogen protection, and a solution of 3-(3-iodophenyl)piperidin-2,6-dione (310 mg, 0.98 mmol) and 1-(2-propyn-1-yl)pyridin-2(1H)-one (262 mg, 1.97 mmol) in triethylamine (5 mL) was added. The reaction mixture was stirred at room temperature for 8 h. After the reaction was completed, ethyl acetate (100 mL) and water (100 mL) were added for extraction three times. The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under vacuum in silica gel to prepare a precipitate, which was purified by rapid silica gel column chromatography with ethyl acetate / petroleum ether (2 / 1) to give 27 mg of white solid, with a yield of 8.57%. 1 H NMR(300MHz,Chloroform-d)δ8.01(s,1H),7.71(d,J=6.8Hz,1H),7.48–7.30(m,4H),7.21(d,J=7.8Hz,1H),6.64(d, J=9.3Hz,1H),6.28(t,J=6.8Hz,1H),4.99(s,2H),3.76(dd,J=9.7,5.6Hz,1H),2.86–2.57(m,2H),2.42–2.15(m,2H).

[0119] Example 5

[0120] Preparation of 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 5)

[0121] Step 1: Preparation of 1-bromo-3-(bromomethyl)-2-chlorobenzene

[0122]

[0123] The procedure was the same as step one in Example 1, except that 2-bromo-6-methylpyridine was replaced with 1-bromo-3-methyl-2-chlorobenzene (10 g, 48.67 mmol), and the product was purified by rapid silica gel column chromatography with petroleum ether to obtain 8.8 g of white oil, with a yield of 63.59%. 1 HNMR (300MHz, Chloroform-d) δ7.56 (dd, J=8.1, 1.6Hz, 1H), 7.37 (dd, J=7.7, 1.6Hz, 1H), 7.09 (t, J=7.8Hz, 1H), 4.59 (s, 2H).

[0124] Step 2: Preparation of 2-(3-bromo-2-chlorophenyl)acetonitrile

[0125]

[0126] The procedure was the same as step two in Example 1, except that 2-bromo-6-(bromomethyl)pyridine was replaced with 1-bromo-3-(bromomethyl)-2-chlorobenzene (8.8 g, 30.9 mmol). After the reaction was complete, the reaction solution was dried under vacuum using silica gel to obtain sand, which was then purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to give 5.64 g of a white solid, with a yield of 79.07%. 1 H NMR (300MHz, Chloroform-d) δ7.65(d,J=7.9Hz,1H),7.50(d,J=7.6Hz,1H),7.20(t,J=7.9Hz,1H),3.90(s,2H).

[0127] Step 3: Preparation of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate

[0128]

[0129] The procedure was the same as step three in Example 1, except that 2-(6-bromopyridin-2-yl)acetonitrile was replaced with 2-(3-bromo-2-chlorophenyl)acetonitrile (5.64 g, 24.47 mmol). After the reaction was complete, the reaction solution was dried under vacuum using silica gel to obtain sand, which was then purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (20 / 1) to give 5.4 g of a white oily substance, with a yield of 61.53%. 1 H NMR(300MHz,Chloroform-d)δ7.73(ddd,J=9.3,7.7,1.6Hz,2H),7.41(t,J=7.7Hz,1 H),4.57(dd,J=8.8,5.7Hz,1H),2.54–2.36(m,2H),2.32–2.06(m,2H),1.45(s,9H).

[0130] Step 4: Preparation of tert-butyl 4-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)-4-cyanobutyrate

[0131]

[0132] The procedure was the same as step four in Example 1, except that tert-butyl 4-(6-bromopyridin-2-yl)-4-cyanobutyrate was replaced with tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (500 mg, 1.39 mmol), and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)pyridin-2(1H)-one was replaced with 1-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphthyl-2-yl)pyridin-2(1H)-one (482 mg, 1.39 mmol). The organic phase was added to silica gel and evaporated under vacuum to obtain sand. The sand was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (2 / 1) to give 227 mg of yellow solid, with a yield of 32.63%. 1 H NMR(300MHz,Chloroform-d)δ8.23(t,J=2.0Hz,1H),8.08–8.03(m,1H),7.87(dd,J=9.1,2.3H z,1H),7.78(dd,J=7.9,1.8Hz,1H),7.70(dd,J=7.5,1.3Hz,1H),7.68–7.62(m,2H),7.54(dd,J =9.1,2.2Hz,1H),7.44–7.37(m,2H),7.34–7.26(m,1H),6.36(td,J=7.4,0.9Hz,1H),6.24(dd ,J=9.1,1.0Hz,1H),4.42(t,J=6.3Hz,1H),2.56–2.42(m,2H),2.35–2.27(m,2H),1.42(s,9H).

[0133] Step 5: Preparation of 3-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)piperidin-2,6-dione

[0134]

[0135] The procedure was the same as step five in Example 1, except that tert-butyl 4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate was replaced with tert-butyl 4-(2-chloro-3-(6-(2-oxopyridin-1(2H)-yl)naphth-2-yl)phenyl)-4-cyanobutyrate (220 mg, 0.44 mmol). 20 mg of a yellow solid was obtained, with a yield of 10.24%. 1H NMR (300MHz, DMSO-d6) δ8.84(s,1H),8.15–7.94(m,4H),7.79(d,J=6.8Hz,1H),7.69–7.51(m,4H),7.44(d,J=9.8Hz,2H), 6.54(d,J=9.3Hz,1H),6.40(d,J=7.5Hz,1H),4.08(q,J=7.2,6.4Hz,1H),2.32(d,J=8.3Hz,2H),2.24(s,1H),1.98(s,1H).

[0136] Example 6

[0137] Preparation of 3-(2-chloro-3-(2-oxo-2H-[1,3'-bipyridin]-6'-yl)phenyl)piperidin-2,6-dione (Compound 6)

[0138] Step 1: Preparation of tert-butyl 4-(2-chloro-3-(2-oxo-2H-[1,3'-bipyridin]-6'-yl)phenyl)-4-cyanobutyrate

[0139]

[0140] The procedure was the same as step four in Example 1, except that tert-butyl 4-(6-bromopyridin-2-yl)-4-cyanobutyrate was replaced with tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate (500 mg, 1.39 mmol), and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)phenyl)pyridin-2(1H)-one was replaced with 6'-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)-2H-[1,3'-bipyridin]-2-one (415 mg, 1.39 mmol). The organic phase was added to silica gel and evaporated under vacuum to obtain sand. The sand was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (2 / 1) to give 164 mg of yellow solid, with a yield of 26.15%. 1 H NMR(300MHz,Chloroform-d)δ9.12(s,1H),7.95–7.86(m,2H),7.75(dd,J=7.8,2.3Hz,1H),7.71(dd,J=7.5,1.3Hz,1H),7.49–7.42(m,1H),7.27– 7.20(m,1H),6.45(td,J=7.5,1.0Hz,1H),6.24(dd,J=9.2,0.9Hz,1H),4 .42(t,J=6.3Hz,1H),2.56–2.42(m,2H),2.35–2.27(m,2H),1.42(s,9H).

[0141] Step 2: Preparation of 3-(2-chloro-3-(2-oxo-2H-[1,3'-bipyridin]-6'-yl)phenyl)piperidin-2,6-dione

[0142]

[0143] The procedure was the same as step five in Example 1, except that tert-butyl 4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate was replaced with tert-butyl 4-(2-chloro-3-(2-oxo-2H-[1,3'-bipyridin]-6'-yl)phenyl)-4-cyanobutyrate (160 mg, 0.35 mmol). 10 mg of a yellow solid was obtained, with a yield of 7.14%. 1 H NMR(300MHz,Chloroform-d)δ8.60(s,1H),8.07(s,1H),8.02–7.85(m,2H),7.67–7.52(m,1H),7.52–7 .35(m,5H),6.68(d,J=9.3Hz,1H),6.35(d,J=7.8Hz,1H),3.67(s,1H),2.37(s,3H),2.27–2.12(m,1H).

[0144] Example 7

[0145] Preparation of 3-(2-chloro-3-((4-(2-oxopyridin-1(2H)-yl)phenyl)amino)phenyl)piperidin-2,6-dione (Compound 7)

[0146] Step 1: Preparation of 1-(bromomethyl)-2-chloro-3-nitrobenzene

[0147]

[0148] The procedure was the same as step one in Example 1, except that 2-bromo-6-methylpyridine was replaced with 2-chloro-1-methyl-3-nitrobenzene (10 g, 58.28 mmol), and the product was purified by rapid silica gel column chromatography with petroleum ether to obtain 8.0 g of white oil, with a yield of 54.80%. 1 H NMR (300MHz, DMSO-d6) δ8.02(dd,J=8.0,1.6Hz,1H),7.95(dd,J=7.8,1.6Hz,1H),7.62(t,J=7.9Hz,1H),4.85(s,2H).

[0149] Step 2: Preparation of 2-(2-chloro-3-nitrophenyl)acetonitrile

[0150]

[0151] The procedure was the same as step two in Example 1, except that 2-bromo-6-(bromomethyl)pyridine was replaced with 1-(bromomethyl)-2-chloro-3-nitrobenzene (8.0 g, 31.9 mmol). After the reaction was complete, the reaction solution was dried under vacuum using silica gel to obtain sand, which was then purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to give 6.2 g of a white solid, with a yield of 98.74%. 1 H NMR (300MHz, DMSO-d6) δ8.06(dd,J=8.2,1.6Hz,1H),7.87(dd,J=7.8,1.6Hz,1H),7.67(t,J=7.9Hz,1H),4.27(s,2H).

[0152] Step 3: Preparation of tert-butyl 4-(2-chloro-3-nitrophenyl)-4-cyanobutyrate

[0153]

[0154] The procedure was the same as step three in Example 1, except that 2-(6-bromopyridin-2-yl)acetonitrile was replaced with 2-(2-chloro-3-nitrophenyl)acetonitrile (6.2 g, 31.54 mmol). After the reaction was complete, the reaction solution was dried under vacuum using silica gel to obtain sand, which was then purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (20 / 1) to give 6.09 g of a white oil, with a yield of 59.46%. 1 H NMR (300MHz, Chloroform-d) δ7.86–7.74(m,2H),7.52(t,J=8.0Hz,1H),4.58(dd,J=9.1,5.6Hz,1H),2.56–2.40(m,2H),2.30–2.09(m,2H),1.46(s,9H).

[0155] Step 4: Preparation of 3-(2-chloro-3-nitrophenyl)piperidine-2,6-dione

[0156]

[0157] The procedure was the same as step five in Example 1, except that tert-butyl 4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate was replaced with tert-butyl 4-(2-chloro-3-nitrophenyl)-4-cyanobutyrate (6.09 g, 18.75 mmol). 3.89 g of a yellow solid was obtained, with a yield of 77.22%. 1H NMR (300MHz, DMSO-d6) δ11.02(s,1H),7.96(dd,J=7.9,1.6Hz,1H),7.71(dd,J=7.8,1.6Hz,1H),7.59(t,J=7.9Hz, 1H),4.42(dd,J=12.7,5.0Hz,1H),2.91–2.73(m,1H),2.60(t,J=3.6Hz,1H),2.48–2.29(m,1H),2.09–1.97(m,1H).

[0158] Step 5: Preparation of 3-(3-amino-2-chlorophenyl)piperidine-2,6-dione

[0159]

[0160] 3-(2-chloro-3-nitrophenyl)piperidin-2,6-dione (3.89 g, 14.48 mmol), reduced iron powder (3.24 g, 57.92 mmol), and ammonium chloride (38.3 mg, 0.72 mmol) were dissolved in ethanol (30 mL) and water (10 mL) and reacted at 80 °C for 4 h. After the reaction was complete, the iron powder was removed by filtration, the filtrate was evaporated to dryness with ethanol, and the mixture was extracted three times with ethyl acetate (100 mL) and water (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was dried under vacuum with silica gel to obtain a sand, which was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 1) to give 3.18 g of a yellow solid, with a yield of 92.02%. 1 H NMR

[0161] (300MHz, DMSO-d6) δ10.86(s,1H),6.96(d,J=8.5Hz,1H),6.73(s,1H),6.46(d,J=7.3Hz,

[0162] 1H),5.37(s,2H),4.14–4.03(m,1H),2.80–2.64(m,1H),2.33–2.15(m,1H),1.97(s,1H).

[0163] Step Six: Preparation of 3-(2-chloro-3-((4-(2-oxopyridin-1(2H)-yl)phenyl)amino)phenyl)piperidin-2,6-dione

[0164]

[0165] 3-(3-amino-2-chlorophenyl)piperidine-2,6-dione (200 mg, 0.83 mmol) and 1-(4-bromophenyl)pyridine-2(1H) were prepared.

[0166] 2-Bicyclohexylphosphine (209 mg, 0.83 mmol), tetraphenylphosphine palladium (48 mg, 0.042 mmol), 2-bis(cyclohexylphosphine)-2',4',6'-triisopropylbiphenyl (219 mg, 0.46 mmol), and cesium carbonate (546 mg, 1.68 mmol) were dissolved in dioxane (5 mL) under nitrogen protection and reacted at 100 °C for 6 h. After the reaction was complete, the mixture was extracted three times with ethyl acetate (100 mL) and water (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under vacuum in silica gel to obtain a sand, which was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 4) to give 19 mg of a yellow solid, with a yield of 5.56%. 1 H NMR

[0167] (300MHz, DMSO-d6) δ10.98(s,1H),8.03(s,1H),7.67(dd,J=7.1,2.0Hz,1H),7.60–7.48

[0168] (m,1H),7.36–7.26(m,4H),7.17(d,J=8.5Hz,2H),7.06–6.97(m,1H),6.52(d,J=9.2Hz,

[0169] 1H),6.35(t,J=6.9Hz,1H),4.33(dd,J=12.2,4.9Hz,1H),2.93–2.76(m,1H),2.63(s,1H),

[0170] 2.40(q,J=13.0,10.9Hz,1H),2.10(s,1H).

[0171] Example 8

[0172] Preparation of N-(2-chloro-3-(2,6-dioxopiridin-3-yl)phenyl)-4-(2-oxopiridin-1(2H)-yl)benzoyl (Compound 8)

[0173]

[0174] 4-(2-oxopyridin-1(2H)-yl)benzoic acid (180 mg, 0.83 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (478 mg, 1.26 mmol), and N,N-diisopropylethylamine (325 mg, 2.51 mmol) were dissolved in N,N-dimethylformamide (5 mL) under ice bath conditions. After activation for half an hour, 3-(3-amino-2-chlorophenyl)piperidin-2,6-dione (200 mg, 0.83 mmol) was added, and the mixture was stirred at room temperature for 12 h. After the reaction was complete, the mixture was extracted three times with ethyl acetate (100 mL) and water (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under vacuum in silica gel to obtain a sand, which was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 1) to give 13 mg of a yellow solid, with a yield of 3.56%. 1 H NMR (300MHz, DMSO-d6) δ10.93(s,1H),10.22(s,1H),8.12(d,J=8.2Hz,2H),7.73–7.50(m,4H),7.41(d,J=8.9Hz,2H),7.29( d,J=8.1Hz,1H),6.52(d,J=9.4Hz,1H),6.36(t,J=6.8Hz,1H),4.32(d,J=12.2Hz,1H),2.87–2.70(m,2H),2.34–2.19(m,2H).

[0175] Example 9

[0176] Preparation of 2-chloro-3-(2,6-dioxopiridin-3-yl)-N-(4-(2-oxopiridin-1(2H)-yl)phenyl)benzoyl (Compound 9)

[0177] Step 1: Preparation of methyl 3-(bromomethyl)-2-chlorobenzoate

[0178]

[0179] The procedure was the same as step one in Example 1, except that 2-bromo-6-methylpyridine was replaced with methyl-2-chloro-3-methylbenzoic acid (1 g, 54.17 mmol), and the product was purified by rapid silica gel column chromatography with petroleum ether to obtain 0.97 g of white oil, with a yield of 67.96%. 1 H NMR (300MHz, Chloroform-d) δ7.71(d,J=7.9Hz,1H),7.58(d,J=7.6Hz,1H),7.39–7.27(m,1H),4.64(s,2H),3.94(s,3H).

[0180] Step 2: Preparation of methyl 2-chloro-3-(cyanomethyl)benzoate

[0181]

[0182] The procedure was the same as step two in Example 1, except that 2-bromo-6-(bromomethyl)pyridine was replaced with methyl 3-(bromomethyl)-2-chlorobenzoate (0.97 g, 36.81 mmol), and the product was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to give 0.69 g of white solid, with a yield of 89.42%. 1 H NMR (300MHz, Chloroform-d) δ7.79(d,J=8.0Hz,1H),7.69(d,J=7.4Hz,1H),7.39(q,J=7.0,5.5Hz,1H),3.95(s,3H),3.91(s,2H).

[0183] Step 3: Preparation of methyl 3-(4-(tert-butoxy)-1-cyano-4-oxobutyl)-2-chlorobenzoic acid

[0184]

[0185] The procedure was the same as step three in Example 1, except that 2-(6-bromopyridin-2-yl)acetonitrile was replaced with methyl 2-chloro-3-(cyanomethyl)benzoate (690 mg, 3.59 mmol), and the product was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (20 / 1) to obtain 315 mg of white oil, with a yield of 28.33%. 1 H NMR(300MHz,Chloroform-d)δ7.73(ddd,J=9.3,7.7,1.6Hz,2H),7.41(t,J=7.7Hz,1H),4. 57(dd,J=8.8,5.7Hz,1H),3.95(s,3H),2.54–2.36(m,2H),2.32–2.06(m,2H),1.45(s,9H).

[0186] Step 4: Preparation of 2-chloro-3-(2,6-dioxadiazin-3-yl)benzoic acid

[0187]

[0188] The procedure was the same as step five in Example 1, except that tert-butyl 4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate was replaced with methyl 3-(4-(tert-butoxy)-1-cyano-4-oxobutyl)-2-chlorobenzoic acid (315 mg, 0.932 mmol), yielding 97 mg of a yellow solid, with a yield of 38.86%. 1H NMR (300MHz, DMSO-d6) δ10.96(s,1H),7.62(dd,J=7.4,1.8Hz,1H),7.50(dd,J=7.7,1.9Hz,1H),7.42(t,J=7.6Hz, 1H),4.36(dd,J=12.4,5.0Hz,1H),2.90–2.71(m,1H),2.59(t,J=3.6Hz,1H),2.44–2.25(m,1H),2.08–1.95(m,1H).

[0189] Step 5: Preparation of 2-chloro-3-(2,6-dioxopiridin-3-yl)-N-(4-(2-oxopiridin-1(2H)-yl)phenyl)benzoyl

[0190]

[0191] The procedure was the same as in Example 8, except that 3-(3-amino-2-chlorophenyl)piperidin-2,6-dione was replaced with 1-(4-aminophenyl)pyridin-2(1H)-one (67 mg, 0.36 mmol) and 4-(2-oxopyridin-1(2H)-yl)benzoic acid was replaced with 2-chloro-3-(2,6-dioxopyridin-3-yl)benzoic acid (97 mg, 0.36 mmol). The mixture was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 1) to give 16 mg of a yellow solid, with a yield of 10.13%. 1 H NMR (300MHz, DMSO-d6) δ10.96(s,1H),10.76(s,1H),7.89–7.79(m,2H),7.63(d,J=6.9Hz,1H),7.49(d,J=8.6Hz,4H),7.43–7.35(m,2 H),6.48(d,J=9.3Hz,1H),6.37–6.26(m,1H),4.36(d,J=8.8Hz,1H),2.90–2.71(m,1H),2.58(s,1H),2.40–2.26(m,1H),2.03(s,1H).

[0192] Example 10

[0193] Preparation of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)benzo[d]oxazol-2-yl)phenyl)piperidin-2,6-dione (Compound 10)

[0194] Step 1: Preparation of 5-bromo-2-(2-chloro-3-methylphenyl)benzo[d]oxazole

[0195]

[0196] 2-Chloro-3-methylbenzoic acid (10 g, 58.62 mmol) and 2-amino-4-bromophenol (11.02 g, 58.62 mmol) were dissolved in polyphosphoric acid, and the mixture was heated to 140 °C and reacted for 6 h. After the reaction was complete, the mixture was extracted three times with ethyl acetate (200 mL) and water (500 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under vacuum in silica gel to obtain a white solid, which was then purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (5 / 1) to give 9.6 g of white solid, with a yield of 50.77%. 1 H NMR (300MHz, Chloroform-d) δ8.00(s,1H),7.93(d,J=8.1Hz,1H),7.52(d,J=1.5Hz,2H),7.46(d,J=7.6Hz,1H),7.34(t,J=7.7Hz,1H),2.52(s,3H).

[0197] Step 2: Preparation of 5-bromo-2-(3-(bromomethyl)-2-chlorophenyl)benzo[d]oxazole

[0198]

[0199] The procedure was the same as step one in Example 1, except that 2-bromo-6-methylpyridine was replaced with 5-bromo-2-(2-chloro-3-methylphenyl)benzo[d]oxazole (9.6 g, 29.76 mmol), and the mixture was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to give 7.2 g of white solid, with a yield of 60.26%. 1 H NMR (300MHz, DMSO-d6) δ8.18(d,J=2.0Hz,1H),8.11(dd,J=7.8,1.7Hz,1H),7.98–7.80(m,2H),7.73–7.56(m,2H),4.90(s,2H).

[0200] Step 3: Preparation of 2-(3-(5-bromobenzo[d]oxazol-2-yl)-2-chlorophenyl)acetonitrile

[0201]

[0202] The procedure was the same as step two in Example 1, except that 2-bromo-6-(bromomethyl)pyridine was replaced with 5-bromo-2-(3-(bromomethyl)-2-chlorophenyl)benzo[d]oxazole (7.2 g, 17.93 mmol), and the mixture was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (10 / 1) to give 3.9 g of yellow solid, with a yield of 62.56%. 1H NMR (300MHz, DMSO-d6) δ8.19–8.07(m,2H),7.88–7.78(m,2H),7.71–7.58(m,2H),4.25(s,2H).

[0203] Step 4: Preparation of tert-butyl 4-(3-(5-bromobenzo[d]oxazol-2-yl)-2-chlorophenyl)-4-cyanobutyrate

[0204]

[0205] The procedure was the same as step three in Example 1, except that 2-(6-bromopyridin-2-yl)acetonitrile was replaced with 2-(3-(5-bromobenzo[d]oxazol-2-yl)-2-chlorophenyl)acetonitrile (3.9 g, 11.22 mmol), and purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (20 / 1) to obtain 1.28 g of yellow solid, with a yield of 23.98%. 1 H NMR(300MHz,Chloroform-d)δ7.89–7.81(m,1H),7.74(d,J=1.7Hz,1H),7.62(dd,J=9.0,1.8Hz,1H),7.57(d ,J=8.8Hz,1H),7.52–7.44(m,2H),4.42(t,J=6.3Hz,1H),2.56–2.42(m,2H),2.36–2.22(m,2H),1.42(s,9H).

[0206] Step 5: Preparation of tert-butyl-4-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)benzo[d]oxazol-2-yl)phenyl)-4-cyanobutyric acid

[0207] tert-butyl 4-(3-(5-bromobenzo[d]oxazol-2-yl)-2-chlorophenyl)-4-cyanobutyrate (1.28 g, 2.69 mmol), pyridone (511 mg, 5.38 mmol), cuprous iodide (768 mg, 4.04 mmol), and potassium carbonate (1.86 g, 13.45 mmol) were dissolved in dimethyl sulfoxide (20 mL). The mixture was heated to 120 °C under nitrogen protection and reacted for 6 h. After the reaction was complete, the solid was removed by filtration. The filtrate was extracted three times with ethyl acetate (200 mL) and water (500 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under vacuum in silica gel to obtain a white solid. The solid was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (5 / 1) to give 354 mg of white solid, with a yield of 26.86%. 1H NMR(300MHz,Chloroform-d)δ8.27(d,J=2.1Hz,1H),7.89–7.81(m,1H),7.72–7.66(m,2H),7.64(d,J=8.4Hz,1H),7.52–7.44(m,2H),7.34–7. 26(m,1H),6.36(td,J=7.4,0.9Hz,1H),6.23(dd,J=9.2,0.9Hz,1H),4.42(t,J=6.3Hz,1H),2.56–2.42(m,2H),2.36–2.22(m,2H),1.42(s,9H).

[0208] Step Six: Preparation of 3-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)benzo[d]oxazol-2-yl)phenyl)piperidin-2,6-dione

[0209]

[0210] The procedure was the same as step five in Example 1, except that tert-butyl 4-cyano-4-(6-(4-(2-oxopyridin-1(2H)-yl)phenyl)pyridin-2-yl)butyrate was replaced with tert-butyl 4-(2-chloro-3-(5-(2-oxopyridin-1(2H)-yl)benzo[d]oxazol-2-yl)phenyl)-4-cyanobutyric acid (340 mg, 0.69 mmol), yielding 15 mg of a yellow solid, with a yield of 4.98%. 1 H NMR (300MHz, DMSO-d6) δ10.99(s,1H),8.03–7.94(m,2H),7.75(d,J=6.9Hz,1H),7.67(d,J=7.4Hz,1H),7.64–7.47(m,3H),6.52(d,J=9.3 Hz,1H),6.35(t,J=6.7Hz,1H),4.46(dd,J=12.7,4.8Hz,1H),2.92–2.71(m,1H),2.65–2.54(m,1H),2.37–2.17(m,1H),2.13–2.01(m,1H).

[0211] Example 11

[0212] Preparation of N-(6-(2-chloro-3-(2,6-dioxadiazin-3-yl)phenyl)naphth-2-yl)-N-methylacetamide (Compound 11)

[0213]

[0214] 400 mg (1.12 mmol) of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate, 362 mg (1.12 mmol) of N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide, and cesium carbonate (1.8 g, 5.55 mmol) were dissolved in dioxane (10 mL) and water (2 mL). [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (67.7 mg, 0.092 mmol) was added under nitrogen protection. The reaction mixture was reacted at 100 °C for 8 h. After the reaction was complete, the mixture was extracted three times with ethyl acetate (100 mL) and water (100 mL). The organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was added to silica gel and evaporated under vacuum to obtain sand. The sand was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (2 / 1). The obtained solid was dissolved in glacial acetic acid (2 mL), and concentrated sulfuric acid (0.4 mL) was added. The reaction solution was reacted at 90 °C for 6 h. After the reaction was complete, the reaction solution was poured into ice water (5 mL), and saturated sodium bicarbonate solution (9 mL) was added dropwise. A yellow solid precipitated. The solid was filtered to obtain 6 mg of yellow solid, with a yield of 1.24%. 1 H NMR (300MHz, DMSO-d6) δ10.37(s,1H),8.36(s,1H),7.97–7.75(m,4H),7.75–7.57(m,2H),7.57–7.41(m,2H),4.37(dd,J=1 2.2,5.0Hz,1H),2.85–2.77(m,1H),2.57(s,1H),2.35(dd,J=9.1,5.7Hz,1H),2.12(s,3H),2.07–1.96(m,1H),1.24(s,3H).

[0215] Example 12

[0216] Preparation of 3-(2-chloro-3-(6-(((1-methyl-1H-pyrazol-3-yl)methoxy)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 12)

[0217]

[0218] The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 1-methyl-3-(((6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)oxy)methyl)-1H-pyrazole (406 mg, 1.12 mmol). 23 mg of a yellow solid was obtained, with a yield of 4.62%. 1H NMR (300MHz, DMSO-d6) δ10.94(s,1H),7.94–7.80(m,3H),7.69(d,J=2.1Hz,1H),7.56–7.46(m,2H),7.41(q,J=6.5,5.4Hz,4H),7.23(dd ,J=9.1,2.5Hz,1H),5.14(s,2H),4.42–4.30(m,1H),3.85(s,3H),2.89–2.72(m,1H),2.58(s,1H),2.36(d,J=10.6Hz,1H),2.08(s,1H).

[0219] Example 13

[0220] Preparation of 3-(2-chloro-3-(6-(pyridin-2-ylmethoxy)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 13)

[0221]

[0222] The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 2-(((6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)oxy)methyl)pyridine (402 mg, 1.12 mmol). 26 mg of a white solid was obtained, with a yield of 5.30%. 1 H NMR (300MHz, DMSO-d6) δ11.05(s,1H),8.73(d,J=4.8Hz,1H),8.04(d,J=9.0Hz,1H),8.01–7.92(m,3H),7.71(d,J=7.8Hz,1H),7.62(dd,J=8.6,2.0Hz ,2H),7.54–7.41(m,5H),5.45(s,2H),4.48(dd,J=12.1,5.0Hz,1H),2.99– 2.82(m,1H),2.69(d,J=3.8Hz,1H),2.56–2.37(m,1H),2.25–2.16(m,1H).

[0223] Example 14

[0224] Preparation of 3-(2-chloro-3-(6-((tetrahydro-2H-pyridine-4-yl)methoxy)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 14)

[0225]

[0226] The procedure was the same as in Example 11. N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 4,4,5,5-tetramethyl-2-(6-((tetrahydro-2H-pyran-4-yl)methoxy)naphth-2-yl)-1,3,2-dioxoboran (410 mg, 1.12 mmol). 31 mg of a white solid was obtained, yield 5.99%. 1 H NMR (300MHz, DMSO-d6) δ10.96 (s, 1H), 7.91 (d, J = 4.4Hz, 1H), 7.88 (d, J = 3.8Hz, 2 H),7.55–7.49(m,1H),7.44–7.37(m,4H),7.26–7.20(m,1H),4.38(dd,J=12.1,5 .0Hz,1H),4.00(d,J=6.4Hz,2H),3.97–3.87(m,2H),2.89–2.73(m,1H),2.60(s, 1H),2.44–2.33(m,1H),2.10(s,2H),1.76(d,J=13.0Hz,2H),1.50–1.27(m,4H).

[0227] Example 15

[0228] Preparation of 3-(2-chloro-3-(3-(2-oxopyridin-1(2H)-yl)prop-1-en-1-yl)phenyl)piperidin-2,6-dione (Compound 15)

[0229] Step 1: Preparation of 3-(2-chloro-3-iodophenyl)piperidine-2,6-dione

[0230]

[0231] 3-(3-amino-2-chlorophenyl)piperidin-2,6-dione (600 mg, 2.75 mmol) was dissolved in concentrated hydrochloric acid (4 mL) under ice bath conditions. Then, under ice bath conditions, the solution was added in portions to a solution of sodium nitrite (210 mg, 3 mmol) in water (5 mL), and the reaction was maintained at 0 °C for 15 minutes. The solution was then added to a solution of potassium iodide (2.19 g, 13.2 mmol) in water (10 mL) under ice bath conditions, and the reaction was carried out at room temperature for 12 hours. After the reaction was complete, the mixture was extracted once with ethyl acetate (200 mL) and water (200 mL). The organic phase was washed once with a saturated sodium thiosulfate aqueous solution (100 mL), and the combined organic phases were dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness under vacuum using silica gel to prepare a precipitate. The precipitate was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (2 / 1) to give 680 mg of a white solid, with a yield of 70.85%. 1H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.77(dd,J=7.3,1.3Hz,1H),7.31–7.25(m,1H),7.24–7.17( m,1H),4.00–3.94(m,1H),2.88–2.79(m,1H),2.58–2.49(m,1H),2.16–2.06(m,1H),1.79–1.69(m,1H).

[0232] Step 2: Preparation of 3-(2-chloro-3-(3-(2-oxopyridin-1(2H)-yl)prop-1-en-1-yl)phenyl)piperidin-2,6-dione

[0233]

[0234] The procedure was the same as step three in Example 4, except that 3-(3-iodophenyl)piperidine-2,6-dione was replaced with 3-(2-chloro-3-iodophenyl)piperidine-2,6-dione (100 mg, 0.28 mmol) and purified by rapid silica gel column chromatography with ethyl acetate / petroleum ether (2 / 1) to obtain 7 mg of white solid, with a yield of 7.06%. 1 H NMR (300MHz, DMSO-d6) δ10.92(s,1H),7.86(dd,J=6.7,2.1Hz,1H),7.52–7.42(m,1H),7.42–7.29(m,2H),7.13–7.01(m,1H),6.44(d,J=9.2H z,1H),6.35–6.28(m,1H),5.04(s,2H),4.26(dd,J=12.4,4.9Hz,1H),2.83–2.72(m,1H),2.56(s,1H),2.39–2.21(m,1H),2.21–2.11(m,1H).

[0235] Example 16

[0236] Preparation of 3-(2-chloro-3-(1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-2,6-dione (Compound 16)

[0237] Step 1: Preparation of 3-(2-chloro-3-ethynylphenyl)piperidine-2,6-dione

[0238]

[0239] Cuprous iodide (17 mg, 0.09 mmol) and palladium dichloride bis(triphenylphosphine) (126 mg, 0.18 mmol) were placed in a reaction flask under nitrogen protection, and a solution of 3-(2-chloro-3-iodophenyl)piperidin-2,6-dione (630 mg, 1.8 mmol) and trimethylsilylacetylene (265 mg, 2.7 mmol) in triethylamine (10 mL) was added. The reaction mixture was stirred at room temperature for 8 h. After the reaction was completed, ethyl acetate (100 mL) and water (100 mL) were added for extraction three times. The organic phases were combined and dried over anhydrous sodium sulfate. After the organic phase was evaporated to dryness under vacuum, tetrabutylammonium fluoride tetrahydrofuran solution (1 M, 3.76 mL) was added, and the mixture was reacted at room temperature for 3 h. After the reaction was completed, silica gel was added to the reaction mixture, and the mixture was evaporated to dryness under vacuum to obtain a white solid. The solid was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (2 / 1) to give 274 mg of white solid, with a yield of 61.62%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.46(dd,J=5.0,2.6Hz,1H),7.39–7.32(m,1H),3.96(t,J= 6.0Hz,1H),3.38(s,1H),2.95–2.86(m,1H),2.68–2.59(m,1H),2.15–2.05(m,1H),1.92–1.82(m,1H).

[0240] Step 2: Preparation of 3-(2-chloro-3-(1-(pyridin-2-ylmethyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-2,6-dione

[0241]

[0242] 3-(2-chloro-3-ethynylphenyl)piperidin-2,6-dione (50 mg, 0.20 mmol) was dissolved in a mixture of tert-butanol (2 mL) and water (2 mL). Copper sulfate pentahydrate (0.5 mg, 0.002 mmol) and sodium ascorbate (12 mg, 0.06 mmol) were added. 2-(azidomethyl)pyridine (54 mg, 0.4 mmol) was slowly added to the reaction mixture at room temperature. The reaction was allowed to proceed for 12 h at room temperature. After the reaction was complete, the mixture was extracted three times with ethyl acetate (30 mL) and water (30 mL). The organic phases were combined and dried over anhydrous sodium sulfate. Silica gel was added to the organic phase, and the mixture was evaporated to dryness under vacuum to obtain a white solid. The solid was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 2) to give 10 mg of white solid, with a yield of 13.12%. 1H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.56(dd,J=4.2,1.7Hz,1H),8.08(s,1H ),7.79(d,J=1.3Hz,1H),7.74–7.67(m,1H),7.55–7.50(m,1H),7.47(dd,J=8.6,7. 9Hz,1H),7.37–7.32(m,1H),7.30(dd,J=6.6,1.5Hz,1H),5.69(s,2H),4.01–3.95( m,1H),2.90–2.81(m,1H),2.63–2.54(m,1H),2.38–2.28(m,1H),2.16–2.05(m,1H).

[0243] Example 17

[0244] Preparation of 3-(2-chloro-3-(1-(((1-methyl-1H-pyrazol-3-yl)methyl)-1H-1,2,3-triazol-4-yl)phenyl)piperidine-2,6-dione (Compound 17)

[0245]

[0246] The procedure was the same as step two in Example 16, except that 2-(azidomethyl)pyridine was replaced with 3-(azidomethyl)-1-methyl-1H-pyrazole (55 mg, 0.4 mmol). 7 mg of a yellow solid was obtained, with a yield of 9.11%. 1 H NMR (300MHz, DMSO-d6) δ10.94(s,1H),8.64(s,1H),7.98–7.88(m,1H),7.70–7.64(m,1H),7.52–7.32(m,2H),6.27(d,J=2.3Hz,1 H),5.62(s,2H),4.41–4.30(m,1H),3.81(s,3H),2.88–2.69(m,1H),2.68–2.55(m,1H),2.41–2.25(m,1H),2.04(d,J=9.5Hz,1H).

[0247] Example 18

[0248] Preparation of 5-((2-chloro-3-(2,6-dioxopiperidin-3-yl)phenyl)vinyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Compound 18)

[0249]

[0250] Cuprous iodide (4 mg, 0.02 mmol) and palladium dichloride bis(triphenylphosphine) (28 mg, 0.04 mmol) were placed in a reaction flask under nitrogen protection, and a triethylamine solution (5 mL) containing 3-(2-chloro-3-ethynylphenyl)piperidin-2,6-dione (100 mg, 0.4 mmol) and 5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (106 mg, 0.4 mmol) was added. The reaction mixture was stirred at room temperature for 8 h. After the reaction was complete, the mixture was extracted three times with ethyl acetate (100 mL) and water (100 mL), and the organic phases were combined and dried over anhydrous sodium sulfate. Silica gel was added to the organic phase, and the mixture was evaporated to dryness under vacuum to obtain a sand. The sand was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 3) to give 11 mg of a yellow solid, with a yield of 7.14%. 1 H NMR (300MHz, DMSO-d6) δ10.94(d,J=6.7Hz,1H),8.27(s,1H),7.74(d,J=7.6Hz,1H),7.51(dt,J=6.4,3.3Hz,1H),7.37(d,J=5.9Hz ,1H),4.30(dd,J=12.3,5.9Hz,1H),3.36(s,6H),2.80(t,J=16.3Hz,1H),2.58(s,1H),2.34(d,J=12.9Hz,1H),2.06–1.96(m,1H).

[0251] Example 19

[0252] Preparation of 3-(2-chloro-3-(pyridin-2-ylethynyl)phenyl)piperidin-2,6-dione (Compound 19)

[0253]

[0254] The procedure was the same as in Example 18, except that 5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione was replaced with 2-iodopyridine (82 mg, 0.4 mmol), and the solution was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 3) to give 56 mg of yellow solid, with a yield of 43.21%. 1 H NMR (300MHz, DMSO-d6) δ10.98(s,1H),8.66(d,J=4.9Hz,1H),7.90(td,J=7.7,1.7Hz,1H),7.79–7.45(m,5H ),4.36(dd,J=12.4,4.9Hz,1H),2.91–2.72(m,1H),2.61(s,1H),2.45–2.28(m,1H),2.04(d,J=12.8Hz,1H).

[0255] Example 20

[0256] Preparation of 3-(2-chloro-3-((1-methyl-1H-pyrazol-3-yl)ethynyl)phenyl)piperidine-2,6-dione (Compound 20)

[0257]

[0258] The procedure was the same as in Example 18, except that 5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione was replaced with 3-iodo-1-methyl-1H-pyrazole (84 mg, 0.4 mmol), and the solution was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 3) to give 8 mg of yellow solid, with a yield of 6.05%. 1 H NMR (300MHz, DMSO-d6) δ10.95(s,1H),7.65–7.47(m,2H),7.47–7.27(m,2H),6.56(d,J=2.3Hz,1H),4.31(dd,J=12.5 ,5.0Hz,1H),3.89(s,3H),2.88–2.70(m,1H),2.58(s,1H),2.33(dd,J=18.2,8.6Hz,1H),2.01(dd,J=8.8,4.5Hz,1H).

[0259] Example 21

[0260] Preparation of 3-(2-chloro-3-((1-methyl-1H-indazol-3-yl)ethynyl)phenyl)piperidine-2,6-dione (Compound 21)

[0261]

[0262] The procedure was the same as in Example 18, except that 5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione was replaced with 3-iodo-1-methyl-1H-indazole (103 mg, 0.4 mmol), and the solution was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 3) to give 5 mg of yellow solid, with a yield of 3.28%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.08(dd,J=7.9,1.4Hz,1H),7.94(dd,J=7.4,1.6Hz,1H),7.49–7.41(m,2H),7.4 0–7.31(m,3H),4.18–4.12(m,1H),3.96(s,3H),2.83–2.74(m,1H),2.64–2.56(m,1H),2.36–2.26(m,1H),2.15–2.05(m,1H).

[0263] Example 22

[0264] Preparation of 3-(2-chloro-3-((1-methyl-1H-pyrazol-4-yl)vinyl)phenyl)piperidine-2,6-dione (Compound 22)

[0265]

[0266] The procedure was the same as in Example 18, except that 5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione was replaced with 4-iodo-1-methyl-1H-pyrazole (84 mg, 0.4 mmol), and the solution was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 3) to give 27 mg of yellow solid, with a yield of 20.40%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.83(d,J=1.7Hz,1H),7.76(d,J=1.7Hz,1H),7.46–7.41(m,1H),7.39–7.34(m,1H), 7.37–7.31(m,1H),4.22–4.16(m,1H),3.89(s,3H),2.72–2.63(m,1H),2.58–2.49(m,1H),2.24–2.14(m,1H),2.08–1.98(m,1H).

[0267] Example 23

[0268] Preparation of 3-(3-(benzofuran-2-ylethynyl)-2-chlorophenyl)piperidine-2,6-dione (Compound 23)

[0269]

[0270] The procedure was the same as in Example 18, except that 5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione was replaced with 2-iodobenzofuran (98 mg, 0.4 mmol), and the mixture was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 1) to give 73 mg of yellow solid, with a yield of 49.70%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.76–7.70(m,1H),7.60–7.54(m,1H),7.43(dd,J=6.3,1.6Hz,1H),7.41–7.30(m ,4H),6.84(d,J=2.2Hz,1H),3.99–3.93(m,1H),2.83–2.74(m,1H),2.58–2.49(m,1H),2.35–2.25(m,1H),2.08–1.98(m,1H).

[0271] Example 24

[0272] Preparation of 3-(2-chloro-3-(quinolin-2-ylethynyl)phenyl)piperidine-2,6-dione (Compound 24)

[0273]

[0274] The procedure was the same as in Example 18, except that 5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione was replaced with 2-iodoquinoline (103 mg, 0.4 mmol), and the solution was purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 1) to give 49 mg of yellow solid, with a yield of 32.38%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.32(d,J=6.8Hz,1H),8.11–8.05(m,1H),7.98–7.92(m,1H),7.74–7.67(m,1H),7.57–7.48(m, 2H),7.46–7.41(m,1H),7.39–7.32(m,2H),3.99–3.93(m,1H),2.88–2 .79(m,1H),2.58–2.49(m,1H),2.31–2.21(m,1H),2.15–2.05(m,1H).

[0275] Example 25

[0276] Preparation of 3-(3-(1-(2-acetylphenyl)-1H-1,2,3-triazol-4-yl)-2-chlorophenyl)piperidine-2,6-dione (Compound 25)

[0277]

[0278] The procedure was the same as step two in Example 16, except that 2-(azidomethyl)pyridine was replaced with 1-(2-azidophenyl)ethane-1-one (65 mg, 0.4 mmol). 18 mg of a white solid was obtained, with a yield of 21.81%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),9.06(s,1H),7.83–7.76(m,3H),7.51–7.43(m,2H),7.37–7.2 8(m,2H),4.01–3.95(m,1H),2.75–2.67(m,1H),2.59–2.49(m,4H),2.34–2.24(m,1H),2.08–1.98(m,1H).

[0279] Example 26

[0280] Preparation of 3-(2-chloro-3-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,3-triazol-4-yl)phenyl)piperidin-2,6-dione (Compound 26)

[0281]

[0282] The procedure was the same as step two in Example 16, except that 2-(azidomethyl)pyridine was replaced with 2-azidotetrahydro-2H-pyran (33 mg, 0.4 mmol). 13 mg of a white solid was obtained, with a yield of 17.18%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.13(d,J=0.7Hz,1H),7.82–7.76(m,1H),7.47(t,J=8.2Hz,1H),7.37–7.32(m,1H),5.93–5.88(m ,1H),4.01–3.95(m,1H),3.89–3.75(m,2H),2.60–2.49(m,2H),2.20– 2.07(m,3H),2.09–1.98(m,1H),1.91–1.73(m,2H),1.71–1.62(m,2H).

[0283] Example 27

[0284] Preparation of 3-(2-chloro-3-(6-(((1-methyl-1H-pyrazol-4-yl)methoxy)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 27)

[0285] The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)naphth-2-yl)acetamide was replaced with 1-methyl-4-(((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)naphth-2-yl)oxy)methyl)-1H-pyrazole (400 mg, 1.12 mmol). 32 mg of a white solid was obtained, with a yield of 6.30%. 1H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.84–7.79(m,1H),7.83–7.74(m,2H),7.6 8(dd,J=7.6,1.2Hz,1H),7.59(dd,J=9.1,2.1Hz,1H),7.43–7.37(m,2H),7.35(d,J=1 .6Hz,1H),7.33–7.26(m,2H),7.08–7.03(m,1H),5.23(s,2H),4.04–3.98(m,1H),3.8 5(s,3H),2.71–2.62(m,1H),2.58–2.49(m,1H),2.15–2.05(m,1H),2.02–1.92(m,1H).

[0286] Example 28

[0287] Preparation of 3-(2-chloro-3-(6-(furan-2-ylmethoxy)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 28)

[0288] The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 2-(6-(furan-2-ylmethoxy)naphth-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxoboran (400 mg, 1.14 mmol). 54 mg of a white solid was obtained, with a yield of 10.55%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.84–7.79(m,1H),7.83–7.74(m,2H),7.68(dd ,J=7.6,1.2Hz,1H),7.59(dd,J=9.1,2.1Hz,1H),7.43–7.37(m,3H),7.32–7.26(m,1H),7.0 8–7.02(m,1H),6.45(dd,J=4.9,1.7Hz,1H),6.36(dd,J=4.8,1.5Hz,1H),5.11(s,2H),4.04 –3.98(m,1H),2.78–2.69(m,1H),2.58–2.49(m,1H),2.15–2.05(m,1H),1.96–1.86(m,1H).

[0289] Example 29

[0290] Preparation of 3-(2-chloro-3-(6-((tetrahydrofuran-2-yl)methoxy)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 29)

[0291] The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 4,4,5,5-tetramethyl-2-(6-((tetrahydrofuran-2-yl)methoxy)naphth-2-yl)-1,3,2-boronecycloalkane (400 mg, 1.13 mmol). 42 mg of a white solid was obtained, with a yield of 8.34%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.84–7.77(m,2H),7.77(dd,J=9.1,1.8Hz,1H),7.68(dd,J=7.6,1.2H z,1H),7.59(dd,J=9.2,2.0Hz,1H),7.40(d,J=15.6Hz,0H),7.32–7.26(m,1H),7.12(t,J=1.9Hz,1H),7.07–7.00( m,1H),4.18–4.12(m,1H),4.11(dd,J=3.1,1.6Hz,2H),4.04–3.98(m,1H),3.87–3.80(m,1H),3.77–3.69(m,1H),2 .73–2.64(m,1H),2.58–2.49(m,1H),2.15–2.05(m,1H),2.08–1.98(m,2H),1.98–1.87(m,2H),1.86–1.76(m,1H).

[0292] Example 30

[0293] Preparation of 3-(2-chloro-3-(6-(oxazol-2-ylmethoxy)naphth-2-yl)phenyl)piperidine-2,6-dione (Compound 30)

[0294] The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)oxymethyl)oxazole (400 mg, 1.14 mmol). 45 mg of a white solid was obtained, with a yield of 8.86%. 1H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.84–7.79(m,1H),7.83–7.74(m, 2H),7.71–7.65(m,1H),7.62–7.56(m,1H),7.54(d,J=1.0Hz,1H),7.43–7.35( m,3H),7.32–7.26(m,1H),7.08–7.03(m,1H),5.27(s,1H),4.04–3.98(m,1H) ,2.79–2.70(m,1H),2.58–2.49(m,1H),2.24–2.14(m,1H),2.08–1.98(m,1H).

[0295] Example 31

[0296] Preparation of 3-(3-(6-((1H-pyrazol-3-yl)methoxy)naphth-2-yl)-2-chlorophenyl)piperidine-2,6-dione (Compound 31) The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 3-((6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)oxymethyl)-1H-pyrazole (400 mg, 1.14 mmol). 24 mg of a white solid was obtained, with a yield of 4.71%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.84–7.79(m,1H),7.83–7.74(m,2H),7.68(d d,J=7.6,1.2Hz,1H),7.59(dd,J=9.1,2.1Hz,1H),7.43–7.36(m,2H),7.36–7.31(m,1H),7 .31–7.26(m,1H),7.08–7.02(m,1H),6.28(d,J=1.8Hz,1H),5.31(d,J=4.9Hz,2H),4.04– 3.98(m,1H),2.74–2.65(m,1H),2.59–2.50(m,1H),2.17–2.07(m,1H),2.04–1.94(m,1H).

[0297] Example 32

[0298] Preparation of 3-(2-chloro-3-(6-(2-oxo-2-(pyridin-2-yl)ethoxy)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 32) The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 1-(pyridin-2-yl)-2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)oxy)ethane-1-one (400 mg, 1.03 mmol). 31 mg of a white solid was obtained, with a yield of 6.77%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),8.72(dt,J=4.2,1.2Hz,1H),7.96–7.88(m,2H),7. 84–7.79(m,1H),7.83–7.74(m,2H),7.68(dd,J=7.6,1.2Hz,1H),7.59(dd,J=9.0,2.2Hz,1H),7 .57–7.50(m,1H),7.40(t,J=7.8Hz,1H),7.35–7.26(m,2H),7.10–7.05(m,1H),5.52(s,1H),4 .04–3.98(m,1H),2.74–2.65(m,1H),2.58–2.49(m,1H),2.20–2.10(m,1H),1.99–1.89(m,1H).

[0299] Example 33

[0300] Preparation of 3-(2-chloro-3-(6-(2-(furan-2-yl)-2-oxoethoxy)naphth-2-yl)phenyl)piperidin-2,6-dione (Compound 33) The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 1-(furan-2-yl)-2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)oxy)ethane-1-one (400 mg, 1.06 mmol). 18 mg of a white solid was obtained, with a yield of 3.82%. 1H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.84–7.72(m,4H),7.68(dd,J=7.6,1.2Hz,1H ),7.59(dd,J=9.0,2.2Hz,1H),7.43–7.37(m,2H),7.36–7.31(m,1H),7.29(dt,J=8.1,0.9 Hz,1H),7.10–7.04(m,1H),6.59(dd,J=4.9,1.6Hz,1H),5.50(s,1H),5.49(s,1H),4.04– 3.98(m,1H),2.68–2.59(m,1H),2.58–2.49(m,1H),2.15–2.05(m,1H),2.03–1.93(m,1H).

[0301] Example 34

[0302] Preparation of 3-(3-(6-(benzo[d]oxazol-2-ylmethoxy)naphth-2-yl)-2-chlorophenyl)piperidine-2,6-dione (Compound 34)

[0303] The procedure was the same as in Example 11, except that N-methyl-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)acetamide was replaced with 2-((6-(4,4,5,5-tetramethyl-1,3,2-dioxoboran-2-yl)naphth-2-yl)oxymethyl)benzo[d]oxazole (400 mg, 0.99 mmol). 25 mg of a white solid was obtained, yield 5.62%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.84–7.79(m,1H),7.83–7.74(m,2H) ,7.68(dd,J=7.6,1.2Hz,1H),7.62–7.54(m,2H),7.49–7.42(m,1H),7.45–7.36(m ,4H),7.29(dt,J=7.9,0.9Hz,1H),7.08–7.03(m,1H),5.23(s,2H),4.04–3.98(m, 1H),2.75–2.67(m,1H),2.58–2.49(m,1H),2.15–2.05(m,1H),1.98–1.88(m,1H).

[0304] Example 35

[0305] Preparation of 3-(2-chloro-3-((2-oxo-1,2-dihydropyridin-3-yl)ethynyl)phenyl)piperidin-2,6-dione (Compound 35)

[0306]

[0307] The procedure was the same as in Example 18, except that 5-iodo-1,3-dimethylpyrimidine-2,4(1H,3H)-dione was replaced with 3-iodopyridin-2(1H)-one (88 mg, 0.4 mmol), and purified by rapid silica gel column chromatography with petroleum ether / ethyl acetate (1 / 3) to obtain 23 mg of yellow solid, with a yield of 16.87%. 1 H NMR(300MHz,Chloroform-d)δ9.44(s,1H),7.81–7.75(m,2H),7.45(dd,J=5.7,2.2Hz,1H),7.41–7.34(m,2H),6.65( t,J=6.0Hz,1H),3.96(t,J=6.0Hz,1H),2.72–2.63(m,1H),2.58–2.49(m,1H),2.15–2.05(m,1H),1.97–1.87(m,1H).

[0308] Example 36

[0309] General Rules for the Preparation of Boronate Intermediates

[0310] Some of the raw materials used in the above embodiments need to be synthesized in-house. Since the synthetic routes are mature and consistent, they will be explained in detail in this embodiment. Specific operations and results are as follows:

[0311]

[0312] 6-Bromonaphthol-2-ol (1 mmol) and the corresponding bromide (1.2 mmol) underwent a nucleophilic substitution reaction in cesium carbonate (3 mmol), N,N-dimethylformamide (10 mL), and at 80 °C for 6 h. After filtration to remove cesium carbonate, the mixture was extracted with water (200 mL) / ethyl acetate (200 mL), and the organic phase was evaporated to dryness. Then, pinacol diboronate (1 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride (0.05 mmol), potassium acetate (3 mmol), and anhydrous dioxane (10 mL) were added, and the mixture underwent a Miyaura reaction at 85 °C for 3 h to obtain the corresponding borate ester.

[0313]

[0314]

[0315] Example 38

[0316] The degradation activity of VAV1 in Jurkat cells was determined by Western blotting, which was used to detect the degradation effect of the compound on VAV1 protein in Jurkat cells. The method is as follows:

[0317] (1) Take 6*10 Jurkat cells in the logarithmic growth phase. 5 Seeds were placed in 6-well plates at different concentrations (initial screening concentration of 1 μM or 200 nM), with DMSO as a blank control, and incubated for 24 h. The positive control drug MRT-6160 was administered at a concentration of 200 nM.

[0318] (2) After cell collection, the cells were processed according to RIPA lysis buffer and protease / phosphatase inhibitor (P0013C, Beyotime).

[0319] Follow the instructions in P1045 (Beyotime) to lyse and prepare proteins.

[0320] (3) After the protein preparation was completed, the sample was loaded, gel was run and transferred. Then, the membrane was blocked with 5% skim milk TBST solution.

[0321] (4) The primary antibody was incubated at 4°C for 12 hours, followed by washing with TBST. The secondary antibody (Clone#21V02, Boster) was incubated at room temperature for half an hour, followed by washing with TBST. Imaging was then performed using a Tanon 5200 imaging system (Tanon, Shanghai, China).

[0322] (5) The imaging results were analyzed using ImageJ. The calculation process is as follows:

[0323] VAV1 protein level = VAV1 protein gray level / GAPDH protein gray level;

[0324] VAV1 protein degradation rate = 1 - (VAV1 protein level in the drug-treated group / VAV1 protein level in the DMSO group)

[0325] (6) Compounds with superior activity in the initial screening were subjected to DC testing. 50 The administered concentrations were determined as follows:

[0326] Compounds exhibiting significant degradation at 1 μM: five concentration gradients from 1 μM to 2-fold dilution;

[0327] Compounds exhibiting significant degradation at 200 nM: five concentration gradients from 200 nM (two-fold dilution);

[0328] DC 50 Compounds smaller than 15 nM: dilute from 50 nM twice, for a total of seven concentration gradients;

[0329] The remaining procedures remained unchanged, and the degradation rate of VAV1 protein in the drug-treated group was measured by DC. 50 Nonlinear fitting yields the corresponding DC 50 .

[0330] Compound DC was measured 50 The results were compared with the positive control drug MRT-6160 as shown in Table 1: DC 50 DC represents the concentration of the compound required for 50% protein degradation. 50 The lower the value, the better the degradation effect; the higher the degradation rate value, the better the degradation effect.

[0331] Table 1 Compound DC 50

[0332]

[0333]

[0334] The data in Table 1 illustrate that the above embodiments possess significant VAV1 protein degradation activity; all compounds exhibit varying degrees of degradation activity at 1 μM. Compared to the positive control drug MRT-6160, some compounds showed comparable degradation activity, with compounds 12, 28, and 29 exhibiting significantly superior activity. The formulation provided by this patent has the potential to be further developed into a VAV1 molecular gel degrader for the treatment of autoimmune diseases, particularly IBD.

[0335] The VAV1 protein degradation activity of representative compounds 5 and 12 was detected by Western blotting. Figure 1 , 2 As shown, within the measured concentration range, compared to the DMSO group, the compound mediated the degradation of VAV1 protein and exhibited a concentration-dependent trend.

[0336] In autoimmune and inflammatory diseases, T cells are deeply involved in the occurrence and development of these diseases. The VAV1 pathway significantly influences T cell physiological functions, including actin remodeling, F-actin polymerization, TCR aggregation, integrin-mediated cell adhesion activation, immune synapse formation between T cells and antigen-presenting cells, and chemokine-mediated cell migration. Therefore, VAV1 deficiency severely impairs the function of T cells in autoimmune and inflammatory diseases. VAV1 molecular degraders can significantly reduce VAV1 levels in T cells, possessing the potential to treat related diseases. Therefore, the compounds provided in this protocol can degrade VAV1 protein, demonstrating the potential for treating autoimmune and inflammatory diseases.

[0337] As described above, although the invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the invention itself. Various changes in form and detail may be made without departing from the spirit and scope of the invention as defined in the appended claims.

[0338] It should be noted that, in this document, relational terms such as "first" and "second" are used only to distinguish one entity or operation from another, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Furthermore, the terms "comprising," "including," or any other variations thereof are intended to cover non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such process, method, article, or apparatus.

[0339] It should be noted that the above content merely illustrates the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. For those skilled in the art, various improvements and modifications can be made without departing from the principle of the present invention, and all such improvements and modifications fall within the scope of protection of the claims of the present invention.

Claims

1. A 3-arylpiperidine-2,6-dione compound of Formula I, its enantiomers, its diastereomers, its racemic mixture or a pharmaceutically acceptable salt thereof; in, X1 and X2 are independently selected from nitrogen atoms or carbon atoms. When X2 is a carbon atom, X3 is selected from H or chlorine atoms. When X2 is a nitrogen atom, there is no substitution of X3. L is selected from amide bonds, alkynes, alkyne methyl groups, or secondary amines, wherein the amide bonds include -CONH- and -NHCO-; Ring A is selected from 5-10 substituted aromatic rings, 5-10 substituted aromatic heterocycles, 5-10 substituted aliphatic heterocycles, or 5-10 fused rings, whether substituted or unsubstituted by R groups. R is selected from H, methyl, -NR2R1, -OCH2R3, -CH2R3, -OCH2(C=O)R3, a 5- to 10-membered heterocycle substituted or unsubstituted with R1 or R2, or a 5- to 10-membered aromatic ring substituted or unsubstituted with R1 or R2, where R1 is selected from C. 1-5 Oxyalkyl, R2 is selected from C 1-5 Alkyl group, R3 is selected from 5- to 10-membered aromatic heterocycles or 5- to 10-membered aliphatic heterocycles, and R1 and R2 can be linked together to form a ring; n is 0 or 1.

2. A 3-arylpiperidine-2,6-dione compound of formula I according to claim 1, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, characterized in that, The L is selected from the following structures:

3. A 3-arylpiperidine-2,6-dione compound of formula I according to claim 1, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, characterized in that, The A ring is selected from the following structures: in, X4 and X7 can be independently selected from carbon atoms or nitrogen atoms; X5 and X6 can be independently selected from carbon atoms, nitrogen atoms, or oxygen atoms; n1 is either 0 or 1; R4 and R5 are selected from hydrogen or connected to form a benzene ring that is substituted or unsubstituted by R.

4. A 3-arylpiperidine-2,6-dione compound of formula I according to claim 1, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, characterized in that, When n is 0, ring A is selected from benzene ring, naphthyl ring, pyridine ring, benzoxazole ring or triazole ring, wherein when X1 or X2 is a nitrogen atom, A is a benzene ring, and when neither X1 nor X2 is a nitrogen atom, A is not a benzene ring; when n is 1, and L is selected from amide bond or secondary amine, ring A is a benzene ring; when n is 1, and L is alkynylmethyl, ring A is a pyridone ring; when n is 1, and L is alkynyl, ring A is selected from pyrimidine-2,4(1H,3H)-dione, pyridine ring, pyrazole ring, benzopyrazole ring, pyridone ring, benzofuran ring or quinoline ring.

5. A 3-arylpiperidine-2,6-dione compound of formula I according to claim 1, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, characterized in that, The 5- to 10-membered aromatic rings or 5- to 10-membered heterocycles mentioned in R include benzene rings and tetrahydropyran rings; the C mentioned in R1 1-5 The oxoalkyl group is acetyl, and the C in R2 is... 1-5 The alkyl group is methyl, and R1 can be connected to R2 to form a pyridone ring; the 5- to 10-membered aromatic heterocycle or 5- to 10-membered aliphatic heterocycle mentioned in R3 includes N-methylpyrrole ring, pyridine ring, tetrahydropyran ring, furan ring, tetrahydrofuran ring, oxazole ring, pyrrole ring, and benzoxazole ring.

6. A 3-arylpiperidine-2,6-dione compound of formula I according to claim 1, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, characterized in that, The 3-arylpiperidine-2,6-dione compounds represented by Formula I include the following structures:

7. The 3-arylpiperidine-2,6-dione compound of formula I according to claim 1, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, characterized in that, The pharmaceutically acceptable salts include: acid addition salts formed by the reaction of a 3-arylpiperidine-2,6-dione compound of Formula I with an acid selected from hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, pyruvic acid, citric acid, tartaric acid, lactic acid, maleic acid, benzenesulfonic acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, fumaric acid, salicylic acid, or phenylacetic acid.

8. A method for preparing a 3-arylpiperidine-2,6-dione compound of formula I as described in claim 1, its enantiomers, its diastereomers, its racemic mixture, or a pharmaceutically acceptable salt thereof, characterized in that, The preparation method includes the following process route: ； The reagents and conditions were as follows: (a) N-bromosuccinimide, azobisisobutyronitrile, carbon tetrachloride, 80°C, 2h; (b) trimethylcyanosilane, tetra-n-butylammonium fluoride tetrahydrofuran solution (1M), tetrahydrofuran, room temperature, 3h; (c) sodium methoxide, tert-butyl acrylate, tetrahydrofuran, room temperature, 6h; (d) the corresponding borate ester, cesium carbonate, [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride, dioxane / water = 5 / 1, 100°C, 8h; (e) acetic acid, concentrated sulfuric acid, 90°C, 3h; (f) reduced iron powder, ammonium chloride, ethanol / water = 3 / 1, 80°C, 4h; (g) sodium nitrite, concentrated hydrochloric acid, potassium iodide, 0 ℃, 12h; (h) corresponding alkyne, cuprous iodide, bis(triphenylphosphine) palladium dichloride, triethylamine, room temperature, 8h; (i) O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate, N,N-diisopropylethylamine, N,N-dimethylformamide, 25℃, 8h; (j) tetra(triphenylphosphine) palladium, 2-bicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, cesium carbonate, dioxane, 100℃, 6h; (k) tetrahydrofuran, tetra-n-butylammonium fluoride tetrahydrofuran solution (1M), room temperature, 3h; (l) sodium ascorbate, copper sulfate pentahydrate, corresponding azide, tert-butanol, water, room temperature, 12h; Unless otherwise specified in the route, X1, X2, X3, and R are defined as in general formula I; ring A in the route represents the other ring system mentioned, excluding triazole, and X8 is bromine or iodine.

9. A pharmaceutical composition, characterized in that, The composition comprises a therapeutically effective amount of a 3-arylpiperidine-2,6-dione compound of formula I as described in any one of claims 1-7, its enantiomer, its diastereomer, its racemic mixture, or a pharmaceutically acceptable salt thereof.

10. Use of a 3-arylpiperidine-2,6-dione compound of formula I as described in any one of claims 1-7, its enantiomers, its diastereomers, its racemic mixtures, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 9, wherein the use is selected from (1) or (2). (1) Preparation of VAV1 protein molecular glue degrading agent; (2) Prepare drugs for the prevention and / or treatment of inflammatory diseases and autoimmune diseases related to VAV1 protein function.

11. The use according to claim 10, characterized in that, The inflammatory and autoimmune diseases associated with VAV1 protein function include systemic lupus erythematosus (SLE), familial frostbite lupus erythematosus (FCL), amyotrophic lateral sclerosis (ALS), non-alcoholic steatohepatitis (NASH), alcoholic liver disease, nerve damage, rheumatoid arthritis, renal fibrosis, systemic sclerosis, intervertebral disc degeneration, pulmonary fibrosis, psoriasis, inflammatory bowel disease, autoimmune colitis, irritable bowel syndrome, ulcerative colitis, Crohn's disease, uveitis, and mucositis.

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