Alk5 protac compounds and uses thereof

Abstract

The application provides an ALK5 PROTAC compound and application thereof, and belongs to the field of pharmaceutical chemistry and biological medicine. A series of PROTAC small-molecule compounds for targeted degradation of ALK5 protein are prepared, and the structure is shown as formula I. The compounds can be degraded through an ALK5 ubiquitination-proteasome pathway, the bioavailability of intraperitoneal injection is greater than 70%, and the tissue distribution is good. The ALK5 PROTAC compound provided by the application provides a new precise intervention means for treating ALK5-mediated fibrosis diseases and tumors.

Description

Technical Field

[0001] This invention belongs to the fields of medicinal chemistry and biomedicine, specifically relating to an ALK5 PROTAC compound and its applications. Background Technology

[0002] TGF-β is a highly conserved family of secretory polypeptide factors that plays a crucial role in physiological processes such as embryogenesis, cell differentiation, immune regulation, and maintenance of adult tissue homeostasis. Furthermore, members of the TGF-β family are widely involved in various pathophysiological mechanisms, including fibrotic diseases, tumor progression, immune escape, and autoimmune diseases. ALK5, as the core kinase of the TGF-β-Smad pathway, can effectively block TGF-β-mediated tumorigenesis or fibrosis by impairing its function or inhibiting its activity. For example, small molecule inhibitors targeting ALK5 have shown significant anti-fibrotic activity, and several candidate compounds are in clinical trials, such as AGMB-447 (NCT06181370).

[0003] However, small molecule inhibitors targeting ALK5 suffer from insufficient selectivity, high toxicity, and the potential for drug resistance with long-term use, limiting their widespread clinical application. PROTAC molecules recruit E3 ubiquitin ligases to label target proteins as ubiquitination degradation substrates, thereby achieving efficient and reversible protein degradation without affecting gene expression levels. Compared to traditional inhibitors, the PROTAC strategy not only inhibits kinase activity but also offers the following advantages: 1) It does not require direct occupation of the target protein's active site, allowing it to act on targets traditionally considered "undruggable"; 2) It induces target protein degradation through a catalytic cycle, requiring low doses and providing a long duration of action; 3) It overcomes drug resistance issues caused by target protein overexpression or mutations in the active site. Summary of the Invention

[0004] The purpose of this invention is to provide a PROTAC compound that can effectively degrade ALK5 protein for the treatment of ALK5-related diseases such as tumors or fibrotic diseases.

[0005] The specific technical solution is as follows:

[0006] This invention provides compounds of Formula I, pharmaceutically acceptable salts thereof, chiral isomers thereof, or diastereomers thereof:

[0007]

[0008] Formula I

[0009] in,

[0010] X is selected from CH or N;

[0011] Y is selected from C 1-5 Alkyl, H or NH2;

[0012] A is selected from none, -L ’ -4-6 membered saturated heterocyclic groups, -CO-;

[0013] L ’ Selected from none or -CONH-C 1-3 Alkylene;

[0014] L is selected from none, C 1-15 Alkylene, 5-12 membered heterospirocyclic group, 5-12 membered saturated heterocyclic group, 5-12 membered heterocyclic group;

[0015] Z is selected from none, O, and C. 2-6 Alkyne group, -CO-, 4-6 membered saturated heterocyclic group, -NH-;

[0016] R 1 Each is independently selected from H, halogens, and halogen-substituted C. 1-5 alkyl;

[0017] n is selected from 0, 1, or 2;

[0018] W selected , ,or .

[0019] Furthermore, X is selected from CH;

[0020] Y is selected from C 1-3 alkyl;

[0021] A is selected from none, -L ’ -5-6 membered saturated heterocyclic groups, -CO-;

[0022] L ’ Selected from none or -CONH-C 1-3 Alkylene;

[0023] L is selected from none, C 3-12 Alkylene, 5-12 membered heterospirocyclic group, 5-12 membered saturated heterocyclic group, 5-12 membered heterocyclic group;

[0024] Z is selected from none, O, and C. 2-4 Alkyne, -CO-, 4-6 membered saturated heterocyclic groups;

[0025] R 1 Each is independently selected from H, F, and Cl;

[0026] n is selected from 0, 1, or 2;

[0027] W selected , ,or .

[0028] Furthermore, the compound has the structure shown in Formula II, Formula III, or Formula IV:

[0029]

[0030] Formula II

[0031]

[0032] Formula III

[0033]

[0034] Formula IV

[0035] Wherein, A is selected from none, , -CO-;

[0036] Z is selected from none, O, and C. 2-3 alkynyl group, -CO-, , ;

[0037] L, R 1 As mentioned above, n...

[0038] Furthermore, the L is selected from the following structures:

[0039] , , , , , , , , , , , .

[0040] Furthermore, the compound is selected from one of the following compounds:

[0041] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0042] The present invention also provides the use of the above-mentioned compounds, their pharmaceutically acceptable salts, their chiral isomers, or their diastereomers in the preparation of ALK protein degrading agents.

[0043] Furthermore, the ALK protein degrading agent is a drug for the prevention and / or treatment of ALK5 protein-related diseases.

[0044] Furthermore, the disease is a tumor or a fibrotic disease.

[0045] Furthermore, the tumor is selected from colorectal cancer, liver cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, or papillary thyroid carcinoma.

[0046] The present invention also provides a pharmaceutical composition, which is a pharmaceutical preparation made by using the above-mentioned compound, its pharmaceutically acceptable salt, its chiral isomer, or its diastereomer as active ingredients, plus pharmaceutically acceptable excipients.

[0047] Furthermore, the pharmaceutical preparation is an oral preparation or an injectable preparation.

[0048] Furthermore, the injectable formulation is preferably an intraperitoneal injection formulation.

[0049] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0050] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0051] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or molecules.

[0052] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a- C b Alkyl indicates any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, "C 1-5 "Alkyl" refers to an alkyl group containing 1 to 5 carbon atoms.

[0053] "Alkyl" refers to a saturated hydrocarbon chain with a specified number of member atoms. For example, C 1-5 An alkyl group is an alkyl group having 1 to 5 member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted by one or more substituents as defined herein. C 1-5 Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), and pentyl (n-pentyl, isopentyl and neopentyl).

[0054] "Halogen" refers to fluorine, chlorine, bromine, or iodine.

[0055] "Spiral ring" refers to a polycyclic ring with two rings sharing a single atom.

[0056] "Parallel rings" refers to polycyclic rings with two rings sharing two adjacent ring atoms.

[0057] The term "salt" refers to the above-mentioned compounds, acidic and / or basic salts formed with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts), and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-mentioned compounds, or their stereoisomers, with a suitable (e.g., equimolar) amount of acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, or by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromates, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0058] The present invention has achieved the following beneficial effects:

[0059] This invention prepares a series of PROTAC small molecule compounds that target and degrade ALK5 protein. These compounds can be degraded via the ALK5 ubiquitination-proteasome pathway, exhibiting >70% bioavailability after intraperitoneal injection and good tissue distribution. The ALK5 PROTAC compounds provided by this invention offer a new and precise intervention for the treatment of ALK5-mediated fibrosis and tumors.

[0060] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0061] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following embodiments. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0062] The raw materials and equipment used in this invention are all known products, obtained by purchasing commercially available products.

[0063] Compound 1 is 2-chloro-4-amino-5-methylpyridine, CAS number 79055-62-2.

[0064] Example 1: Preparation of compound A1

[0065] 4-(4-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c]Pyridin-3-yl)methyl)piperidin-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A1)

[0066]

[0067] The synthesis route is as follows:

[0068]

[0069] Step 1: 2-(5-chloro-2-fluorophenyl)-5-methylpyridine-4-amine

[0070] Compound 1 (2.00 g, 14.03 mmol) and (5-chloro-2-fluorophenyl)boronic acid (2.57 g, 14.73 mmol) were added to a mixed solution of 1,4-dioxane / water (40 mL / 10 mL). Potassium carbonate (5.85 g, 42.08 mmol) and Pd(dppf)Cl2 (307 mg, 0.42 mmol) were then added to the solution, and the mixture was purged under nitrogen for 15 min. The reaction mixture was reacted at 100 °C for 18 h. The reaction solution was then cooled to room temperature, concentrated under reduced pressure to remove the solvent, and the residual solid was dissolved in ethyl acetate and filtered through diatomaceous earth. The filtrate was concentrated and purified by column chromatography to give compound 2 as a 900 mg white solid, yield: 27%. 1 H NMR (400MHz, Chloroform- d ) δ 8.21 (s, 1H), 7.95 (dd, J = 6.8, 2.7 Hz, 1H), 7.29 – 7.26(m, 1H), 7.05 (dd, J = 10.6, 8.7 Hz, 1H), 7.02 (d, J = 1.9 Hz, 1H), 4.17 (s, 2H), 2.15 (s, 3H). MS (ESI) m / z 237.9 [M + H] + .

[0071] Step 2: (4-((2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)amino)pyridin-3-yl)tert-butyl carbamate

[0072] Compound 2 (850 mg, 3.59 mmol), tert-butyl (4-aminopyridin-3-yl)carbamate (1.21 g, 3.77 mmol), and cesium carbonate (1.75 g, 5.39 mmol) were weighed into a 100 mL two-necked flask. Under a nitrogen atmosphere, ultra-dry 1,4-dioxane (25 mL) was added, and the mixture was purged with nitrogen for 5 min. RuPhos Pd G2 (278 mg, 0.359 mmol) was added, and the mixture was purged with nitrogen five times. The reaction was carried out at 105 °C for 24 h. After the reaction was complete (detected by LC-MS), the organic solvent was removed by concentration under reduced pressure. The solid was dissolved in ethyl acetate, filtered through diatomaceous earth, and concentrated to obtain the crude product. The crude product was purified by column chromatography to give the target compound 3.550 mg as a white solid, yield: 36%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.33 (s, 1H), 8.29 (s, 1H),8.25 (d, J = 5.6 Hz, 1H), 8.04 (s, 1H), 7.85 (dd, J = 6.7, 2.8 Hz, 1H), 7.46 (d, J = 1.7 Hz, 1H), 7.33 (d, J = 5.6 Hz, 1H), 7.17 (m, 1H), 6.95 (dd, J = 10.6, 8.7Hz, 1H), 2.23 (s, 3H), 1.47 (s, 9H). MS (ESI) m / z 430.1 [M + H] + .

[0073] Step 3: N 4 -(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)pyridin-3,4-diamine

[0074] A solution of compound 3 (500 mg) in dichloromethane was added to 5 mL of HCl / dioxane solution, and the mixture was stirred at room temperature for 8 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain the hydrochloride salt of compound 4, which could be used directly in the next step without purification. MS (ESI) m / z 329.9 [M + H] + .

[0075] Step 4: 1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-1,3-dihydro-2 H -imidazo[4,5- c]Pyridin-2-one

[0076] Carbonyl diimidazole (80 mg, 0.49 mmol) was added to an acetonitrile solution of compound 4 (150 mg, 0.41 mmol) and DIPEA (160 mg, 1.24 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete (as detected by TLC), the mixture was filtered and dried to give compound 5, a white solid, 91%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.58 (s, 1H), 8.86 (s, 1H), 8.35 (s, 1H), 8.20 (d, J = 5.3 Hz, 1H), 8.02 (dd, J = 6.7, 2.8 Hz, 1H),7.90 (s, 1H), 7.58 (m, 1H), 7.43 (dd, J = 10.9, 8.8 Hz, 1H), 6.94 (d, J = 5.2 Hz,1H), 2.23 (s, 3H). MS (ESI) m / z 356.0 [M + H] + .

[0077] Step 5: 4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)methyl)piperidin-1-carboxylic acid tert-butyl ester

[0078] Compound 5 (230 mg, 0.65 mmol), tert-butyl 4-(bromomethyl)piperidin-1-carboxylate (271 mg, 0.97 mmol), cesium carbonate (424 mg, 1.3 mmol), and potassium iodide (11 mg, 0.065 mmol) were weighed into a round-bottom flask, and DMF (5 mL) was added. The reaction was carried out at 100 °C for 6 h. After the reaction was completed (as detected by TLC), the reaction system was extracted three times with ethyl acetate, the organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 6 as a pale yellow solid, 80%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80(s, 1H), 8.41 (s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.10 (dd, J= 6.8, 2.8 Hz, 1H),7.79 (s, 1H), 7.35 (m, 1H), 7.11 (dd, J = 10.7, 8.8 Hz, 1H), 6.85 (d, J = 5.3 Hz, 1H), 3.91 (d, J = 7.2 Hz, 2H), 2.70 (d, J = 13.4 Hz, 2H), 2.29 (m, 4H), 2.14 (m,1H), 1.77 – 1.67 (m, 2H), 1.46 (s, 9H). MS (ESI) m / z 553.3 [M + H] + .

[0079] Step 6: 1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-3-(piperidin-4-ylmethyl)-1,3-dihydro-2 H -imidazo[4,5- c ]Pyridin-2-one

[0080] Compound 6 (270 mg) was dissolved in dichloromethane, and 5 mL of HCl / dioxane solution was added. The reaction was carried out at room temperature for 5 h. After the reaction was complete (as detected by TLC), the solvent was removed by concentration under reduced pressure to obtain compound 7. This compound did not require purification and was used directly in the next step.

[0081] Step 7: 4-(4-bromobutoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0082] To a DMF solution of compound 8 (200 mg, 0.73 mmol), 1,4-dibromobutane (394 mg, 1.83 mmol), sodium bicarbonate (184 mg, 2.19 mmol), and potassium iodide (12 mg, 0.073 mmol) were added. The reaction mixture was reacted at 75 °C for 6 h. After the reaction was complete (as detected by TLC), the mixture was extracted three times with ethyl acetate, and the combined organic phases were washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain compound 9 as a white solid, yield: 61%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.15 (s, 1H), 7.68 (dd, J = 8.5, 7.3Hz, 1H), 7.47 (d, J= 7.2 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 4.99 – 4.92 (m, 1H), 4.22 (t, J = 5.9 Hz, 2H), 3.55 (t, J = 6.3 Hz, 2H), 2.93 – 2.71 (m, 3H), 2.19 –2.01 (m, 5H). MS (ESI) m / z 410.5 [M + H] + .

[0083] Step 8: 4-(4-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0084] Compound 7 (80 mg, 0.16 mmol) was added to a DMF solution of 9 (74 mg, 0.18 mmol), sodium bicarbonate (41 mg, 0.48 mmol), and potassium iodide (3 mg, 0.016 mmol). The reaction mixture was reacted at 75 °C for 6 h. After the reaction was complete, the endpoint was confirmed by thin-layer chromatography (TLC). Subsequently, the reaction mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with water and once with saturated brine to remove water-soluble impurities. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. Finally, the crude product was purified by column chromatography to obtain the target compound A1 as a white solid, in a yield of 61%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.49(s, 1H), 8.34 (t, J = 4.9 Hz, 1H), 8.09 (m, 1H), 7.76 (dd, J = 16.0, 1.5 Hz, 1H), 7.68 (dd, J = 8.4, 7.3 Hz, 1H), 7.46 (dd, J = 7.3, 1.6 Hz, 1H), 7.35 (m, 1H), 7.23 – 7.17 (m, 1H), 7.16 – 7.06 (m, 1H), 6.81 (dd,J = 13.8, 5.3 Hz, 1H), 4.99– 4.90 (m, 1H), 4.30 – 4.21 (m, 1H), 4.20 – 4.11 (m, 1H), 3.99 – 3.83 (m,2H), 3.14 (dd, J = 20.0, 8.5 Hz, 2H), 2.89 – 2.61 (m, 5H), 2.27 (s, 3H), 2.13 –2.05 (m, 2H), 1.90 (q, J = 9.2, 7.7 Hz, 2H), 1.78 (q, J = 11.4, 8.2 Hz, 3H). 13 CNMR (101 MHz, Chloroform- d ) δ 171.62, 168.87, 166.96, 165.87, 157.67, 156.36,156.30, 153.26, 151.98, 151.33, 143.38, 140.38, 136.66, 135.00, 133.76,130.83, 130.80, 130.43, 130.03, 129.64, 127.80, 127.49, 122.58, 118.75,117.58, 116.99, 115.94, 103.95, 69.44, 57.59, 52.04, 49.18, 47.04, 35.00,31.48, 29.69, 28.89, 26.43, 22.69, 15.13. HRMS m / z Calculated for C 41 H 39 ClFN7O6[M+ H] + 780.2707, found 780.2716.

[0085] Following the method used to synthesize compound A1, similar reactions were carried out to prepare the following compounds A2 to A19.

[0086] Example 2, Preparation of compound A2

[0087] 4-((5-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c]Pyridin-3-yl)methyl)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A2)

[0088]

[0089] White solid, yield: 54%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.50 (d, J = 2.8 Hz, 1H), 8.35 (t, J = 5.4 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.76(d, J = 20.4 Hz, 1H), 7.68 (t, J = 7.9 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.39 –7.31 (m, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.18 – 7.05 (m, 1H), 6.80 (dd, J = 15.5,5.3 Hz, 1H), 4.93 (m, 1H), 4.18 (t, J = 5.6 Hz, 2H), 4.01 – 3.83 (m, 2H), 3.21(d, J = 11.7 Hz, 2H), 2.76 (m, 5H), 2.47 – 2.28 (m, 2H), 2.26 (s, 3H), 2.15 –2.03 (m, 2H), 1.94 – 1.72 (m, 8H), 1.61 (m, 2H). 13 C NMR (101 MHz, Chloroform- d) δ 171.58, 169.00, 168.80, 166.94, 165.93, 160.13, 157.67, 156.41, 156.36,153.26, 152.03, 151.31, 143.46, 140.30, 136.68, 134.84, 133.73, 130.85,130.43, 129.70, 127.68, 122.59, 118.81, 117.92, 117.67, 116.93, 115.89,103.97, 69.66, 57.44, 52.75, 49.13, 46.88, 34.64, 31.49, 28.37, 27.96, 24.78,24.43, 22.64, 15.13. HRMS m / z Calculated for C 42 H 41 ClFN7O6[M + H] + 794.2864, found 794.2872.

[0090] Example 3: Preparation of compound A3

[0091] 4-((6-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A3)

[0092]

[0093] White solid, yield: 60%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.46 (s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.78 (s, 1H),7.67 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.35 (dt, J= 8.7, 3.2 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.10 (t, J = 8.6 Hz, 1H), 6.83 (dd, J = 5.3, 3.0 Hz, 1H),5.00 – 4.88 (m, 1H), 4.17 (t, J = 6.2 Hz, 2H), 3.93 (d, J = 7.1 Hz, 2H), 3.14 (d, J = 11.4 Hz, 2H), 2.86 – 2.71 (m, 3H), 2.55 (t, J = 7.9 Hz, 2H), 2.28 (s, 3H), 2.22 (m, 1H), 2.10 (m, 2H), 1.83 (m, 4H), 1.77 – 1.60 (m, 4H), 1.55 (h, J =7.5, 7.0 Hz, 2H), 1.42 (q, J = 7.3 Hz, 2H), 1.26 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.54, 168.67, 168.64, 167.09, 165.79, 160.15, 157.66,156.58, 153.28, 151.90, 151.33, 143.45, 140.39, 136.54, 135.00, 133.77,130.80, 130.43, 130.04, 129.52, 127.74, 122.54, 118.95, 117.83, 117.59,117.08, 115.75, 103.95, 69.26, 57.93, 49.14, 46.91, 31.46, 29.69, 28.70,28.44, 26.70, 25.43, 22.68, 15.17. HRMS m / z Calculated for C 43 H 43 ClFN7O6[M + H] + 808.3020, found 808.3014.

[0094] Example 4: Preparation of compound A4

[0095] 4-((7-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)heptyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A4)

[0096]

[0097] White solid, yield: 52%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.47(s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.10 (dd, J = 6.8, 2.7 Hz, 1H), 7.78 (s, 1H),7.67 (d, J = 15.8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.34 (dd, J = 7.9, 4.3 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.14 – 7.07 (m, 1H), 6.83 (dd, J = 5.4, 2.2 Hz,1H), 5.01 – 4.91 (m, 1H), 4.23 – 4.12 (m, 2H), 3.97 (dd, J = 6.8, 3.6 Hz, 2H),3.36 (m, 2H), 2.80 – 2.72 (m, 3H), 2.28 (s, 3H), 2.15 (m, 2H), 1.94 – 1.84(m, 4H), 1.75 (m, 2H), 1.54 (m, 3H), 1.48 – 1.35 (m, 5H), 1.26 (s, 4H). 13 C NMR (101 MHz, Chloroform- d) δ 170.40, 167.68, 166.05, 164.75, 155.57, 152.29,150.85, 142.63, 139.27, 135.53, 133.98, 132.77, 129.72, 129.55, 129.45,129.06, 128.45, 126.57, 121.48, 121.37, 117.92, 116.82, 116.57, 116.07,114.71, 103.00, 68.32, 48.14, 30.44, 28.68, 27.47, 27.35, 25.58, 24.63,24.56, 21.63, 14.16. HRMS m / z Calculated for C 44 H 45 ClFN7O6[M + H] + 822.3177, found 822.3165.

[0098] Example 5: Preparation of compound A5

[0099] 4-((8-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)octyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A5)

[0100]

[0101] White solid, yield: 63%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.44(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.79 (s, 1H),7.66 (dd, J = 8.5, 7.3 Hz, 1H), 7.44 (d, J = 7.3 Hz, 1H), 7.35 (m, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.10 (dd,J = 10.7, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 4.94(dd, J = 12.1, 5.4 Hz, 1H), 4.17 (m, 2H), 3.92 (d, J = 7.1 Hz, 2H), 3.10 (d, J =9.2 Hz, 2H), 2.83 – 2.70 (m, 2H), 2.44 (t, J = 7.5 Hz, 2H), 2.28 (s, 3H), 2.18– 2.01 (m, 4H), 1.86 (m, 2H), 1.79 (d, J = 15.6 Hz, 2H), 1.66 (t, J = 12.2 Hz, 2H), 1.58 – 1.47 (m, 4H), 1.39 – 1.25 (m, 7H). 13 C NMR (101 MHz, Chloroform- d )δ 171.77, 168.84, 167.14, 165.75, 160.14, 157.66, 156.64, 153.27, 151.85,151.28, 143.39, 140.43, 136.46, 134.99, 133.80, 130.79, 130.41, 129.98,129.47, 127.76, 127.40, 122.52, 118.98, 117.82, 117.11, 115.66, 103.91,69.49, 58.40, 49.14, 47.01, 35.09, 31.46, 29.68, 29.18, 28.93, 28.69, 27.30,25.82, 22.71, 15.18. HRMS m / z Calculated for C 45 H 47 ClFN7O6[M + H] + 836.3333, found 836.3313.

[0102] Example 6: Preparation of compound A6

[0103] 4-((9-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)nonyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A6)

[0104]

[0105] White solid, yield: 89%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.42(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.79 (d, J = 3.0Hz, 1H), 7.66 (dd, J = 8.5, 7.3 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.35 (m, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.10 (dd, J = 10.7, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz,1H), 4.93 (m, 1H), 4.25 – 4.09 (m, 2H), 3.90 (d, J = 7.0 Hz, 2H), 3.04 (t, J =11.8 Hz, 2H), 2.87 – 2.81 (m, 1H), 2.42 – 2.32 (m, 2H), 2.28 (s, 3H), 2.14 –2.09 (m, 1H), 2.04 – 1.93 (m, 3H), 1.89 – 1.81 (m, 2H), 1.77 – 1.69 (m, 2H), 1.51 (m, 5H), 1.40 – 1.23 (m, 10H). 13 C NMR (101 MHz, Chloroform- d) δ 171.79,168.87, 167.17, 165.72, 160.16, 157.68, 156.67, 153.27, 151.85, 151.32,143.38, 140.48, 136.38, 134.99, 133.88, 130.80, 130.44, 130.01, 129.49,127.81, 122.42, 118.83, 117.82, 117.57, 117.21, 115.63, 103.88, 69.34, 58.65,52.93, 49.17, 47.25, 35.47, 31.52, 29.70, 29.57, 29.15, 28.90, 28.74, 27.55,26.51, 25.57, 22.76, 15.19. HRMS m / z Calculated for C 46 H 49 ClFN7O6[M + H] + 850.3490, found 850.3473.

[0106] Example 7: Preparation of compound A7

[0107] 4-((10-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)decyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A7)

[0108]

[0109] White solid, yield: 60%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.44(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.78 (s, 1H),7.66 (dd, J = 8.5, 7.3 Hz, 1H), 7.43 (d, J= 7.3 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.14 – 7.06 (m, 1H), 6.84 (d, J = 5.3 Hz, 1H), 4.94 (m, 1H),4.21 – 4.11 (m, 2H), 3.91 (d, J = 7.1 Hz, 2H), 3.12 (d, J = 11.3 Hz, 2H), 2.89 –2.72 (m, 3H), 2.43 (t, J = 8.0 Hz, 2H), 2.28 (s, 3H), 2.16 – 2.00 (m, 4H), 1.86(t, J = 6.7 Hz, 2H), 1.76 (d, J = 9.1 Hz, 2H), 1.69 – 1.60 (m, 2H), 1.57 – 1.47(m, 4H), 1.38 (d, J = 6.8 Hz, 2H), 1.29 (m, 8H). 13 C NMR (101 MHz, Chloroform- d )δ 171.84, 168.83, 167.17, 165.70, 160.15, 157.66, 156.66, 153.27, 151.83,151.28, 143.39, 140.44, 136.41, 134.99, 133.83, 130.79, 130.45, 130.02,129.45, 127.76, 122.51, 118.80, 117.82, 117.57, 117.10, 115.59, 103.91,69.45, 58.49, 52.59, 49.15, 47.03, 35.14, 31.54, 29.34, 29.15, 29.06, 28.99,28.82, 27.51, 26.00, 25.83, 22.69, 15.18. HRMS m / z calculated for C 47 H 51 ClFN7O6[M+ H] + 864.3646, found 864.3632.

[0110] Example 8: Preparation of compound A8

[0111] 4-((11-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)undecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A8)

[0112]

[0113] White solid, yield: 55%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.44(s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.78 (s, 1H),7.66 (t, J = 7.9 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.35 (m, 1H), 7.21 (d, J = 8.5Hz, 1H), 7.10 (dd, J = 10.7, 8.8 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 4.95 (dd, J =11.9, 5.3 Hz, 1H), 4.17 (t, J = 6.5 Hz, 2H), 3.93 (d, J = 7.1 Hz, 2H), 3.16 (d, J =10.9 Hz, 2H), 2.91 – 2.73 (m, 3H), 2.50 (t, J = 8.0 Hz, 2H), 2.28 (s, 3H), 2.23– 2.04 (m, 4H), 1.86 (m, 3H), 1.76 (dd, J = 28.7, 11.3 Hz, 3H), 1.58 (t, J = 7.6Hz, 2H), 1.50 (t,J = 7.6 Hz, 2H), 1.38 – 1.26 (m, 12H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.60, 168.62, 167.16, 165.72, 160.15, 157.67, 156.70,153.28, 151.84, 151.31, 143.45, 140.41, 136.43, 135.01, 133.82, 130.78,130.46, 130.04, 129.43, 127.73, 122.50, 118.88, 117.82, 117.57, 117.10,115.61, 103.93, 69.42, 58.26, 49.16, 46.91, 34.94,31.53,29.69,29.30,29.27,29.23,29.08,28.84,28.73,27.29,25.74,25.67,22.66,15.18. HRMS m / z Calculated for C 48 H 53 ClFN7O6[M + H] + 878.3803, found 878.3789.

[0114] Example 9: Preparation of compound A9

[0115] 4-((12-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)dodecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A9)

[0116]

[0117] White solid, yield: 58%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.44(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J= 6.8, 2.8 Hz, 1H), 7.78 (s, 1H),7.65 (d, J = 7.8 Hz, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.35 (dt, J = 8.7, 3.5 Hz, 1H),7.21 (d, J = 8.5 Hz, 1H), 7.10 (dd, J = 10.7, 8.8 Hz, 1H), 6.83 (d, J = 5.3 Hz,1H), 5.00 – 4.90 (m, 1H), 4.17 (t, J = 6.5 Hz, 2H), 3.92 (d, J = 7.0 Hz, 2H),3.14 (d, J = 11.4 Hz, 2H), 2.90 – 2.73 (m, 3H), 2.48 (t, J = 8.1 Hz, 2H), 2.28(s, 3H), 2.20 – 2.04 (m, 4H), 1.88 (m, 2H), 1.75 (dd, J = 34.7, 10.2 Hz, 4H),1.57 (t, J = 7.6 Hz, 2H), 1.49 (q, J = 7.7 Hz, 2H), 1.39 – 1.26 (m, 14H). 13 C NMR(101 MHz, Chloroform- d) δ 171.53, 168.55, 167.15, 165.72, 160.16, 157.68,156.72, 153.28, 151.84, 151.32, 143.45, 140.42, 136.43, 135.01, 133.82,130.78, 130.47, 130.02, 129.44, 127.74, 122.50, 118.86, 117.82, 117.57,117.10, 115.61, 103.92, 69.47, 58.40, 49.17, 46.96, 35.04, 31.53, 29.69,29.43, 29.35, 29.30, 29.16, 28.88, 27.39, 25.83, 25.72, 22.66, 15.18. HRMS m / z Calculated for C 49 H 55 ClFN7O6[M + H] + 892.3959, found 892.3943.

[0118] Example 10: Preparation of compound A10

[0119] 5-(4-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)butoxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A10)

[0120]

[0121] White solid, yield: 55%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.45(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.78 (s, 1H),7.76 (d, J = 8.3 Hz, 1H), 7.34 (m, 2H), 7.17 (dd, J= 8.3, 2.3 Hz, 1H), 7.10 (dd, J = 10.7, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 4.96 (dd, J = 12.2, 5.2 Hz, 1H), 4.11 (t, J = 6.4 Hz, 2H), 3.91 (d, J = 7.1 Hz, 2H), 3.02 (d, J = 11.2 Hz, 2H), 2.89– 2.74 (m, 3H), 2.45 (t, J = 7.4 Hz, 2H), 2.28 (s, 3H), 2.17 – 2.11 (m, 1H), 2.03 (d, J = 12.2 Hz, 2H), 1.84 (m, 2H), 1.71 (dd, J = 12.5, 11.6 Hz, 4H), 1.57(t, J = 12.6 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 170.11, 167.16, 165.72,165.53, 162.87, 156.11, 151.70, 150.28, 149.74, 141.76, 138.87, 133.44,132.74, 129.21, 128.88, 128.48, 127.87, 126.25, 123.90, 121.76, 120.95,119.21, 116.25, 116.00, 107.24, 102.34, 67.17, 56.37, 51.41, 47.77, 45.67,33.88, 29.93, 25.27, 21.42, 21.18, 13.61. HRMS m / z Calculated for C 41 H 39 ClFN7O6[M+ H] + 780.2707, found 780.2692.

[0122] Example 11, Preparation of Compound A11

[0123] 5-((5-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)pentyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A11)

[0124]

[0125] White solid, yield: 53%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.78 (d, J = 10.3Hz, 1H), 8.43 (d, J = 9.4 Hz, 1H), 8.33 (d, J = 10.5 Hz, 1H), 8.11 – 8.03 (m,1H), 7.79 – 7.68 (m, 2H), 7.36 – 7.28 (m, 2H), 7.18 – 7.07 (m, 2H), 6.82 (q, J = 5.5 Hz, 1H), 4.95 (dd, J = 13.1, 5.5 Hz, 1H), 4.07 (q, J = 7.1, 6.5 Hz, 2H), 3.93 (d, J = 7.7 Hz, 2H), 3.70 (m, 2H), 3.16 (m, 2H), 2.90 – 2.73 (m, 3H), 2.55(m, 2H), 2.28 (s, 3H), 2.10 (d, J = 13.5 Hz, 2H), 1.84 (m, 4H), 1.75 – 1.64 (m, 4H), 1.53 – 1.46 (m, 2H). 13 C NMR (101 MHz, Chloroform- d) δ 171.65, 168.72,167.25, 167.07, 164.43, 160.14, 157.65, 153.28, 151.85, 151.31, 143.46,140.38, 135.02, 134.28, 130.77, 130.44, 130.02, 127.71, 127.36, 125.48,123.33, 122.49, 120.62, 117.83, 117.58, 108.92, 103.96, 68.72, 58.20, 52.62,49.34, 46.83, 31.49, 29.68, 28.60, 25.45, 23.72, 22.71, 18.43, 15.17. HRMS m / z Calculated for C 42 H 41 ClFN7O6[M + H] + 794.2864, found 794.2854.

[0126] Example 12, Preparation of Compound A12

[0127] 5-((6-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)hexyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A12)

[0128]

[0129] White solid, yield: 60%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.45(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.10 (dd, J = 6.8, 2.8 Hz, 1H), 7.80 – 7.72(m, 2H), 7.38 – 7.30 (m, 2H), 7.17 (dd, J = 8.3, 2.3 Hz, 1H), 7.10 (dd, J= 10.7, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 4.95 (dd, J = 12.2, 5.2 Hz, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.93 (d, J = 7.0 Hz, 2H), 3.17 (d, J = 11.3 Hz, 2H), 2.91 – 2.73(m, 3H), 2.54 (d, J = 8.9 Hz, 2H), 2.28 (s, 3H), 2.22 (m, 2H), 2.16 – 2.07 (m,2H), 1.83 (q, J = 7.2 Hz, 4H), 1.73 (d, J = 11.4 Hz, 2H), 1.65 (m, 2H), 1.50 (t, J = 7.7 Hz, 2H), 1.43 – 1.37 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 170.48,167.59, 166.26, 166.06, 163.48, 156.66, 152.29, 150.84, 150.33, 142.49,139.38, 134.00, 133.29, 129.76, 129.45, 129.05, 128.45, 126.71, 124.50,122.29, 121.49, 119.70, 116.82, 116.57, 107.89, 102.96, 67.85, 57.10, 51.63,48.33, 45.89, 33.86, 30.48, 28.69, 27.66, 25.94, 24.62, 21.71, 14.18. HRMS m / z Calculated for C 43 H 43 ClFN7O6[M + H] + 808.3020 was found to be 808.3009.

[0130] Example 13, Preparation of compound A13

[0131] 5-((7-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)heptyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A13)

[0132]

[0133] White solid, yield: 51%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.45(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.10 (dd, J = 7.0, 2.7 Hz, 1H), 7.81 – 7.72(m, 2H), 7.38 – 7.30 (m, 2H), 7.18 (dd, J = 8.4, 2.2 Hz, 1H), 7.10 (dd, J = 10.8, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 4.95 (dd, J = 12.2, 5.1 Hz, 1H), 4.08 (t, J = 6.4 Hz, 2H), 3.93 (d, J = 7.0 Hz, 2H), 3.17 (d, J = 10.7 Hz, 2H), 2.91 – 2.73(m, 3H), 2.54 (s, 2H), 2.28 (s, 3H), 2.18 (s, 2H), 2.16 – 2.08 (m, 2H), 1.82(m, 6H), 1.64 (m, 2H), 1.50 – 1.43 (m, 2H), 1.41 – 1.32 (m, 4H). 13 C NMR (101MHz, Chloroform- d) δ 171.42, 168.55, 167.27, 167.07, 164.53, 160.15, 157.67,153.30, 151.84, 151.31, 143.52, 140.39, 135.00, 134.29, 130.76, 130.43,130.05, 129.45, 127.70, 125.50, 123.27, 122.37, 120.67, 117.82, 117.57,108.92, 103.95, 68.97, 63.74, 58.19, 49.33, 31.48, 29.69, 28.91, 28.71,27.15, 25.70, 22.72, 15.19. HRMS m / z Calculated for C 44 H 45 ClFN7O6[M + H] + 822.3177, found 822.3165.

[0134] Example 14, Preparation of compound A14

[0135] 5-((8-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)octyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A14)

[0136]

[0137] White solid, yield: 58%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.45(s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.10 (dd, J = 6.8, 2.8 Hz, 1H), 7.77 (d, J = 8.6Hz, 2H), 7.37 – 7.30 (m, 2H), 7.18 (dd, J = 8.3, 2.3 Hz, 1H), 7.10 (dd, J= 10.8, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 4.95 (dd, J = 12.3, 5.2 Hz, 1H), 4.08 (t, J = 6.4 Hz, 2H), 3.94 (d, J = 7.0 Hz, 2H), 3.20 (m, 2H), 2.92 – 2.73 (m, 3H), 2.58 (m, 2H), 2.28 (m, 5H), 2.13 (dd, J = 12.0, 5.6 Hz, 2H), 1.89 – 1.77 (m,6H), 1.65 (m, 2H), 1.45 (d, J = 7.2 Hz, 2H), 1.34 (m, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.46, 168.59, 167.29, 167.08, 164.56, 160.15, 157.67,153.30, 151.84, 151.33, 143.52, 140.37, 135.01, 134.29, 130.76, 130.43,130.02, 129.44, 127.37, 125.49, 123.24, 122.37, 120.67, 117.83, 117.57,108.93, 103.97, 69.00, 63.74, 58.13, 49.33, 46.75, 31.48, 29.69, 29.10,28.97, 28.75, 27.11, 25.71, 22.72, 15.18. HRMS m / z Calculated for C 45 H 47 ClFN7O6[M+ H] + 836.3333, found 836.3321.

[0138] Example 15: Preparation of Compound A15

[0139] 5-((9-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c]Pyridin-3-yl)methyl)piperidin-1-yl)nonyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A15)

[0140]

[0141] White solid, yield: 63%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.44(s, 1H), 8.35 (d, J = 5.1 Hz, 1H), 8.10 (dd, J = 6.8, 2.8 Hz, 1H), 7.77 (d, J = 8.8Hz, 2H), 7.37 – 7.29 (m, 2H), 7.18 (dd, J = 8.4, 2.4 Hz, 1H), 7.10 (dd, J = 10.7, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 5.00 – 4.90 (m, 1H), 4.08 (t, J = 6.3 Hz, 2H), 3.93 (d, J = 7.1 Hz, 2H), 3.17 (d, J = 11.4 Hz, 2H), 2.91 – 2.74 (m, 3H), 2.51 (d, J = 9.5 Hz, 2H), 2.28 (s, 3H), 2.25 – 2.17 (m, 2H), 2.16 – 2.09 (m,2H), 1.82 (m, 4H), 1.78 – 1.70 (m, 2H), 1.63 – 1.57 (m, 2H), 1.45(d, J = 7.6Hz, 2H), 1.37 – 1.30 (m, 8H). 13 C NMR (101 MHz, Chloroform- d) δ 170.04, 167.17,165.95, 165.74, 163.25, 158.81, 151.96, 150.50, 150.01, 142.17, 139.04,133.66, 132.96, 129.41, 129.20, 129.12, 128.71, 128.09, 124.15, 121.89,121.15, 119.34, 116.48, 116.23, 107.57, 102.64, 67.70, 56.95, 51.33, 47.99,45.53, 33.55, 30.14, 28.36, 27.92, 27.71, 27.45, 27.32, 25.93, 24.43, 21.38,13.85. HRMS m / z Calculated for C 46 H 49 ClFN7O6[M + H] + 850.3490, found 850.3469.

[0142] Example 16: Preparation of compound A16

[0143] 5-((10-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)decyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A16)

[0144]

[0145] White solid, yield: 63%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.46 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.80 – 7.73(m, 2H), 7.37 – 7.30 (m, 2H), 7.18 (dd, J = 8.3, 2.3 Hz, 1H), 7.10 (dd, J= 10.8, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 5.00 – 4.91 (m, 1H), 4.08 (t, J = 6.5 Hz, 2H), 3.93 (d, J = 7.1 Hz, 2H), 3.25 – 3.15 (m, 2H), 2.91 – 2.74 (m, 3H), 2.56(t, J = 8.1 Hz, 2H), 2.28 (m, 5H), 2.16 – 2.08 (m, 2H), 1.82 (m, 6H), 1.63 (m,2H), 1.45 (dd, J = 14.5, 6.7 Hz, 2H), 1.30 (m, 10H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.80, 168.83, 167.29, 167.11, 164.55, 160.12, 157.63,153.26, 151.83, 151.24, 143.39, 140.37, 135.00, 134.27, 130.78, 130.41,129.95, 127.69, 125.42, 123.20, 122.47, 120.59, 117.82, 117.57, 108.90,103.94, 69.04, 58.11, 52.40, 49.33, 46.75, 34.65, 31.49, 29.67, 29.29, 29.11,28.80, 28.35, 27.25, 25.78, 25.43, 22.70, 18.41, 15.16. HRMS m / z Calculated for C 47 H 51 ClFN7O6[M + H] + 864.3646, found 864.3631.

[0146] Example 17, Preparation of Compound A17

[0147] 5-((11-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c]Pyridin-3-yl)methyl)piperidin-1-yl)undecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A17)

[0148]

[0149] White solid, yield: 55%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.44(s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.10 (dd, J = 6.8, 2.8 Hz, 1H), 7.77 (d, J = 8.5Hz, 2H), 7.37 – 7.31 (m, 2H), 7.18 (dd, J = 8.3, 2.3 Hz, 1H), 7.10 (dd, J = 10.7, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 4.99 – 4.91 (m, 1H), 4.08 (t, J = 6.5 Hz, 2H), 3.92 (d, J = 7.0 Hz, 2H), 3.16 (d, J = 11.3 Hz, 2H), 2.91 – 2.74 (m, 3H), 2.50 (q, J = 11.4, 10.4 Hz, 2H), 2.28 (s, 3H), 2.24 – 2.08 (m, 4H), 1.82 (t, J =7.3 Hz, 4H), 1.77 – 1.68 (m, 2H), 1.63 – 1.57 (m, 2H), 1.45 (q, J = 7.0 Hz, 2H), 1.28 (m, 12H). 13 C NMR (101 MHz, Chloroform- d) δ 171.27, 168.43, 167.30,167.09, 164.62, 157.68, 153.30, 151.84, 151.34, 143.52, 140.40, 135.00,134.32, 130.76, 130.47, 130.07, 129.43, 127.73, 125.49, 123.24, 122.39,120.73, 117.82, 117.57, 108.89, 103.95, 69.07, 58.38, 49.33, 31.49, 29.70,29.37, 29.32, 29.12, 28.79, 27.34, 25.79, 22.73, 15.19. HRMS m / z Calculated for C 48 H 53 ClFN7O6[M + H] + 878.3803, found 878.3791.

[0150] Example 18, Preparation of Compound A18

[0151] 5-((12-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)methyl)piperidin-1-yl)dodecyl)oxy)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A18)

[0152]

[0153] White solid, yield: 55%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.45(s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.81 – 7.73(m, 2H), 7.34 (dd, J = 8.2, 3.0 Hz, 2H), 7.18 (dd, J = 8.3, 2.3 Hz, 1H), 7.10(dd, J= 10.7, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 4.96 (dd, J = 12.1, 5.3 Hz, 1H), 4.08 (t, J = 6.5 Hz, 2H), 3.93 (d, J = 7.0 Hz, 2H), 3.16 (d, J = 11.3 Hz, 2H),2.91 – 2.71 (m, 3H), 2.52 (t, J = 7.9 Hz, 2H), 2.28 (s, 3H), 2.25 – 2.05 (m,4H), 1.82 (m, 4H), 1.73 (d, J = 11.9 Hz, 2H), 1.59 (m, 2H), 1.46 (t, J = 7.6 Hz,2H), 1.35 – 1.26 (m, 14H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.62, 168.69,167.30, 164.60, 160.14, 157.67, 153.28, 151.84, 151.31, 143.44, 140.39,135.01, 134.30, 130.78, 130.45, 130.02, 129.41, 127.73, 127.50, 125.46,123.22, 122.39, 120.65, 117.82, 117.57, 108.91, 103.95, 69.11, 58.31, 52.56,49.33, 46.90, 34.87, 31.50, 29.69, 29.43, 29.18, 28.85, 28.67, 27.35, 25.82,25.73, 22.73, 15.18. HRMS m / z Calculated for C 49 H 55 ClFN7O6[M + H] + 892.3959, found 892.3945.

[0154] Example 19, Preparation of Compound A19

[0155] 4-(5-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)pent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A19)

[0156]

[0157] The synthesis route is as follows:

[0158]

[0159] Step 1: 2-(2,6-dioxadiazin-3-yl)-4-(5-hydroxypent-1-yn-1-yl)isoindoline-1,3-dione

[0160] Compound 10 (300 mg, 0.89 mmol), 4-pentyn-1-ol (112 mg, 1.3 mmol), Pd(PPh3)2Cl2 (126 mg, 0.18 mmol), CuI (68 mg, 0.36 mmol), and TEA (1.5 ml) were weighed into a 50 ml two-necked flask. Anhydrous DMF (10 ml) was added, and the mixture was purged with nitrogen five times. The reaction was carried out at 100 °C for 6 h. After the reaction was complete (monitored by LC-MS), the reaction mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate, dried, and concentrated to obtain the crude product. The crude product was purified by pulping to obtain the target compound 11, a pale yellow solid, with a yield of 63%. MS (ESI) m / z 341.5 [M + H] + .

[0161] Step 2: 5-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)pent-4-yn-1-yl 4-methylbenzenesulfonate

[0162] Compound 11 (150 mg, 0.44 mmol), TEA (58 mg, 0.57 mmol), and DMAP (5 mg, 0.044 mmol) were weighed and dissolved in DCM (5 ml). Then, p-toluenesulfonyl chloride (88 mg, 0.46 mmol) was added, and the reaction was carried out at room temperature for 48 h. After the reaction was complete (monitored by TLC), the solvent was removed by concentration under reduced pressure, and the solution was purified by thin-layer chromatography to give target compound 12 as a white solid, yield: 79%. MS (ESI) m / z 495.6 [M + H] + .

[0163] Step 3: 4-(5-bromopent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0164] Intermediate 12 (118 mg, 0.24 mmol) was weighed and dissolved in DMF (5 mL). LiBr (63 mg, 0.72 mmol) was added at 0 °C, and the reaction was carried out overnight at room temperature. After the reaction was complete (monitored by LC-MS), water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried, and concentrated to obtain the crude product. The crude product was purified by thin-layer chromatography to give compound 13 as a white solid, yield: 61%. MS (ESI) m / z 404.8 [M + H] + .

[0165] Step 4: 4-(5-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]pyridin-3-yl)methyl)piperidin-1-yl)pent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0166] To a DMF solution of compound 7 (80 mg, 0.16 mmol), 13 (74 mg, 0.18 mmol), sodium bicarbonate (41 mg, 0.48 mmol), and potassium iodide (3 mg, 0.016 mmol) were added, and the reaction mixture was reacted at 75 °C for 6 h. The reaction endpoint was confirmed by TLC after the reaction was complete. Subsequently, the reaction mixture was extracted three times with ethyl acetate, and the organic phases were combined. The mixture was washed once with water and once with saturated brine to remove water-soluble impurities. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to remove the solvent. Finally, the crude product was purified by column chromatography to obtain the target compound A19 as a white solid, yield: 37%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.09 (m, 1H), 7.77 (d, J = 6.9 Hz, 2H), 7.70 – 7.57 (m, 2H), 7.38– 7.31 (m, 1H), 7.12 (m, 1H), 6.82 (t, J= 6.4 Hz, 1H), 4.94 (m, 1H), 3.90 (m,2H), 3.09 – 2.93 (m, 2H), 2.88 – 2.68 (m, 3H), 2.55 (t, J = 6.7 Hz, 2H), 2.50 –2.40 (m, 2H), 2.27 (s, 3H), 2.10 (d, J = 6.0 Hz, 1H), 2.01 (m, 4H), 1.78 – 1.73 (m, 2H), 1.69 – 1.64 (m, 2H), 1.61 – 1.49 (m, 3H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.21, 168.29, 168.20, 166.03, 153.29, 152.03, 151.37,143.42, 140.44, 138.71, 138.49, 135.02, 133.83, 132.25, 130.83, 130.66,130.47, 130.06, 129.60, 122.57, 121.64, 117.59, 103.95, 52.90, 49.34, 47.32,31.51, 29.71, 26.01, 22.61, 19.46, 15.17, 14.14. HRMS m / z Calculated for C 42 H 37 ClFN7O5[M + H] + 774.2602, found 774.2594.

[0167] Following the method used to synthesize compound A19, similar reactions were carried out to prepare the following compounds A20~A30.

[0168] Example 20: Preparation of compound A20

[0169] 4-(6-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)hex-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A20)

[0170]

[0171] White solid, yield: 37%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.09 (m, 1H), 7.77 (d, J = 6.9 Hz, 2H), 7.70 – 7.57 (m,2H), 7.38 – 7.31 (m, 1H), 7.12 (m, 1H), 6.82 (t, J = 6.4 Hz, 1H), 4.94 (m, 1H), 3.90 (m, 2H), 3.09 – 2.93 (m, 2H), 2.88 – 2.68 (m, 3H), 2.55 (t, J = 6.7 Hz,2H), 2.50 – 2.40 (m, 2H), 2.27 (s, 3H), 2.10 (d, J = 6.0 Hz, 1H), 2.01 (m, 4H), 1.78 – 1.73 (m, 2H), 1.69 – 1.64 (m, 2H), 1.61 – 1.49 (m, 3H). 13 C NMR (101MHz, Chloroform- d ) δ 171.21, 168.29, 168.20, 166.03, 153.29, 152.03, 151.37,143.42, 140.44, 138.71, 138.49, 135.02, 133.83, 132.25, 130.83, 130.66,130.47, 130.06, 129.60, 122.57, 121.64, 117.59, 103.95, 52.90, 49.34, 47.32,31.51, 29.71, 26.01, 22.61, 19.46, 15.17, 14.14. HRMS m / z Calculated for C 43 H 39 ClFN7O5[M + H] + 788.2758, found 788.2744.

[0172] Example 21, Preparation of compound A21

[0173] 4-(7-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)hepta-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A21)

[0174]

[0175] White solid, yield: 40%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.45(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.7, 2.8 Hz, 1H), 7.80 – 7.74(m, 2H), 7.69 – 7.61 (m, 2H), 7.34 (m, 1H), 7.10 (dd, J = 10.7, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 5.01 – 4.92 (m, 1H), 3.91 (d, J = 7.1 Hz, 2H), 3.06 (d, J = 12.8 Hz, 2H), 2.88 – 2.72 (m, 3H), 2.51 (m, 2H), 2.45 (m, 2H), 2.28 (s,3H), 2.15 – 2.10 (m, 1H), 2.08 – 1.97 (m, 3H), 1.70 (m, 4H), 1.56 (m, 6H). 13 CNMR (101 MHz, Chloroform- d ) δ 171.60, 168.64, 166.55, 166.13, 157.68, 153.29,151.88, 151.33 (d, J= 2.6 Hz), 143.41, 140.45, 138.30, 135.00, 133.85, 132.25,129.51, 127.80, 122.51, 121.67, 117.84, 117.59, 103.92, 99.48, 58.29, 52.66,49.32, 47.11, 35.27, 31.41, 29.70, 28.02, 26.67, 25.86, 22.74, 19.70, 15.18.HRMS m / z Calculated for C 44 H 41 ClFN7O5[M + H] + 802.2915 was found to be 802.2906.

[0176] Example 22, Preparation of compound A22

[0177] 3-(4-(5-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)pent-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (A22)

[0178]

[0179] White solid, yield: 40%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.42(s, 1H), 8.09 (m, 1H), 7.79 (d, J = 6.4 Hz, 2H), 7.55 (d, J = 7.5 Hz, 1H), 7.42(t, J = 7.5 Hz, 1H), 7.34 (m, 1H), 7.10 (m, 1H), 6.85 (s, 1H), 5.24 (m, 1H), 4.51 (d, J = 16.6 Hz, 1H), 4.34 (d, J = 16.8 Hz, 1H), 3.91 (d, J = 7.1 Hz, 2H), 2.98 (d, J= 11.2 Hz, 2H), 2.92 – 2.78 (m, 2H), 2.48 (t, J = 7.0 Hz, 3H), 2.37(dd, J = 12.8, 5.1 Hz, 2H), 2.28 (s, 3H), 2.20 (d, J = 10.3 Hz, 1H), 2.02 (t, J =11.2 Hz, 3H), 1.79 (dd, J = 18.9, 11.5 Hz, 4H), 1.58 – 1.47 (m, 2H). 13 C NMR (101MHz, Chloroform- d ) δ 171.69, 170.01, 169.07, 153.29, 151.96, 151.36, 143.61,140.43, 134.55, 131.56, 130.77, 130.47, 130.03, 128.38, 123.26, 122.55,122.45, 119.44, 117.60, 95.54, 57.40, 53.20, 53.05, 51.81, 47.19, 46.97,35.45, 31.61, 29.68, 25.80, 23.52, 17.52, 15.16. HRMS m / z Calculated for C 42 H 39 ClFN7O4[M + H] + 760.2809, found 760.2790.

[0180] Example 23, Preparation of compound A23

[0181] 3-(4-(6-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)hex-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (A23)

[0182]

[0183] White solid, yield: 44%. 1H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.46(s, 1H), 8.35 (dd, J = 9.8, 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.6 Hz, 1H), 7.79 (d, J = 6.5 Hz, 2H), 7.54 (dd, J = 7.7, 4.6 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.35(m, 1H), 7.18 – 7.05 (m, 1H), 6.83 (t, J = 4.4 Hz, 1H), 5.24 (m, 1H), 4.53 (t, J = 16.7 Hz, 1H), 4.43 – 4.33 (m, 1H), 3.92 (m, 2H), 3.06 (d, J = 11.4 Hz, 2H),2.95 – 2.77 (m, 2H), 2.53 – 2.46 (m, 3H), 2.27 (s, 3H), 2.19 (m, 1H), 2.07(m, 3H), 1.75 (dd, J = 17.1, 9.4 Hz, 4H), 1.67 – 1.55 (m, 4H). 13 C NMR (101 MHz,Chloroform- d ) δ 170.24, 153.29, 151.95, 151.34, 143.42, 140.38, 134.57,131.62, 130.63, 130.44, 130.05, 129.47, 128.33, 123.21, 122.52, 119.44,117.83, 117.58, 103.99, 95.48, 57.83, 52.88, 51.82, 47.06, 35.32, 31.66,30.39, 29.40, 26.27, 23.50, 19.37, 15.16. HRMS m / z calculated for C 43 H 41 ClFN7O4[M+ H] +774.2966, found 774.2953.

[0184] Example 24, Preparation of compound A24

[0185] 3-(4-(7-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)hepta-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (A24)

[0186]

[0187] White solid, yield: 39%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.44(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.78 (t, J = 3.8Hz, 2H), 7.55 (d, J = 7.6 Hz, 1H), 7.42 (t, J = 7.6 Hz, 1H), 7.36 – 7.31 (m, 1H), 7.10 (t, J = 9.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 5.23 (dd, J = 13.2, 5.2 Hz, 1H), 4.49 (d, J = 16.8 Hz, 1H), 4.34 (d, J = 16.8 Hz, 1H), 3.91 (d, J = 7.1 Hz, 2H), 3.03 (d, J = 11.4 Hz, 2H), 2.93 – 2.77 (m, 3H), 2.44 (dd, J = 14.7, 7.7 Hz,4H), 2.28 (s, 3H), 2.22 (dd, J= 8.8, 3.7 Hz, 1H), 2.06 – 1.98 (m, 3H), 1.78 –1.72 (m, 2H), 1.62 (d, J = 7.1 Hz, 2H), 1.56 (dd, J = 15.4, 8.1 Hz, 4H), 1.50 –1.45 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.68, 170.04, 169.07, 153.29,151.89, 151.36, 143.57, 143.42, 140.45, 135.02, 134.52, 131.57, 130.78,130.45, 129.47, 128.36, 127.80, 123.18, 122.52, 117.83, 103.93, 96.01, 58.37,52.85, 51.86, 47.02, 35.34, 31.57, 29.69, 28.47, 26.81, 26.11, 23.51, 19.40, 15.17. HRMS m / z Calculated for C 44 H 43 ClFN7O4[M + H] + 788.3122, found 788.3118.

[0188] Example 25: Preparation of compound A25

[0189] 5-(5-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)pent-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A25)

[0190]

[0191] White solid, yield: 35%. 1 H NMR (400 MHz, Chloroform- d) δ 8.79 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.09 (m, 1H), 7.79 (d, J = 6.9 Hz, 2H), 7.70 – 7.57 (m,2H), 7.38 – 7.31 (m, 1H), 7.12 (m, 1H), 6.82 (t, J = 6.4 Hz, 1H), 4.94 (m, 1H), 3.90 (m, 2H), 3.09 – 2.93 (m, 2H), 2.88 – 2.68 (m, 3H), 2.55 (t, J = 6.7 Hz,2H), 2.50 – 2.40 (m, 2H), 2.27 (s, 3H), 2.10 (d, J = 6.0 Hz, 1H), 2.01 (m, 4H), 1.78 – 1.73 (m, 2H), 1.64 – 1.50 (m, 3H). HRMS m / z Calculated for C 42 H 37 ClFN7O5[M+ H] + 774.2602, found 774.2603.

[0192] Example 26: Preparation of compound A26

[0193] 5-(6-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)hex-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A26)

[0194]

[0195] White solid, yield: 42%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.45(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J= 6.8, 2.8 Hz, 1H), 7.83 (s, 1H),7.78 (t, J = 3.9 Hz, 2H), 7.71 (d, J = 7.7 Hz, 1H), 7.37 – 7.32 (m, 1H), 7.10(dd, J = 10.7, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 5.01 – 4.92 (m, 1H), 3.91(d, J = 7.0 Hz, 2H), 3.04 (d, J = 11.1 Hz, 2H), 2.90 – 2.75 (m, 3H), 2.45 (dd, J =18.8, 7.0 Hz, 4H), 2.28 (s, 3H), 2.16 – 2.11 (m, 1H), 2.02 (m, 2H), 1.79 –1.56 (m, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.27, 168.25, 166.81, 153.29,151.88, 143.43, 140.48, 137.28, 135.01, 131.90, 130.92, 130.78, 130.49,129.50, 127.82, 126.60, 123.63, 122.52, 117.57, 103.90, 95.89, 57.96, 52.99,49.45, 47.23, 35.45, 31.45, 29.61, 26.35, 25.87, 22.65, 19.45, 15.17. HRMS m / z Calculated for C 43 H 39 ClFN7O5[M + H] + 788.2758, found 788.2761.

[0196] Example 27, Preparation of Compound A27

[0197] 5-(7-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5-c ]Pyridin-3-yl)methyl)piperidin-1-yl)hepta-1-yn-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A27)

[0198]

[0199] White solid, yield: 39%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.43 (s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.83 (s, 1H),7.78 (t, J = 3.9 Hz, 2H), 7.71 (d, J = 7.7 Hz, 1H), 7.37 – 7.30 (m, 1H), 7.10(dd, J = 10.7, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 5.01 – 4.92 (m, 1H), 3.91(d, J = 7.0 Hz, 2H), 3.04 (d, J = 11.1 Hz, 2H), 2.90 – 2.75 (m, 3H), 2.45 (dd, J =18.8, 7.0 Hz, 4H), 2.28 (s, 3H), 2.16 – 2.11 (m, 1H), 2.01 (s, 2H), 1.79 –1.52 (m, 11H). HRMS m / z Calculated for C 44 H 41 ClFN7O5[M + H] + 802.2915, found 802.2909.

[0200] Example 28, Preparation of Compound A28

[0201] 3-(5-(5-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c]Pyridin-3-yl)methyl)piperidin-1-yl)pent-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (A28)

[0202]

[0203] White solid, yield: 43%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.42(s, 1H), 8.35 (d, J = 5.3 Hz, 1H), 8.10 (dd, J = 6.8, 2.8 Hz, 1H), 7.78 (t, J = 4.0Hz, 2H), 7.51 – 7.45 (m, 2H), 7.34 (m, 1H), 7.10 (dd, J = 10.7, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 5.20 (dd, J = 13.3, 5.2 Hz, 1H), 4.46 (d, J = 16.2 Hz, 1H), 4.30 (d, J = 16.1 Hz, 1H), 3.91 (d, J = 7.0 Hz, 2H), 2.99 (d, J = 11.3 Hz, 2H), 2.88 (dd, J = 5.5, 2.9 Hz, 1H), 2.48 (m, 4H), 2.28 (s, 3H), 2.22 – 2.19(m, 1H), 2.03 – 1.96 (m, 3H), 1.80 (q, J = 6.7, 6.0 Hz, 2H), 1.73 (d, J = 10.9Hz, 2H), 1.56 – 1.48 (m, 2H). 13 C NMR (101 MHz, Chloroform- d) δ 171.34, 169.71,153.29, 151.89, 151.38, 143.46, 141.41, 140.49, 135.02, 131.73, 130.78,130.64, 130.49, 130.08, 129.48, 127.82, 127.44, 125.92, 123.91, 122.53,117.57, 103.91, 92.85, 57.55, 53.14, 51.91, 47.30, 46.83, 35.57, 31.59,29.90, 25.91, 23.42, 17.55, 15.16. HRMS m / z Calculated for C 42 H 39 ClFN7O4[M + H] + 760.2809, found 760.2796.

[0204] Example 29, Preparation of Compound A29

[0205] 3-(5-(6-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3- H -imidazo[4,5- c ]Pyridin-3-yl)methyl)piperidin-1-yl)hex-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (A29)

[0206]

[0207] White solid, yield: 40%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.42(s, 1H), 8.34 (d, J = 5.4 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.78 (t, J = 4.0Hz, 2H), 7.48 (d, J = 8.8 Hz, 2H), 7.39 – 7.32 (m, 1H), 7.10 (dd, J = 10.7, 8.7Hz, 1H), 6.83 (d, J= 5.4 Hz, 1H), 5.19 (dd, J = 13.3, 5.2 Hz, 1H), 4.45 (d, J =16.2 Hz, 1H), 4.30 (d, J = 16.1 Hz, 1H), 3.91 (d, J = 7.1 Hz, 2H), 3.01 (d, J =11.1 Hz, 2H), 2.89 – 2.78 (m, 2H), 2.47 (d, J = 6.8 Hz, 2H), 2.42 (d, J = 7.0 Hz,2H), 2.28 (s, 3H), 2.20 (m, 1H), 2.02 – 1.95 (m, 3H), 1.74 (m, 3H), 1.63 (dd, J = 13.1, 6.5 Hz, 4H), 1.54 (d, J = 12.2 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d )δ 171.46, 169.81, 168.81, 153.29, 151.88, 143.45, 141.42, 140.48, 135.01,131.70, 130.78, 130.63, 130.48, 129.48, 125.96, 123.89, 122.41, 117.83,117.58, 103.91, 58.11, 53.07, 51.91, 47.26, 46.84, 35.52, 31.61, 29.76,26.55, 26.01, 23.42, 19.41, 15.16. HRMS m / z Calculated for C 43 H 41 ClFN7O4[M + H] + 774.2966, found 774.2948.

[0208] Example 30: Preparation of compound A30

[0209] 3-(5-(7-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5-c ]Pyridin-3-yl)methyl)piperidin-1-yl)hepta-1-yn-1-yl)-1-oxoisoindoline-2-yl)piperidin-2,6-dione (A30)

[0210]

[0211] White solid, yield: 47%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.72 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 8.02 (dd, J = 6.8, 2.8 Hz, 1H), 7.71 (t, J = 3.9Hz, 2H), 7.43 – 7.38 (m, 2H), 7.29 – 7.24 (m, 1H), 7.05 – 7.00 (m, 1H), 6.76(d, J = 5.3 Hz, 1H), 5.12 (dd, J = 13.3, 5.1 Hz, 1H), 4.38 (d, J = 16.2 Hz, 1H), 4.23 (d, J = 16.1 Hz, 1H), 3.82 (d, J = 7.0 Hz, 2H), 2.93 (d, J = 11.2 Hz, 2H),2.81 – 2.69 (m, 2H), 2.37 (d, J = 6.9 Hz, 2H), 2.30 (d, J = 8.0 Hz, 2H), 2.20 (s,3H), 2.15 – 2.10 (m, 1H), 1.91 (t, J = 11.6 Hz, 3H), 1.66 (d, J = 10.5 Hz, 3H), 1.56 (t, J = 7.2 Hz, 2H), 1.48 (m, 4H), 1.40 (d, J = 6.9 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d) δ 171.45, 169.81, 168.83, 153.29, 151.88, 143.45, 141.43,140.48, 135.01, 131.70, 130.78, 130.49, 130.04, 129.49, 128.05, 127.81,125.93, 123.89, 122.42, 117.82, 103.90, 93.24, 58.55, 53.05, 51.91, 47.24,46.84, 35.49, 31.61, 29.69, 28.39, 26.87, 26.27, 23.41, 19.43, 15.16. HRMS m / z Calculated for C 44 H 43 ClFN7O4[M + H] + 788.3122, found 788.311.

[0212] Example 31, Preparation of compound A31

[0213] (2 R 4 S )-1-((2 R )-2-(4-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)butamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A31)

[0214]

[0215] The synthesis route is as follows:

[0216]

[0217] Step 1: 4-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c 3-ylpyridinylmethylpiperidin-1-yltert-butyl butyrate

[0218] Compound 7 (100 mg, 0.20 mmol), tert-butyl 3-bromopropionate (52 mg, 0.25 mmol), potassium carbonate (83 mg, 0.6 mmol), and potassium iodide (3 mg, 0.02 mmol) were weighed into a round-bottom flask, and DMF (5 mL) was added. The mixture was reacted at 100 °C for 8 h. After the reaction was complete (detected by TLC), the mixture was extracted three times with ethyl acetate, and the combined organic phases were washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography to obtain compound 14 as a white solid, yield: 81%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.41 (s, 1H), 8.34 (d, J = 5.2 Hz, 1H), 8.10 (dd, J = 6.8, 2.7 Hz, 1H), 7.79 (d, J = 1.4 Hz, 1H), 7.35 (m, 1H), 7.11 (dd, J = 10.7, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 3.90 (dd, J = 7.0, 1.7 Hz, 2H), 2.98 (d, J = 11.2 Hz, 2H), 2.37 (dd, J = 8.7, 6.3 Hz, 2H), 2.29 (s, 3H), 2.24 (t, J = 7.4 Hz, 2H), 2.05 – 1.94 (m, 3H), 1.77 (m, 4H), 1.54 (m, 2H), 1.44 (s,9H). MS (ESI) m / z 595.5 [M + H] + .

[0219] Step 2: 4-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)butyric acid

[0220] HCl / dioxane solution (5 mL) was added to a 1,4-dioxane solution of compound 14 (100 mg, 0.19 mmol) and the reaction was carried out at 80 °C for 6 h. After the reaction was completed (monitored by TLC), the solvent was removed by concentration under reduced pressure to obtain compound 15.

[0221] Step 3: (2) R 4 S )-1-((2 R )-2-(4-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)butamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S 1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide

[0222] To a DMF solution containing compound 15 (65 mg, 0.12 mmol), HATU (59 mg, 0.16 mmol), and DIPEA (47 mg, 0.36 mmol), add (2... R 4 S )-1-(( R )-2-amino-3,3-dimethylbutyryl)-4-hydroxy- N -(( S 1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide hydrochloride (64 mg, 0.13 mmol). The reaction was carried out at room temperature for 8 h, and the reaction progress was monitored by TLC. After the reaction was completed, the mixture was extracted three times with ethyl acetate, and the organic phases were combined. The organic phase was washed successively with water and saturated brine, and then dried over anhydrous sodium sulfate. Finally, the target compound A31 was purified by thin-layer chromatography to give a white solid, yield: 66%. 1 H NMR (400 MHz, Chloroform- d ) δ8.78 (s, 1H), 8.66 (s, 1H), 8.47 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 8.08 (m,1H), 7.78 (s, 1H), 7.75 (dd, J = 7.8, 1.8 Hz, 1H), 7.40 – 7.31 (m, 5H), 7.09(dd, J= 10.7, 8.7 Hz, 1H), 6.92 (dd, J = 8.9, 2.8 Hz, 1H), 6.83 (d, J = 5.3 Hz,1H), 5.09 (m, 1H), 4.74 (t, J = 7.4 Hz, 1H), 4.61 (d, J = 9.0 Hz, 1H), 4.48 (s,1H), 4.06 (d, J = 11.3 Hz, 1H), 3.94 – 3.86 (m, 2H), 3.62 (dd, J = 11.3, 3.5 Hz,1H), 3.06 (t, J = 10.8 Hz, 2H), 2.51 (d, J = 0.9 Hz, 3H), 2.50 – 2.40 (m, 2H),2.36 – 2.25 (m, 6H), 2.16 – 1.98 (m, 4H), 1.84 (q, J = 7.3 Hz, 2H), 1.80 – 1.71(m, 2H), 1.64 – 1.53 (m, 2H), 1.46 (d, J = 6.9 Hz, 3H), 1.05 (s, 9H). 13 C NMR(101 MHz, Chloroform- d ) δ 173.37, 171.57, 170.23, 160.13, 157.64, 153.27,151.85, 151.32, 150.33, 148.34, 143.49, 143.38, 140.38, 134.99, 131.62,130.75, 130.64, 130.58, 130.40, 130.05, 129.54, 129.44, 127.73, 127.31,126.41, 122.38, 117.82, 117.57, 103.98, 69.86, 58.83, 57.70, 57.02, 52.78,48.72, 47.03, 36.41, 35.42, 35.04, 33.68, 29.68, 29.07, 26.57, 22.23, 22.07,16.07, 15.16. HRMS m / z calculated for C51 H 59 ClFN9O5S [M + H] + 964.4105, found964.4082.

[0223] Following the method used to synthesize compound A31, similar reactions were carried out to prepare the following compounds A32 to A39.

[0224] Example 32, Preparation of compound A32

[0225] (2 R 4 S )-1-((2 R )-2-(5-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)pentanamide)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A32)

[0226]

[0227] White solid, yield: 69%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.78 (s, 1H), 8.66(s, 1H), 8.48 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 8.09 (m, 1H), 7.78 (dd, J = 3.4,1.3 Hz, 1H), 7.71 – 7.66 (m, 1H), 7.38 – 7.32 (m, 5H), 7.09 (dd, J = 10.7, 8.8Hz, 1H), 6.82 (d, J = 5.3 Hz, 1H), 6.70 (d, J = 9.0 Hz, 1H), 5.09 (m, 1H), 4.73(t, J = 8.2 Hz, 1H), 4.62 (d, J = 9.1 Hz, 1H), 4.48 (s, 1H), 4.04 (d,J = 11.3 Hz, 1H), 3.92 (d, J = 7.1 Hz, 2H), 3.62 (dd, J = 11.2, 3.4 Hz, 2H), 3.12 (d, J = 9.5Hz, 2H), 2.51 (s, 3H), 2.27 (m, 6H), 2.19 (m, 4H), 1.79 (t, J = 10.7 Hz, 2H),1.69 – 1.54 (m, 6H), 1.47 (d, J = 8.5 Hz, 3H), 1.04 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.43, 171.63, 170.21, 160.12, 157.64, 153.27, 151.84,151.32, 150.32, 148.34, 143.51, 143.40, 140.37, 134.98, 131.62, 130.74,130.65, 130.57, 130.41, 130.05, 129.59, 129.45, 127.75, 127.32, 126.42,122.38, 117.82, 117.57, 103.96, 69.83, 58.90, 57.60, 57.07, 52.77, 52.71,48.75, 46.93, 36.51, 35.69, 35.45, 34.82, 28.76, 26.56, 25.39, 23.26, 22.25,16.08, 15.16. HRMS m / z Calculated for C 52 H 61 ClFN9O5S [M + H] + 978.4262, found 978.4250.

[0228] Example 33, Preparation of compound A33

[0229] (2 R 4 S )-1-((2 R )-2-(6-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H-imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)hexamamide)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A33)

[0230]

[0231] White solid, yield: 62%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.70 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.22 (d, J = 5.3 Hz, 1H), 8.00 (dd, J = 6.8, 2.8 Hz, 1H), 7.70 (t, J = 6.1 Hz, 2H), 7.31 – 7.23 (m, 5H), 7.01 (t, J = 10.1 Hz, 1H), 6.74(d, J = 5.2 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 5.00 (q, J = 7.2 Hz, 1H), 4.66 (t, J =8.2 Hz, 1H), 4.55 (d, J = 9.1 Hz, 1H), 4.40 (m, 1H), 3.97 (d, J = 11.3 Hz, 2H), 3.87 (d, J = 7.2 Hz, 2H), 3.54 (dd, J = 11.4, 3.4 Hz, 1H), 3.26 – 3.17 (m, 2H), 2.60 (d, J = 8.6 Hz, 2H), 2.42 (s, 3H), 2.29 (d, J = 10.4 Hz, 2H), 2.19 (s, 3H), 2.17 – 2.03 (m, 4H), 1.75 (d, J = 12.2 Hz, 4H), 1.55 (m, 4H), 1.39 (d, J= 7.0Hz, 3H), 1.23 (t, J = 7.5 Hz, 2H), 1.19 (d, J = 5.5 Hz, 2H), 0.95 (s, 9H). 13 C NMR (101 MHz, Chloroform- d ) δ 173.69, 171.59, 170.26, 160.13, 157.65, 153.28,151.85, 151.33, 150.31, 148.34, 143.59, 143.44, 140.33, 135.00, 131.65,130.74, 130.68, 130.60, 130.44, 130.07, 129.63, 129.43, 127.73, 127.30,126.41, 122.38, 117.83, 117.58, 103.99, 69.87, 58.93, 57.59, 57.14, 48.74,46.65, 36.64, 35.75, 35.45, 34.34, 31.65, 29.69, 27.98, 26.55, 26.30, 24.94,22.29, 16.08, 15.17. HRMS m / z Calculated for C 53 H 63 ClFN9O5S [M + H] + 992.4418, found 992.4403.

[0232] Example 34, Preparation of compound A34

[0233] (2 R 4 S )-1-((2 R )-2-(7-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)heptamide)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A34)

[0234]

[0235] White solid, yield: 70%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.66(s, 1H), 8.47 (s, 1H), 8.32 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H),7.78 (d, J = 1.6 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.38 – 7.32 (m, 5H), 7.10(dd, J = 10.7, 8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 6.45 (d, J = 9.0 Hz, 1H),5.08 (q, J = 7.2 Hz, 1H), 4.73 (t, J = 8.2 Hz, 1H), 4.62 (d, J = 9.1 Hz, 1H), 4.49(s, 1H), 4.06 (d, J = 11.3 Hz, 1H), 3.93 (d, J = 7.1 Hz, 2H), 3.65 – 3.58 (m,2H), 3.19 (s, 2H), 2.5 – 2.52 (m, 2H), 2.51 (s, 3H), 2.28 (s, 3H), 2.20 (m,5H), 2.11 – 2.04 (m, 1H), 1.86 – 1.78 (m, 2H), 1.72 (d, J = 12.4 Hz, 2H), 1.58(m, 4H), 1.44 (d, J = 6.7 Hz, 3H), 1.32 – 1.27 (m, 4H), 1.04 (s, 9H). 13 C NMR(101 MHz, Chloroform- d) δ 173.74, 171.64, 170.20, 160.14, 157.66, 153.28,151.84, 151.35, 150.33, 148.36, 143.49, 143.45, 140.37, 135.00, 131.64,130.76, 130.67, 130.57, 130.45, 130.06, 129.53, 129.47, 127.74, 127.47,126.45, 122.49, 117.83, 117.58, 103.97, 69.84, 58.85, 57.94, 57.45, 56.99,53.46, 48.78, 46.84, 36.11, 35.37, 31.66, 29.69, 28.55, 26.53, 25.17, 22.25,18.18, 16.08, 15.17, 12.44. HRMS m / z Calculated for C 54 H 65 ClFN9O5S [M + H] + 1006.4575, found 1006.4568.

[0236] Example 35: Preparation of compound A35

[0237] (2 R 4 S )-1-((2 R )-2-(8-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)octamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A35)

[0238]

[0239] White solid, yield: 69%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.67(s, 1H), 8.46 (s, 1H), 8.32 (d, J= 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H),7.78 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 7.40 – 7.32 (m, 5H), 7.10 (dd, J = 10.7,8.8 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 6.38 (d, J = 8.9 Hz, 1H), 5.09 (q, J = 7.1Hz, 1H), 4.72 (t, J = 8.0 Hz, 1H), 4.63 (d, J = 9.0 Hz, 1H), 4.50 (s, 1H), 4.05(d, J = 11.3 Hz, 1H), 3.92 (d, J = 7.1 Hz, 2H), 3.63 (dd, J = 11.4, 3.7 Hz, 2H),3.09 (dd, J = 11.1, 5.7 Hz, 2H), 2.52 (s, 3H), 2.47 – 2.35 (m, 3H), 2.28 (s,3H), 2.22 – 2.02 (m, 6H), 1.82 – 1.73 (m, 2H), 1.68 – 1.53 (m, 5H), 1.49 (d, J = 6.9 Hz, 3H), 1.32 – 1.26 (m, 6H), 1.04 (s, 9H). 13 C NMR (101 MHz, Chloroform- d) δ 173.61, 171.62, 170.20, 160.12, 157.64, 153.26, 151.82, 151.30, 151.28,150.36, 148.34, 143.43, 143.38, 140.39, 134.96, 131.60, 130.75, 130.69,130.42, 130.01, 129.49, 129.46, 127.79, 127.35, 126.46, 122.48, 117.82,117.57, 103.93, 69.75, 58.90, 58.38, 57.35, 56.93, 52.85, 48.74, 47.04,36.25, 35.48, 35.07, 29.66, 29.05, 28.69, 26.95, 26.52, 25.90, 25.26, 22.19,16.06, 15.16. HRMS m / z Calculated for C 55 H 67 ClFN9O5S [M + H] + 1020.4731, found 1020.4731.

[0240] Example 36: Preparation of compound A36

[0241] (2 R 4 S )-1-((2 R )-2-(9-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3H-imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)nonamido)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A36)

[0242]

[0243] White solid, yield: 70%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.67(s, 1H), 8.46 (s, 1H), 8.32 (d, J= 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H),7.78 (s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.41 – 7.33 (m, 5H), 7.10 (dd, J = 10.7,8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 6.37 (d, J = 8.9 Hz, 1H), 5.11 (q, J = 7.1Hz, 1H), 4.70 (t, J = 8.0 Hz, 1H), 4.61 (d, J = 8.9 Hz, 1H), 4.51 (s, 1H), 4.05(d, J = 11.3 Hz, 1H), 3.93 (d, J = 7.1 Hz, 2H), 3.63 (dd, J = 11.2, 3.7 Hz, 2H),3.13 (d, J = 11.4 Hz, 2H), 2.52 (s, 3H), 2.49 (t, J = 8.2 Hz, 2H), 2.41 – 2.34(m, 1H), 2.28 (s, 3H), 2.20 – 2.05 (m, 6H), 1.81 (t, J = 10.3 Hz, 2H), 1.69 (d, J = 12.4 Hz, 2H), 1.57 (t, J = 6.8 Hz, 4H), 1.49 (d, J = 6.9 Hz, 3H), 1.26 (m,8H), 1.04 (s, 9H). 13 C NMR (101 MHz, Chloroform- d) δ 173.61, 171.59, 170.24,160.11, 157.63, 153.25, 151.81, 151.28, 151.25, 150.38, 148.30, 143.44,143.38, 140.38, 134.96, 131.60, 130.75, 130.66, 130.38, 129.99, 129.52,129.44, 127.76, 127.45, 126.46, 122.47, 117.82, 117.57, 103.93, 69.76, 58.93,58.32, 57.35, 56.86, 48.72, 46.93, 36.32, 35.49, 34.92, 29.65, 28.95, 28.88,27.07, 26.52, 25.84, 25.48, 22.18, 16.06, 15.16. HRMS m / z Calculated for C 56 H 69 ClFN9O5S [M + H] + 1034.4888, found 1034.4889.

[0244] Example 37, Preparation of Compound A37

[0245] (2 R 4 S )-1-((2 R )-2-(10-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)decanoamide)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A37)

[0246]

[0247] White solid, yield: 65%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.67(s, 1H), 8.47 (s, 1H), 8.32 (d, J= 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H),7.78 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.41 – 7.32 (m, 5H), 7.10 (dd, J = 10.7,8.7 Hz, 1H), 6.83 (d, J = 5.2 Hz, 1H), 6.35 (d, J = 8.9 Hz, 1H), 5.09 (p, J = 7.0Hz, 1H), 4.71 (t, J = 8.0 Hz, 1H), 4.61 (d, J = 8.9 Hz, 1H), 4.50 (s, 1H), 4.06(d, J = 11.3 Hz, 1H), 3.94 (d, J = 7.1 Hz, 2H), 3.65 – 3.61 (m, 1H), 3.18 (d, J =11.7 Hz, 2H), 2.54 (d, J = 10.0 Hz, 2H), 2.52 (s, 3H), 2.39 (m, 1H), 2.28 (s,3H), 2.24 – 2.05 (m, 6H), 1.92 – 1.66 (m, 5H), 1.58 (m, 4H), 1.49 (d, J = 6.9Hz, 3H), 1.27 (d, J = 8.9 Hz, 12H), 1.04 (s, 9H). 13 C NMR (101 MHz, Chloroform- d)δ 173.77, 171.73, 170.10, 160.14, 157.66, 153.29, 151.84, 151.35, 150.36,148.39, 143.45, 143.36, 140.37, 135.00, 131.60, 130.76, 130.66, 130.57,130.45, 130.03, 129.50, 127.76, 127.48, 127.35, 126.47, 122.49, 117.83,117.58, 103.96, 69.85, 58.84, 58.28, 57.40, 56.86, 52.69, 48.78, 46.87,36.40, 36.10, 35.38, 34.79, 29.69, 28.98, 28.92, 28.61, 27.07, 26.52, 25.60,25.43, 22.20, 16.08, 15.17. HRMS m / z Calculated for C 57 H 71 ClFN9O5S [M + H] + 1048.5044, found 1048.5056.

[0248] Example 38, Preparation of Compound A38

[0249] (2 R 4 S )-1-((2 R )-2-(11-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)undecanoamide)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A38)

[0250]

[0251] White solid, yield: 73%. 1 H NMR (400 MHz, Chloroform- d) δ 8.79 (s, 1H), 8.67(s, 1H), 8.45 (s, 1H), 8.32 (d, J = 5.4 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H),7.78 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.37 (m, 5H), 7.10 (t, J = 9.7 Hz, 1H),6.83 (d, J = 5.3 Hz, 1H), 6.29 (d, J = 8.9 Hz, 1H), 5.09 (p, J = 7.0 Hz, 1H), 4.71(t, J = 7.9 Hz, 1H), 4.60 (d, J = 8.9 Hz, 1H), 4.51 (s, 1H), 4.08 (d, J = 11.4 Hz,1H), 3.92 (d, J = 7.1 Hz, 2H), 3.62 (d, J = 11.0 Hz, 1H), 3.09 (d, J = 9.9 Hz, 2H),2.52 (s, 3H), 2.43 (dd, J = 11.0, 5.7 Hz, 2H), 2.28 (s, 3H), 2.17 (t, J = 7.6 Hz,2H), 2.14 – 2.00 (m, 4H), 1.77 (d, J = 9.9 Hz, 2H), 1.68 – 1.52 (m, 6H), 1.49(d, J = 6.9 Hz, 3H), 1.32 – 1.22 (m, 14H), 1.04 (s, 9H). 13 C NMR (101 MHz,Chloroform- d) δ 173.78, 171.77, 170.06, 153.29, 151.84, 151.33, 150.37,148.40, 143.42, 143.31, 140.42, 134.99, 131.59, 130.78, 130.64, 130.56,130.45, 130.44, 130.06, 130.01, 129.51, 127.81, 126.48, 122.51, 122.40,117.83, 117.58, 103.94, 69.85, 58.81, 58.57, 57.39, 56.83, 52.89, 48.79,47.08, 36.50, 35.98, 35.35, 35.15, 29.69, 27.32, 26.52, 26.17, 25.55, 22.19,16.08, 15.18. HRMS m / z Calculated for C 58 H 73 ClFN9O5S [M + H] + 1062.5201, found 1062.5198.

[0252] Example 39, Preparation of compound A39

[0253] (2 R 4 S )-1-((2R)-2-(12-(4-((1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3 H -imidazo[4,5] -c ]pyridin-3-yl)methyl)piperidin-1-yl)dodecanoamide)-3,3-dimethylbutyryl)-4-hydroxy- N -(( S )-1-(4-(4-methylthiazolyl-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide (A39)

[0254]

[0255] White solid, yield: 70%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.67(s, 1H), 8.44 (s, 1H), 8.33 (d, J = 5.3 Hz, 1H), 8.10 (dd,J = 6.8, 2.8 Hz, 1H),7.78 (s, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.41 – 7.34 (m, 5H), 7.10 (dd, J = 10.7,8.7 Hz, 1H), 6.83 (d, J = 5.3 Hz, 1H), 6.22 (d, J = 8.8 Hz, 1H), 5.09 (p, J = 7.1Hz, 1H), 4.72 (t, J = 7.9 Hz, 1H), 4.58 (d, J = 8.8 Hz, 1H), 4.52 (s, 1H), 4.10(d, J = 11.4 Hz, 1H), 3.93 (d, J = 7.0 Hz, 2H), 3.61 (dd, J = 11.4, 3.7 Hz, 1H),3.16 (d, J = 11.3 Hz, 2H), 2.53 (s, 3H), 2.50 (d, J = 11.9 Hz, 4H), 2.28 (s, 3H),2.19 (t, J = 7.6 Hz, 3H), 2.08 (dd, J = 13.6, 8.2 Hz, 2H), 1.87 – 1.71 (m, 4H),1.63 – 1.56 (m, 4H), 1.48 (d, J = 6.9 Hz, 3H), 1.26 (t, J = 6.8 Hz, 16H), 1.04(s, 9H). 13 C NMR (101 MHz, Chloroform- d) δ 173.74, 171.85, 169.97, 160.15,157.67, 153.29, 151.83, 151.35, 150.34, 148.42, 143.49, 143.27, 140.39,134.99, 131.58, 130.81, 130.76, 130.65, 130.46, 130.03, 129.52, 127.76,127.50, 126.47, 122.49, 122.38, 117.83, 117.58, 103.95, 69.86, 58.75, 58.38,57.39, 56.78, 52.71, 48.80, 46.91, 36.51, 35.87, 35.31, 34.89, 29.69, 29.29,29.24, 29.14, 28.74, 27.25, 26.53, 25.78, 25.59, 22.21, 16.09, 15.18. HRMS m / z Calculated for C 59 H 75 ClFN9O5S [M + H] + 1076.5357, found 1076.5352.

[0256] Example 40: Preparation of compound A40

[0257] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)butyl)piperazin-1-yl)ethyl)acetamide (A40)

[0258]

[0259] The synthesis route is as follows:

[0260]

[0261] Step 1: 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c 3-pyridinyl)tert-butyl acetate

[0262] Compound 5 (130 mg, 0.37 mmol), tert-butyl bromoacetate (107 mg, 0.55 mmol), potassium carbonate (153 mg, 1.09 mmol), and potassium iodide (6 mg, 0.037 mmol) were weighed into a round-bottom flask, and DMF (5 mL) was added. The reaction was carried out at 100 °C for 6 h. After the reaction was completed (as detected by TLC), the reaction system was extracted three times with ethyl acetate, the organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain target compound 16, a pale yellow solid, 71%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.31 (s, 1H), 8.11 (dd, J = 6.7, 2.8 Hz, 1H), 7.80 (d, J = 1.4Hz, 1H), 7.35 (m, 1H), 7.11 (dd, J = 10.8, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 4.65 (q, J = 17.7 Hz, 2H), 2.30 (s, 3H), 1.50 (s, 9H). MS(ESI) m / z 470.2 [M + H] + .

[0263] Step 2: 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5- c pyridin-3-yl)acetic acid

[0264] An HCl / dioxane solution was added to a 1,4-dioxane solution of compound 16 (330 mg), and the reaction was carried out at 80 °C for 5 h. After the reaction was complete (as detected by TLC), the solvent was removed by concentration under reduced pressure to obtain compound 17. This compound did not require purification and was used directly in the next step.

[0265] Step 3: 4-(2-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c]Pyridin-3-yl)acetamyl)ethyl)piperazine-1-carboxylic acid tert-butyl ester.

[0266] Compound 17 (190 mg, 0.46 mmol), HATU (210 mg, 0.55 mmol), and DIPEA were dissolved in DMF (6 mL), and tert-butyl 4-(2-aminoethyl)piperazine-1-carboxylate (127 mg, 0.55 mmol) was added. The mixture was stirred overnight at room temperature. After the reaction was complete (detected by TLC), the mixture was extracted three times with ethyl acetate. The combined organic phases were washed successively with water, saturated brine, and dried over anhydrous sodium sulfate. The purified solution was obtained by thin-layer chromatography to give compound 18 as a white solid, yield: 89%. 1 H NMR (400MHz, Chloroform- d ) δ 8.81 (s, 1H), 8.45 (s, 1H), 8.38 (d, J = 5.3 Hz, 1H), 8.12(dd, J = 6.8, 2.8 Hz, 1H), 7.80 (d, J = 1.3 Hz, 1H), 7.35 (m, 1H), 7.11 (dd, J =10.8, 8.8 Hz, 1H), 6.85 (d, J = 5.3 Hz, 1H), 6.56 (t, J = 4.3 Hz, 1H), 4.66 (d, J =2.9 Hz, 2H), 3.42 (q, J = 5.6 Hz, 2H), 3.32 (t, J = 5.0 Hz, 4H), 2.51 (t, J = 5.9Hz, 2H), 2.36 (t, J = 5.0 Hz, 4H), 2.30 (s, 3H), 1.44 (s, 9H). MS (ESI) m / z 625.5 [M + H] + .

[0267] Step 4: 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(piperazin-1-yl)ethyl)acetamide.

[0268] Compound 18 (220 mg, 0.35 mmol) was dissolved in dichloromethane (5 mL), and HCl / dioxane solution (5 mL) was added. The mixture was stirred overnight at room temperature. After the reaction was complete (as detected by TLC), the solvent was removed by concentration under reduced pressure to obtain the target compound 19.

[0269] Step 5: 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)butyl)piperazin-1-yl)ethyl)acetamide

[0270] Intermediate 9 (82 mg, 0.20 mmol), sodium bicarbonate (45 mg, 0.54 mmol), and potassium iodide (3 mg, 0.018 mmol) were added to a DMF solution of compound 19 (100 mg, 0.18 mmol). The reaction mixture was reacted at 75 °C for 6 h. After the reaction was complete (as detected by TLC), the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound A40 as a white solid, yield: 50%, purity: 97.09%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.45 (s, 1H), 8.36 (d, J = 5.3 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.81 (s, 1H), 7.66(t, J = 7.9 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.33 (m, 1H), 7.20 (d, J = 8.5 Hz,1H), 7.17 – 7.12 (m, 1H), 7.09 (dd, J = 10.7, 8.7 Hz, 1H), 6.84 (d, J= 5.3 Hz,1H), 4.98 – 4.88 (m, 1H), 4.66 (s, 2H), 4.25 – 4.12 (m, 2H), 3.44 – 3.36 (m,2H), 2.75 (m, 3H), 2.58 – 2.37 (m, 12H), 2.29 (s, 3H), 2.12 – 2.07 (m, 1H), 1.86 (q, J = 6.8 Hz, 2H), 1.76 – 1.69 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ166.95, 153.36, 151.84, 143.89, 140.32, 136.67, 135.35, 133.82, 130.48,130.06, 129.92, 127.27, 122.56, 122.46, 119.03, 117.87, 117.62, 117.24,116.04, 104.13, 69.26, 57.35, 51.97, 51.70, 49.15, 44.68, 35.86, 31.30,29.71, 26.34, 22.80, 22.48, 15.19. HRMS m / z Calculated for C 43 H 43 ClFN9O7[M + H] + 852.3031, found 852.3030.

[0271] Following the method used to synthesize compound A40, similar reactions were carried out to prepare the following compounds A41 to A51.

[0272] Example 41, Preparation of compound A41

[0273] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)pentyl)piperazin-1-yl)ethyl)acetamide (A41)

[0274]

[0275] White solid, yield: 43%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.81 (s, 1H), 8.47(s, 1H), 8.37 (d, J = 5.5 Hz, 1H), 8.11 (dd, J = 7.3, 2.8 Hz, 1H), 7.81 (s, 1H), 7.67 (m, 1H), 7.44 (t, J = 7.2 Hz, 1H), 7.33 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H),7.16 – 7.03 (m, 2H), 6.84 (dd, J = 5.6, 2.8 Hz, 1H), 4.93 (m, 1H), 4.64 (d, J =4.5 Hz, 2H), 4.23 – 4.12 (m, 2H), 3.49 – 3.37 (m, 2H), 2.77 – 2.65 (m, 3H), 2.63 – 2.41 (m, 10H), 2.30 (s, 3H), 2.10 (d, J = 9.2 Hz, 1H), 1.87 (q, J = 6.8Hz, 2H), 1.69 – 1.44 (m, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 172.18, 171.71,169.02, 166.96, 165.99, 165.89, 160.18, 157.70, 156.56, 153.41, 151.75,151.32, 144.05, 140.32, 136.59, 135.27, 133.85, 130.50, 130.09, 127.21,122.50, 118.98, 117.87, 117.62, 115.90, 104.10, 69.52, 57.80, 56.27, 52.24,49.04, 44.78, 35.95, 31.28, 29.71, 28.30, 25.78, 24.16, 22.79, 15.22. HRMS m / zCalculated for C 44 H 45 ClFN9O7[M + H] + 866.3188, found 866.3171.

[0276] Example 42, Preparation of compound A42

[0277] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)hexyl)piperazin-1-yl)ethyl)acetamide (A42)

[0278]

[0279] 1 H NMR (400 MHz, Chloroform- d ) δ 8.81 (s, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.14 (m, 1H), 7.79 (s, 1H), 7.66 (m, 1H), 7.43(dd, J = 25.5, 7.2 Hz, 1H), 7.33 (m, 1H), 7.14 (m, 3H), 6.83 (dd, J = 10.1, 5.3Hz, 1H), 5.04 – 4.90 (m, 1H), 4.66 – 4.45 (m, 2H), 4.19 (dd, J = 9.5, 4.3 Hz,1H), 4.14 – 4.06 (m, 1H), 3.57 – 3.46 (m, 1H), 3.43 – 3.35 (m, 1H), 2.78 (s,2H), 2.70 – 2.51 (m, 8H), 2.51 – 2.34 (m, 2H), 2.29 (d, J= 9.0 Hz, 3H), 2.12 –1.95 (m, 4H), 1.90 – 1.79 (m, 2H), 1.57 (m, 4H), 1.40 – 1.36 (m, 4H). HRMS m / z Calculated for C 45 H 47 ClFN9O7[M + H] + 880.3344, found 866.3410.

[0280] Example 43, Preparation of compound A43

[0281] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)heptyl)piperazin-1-yl)ethyl)acetamide (A43)

[0282]

[0283] White solid, yield: 55%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.83 (d, J = 7.4 Hz, 1H), 8.51 (d, J = 5.0 Hz, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.14 (q, J = 5.9, 4.4 Hz,1H), 7.79 (s, 1H), 7.66 (m, 1H), 7.43 (dd, J = 25.5, 7.2 Hz, 1H), 7.33 (m, 1H), 7.14 (m, 3H), 6.83 (dd, J = 10.1, 5.3 Hz, 1H), 5.04 – 4.90 (m, 1H), 4.66 – 4.45(m, 2H), 4.19 (dd, J= 9.5, 4.3 Hz, 1H), 4.14 – 4.06 (m, 1H), 3.57 – 3.46 (m,1H), 3.43 – 3.35 (m, 1H), 2.78 (s, 2H), 2.70 – 2.51 (m, 8H), 2.51 – 2.34 (m,4H), 2.29 (d, J = 9.0 Hz, 3H), 2.12 – 1.95 (m, 2H), 1.90 – 1.79 (m, 2H), 1.57(m, 4H), 1.40 – 1.30 (m, 4H). HRMS m / z Calculated for C 46 H 49 ClFN9O7[M + H] + 894.3501, found 894.3495.

[0284] Example 44, Preparation of compound A44

[0285] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)octyl)piperazin-1-yl)ethyl)acetamide (A44)

[0286]

[0287] White solid, yield: 48%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.81 (s, 1H), 8.48(s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.15 – 8.08 (m, 1H), 7.81 (d, J = 4.3 Hz, 1H),7.66 (m, 1H), 7.43 (dd, J = 12.2, 7.3 Hz, 1H), 7.34 (m, 1H), 7.20 (dd, J = 8.5, 3.8 Hz, 1H), 7.14 (d, J= 10.8 Hz, 1H), 7.12 – 7.05 (m, 1H), 6.84 (t, J = 4.8 Hz,1H), 4.96 (m, 1H), 4.63 (s, 2H), 4.15 (t, J = 6.2 Hz, 2H), 3.43 (m, 2H), 2.77(m, 3H), 2.57 (m, 8H), 2.42 – 2.35 (m, 2H), 2.30 (s, 3H), 2.08 (d, J = 7.2 Hz, 1H), 1.85 (q, J = 6.2 Hz, 2H), 1.51 (q, J = 7.1 Hz, 4H), 1.40 – 1.28 (m, 8H). 13 CNMR (101 MHz, Chloroform- d ) δ 172.45, 169.18, 166.06, 160.18, 157.70, 156.67,153.43, 153.32, 151.75, 143.97, 140.32, 136.47, 135.27, 133.82, 130.47,130.13, 127.32, 122.49, 118.86, 117.87, 117.62, 115.69, 104.08, 69.44, 58.42,56.33, 52.25, 51.86, 49.04, 44.71, 35.95, 31.41, 29.70, 28.63, 28.43, 26.75,25.65, 25.50, 22.79, 15.19. HRMS m / z Calculated for C 47 H 51 ClFN9O7[M + H] + 908.3657, found 908.3645.

[0288] Example 45: Preparation of compound A45

[0289] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N-(2-(4-(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-4-yl)oxy)nonyl)piperazin-1-yl)ethyl)acetamide (A45)

[0290]

[0291] White solid, yield: 41%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.81 (s, 1H), 8.45 (d, J = 4.2 Hz, 1H), 8.37 (d, J = 5.3 Hz, 1H), 8.11 (dd, J = 6.9, 2.8 Hz, 1H), 7.81(s, 1H), 7.66 (t, J = 7.9 Hz, 1H), 7.43 (dd, J = 7.3, 4.3 Hz, 1H), 7.35 (dd, J =8.2, 3.8 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 7.14 – 7.07 (m, 1H), 6.96 (d, J = 5.3Hz, 1H), 6.85 (d, J = 5.2 Hz, 1H), 4.93 (dd, J = 11.8, 5.4 Hz, 1H), 4.64 (s, 2H), 4.17 (m, 2H), 3.41 (t, J = 5.8 Hz, 2H), 2.77 (m, 3H), 2.53 (t, J = 5.6 Hz, 6H), 2.42 (d, J = 26.8 Hz, 4H), 2.30 (s, 3H), 2.09 (m, 1H), 1.84 (m, 2H), 1.49 (m,5H), 1.39 – 1.25 (m, 11H). 13 C NMR (101 MHz, Chloroform- d) δ 172.21, 169.12,167.15, 165.82, 165.69, 160.18, 157.70, 156.69, 153.35, 151.74, 151.35,144.06, 140.31, 136.42, 135.24, 133.86, 130.68, 130.60, 130.45, 130.06,127.23, 122.53, 118.81, 117.87, 117.62, 115.64, 104.08, 69.31, 58.34, 52.49,52.22, 49.10, 44.76, 35.96, 31.50, 29.71, 29.00, 28.83, 28.75, 27.33, 26.16,25.49, 22.71, 15.21. HRMS m / z Calculated for C 47 H 51 ClFN9O7[M + H] + 922.3814, found 922.3820.

[0292] Example 46: Preparation of compound A46

[0293] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(4-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)butyl)piperazin-1-yl)ethyl)acetamide (A46)

[0294]

[0295] White solid, yield: 50%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.46 (s, 1H), 8.35 (d, J = 5.4 Hz, 1H), 8.09 (dd, J = 6.8, 2.8 Hz, 1H), 7.84 (s, 1H), 7.75 (d, J= 8.3 Hz, 1H), 7.50 (s, 1H), 7.33 (m, 2H), 7.16 (dd, J = 8.5, 2.3 Hz, 1H), 7.09 (dd, J = 10.7, 8.7 Hz, 1H), 6.84 (d, J = 5.4 Hz, 1H), 5.00 – 4.90 (m,1H), 4.78 – 4.62 (m, 2H), 4.09 (t, J = 6.1 Hz, 2H), 3.50 (s, 2H), 2.77 (m,13H), 2.52 (t, J = 7.5 Hz, 2H), 2.30 (s, 3H), 2.12 (d, J = 7.5 Hz, 1H), 1.88 –1.77 (m, 2H), 1.76 – 1.65 (m, 2H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.51,168.73, 167.29, 167.02, 166.31, 164.33, 157.69, 153.32, 151.90, 151.35,144.08, 143.67, 140.35, 135.37, 134.29, 130.92, 130.47, 130.08, 127.36,125.58, 123.40, 122.49, 120.83, 117.88, 117.63, 108.88, 104.16, 68.46, 57.14,56.40, 51.67, 49.34, 44.66, 35.58, 31.46, 29.71, 26.42, 22.72, 22.33, 15.18.HRMS m / z Calculated for C 43 H 43 ClFN9O7[M + H] + 852.3031, found 852.3046.

[0296] Example 47, Preparation of Compound A47

[0297] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5]-c ]pyridin-3-yl)- N -(2-(4-(5-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)pentyl)piperazin-1-yl)ethyl)acetamide (A47)

[0298]

[0299] White solid, yield: 53%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.46 (s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.10 (dd, J = 6.8, 2.8 Hz, 1H), 7.83 (s, 1H),7.75 (d, J = 8.3 Hz, 1H), 7.33 (m, 2H), 7.23 (s, 1H), 7.16 (dd, J = 8.4, 2.3 Hz, 1H), 7.10 (dd, J = 10.7, 8.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 4.95 (dd, J = 12.0, 5.5 Hz, 1H), 4.68 (d, J = 3.3 Hz, 2H), 4.07 (t, J = 6.4 Hz, 2H), 3.44 (t, J = 6.0Hz, 2H), 2.88 – 2.73 (m, 3H), 2.68 – 2.53 (m, 9H), 2.47 – 2.37 (m, 3H), 2.30(s, 3H), 2.12 (d, J = 6.1 Hz, 1H), 1.83 – 1.76 (m, 2H), 1.58 (q, J = 7.7 Hz, 2H), 1.44 (d, J = 7.6 Hz, 2H). 13 C NMR (101 MHz, Chloroform- d) δ 171.19, 168.45,167.25, 167.02, 165.96, 164.48, 153.35, 151.82, 144.08, 140.33, 135.31,134.32, 130.87, 130.71, 130.49, 129.94, 127.22, 125.58, 123.37, 122.43,120.69, 117.87, 117.62, 108.97, 104.14, 68.75, 57.80, 56.23, 52.22, 49.34,44.80, 35.76, 31.47, 28.59, 23.65, 22.73, 15.21. HRMS m / z Calculated for C 44 H 45 ClFN9O7[M + H] + 866.3188, found 866.3195.

[0300] Example 48, Preparation of Compound A48

[0301] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(6-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)hexyl)piperazin-1-yl)ethyl)acetamide (A48)

[0302]

[0303] White solid, yield: 49%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.46 (s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.10 (dd, J = 6.8, 2.8 Hz, 1H), 7.83 (s, 1H),7.76 (d, J = 8.2 Hz, 1H), 7.39 – 7.28 (m, 2H), 7.17 (dd, J= 8.4, 2.3 Hz, 2H),7.12 – 7.07 (m, 1H), 6.84 (d, J = 5.3 Hz, 1H), 4.95 (dd, J = 12.2, 5.4 Hz, 1H), 4.68 (d, J = 4.3 Hz, 2H), 4.07 (t, J = 6.4 Hz, 2H), 3.46 (m, 2H), 2.85 (dd, J =15.4, 11.9 Hz, 3H), 2.74 – 2.59 (m, 10H), 2.44 (d, J = 7.7 Hz, 2H), 2.30 (s,3H), 2.16 – 2.11 (m, 1H), 1.82 (dd, J = 13.0, 5.8 Hz, 2H), 1.59 – 1.53 (m, 2H), 1.47 (t, J = 7.7 Hz, 2H), 1.37 – 1.32 (m, 2H). HRMS m / z Calculated for C 45 H 47 ClFN9O7[M + H] + 880.3344, found 880.3352.

[0304] Example 49, Preparation of Compound A49

[0305] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(7-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)heptyl)piperazin-1-yl)ethyl)acetamide (A49)

[0306]

[0307] White solid, yield: 56%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.79 (s, 1H), 8.46 (s, 1H), 8.35 (d, J= 5.4 Hz, 1H), 8.09 (dd, J = 6.8, 2.7 Hz, 1H), 7.82 (s, 1H),7.74 (d, J = 8.3 Hz, 1H), 7.41 – 7.31 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 9.7 Hz, 1H), 6.84 (d, J = 5.3 Hz, 1H), 4.96 (q, J = 5.6 Hz, 1H), 4.74 – 4.61(m, 2H), 4.06 (t, J = 6.5 Hz, 2H), 3.43 (d, J = 7.4 Hz, 2H), 2.79 (m, 3H), 2.70 –2.53 (m, 8H), 2.44 (d, J = 7.8 Hz, 2H), 2.29 (s, 3H), 2.11 (t, J = 6.9 Hz, 1H),1.80 (m, 2H), 1.55 (m, 2H), 1.44 (q, J = 7.1 Hz, 2H), 1.39 – 1.27 (m, 4H). 13 CNMR (101 MHz, Chloroform- d ) δ 171.87, 168.98, 167.29, 167.08, 166.14, 164.54,160.15, 157.67, 153.31, 151.85, 151.28, 143.83, 140.35, 135.28, 134.27,130.90, 130.44, 130.01, 127.33, 125.50, 123.23, 122.43, 120.65, 117.87,117.61, 108.92, 104.10, 68.93, 57.89, 56.23, 52.13, 51.59, 49.30, 44.63,35.93, 31.46, 29.68, 28.85, 27.06, 25.66, 22.73, 15.17. HRMS m / z calculated forC 46 H 49ClFN9O7[M + H] + 894.3501, found 894.3506.

[0308] Example 50: Preparation of compound A50

[0309] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)octyl)piperazin-1-yl)ethyl)acetamide (A50)

[0310]

[0311] White solid, yield: 59%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.46 (s, 1H), 8.36 (d, J = 5.4 Hz, 1H), 8.10 (dd, J = 6.8, 2.8 Hz, 1H), 7.82 (s, 1H), 7.76 (dd, J = 8.3, 1.5 Hz, 1H), 7.37 – 7.30 (m, 2H), 7.24 (s, 1H), 7.17 (dd, J =8.3, 2.3 Hz, 1H), 7.09 (dd, J = 10.7, 8.7 Hz, 1H), 6.84 (d, J = 5.4 Hz, 1H), 4.95(dd, J = 11.9, 5.5 Hz, 1H), 4.74 – 4.63 (m, 2H), 4.08 (t, J = 6.4 Hz, 2H), 3.45(d, J = 6.9 Hz, 2H), 2.88 – 2.75 (m, 3H), 2.73 – 2.57 (m, 10H), 2.45 (t, J = 8.0Hz, 2H), 2.30 (s, 3H), 2.12 (m, 1H), 1.80 (q, J= 7.0 Hz, 2H), 1.54 (t, J = 8.0Hz, 2H), 1.47 – 1.42 (m, 2H), 1.37 – 1.28 (m, 6H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.84, 168.96, 167.09, 166.19, 164.57, 153.30, 151.88,143.82, 140.35, 135.29, 130.91, 130.66, 130.42, 129.96, 127.34, 125.50,123.22, 120.69, 117.86, 108.91, 104.09, 69.01, 57.93, 56.26, 52.10, 51.55,49.30, 44.62, 35.94, 31.45, 29.10, 28.93, 28.70, 27.07, 25.67, 25.61, 22.72,15.16. HRMS m / z Calculated for C 47 H 51 ClFN9O7[M + H] + 908.3657 was found.

[0312] Example 51: Preparation of compound A51

[0313] 2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)- N -(2-(4-(9-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)oxy)nonyl)piperazin-1-yl)ethyl)acetamide (A51)

[0314]

[0315] White solid, yield: 59%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.80 (s, 1H), 8.46(s, 1H), 8.35 (d, J = 5.4 Hz, 1H), 8.10 (dd, J= 6.7, 2.8 Hz, 1H), 7.82 (s, 1H),7.75 (d, J = 8.4 Hz, 1H), 7.36 – 7.27 (m, 3H), 7.17 (d, J = 8.4 Hz, 1H), 7.09 (t, J = 9.7 Hz, 1H), 6.84 (d, J = 5.4 Hz, 1H), 5.00 – 4.89 (m, 1H), 4.68 (d, J = 4.4Hz, 2H), 4.08 (t, J = 6.5 Hz, 2H), 3.43 (d, J = 9.5 Hz, 2H), 2.81 (m, 3H), 2.72 –2.54 (m, 10H), 2.45 (t, J = 8.0 Hz, 2H), 2.30 (s, 3H), 2.14 – 2.10 (m, 1H),1.80 (q, J = 7.1 Hz, 2H), 1.52 (d, J = 7.8 Hz, 2H), 1.45 (t, J = 7.5 Hz, 2H), 1.29(d, J = 14.9 Hz, 8H). 13 C NMR (101 MHz, Chloroform- d ) δ 171.76, 168.89, 167.29,166.15, 164.60, 153.30, 151.87, 143.85, 140.35, 134.28, 130.89, 130.66,130.45, 129.97, 127.34, 125.49, 122.43, 120.65, 108.96, 104.09, 69.06, 58.01,56.26, 52.13, 51.58, 49.30, 44.65, 35.94, 31.45, 29.25, 29.17, 29.01, 28.75,27.19, 25.74, 25.69, 22.73, 15.16. HRMS m / z calculated for C 48 H 53 ClFN9O7[M + H] +922.3814, found 922.3820.

[0316] Example 52, Preparation of compound A52

[0317] 5-(2-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)acetyl)-2,7-diazaspiro[3.5]non-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A52)

[0318]

[0319] The synthesis route is as follows:

[0320]

[0321] Step 1: 7-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindoline-5-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester

[0322] To a solution of compound 20 (150 mg, 0.54 mmol) and DIPEA (211 mg, 1.63 mmol) in DMSO (5 mL), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylic acid (147 mg, 0.65 mmol) was added, and the reaction was carried out at 100 °C for 6 h. After the reaction was complete (as detected by TLC), the mixture was extracted three times with ethyl acetate, and the combined organic phases were washed once with water and once with saturated brine. The mixture was dried over anhydrous sodium sulfate and purified by thin-layer chromatography to give compound 21 as a yellow solid, yield: 68%. 1 H NMR (400 MHz, Chloroform- d ) δ 8.27 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.29 (d, J =2.3 Hz, 1H), 7.06 (dd, J = 8.6, 2.4 Hz, 1H), 4.94 (dd, J= 12.4, 5.3 Hz, 1H),3.71 (s, 4H), 3.45 – 3.36 (m, 4H), 2.94 – 2.70 (m, 3H), 2.16 – 2.08 (m, 1H),1.91 – 1.83 (m, 4H), 1.46 (s, 9H). MS (ESI) m / z 483.7 [M + H] + .

[0323] Step 2: 2-(2,6-dioxadiazin-3-yl)-5-(2,7-diazaspiro[3.5]nonane-7-yl)isoindoline-1,3-dione

[0324] Compound 21 (100 mg, 0.21 mmol) was dissolved in dichloromethane, and 5 mL of HCl / dioxane solution was added. The mixture was reacted at 80 °C for 6 h. After the reaction was completed (monitored by TLC), the solvent was removed by concentration under reduced pressure to obtain compound 22.

[0325] Step 3: 5-(2-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c [3.5]Pyridin-3-yl)acetyl)-2,7-diazaspiro[3.5]non-7-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione

[0326] Compound 8 (100 mg, 0.24 mmol), compound 20a (108 mg, 0.26 mmol), HATU (120 mg, 0.16 mmol), and DIPEA (94 mg, 0.72 mmol) were dissolved in anhydrous DMF. The reaction was carried out at room temperature for 8 h, and the reaction progress was monitored by thin-layer chromatography (TLC) until the reaction was complete. After the reaction was completed, the organic phase was extracted three times with ethyl acetate. The combined organic phases were washed successively with water and saturated brine, and finally dried over anhydrous sodium sulfate. Finally, the product was purified by thin-layer chromatography to obtain the target compound A52 as a yellow solid, in a yield of 77%. 1 H NMR (400 MHz, DMSO-) d 6) δ 11.09 (s, 1H), 8.88 (s, 1H), 8.53 (s, 1H), 8.27 (d, J =5.3 Hz, 1H), 8.04 (dd, J= 6.7, 2.8 Hz, 1H), 7.90 (s, 1H), 7.67 (d, J = 8.5 Hz,1H), 7.57 (m, 1H), 7.42 (dd, J = 10.8, 8.8 Hz, 1H), 7.38 (d, J = 2.2 Hz, 1H), 7.29 (dd, J = 8.8, 2.3 Hz, 1H), 7.02 (d, J = 5.3 Hz, 1H), 5.08 (dd, J = 12.9, 5.4Hz, 1H), 4.75 (d, J = 2.6 Hz, 2H), 4.12 (s, 2H), 3.73 (s, 2H), 3.51 (m, 4H), 2.95 – 2.86 (m, 1H), 2.63 – 2.54 (m, 2H), 2.22 (s, 3H), 2.05 – 2.00 (m, 1H),1.86 (d, J = 6.1 Hz, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 172.67, 169.97, 167.45,166.81, 165.64, 159.60, 157.14, 154.61, 152.96, 151.46, 150.13, 142.98,140.33, 134.33, 133.87, 130.93, 130.63, 130.05, 129.68, 128.70, 127.42,124.85, 122.28, 118.47, 118.24, 117.67, 107.89, 103.90, 58.77, 57.67, 48.65,44.40, 34.12, 33.67, 30.89, 22.09, 14.35. HRMS m / z Calculated for C 40 H 34 ClFN8O6[M+ H] + 777.2347, found 777.2331.

[0327] Following the method used to synthesize compound A52, similar reactions were carried out to prepare the following compounds A53~A60.

[0328] Example 53, Preparation of compound A53

[0329] 5-(8-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)acetyl)-2,8-diazaspiro[4.5]decane-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A53)

[0330]

[0331] Yellow solid, yield: 81%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.07 (s, 1H), 8.88 (s,1H), 8.50 (s, 1H), 8.26 (d, J = 5.3 Hz, 1H), 8.05 (dd, J = 6.7, 2.8 Hz, 1H), 7.89(s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.58 (m, 1H), 7.46 – 7.38 (m, 1H), 7.02 (d, J = 5.3 Hz, 1H), 6.97 (d, J = 2.1 Hz, 1H), 6.84 (dd, J = 8.7, 2.2 Hz, 1H), 5.10 –5.05 (m, 1H), 5.04 – 4.93 (m, 2H), 3.63 (d, J = 17.7 Hz, 3H), 3.54 – 3.49 (m,2H), 3.46 (d, J = 7.6 Hz, 1H), 3.40 (s, 2H), 2.94 – 2.85 (m, 1H), 2.63 – 2.53(m, 2H), 2.22 (s, 3H), 1.99 (q, J = 9.5, 7.1 Hz, 3H), 1.72 (m, 2H), 1.56 (m,2H). 13 C NMR (101 MHz, DMSO- d6) δ 173.28, 170.61, 168.20, 167.71, 164.51,160.25, 157.77, 153.57, 152.47, 150.77, 143.50, 141.00, 134.97, 134.46,131.61, 131.20, 130.65, 130.33, 129.31, 128.33, 125.38, 122.85, 119.14,118.89, 116.05, 115.69, 106.06, 104.47, 63.27, 57.76, 49.17, 46.76, 43.21,42.31, 34.94, 34.25, 31.48, 22.74, 14.96. HRMS m / z Calculated for C 41 H 36 ClFN8O6[M+ H] + 791.2503, found 791.2490.

[0332] Example 54: Preparation of compound A54

[0333] 5-(2-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)acetyl)-2,8-diazaspiro[4.5]decane-8-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A54)

[0334]

[0335] Yellow solid, yield: 80%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.08 (s, 1H), 8.88 (s, 1H), 8.52 (d, J = 6.6 Hz, 1H), 8.26 (d, J = 5.3 Hz, 1H), 8.04 (dd, J = 6.8, 2.8 Hz,1H), 7.89 (s, 1H), 7.67 (t, J = 8.1 Hz, 1H), 7.57 (m, 1H), 7.42 (t, J= 9.8 Hz, 1H), 7.37 (d, J = 10.9 Hz, 1H), 7.27 (t, J = 9.9 Hz, 1H), 7.02 (d, J = 5.3 Hz, 1H), 5.08 (d, J = 11.9 Hz, 1H), 4.89 (d, J = 4.9 Hz, 2H), 3.76 (m, 1H), 3.59 (m, 4H), 3.54 – 3.41 (m, 3H), 2.95 – 2.85 (m, 1H), 2.59 (d, J = 19.3 Hz, 2H), 2.22 (s,3H), 2.03 (m, 1H), 1.95 (d, J = 7.2 Hz, 1H), 1.81 (t, J = 7.0 Hz, 1H), 1.74 –1.57 (m, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 172.52, 169.84, 167.37, 166.67,163.93, 159.47, 156.99, 154.52, 152.83, 151.47, 149.98, 142.80, 140.26,134.18, 133.74, 130.86, 130.51, 129.97, 129.55, 128.57, 127.48, 124.74,122.19, 118.39, 118.12, 117.35, 107.60, 103.70, 54.99, 54.13, 48.49, 44.54,43.11, 33.50, 32.84, 30.75, 28.74, 21.96, 14.21. HRMS m / z Calculated for C 41 H 36 ClFN8O6[M + H] + 791.2503, found 791.2491.

[0336] Example 55: Preparation of compound A55

[0337] 5-(2-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl)H -imidazo[4,5] -c ]pyridin-3-yl)acetyl)-2,6-diazaspiro[3.4]octane-6-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A55)

[0338]

[0339] Yellow solid, yield: 86%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.08 (s, 1H), 8.88 (s, 1H), 8.52 (s, 1H), 8.27 (d, J = 5.3 Hz, 1H), 8.04 (dd, J = 6.8, 2.8 Hz, 1H), 7.90(s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.58 (m, 1H), 7.42 (dd, J = 10.8, 8.8 Hz, 1H), 7.02 (d, J = 5.3 Hz, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.07(dd, J = 12.9, 5.4 Hz, 1H), 4.75 (d, J = 4.2 Hz, 2H), 4.36 (q, J = 9.4, 8.8 Hz, 2H), 3.98 (q, J = 10.6 Hz, 2H), 3.71 (q, J = 10.6 Hz, 2H), 3.51 (t, J = 6.8 Hz,2H), 2.94 – 2.85 (m, 1H), 2.57 (m, 2H), 2.31 (q, J = 6.3 Hz, 2H), 2.22 (s, 3H), 2.05 – 1.99 (m, 1H). 13 C NMR (101 MHz, DMSO- d6) δ 173.28, 170.60, 168.12,167.68, 166.15, 160.24, 157.76, 153.57, 152.24, 152.07, 150.77, 143.63,140.97, 134.95, 134.44, 131.58, 130.63, 130.33, 129.30, 128.02, 125.44,122.97, 119.14, 118.90, 116.44, 115.84, 106.08, 104.54, 63.26, 59.20, 57.71,57.32, 49.19, 47.18, 35.48, 31.47, 22.73, 14.94. HRMS m / z Calculated for C 39 H 32 ClFN8O6[M + H] + 763.2190, found 763.2168.

[0340] Example 56: Preparation of compound A56

[0341] 5-(9-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)acetyl)-3,9-diazaspiro[5.5]undecane-3-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A56)

[0342]

[0343] Yellow solid, yield: 83%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.10 (s, 1H), 8.88 (s,1H), 8.50 (s, 1H), 8.26 (d, J = 5.3 Hz, 1H), 8.04 (dd, J = 6.7, 2.9 Hz, 1H), 7.89(s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.57 (m, 1H), 7.42 (dd, J= 10.9, 8.8 Hz, 1H),7.32 (s, 1H), 7.27 – 7.19 (m, 1H), 7.02 (d, J = 5.3 Hz, 1H), 5.08 (dd, J = 12.8,5.4 Hz, 1H), 5.04 – 4.92 (m, 2H), 3.58 (m, 2H), 3.50 (s, 6H), 2.90 (m, 1H),2.65 – 2.53 (m, 2H), 2.22 (s, 3H), 2.02 (dd, J = 12.4, 6.7 Hz, 1H), 1.69 – 1.55(m, 6H), 1.48 (t, J = 5.8 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.28, 170.59,168.12, 167.45, 164.50, 160.25, 157.77, 155.41, 153.57, 152.25, 150.76,143.49, 141.00, 134.95, 134.46, 131.60, 131.29, 130.69, 130.33, 129.31,128.33, 127.93, 125.42, 122.94, 119.14, 117.82, 107.99, 104.46, 49.21, 43.28,38.00, 35.64, 34.80, 34.53, 31.47, 30.29, 22.69, 14.96. HRMS m / z Calculated for C 42 H 38 ClFN8O6[M + H] + 805.2660, found 805.2652.

[0344] Example 57: Preparation of compound A57

[0345] 5-(7-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)acetyl)-2,7-diazaspiro[4.4]non-2-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A57)

[0346]

[0347] Yellow solid, yield: 85%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.07 (s, 1H), 8.88 (s, 1H), 8.52 (d, J = 9.2 Hz, 1H), 8.26 (dd, J = 5.4, 1.7 Hz, 1H), 8.04 (dd, J = 6.8,2.8 Hz, 1H), 7.89 (s, 1H), 7.67 (dd, J = 8.4, 4.8 Hz, 1H), 7.58 (m, 1H), 7.42(dd, J = 10.9, 8.8 Hz, 1H), 7.04 – 6.99 (m, 1H), 6.95 (d, J = 16.7 Hz, 1H), 6.89– 6.78 (m, 1H), 5.06 (dd, J = 9.8, 6.5 Hz, 1H), 4.88 (d, J = 15.6 Hz, 2H), 3.82(m, 1H), 3.69 (d, J = 4.3 Hz, 1H), 3.62 – 3.49 (m, 4H), 3.49 – 3.36 (m, 3H), 2.93 – 2.84 (m, 1H), 2.62 – 2.52 (m, 2H), 2.22 (s, 3H), 2.06 (m, 4H), 1.97 –1.87 (m, 1H). 13 C NMR (101 MHz, DMSO- d6) δ 173.28, 170.61, 168.17, 167.71,164.67, 160.24, 157.77, 153.57, 152.20, 150.75, 143.54, 141.00, 134.92,134.45, 131.60, 131.29, 130.32, 129.27, 128.19, 127.94, 125.40, 122.85,119.13, 118.88, 116.25, 106.02, 104.46, 56.90, 54.87, 54.29, 49.40, 49.19,47.23, 33.48, 31.48, 22.74, 14.95. HRMS m / z Calculated for C 40 H 34 ClFN8O6[M + H] + 777.2347, found 777.2331.

[0348] Example 58: Preparation of compound A58

[0349] 5-(4-(1-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)acetyl)piperidin-4-yl)piperazin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A58)

[0350]

[0351] Yellow solid, yield: 79%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.09 (s, 1H), 8.88 (s, 1H), 8.51 (d, J = 3.0 Hz, 1H), 8.26 (d, J = 5.3 Hz, 1H), 8.04 (dd, J = 6.7, 2.8 Hz,1H), 7.89 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.57 (m, 1H), 7.42 (dd, J = 10.9, 8.8 Hz, 1H), 7.34 (d,J = 2.3 Hz, 1H), 7.26 (dd, J = 8.7, 2.3 Hz, 1H), 7.02 (d, J =5.3 Hz, 1H), 5.08 (dd, J = 12.8, 5.3 Hz, 1H), 4.99 (dd, J = 13.1, 9.0 Hz, 2H),4.32 (d, J = 12.6 Hz, 1H), 4.03 (d, J = 13.2 Hz, 1H), 3.43 (d, J = 5.2 Hz, 4H),3.16 (t, J = 12.8 Hz, 1H), 2.93 – 2.83 (m, 1H), 2.76 – 2.52 (m, 8H), 2.22 (s,3H), 2.02 (m, 1H), 1.86 (dd, J = 29.7, 12.1 Hz, 2H), 1.57 (t, J = 11.6 Hz, 1H),1.35 (d, J = 5.6 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.28, 170.55, 168.03,167.45, 164.40, 160.24, 157.76, 155.69, 153.57, 152.24, 150.74, 143.50,140.99, 134.94, 134.29, 131.60, 130.68, 130.31, 129.31, 128.31, 127.90,125.33, 122.92, 119.12, 118.77, 118.19, 108.27, 104.45, 60.86, 49.25, 48.72,47.71, 43.95, 43.16, 31.47, 28.62, 22.67, 14.96. HRMS m / z calculated forC 42 H 39 ClFN9O6[M + H] + 820.2769, found 820.2760.

[0352] Example 59: Preparation of compound A59

[0353] 5-(4-(4-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]Pyridin-3-yl)acetyl)piperazin-1-yl)piperidin-1-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A59)

[0354]

[0355] Yellow solid, yield: 75%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.09 (s, 1H), 8.88 (s,1H), 8.49 (s, 1H), 8.25 (d, J = 5.4 Hz, 1H), 8.04 (dd, J = 6.7, 2.9 Hz, 1H), 7.88(s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.57 (m, 1H), 7.42 (t, J = 9.8 Hz, 1H), 7.33(s, 1H), 7.25 (d, J = 8.8 Hz, 1H), 7.01 (d, J = 5.3 Hz, 1H), 5.08 (dd, J = 12.8,5.4 Hz, 1H), 5.04 – 4.90 (m, 2H), 4.09 (d, J = 12.7 Hz, 2H), 3.57 (s, 2H), 3.43(d, J = 25.5 Hz, 4H), 3.02 – 2.85 (m, 3H), 2.60 (d, J = 13.0 Hz, 5H), 2.22 (s,3H), 2.06 – 1.98 (m, 1H), 1.86 (d, J = 12.2 Hz, 2H), 1.49 (q, J = 12.1 Hz, 2H). 13 CNMR (101 MHz, DMSO- d6) δ 173.28, 170.58, 168.07, 167.42, 164.56, 160.24,157.76, 155.19, 153.57, 152.22, 150.74, 143.51, 140.99, 134.95, 134.49,131.59, 131.29, 130.67, 130.30, 129.30, 128.28, 128.07, 125.46, 122.85,119.13, 118.11, 108.28, 104.46, 61.06, 49.22, 48.85, 47.12, 45.06, 43.11,31.47, 27.54, 22.67, 14.95. HRMS m / z Calculated for C 42 H 39 ClFN9O6[M + H] + 820.2769, found 820.2758.

[0356] Example 60: Preparation of compound A60

[0357] 5-(5-(2-(1-(2-(5-chloro-2-fluorophenyl)-5-methylpyridin-4-yl)-2-oxo-1,2-dihydro-3-yl) H -imidazo[4,5] -c ]pyridin-3-yl)acetyl)hexahydropyrrolo[3,4] -c ]Pyrrole-2(1 H )-yl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione (A60)

[0358]

[0359] Yellow solid, yield: 75%. 1 H NMR (400 MHz, DMSO- d 6) δ 11.08 (s, 1H), 8.88 (s,1H), 8.51 (s, 1H), 8.25 (dd, J = 5.3, 1.5 Hz, 1H), 8.04 (dd, J = 6.8, 2.8 Hz,1H), 7.89 (s, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.58 (m, 1H), 7.42 (dd, J= 10.9, 8.8 Hz, 1H), 7.01 (dd, J = 5.2, 1.6 Hz, 1H), 6.96 (t, J = 2.1 Hz, 1H), 6.90 –6.82 (m, 1H), 5.07 (dd, J = 12.8, 5.3 Hz, 1H), 4.88 (s, 2H), 4.03 – 3.96 (m,1H), 3.72 (m, 3H), 3.66 – 3.60 (m, 1H), 3.47 (dd, J = 11.1, 4.3 Hz, 2H), 3.38(d, J = 4.7 Hz, 1H), 3.27 – 3.20 (m, 1H), 3.10 (m, 1H), 2.94 – 2.85 (m, 1H), 2.55 (d, J = 13.9 Hz, 2H), 2.21 (s, 3H), 2.07 – 1.99 (m, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 173.29, 170.61, 168.14, 167.70, 164.79, 160.24, 157.76, 153.57,152.34, 150.75, 143.53, 141.00, 134.90, 134.40, 131.60, 131.28, 130.78,130.31, 129.30, 128.18, 125.39, 122.95, 119.12, 118.88, 116.51, 116.12,106.32, 104.45, 52.24, 50.38, 49.40, 49.21, 42.42, 31.49, 22.74, 14.95.HRMS m / z Calculated for C 39 H 32 ClFN8O6[M + H] + 763.2190, found 763.2166.

[0360] The following experimental examples demonstrate the beneficial effects of the present invention.

[0361] Experimental Example 1: In vitro activity test of the compound

[0362] 1. Experimental Methods

[0363] NIH3T3 cells in logarithmic growth phase were seeded at an appropriate density in 6 cm cell culture dishes and cultured overnight in a 37°C, 5% CO2 incubator with DMEM high-glucose medium containing 10% FBS. The next day, when cell confluence reached 70%-80%, the original medium was discarded, and 5 mL of serum-free DMEM high-glucose medium was added. Cells were cultured for another 6 h to synchronize the cell cycle. Using 10% FBS DMEM high-glucose medium containing 5 ng / mL TGF-β1 as the solvent, a gradient of final concentrations of the experimental drug was added after 1 h of pre-incubation. The drug-containing medium was added to the cell culture dishes, and incubation was carried out for a total of 24 h. The control group received only TGF-β1 stimulation, while the blank group received 10% FBS medium without TGF-β1. Subsequently, the cells were washed twice with PBS and collected in PBS. After centrifugation at 1200 r / min, 4°C for 3 min, the cells were washed twice more with PBS. Cells were then lysed at 4°C for 1 h using radioimmunoprecipitation (RIPA) lysis buffer containing appropriate amounts of protease and phosphatase inhibitors, followed by sonication to ensure complete lysis. After centrifugation at 13300 r / min and 4°C for 15 min, the supernatant was collected, and the sample concentration was determined using a standard curve method to adjust the total protein concentration. Sodium dodecyl sulfate (SDS) was then added to the sample, and the mixture was heated at 100°C for 10 min. After cooling to room temperature, approximately 50 µg of total protein from each sample was collected, separated by SDS-PAGE, and transferred to a polyvinylidene fluoride (PVDF) membrane (Amersham Bioscience, Piscataway, NJ, USA) according to the instructions of the Western Blot assay kit (Chengdu Bailu Technology Co., Ltd., Chengdu, China). The membrane strips were then incubated overnight at 4°C with primary antibody, followed by incubation with secondary antibody, and detected using a fluorescence and chemiluminescence imaging system. ImageJ software was used for grayscale quantitative analysis of the target bands.

[0364] 2. Experimental Results

[0365] Table 1: Degradation rate of ALK5 by the compounds

[0366]

[0367] Note: A > 60%; 60% > B > 30%; C < 30%.

[0368] The above results show that most of the compounds prepared in this invention have excellent degradation effects on ALK5. Among them, A40~A42, A52, A54 and A58 have excellent degradation rates at low concentrations (0.1 μM). In particular, A40 has a significantly better degradation rate than other compounds at a concentration of 1 μM, achieving unexpected technical effects.

[0369] Experimental Example 2: In vivo pharmacokinetic testing of the compound

[0370] 1. Experimental Methods

[0371] This invention administers the test compound A40 to Balb / c mice via intravenous (IV), intraperitoneal (IP), and oral (PO) routes, and tests the concentration of the test compound in mouse plasma at different time points to evaluate the metabolic characteristics of the test compound in mice. The specific procedure is as follows: Nine male Balb / c mice were used. Three mice were administered 10 mg / kg via IV, gavage, and intraperitoneal administration. Approximately 0.02 mL of blood was collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after administration. The collected blood was centrifuged at 3500 rpm for 10 min, and the supernatant plasma was collected and stored at -40°C for later analysis. After thawing at room temperature, the collected plasma samples were vortexed to ensure homogeneity. 5 µL of plasma was transferred to each EP tube, and 100 µL of acetonitrile containing 20 ng / mL internal standard SAHA was added to precipitate the protein. The tubes were vortexed for 10 s, centrifuged at 13000 rpm for 10 min, and the supernatant was collected and placed in sample vials for analysis. Plasma samples were analyzed by LC-MS / MS.

[0372] 2. Experimental Results

[0373] Table 2 Pharmacokinetic parameters of compound A40

[0374]

[0375] The above results indicate that the pharmacokinetic characteristics of compound A40 in rats exhibit an exposure gradient of "intraperitoneal > intravenous > oral". Intraperitoneal injection of compound A40 offers a combination of high exposure, high bioavailability, and a relatively long residence time, making it the preferred route of administration for further pharmacodynamic evaluation.

[0376] In summary, this invention provides an ALK5 PROTAC compound and its preparation and application. This invention prepares a series of small PROTAC compounds that target and degrade ALK5 protein. These compounds can be degraded via the ALK5 ubiquitination-proteasome pathway, exhibiting >70% bioavailability after intraperitoneal injection and good tissue distribution. The ALK5 PROTAC compounds provided by this invention offer a new and precise intervention for the treatment of ALK5-mediated fibrosis and tumors.

Claims

1. The compound represented by Formula I and its pharmaceutically acceptable salt: Formula I in, X is CH; Y is selected from C 1-3 alkyl; A is selected from , , -CO-; L is selected from C 3-12 Alkylene , , , , , , , , , , , ; Z is selected from the group consisting of none, O, C 2-3 alkynyl, -CO-, , ; R 1 each independently selected from H, halogen; n is selected from 0, 1, or 2; W is selected from , , or .

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, wherein, The compound has the structure shown in Formula II, Formula III or Formula IV: Formula II Formula III Formula IV wherein A, Z, X, L, n are as described in claim 1, R 1 each independently selected from H, F, Cl.

3. The compound, or pharmaceutically acceptable salt thereof, of any one of claims 1-2, wherein, The compound is selected from one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. Use of the compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, in the preparation of an ALK protein degrading agent.

5. Use according to claim 4, characterized in that, The ALK protein degrader is a drug for the prevention and / or treatment of ALK5 protein-related diseases.

6. Use according to claim 5, characterized in that, The disease in question is either a tumor or a fibrotic disease.

7. A pharmaceutical composition, characterized by, The pharmaceutical composition is a pharmaceutical preparation made from the compound of any one of claims 1 to 3, a pharmaceutically acceptable salt thereof as the active ingredient, and pharmaceutically acceptable excipients.

8. The pharmaceutical composition according to claim 7, characterized in that, The pharmaceutical preparation is an oral or injectable preparation.

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