A tricyclic compound and application thereof

Abstract

The application provides a kind of tri-cyclic compound and its application, the tri-cyclic compound has the structure shown in the following formula I.The tri-cyclic compound has significant degradation activity to IRAK4 in cell, and can be used for preparing drug for treating and / or preventing relevant disease or disorder mediated by IRAK4.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and relates to a tri-pericyclic compound and application thereof, in particular to a tri-pericyclic IRAK4 degrading agent and application thereof. BACKGROUND

[0002] Interleukin-1 receptor kinase 4 (IRAK4) is one of the isozymes of the intracellular serine-threonine kinase IRAK protein family, is a key node in the downstream signaling pathway of Toll-like receptor (TLR) and interleukin-1 receptor (IL-1R), and plays an important role in the immune system. Its overactivation or abnormal activation due to mutation is involved in the occurrence and development of inflammatory diseases and tumors.

[0003] TLR and IL-1R commonly use a conserved TLR / IL-1R (TIR) domain to recruit the adaptor protein MyD88 in cells, MyD88 continues to recruit IRAK4 to form Myddosome. In Myddosome, IRAK4 is activated by trans-autophosphorylation, and then activates a series of transcription factors downstream, such as NF-κB, CREB, AP-1, IRF, etc., promotes the secretion of pro-inflammatory cytokines, immune cell proliferation and differentiation, etc. Therefore, IRAK4 plays an important role in the pathogenesis and progression of inflammatory diseases.

[0004] The disorder of TLR / IL-1R signaling pathway is also closely related to the occurrence and progression of cancer, and the mutation of proteins in the TLR / IL-1R pathway can lead to overactive signals and increase NF-κB activity, and promote cancer.

[0005] IRAK4 mediates the IL-1R / TLR downstream signaling pathway through two pathways and participates in immune surveillance: on the one hand, IRAK4 has kinase activity and can phosphorylate downstream proteins IRF5 / 7; on the other hand, IRAK4 plays a scaffold structure role and is responsible for assembling the protein multimer myddosome complex. Although there are many IRAK4 small molecule kinase inhibitors in the prior art, they can only inhibit the activity of the kinase itself, showing moderate efficacy, and cannot completely block the generation of inflammatory response signals by destroying the formation of the complex.

[0006] Targeted protein degradation (TPD) is an emerging therapeutic approach that has attracted much attention due to its ability to modulate proteins that are difficult to target with traditional small molecules. Proteolysis targeting chimeras (PROTACs) take advantage of the ubiquitin proteasome system (UPS), a natural protein degradation system in cells, to achieve targeted degradation of a protein of interest (POI). PROTACs are heterobifunctional small molecules that target a POI on one end and recruit an E3 ubiquitin ligase to form a ternary complex, which ubiquitinates the POI for recognition and degradation by the proteasome.

[0007] Compared with traditional small molecule drugs, PROTAC molecules have the following advantages: (1) have catalytic degradation function, unlike each small molecule inhibitor which can only act on one protein molecule, each PROTAC molecule can degrade many protein molecules, so a very low dose can have a very good drug effect; (2) act by degrading target proteins, so it can overcome the problem of small molecule drug resistance caused by increased expression of target proteins, and can also block the non-enzyme function of the target. Therefore, according to the characteristics of IRAK4 having both kinase activity and scaffold function, the use of PROTAC technology can degrade IRAK4 protein, block kinase activity and destroy the scaffold function of the target protein at the same time, achieve complete inhibition of the pathway, and produce better inhibitory effect on inflammatory response or anti-tumor activity compared with conventional kinase inhibitors. Therefore, in the field, further development of such molecules is of great significance. SUMMARY

[0008] In view of the deficiencies of the prior art, the purpose of the present application is to provide a kind of tripericyclic compound and its application, in particular to provide a kind of tripericyclic IRAK4 degrading agent and its application.

[0009] To achieve the purpose of the present application, the following technical solutions are adopted:

[0010] In one aspect, the present application provides a kind of tripericyclic compound, its stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt, the tripericyclic compound has the structure shown in the following formula I:

[0011]

[0012] Wherein:

[0013] Indicates a single bond or a double bond, provided that the valence requirement is met;

[0014] A is 6-10 membered aryl or 5-10 membered heteroaryl;

[0015] B is substituted or unsubstituted C2-C4 alkyl, substituted or unsubstituted 4-10 membered cycloalkyl, or substituted or unsubstituted 4-10 membered heterocycloalkyl.

[0016] C is substituted or unsubstituted C2-C4alkyl, substituted or unsubstituted 4-10 membered cycloalkyl, or substituted or unsubstituted 4-10 membered heterocycloalkyl;

[0017] one of X and Y is a nitrogen atom, and the other is a carbon atom;

[0018] Z is CH2or C=0;

[0019] R a each independently selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4alkoxy, di(C1-C4alkyl)amino, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl;

[0020] m is an integer from 0 to 5 (e.g., 0, 1, 2, 3, 4, or 5);

[0021] R b is selected from C1-C4alkoxy, C3-C6cycloalkyloxy, or R1and R2are each independently selected from C1-C4alkyl, and the wavy line represents the site of attachment of the group.

[0022] In the present application, the substituents in the groups substituted as described above are selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6alkyl, or -0-(C1-C6alkyl).

[0023] In the present application, the 6-10 membered aryl group can be a 6-, 7-, 8-, 9-, or 10-membered aryl group, the 5-10 membered heteroaryl group can be a 5-, 6-, 7-, 8-, 9-, or 10-membered heteroaryl group, the 4-10 membered cycloalkyl group can be a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered cycloalkyl group, the 5-10 membered heterocycloalkyl group can be a 5-, 6-, 7-, 8-, 9-, or 10-membered heterocycloalkyl group, the C2-C4alkyl group can be a C2-, C3-, or C4alkyl group, the C1-C4alkyl group can be a C1-, C2-, C3-, or C4alkyl group, and the C3-C6cycloalkyloxy group can be a C3-, C4-, C5-, or C6cycloalkyloxy group.

[0024] Preferably, the ring A is the wavy line represents the site of attachment of the group.

[0025] Preferably, the B structure is or -CH2CH2-, and the wavy line represents the site of attachment of the group.

[0026] Preferably, the C structure is -CH2-, -CH2CH2-, or -CH2CH2CH2-, and the wavy line represents the site of attachment of the group.

[0027] Preferably, Ra each independently selected from hydrogen, fluorine, chlorine, cyano, trifluoromethyl, trifluoromethoxy, a wavy line represents the point of attachment of the group.

[0028] Preferably, selected from a wavy line represents the point of attachment of the group.

[0029] Preferably, R b selected from methoxy, ethoxy, isopropoxy, cyclopropyloxy or any one of, a wavy line represents the point of attachment of the group.

[0030] Preferably, the compound of formula I according to the present application is selected from any one of the following structures:

[0031]

[0032]

[0033]

[0034]

[0035] Preferably, the pharmaceutically acceptable salt comprises any one of a sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, hydrochloride, hydrobromide, hydroiodide, acetate, propionate, decanoate, octanoate, acrylate, formate, isobutyrate, hexanoate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-1, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate or mandelate.

[0036] In another aspect, the present application provides a tri-cyclic IRAK4 degrader comprising a tri-cyclic compound, a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt thereof as described above.

[0037] In another aspect, the present application provides a pharmaceutical composition comprising the tri-cyclic compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof as described above.

[0038] In another aspect, the present application provides the use of the tri-cyclic compound, stereoisomer, geometric isomer, tautomer or pharmaceutically acceptable salt thereof as described above or the pharmaceutical composition in the preparation of a medicament for treating a disease or disorder mediated by IRAK4.

[0039] Preferably, the disease comprises an inflammatory disease, an autoimmune disease or a tumor.

[0040] Preferably, the inflammatory disease is selected from Crohn's disease, ulcerative colitis, asthma, graft-versus-host disease, chronic obstructive pulmonary disease, atopic dermatitis, gout, gouty arthritis, conjunctivitis, hepatitis, chronic pulmonary inflammatory disease, thyroiditis or interstitial cystitis.

[0041] Preferably, the autoimmune disease is selected from Graves' disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, psoriatic arthritis, cryopyrin-associated periodic syndromes, TNF receptor-associated periodic syndromes, multiple sclerosis, allergic rhinitis, scleroderma, dermatomyositis, vasculitis or nephritis.

[0042] Preferably, the tumor is selected from lung cancer, breast cancer, prostate cancer, pancreatic cancer, renal cancer, liver cancer, gastrointestinal cancer, cervical cancer, endometrial cancer, testicular cancer, genitourinary tract cancer, colorectal cancer, laryngeal cancer, skin cancer, bone cancer, head and neck tumor, sarcoma, brain tumor, glioblastoma, melanoma, multiple myeloma, lymphoma or leukemia.

[0043] Compared with the prior art, the present application has the following beneficial effects:

[0044] The compound of the present application has a significant degradation ability on IRAK4 in THP1-HIBiT-IRAK4 cells, and the half-degradation concentration (DC 50 ) of some compounds can reach the nanomolar level; the results of Western blotting experiments also show that the compound of the present application has a very strong degradation activity on IRAK4 protein in OCI-LY10 cells at a concentration of 100 nM and 1000 nM. BRIEF DESCRIPTION OF DRAWINGS

[0045] Figure 1 Figure 2 is a Western blot result diagram of the degradation of IRAK4 protein in OCI-LY10 cells by the compound of Example 1 at a concentration of 100 nM and 1000 nM.

[0046] Figure 2Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 2.

[0047] Figure 3 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 3.

[0048] Figure 4 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 4.

[0049] Figure 5 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 5.

[0050] Figure 6 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 6.

[0051] Figure 7 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 7.

[0052] Figure 8 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 8.

[0053] Figure 9 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 9.

[0054] Figure 10 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 10.

[0055] Figure 11 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells at 100 nM and 1000 nM concentration for the compound of Example 11.

[0056] Figure 12Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells for the compound of Example 12 at 100 nM and 1000 nM concentrations.

[0057] Figure 13 Figure of Western blot results for IRAK4 protein degradation in OCI-LY10 cells for the compound of Example 13 at 100 nM and 1000 nM concentrations. DETAILED DESCRIPTION

[0058] The technical solutions of the present application are further illustrated below by means of specific embodiments. Those skilled in the art should understand that the embodiments are only used to help understand the present application and should not be regarded as specific limitations on the present application.

[0059] In the following examples, unless otherwise noted by structural formula or chemical name, molecules with a single chiral center exist as racemic mixtures. Unless otherwise noted by structural formula or chemical name, those molecules with two or more chiral centers exist as racemic mixtures of diastereomers. Single enantiomers / diastereomers can be obtained by methods known to those skilled in the art.

[0060] Preparation methods

[0061] The compounds described herein can be synthesized according to the synthetic methods herein and / or techniques well known in the art.

[0062] Preparation examples

[0063] The compounds described herein can be synthesized according to one or more of the synthetic schemes herein and / or techniques well known in the art. Those skilled in the art will recognize that the synthetic methods detailed for certain embodiments in the present application can be readily adapted for use in synthesizing other embodiments. In some embodiments, the compounds described herein can be prepared by appropriate combinations of synthetic methods well known in the art. Many of the starting materials and other reagents were purchased from commercial suppliers, such as Alfa-Aesar (China) Chemical Co., Ltd., or were readily prepared using synthetic methods commonly employed in the art.

[0064] 1 HNMR spectra were recorded on an instrument operating at 400 MHz. 1 HNMR spectra were obtained in solution form (reported in ppm). When reporting peak multiplicity, the following abbreviations were used: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants given in Hertz (Hz) are given.

[0065] When desired, the (R)- and (S)-isomers of the non-limiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, for example, by forming diastereomeric salts or complexes, which can be separated by, for example, crystallization; by forming diastereomeric derivatives, which can be separated by, for example, crystallization or chromatography; by selective reaction of one enantiomer with an enantiomer-specific reagent followed by separation of the modified and unmodified enantiomers; or by chromatographic separation in a chiral environment. Alternatively, specific enantiomers can be prepared by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0066] Preparation of compounds:

[0067] Key intermediate IM-1:

[0068]

[0069] First step: synthesis of IM-1a

[0070]

[0071] N-Boc-propargylamine (50.0 g, 322 mmol, 1.00 eq) was dissolved in N,N- dimethylformamide (500 mL), the system was cooled to 0 °C, sodium hydride (15.4 g, 386 mmol, 60% mineral oil dispersion, 1.20 eq) was added to the system slowly in batches at 0 °C, and the addition was completed in 30 minutes. The system was warmed to 25 °C and stirred for 1 hour. Then 3-bromopropyne (53.6 g, 451 mmol, 38.8 mL, 1.40 eq) was added to the reaction system at 25 °C, and the reaction was stirred at 25 °C for 1.5 hours. The reaction was quenched with ice water (500 mL), extracted with ethyl acetate (600 ml*3). The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 ~ 0 / 1) to give compound IM-1a (40.0 g, 206 mmol) as a yellow oil.

[0072] Second step: synthesis of IM-1b

[0073]

[0074] Compound IM-1a (23.0 g, 119 mmol, 1.00 eq) and dimethyl butyne dicarboxylate (16.9 g, 119 mmol, 1.00 eq) were dissolved in ethanol (230 mL), and tris(triphenylphosphine)rhodium chloride (1.10 g, 1.19 mmol, 0.01 eq) was added to the reaction system under nitrogen protection at 25 °C. The reaction was warmed to 80 °C and stirred at 80 °C for 12 h. The reaction mixture was filtered under reduced pressure and concentrated. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 ~ 0 / 1) to give compound IM-1b as a black-brown solid (4.00 g).

[0075] Third step: synthesis of IM-1c

[0076]

[0077] Compound IM-1b (3.50 g, 10.4 mmol, 1.00 eq) was dissolved in ethanol (35.0 mL), and sodium hydroxide solution (3.00 M, 17.3 mL, 5.00 eq) was added to the reaction system at 25 °C. The reaction was heated to 80 °C and stirred at 80 °C for 12 h. The reaction was concentrated under reduced pressure, and the mixture was dissolved in water (30.0 mL) and ethyl acetate (30.0 mL). The organic layer was separated, and then the aqueous layer was acidified to pH = 4 with 1 N dilute hydrochloric acid in an ice bath. The aqueous layer was extracted with ethyl acetate (50.0 mL*3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound IM-1c as a black-brown solid (3.00 g, crude).

[0078] Fourth step: synthesis of IM-1d

[0079]

[0080] Compound IM-1c (3.00 g, 9.76 mmol, 1.00 eq) was dissolved in acetic anhydride (40.0 mL) at 25 °C, and the reaction was warmed to 80 °C and stirred at 80 °C for 12 h. The reaction mixture was quenched with 50 mL of water at 25 °C, and then extracted with ethyl acetate (50.0 mL*3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 ~ 0 / 1) to give compound IM-1d as a white solid (2.00 g).

[0081] Fifth step: synthesis of IM-1e

[0082]

[0083] Compound IM-1d (2.00 g, 6.91 mmol, 1.00 eq) and 3-amino-2,6-piperidinedione hydrochloride (1.25 g, 7.61 mmol, 1.10 eq) were added to toluene (20.0 mL). Triethylamine (2.10 g, 20.7 mmol, 2.89 mL, 3.00 eq) was added to the reaction system at 25 °C, the reaction was warmed to 60 °C and stirred at 60 °C for 12 h. The reaction mixture was quenched with 20 mL water at 25 °C, then extracted with ethyl acetate (30.0 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography (formic acid system) to give compound IM-1e as a white solid (1.00 g, 2.50 mmol).

[0084] 1 HNMR: (400 MHz, DMSO-d6) δ 11.12 (s, 1H), 7.89 (d, J = 2.4 Hz, 2H), 5.15 (dd, J = 5.4, 13.0 Hz, 1H), 4.72 (br d, J = 9.7 Hz, 4H), 2.80-2.97 (m, 1H), 2.53-2.65 (m, 2H), 2.02-2.12 (m, 1H), 1.47 (s, 9H).

[0085] Sixth step: synthesis of IM-1

[0086]

[0087] Compound IM-1e (100 mg, 250 μmol, 1.00 eq) was dissolved in dioxane (1.00 mL), and hydrochloric acid / dioxane (4.00 M, 250 μL, 4.00 eq) was added to the reaction system at 25 °C. The reaction mixture was stirred at 25 °C for 12 h, then concentrated under reduced pressure to give compound IM-1 (80.0 mg, hydrochloride) as a white solid.

[0088] Key intermediate IM-2:

[0089]

[0090] First step: synthesis of IM-2a

[0091]

[0092] Compound IM-1e (1.00 g, 2.50 mmol, 1.00 eq) was dissolved in glacial acetic acid (10.0 mL), zinc powder (1.45 g, 22.1 mmol, 8.86 eq) was added at 25 °C, the reaction system was warmed to 60 °C and stirred for 12 hours. The mixture was filtered, washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. Compound IM-2a (1.00 g, crude) was obtained as a red-brown solid.

[0093] LCMS: m / z = 346.1 [M-55].

[0094] Second step: synthesis of IM-2b

[0095]

[0096] Compound IM-2a (1.00 g, 2.49 mmol, 1.00 eq) was dissolved in dichloromethane (10.0 mL), and trifluoroacetic acid (1.70 g, 14.9 mmol, 1.11 mL, 6.00 eq) and triethylsilane (2.90 g, 24.9 mmol, 3.98 mL, 10.0 eq) were added to the system in turn at 25 °C, and the mixture was stirred at 25 °C for 2 hours. The mixture was concentrated in vacuum. Compound IM-2b (900 mg, crude) was obtained as a black-brown solid.

[0097] LCMS: m / z = 386.2 [M+H + ].

[0098] Third step: synthesis of IM-2

[0099]

[0100] Compound IM-2b (500 mg, 1.30 mmol, 1.00 eq) was dissolved in dichloromethane (5.00 mL), and trifluoroacetic acid (890 mg, 7.84 mmol, 584 μL, 6.00 eq) was added to the reaction system under nitrogen protection at 25 °C, and the reaction was stirred at 25 °C for 4 hours. The reaction liquid was filtered and concentrated under reduced pressure to obtain compound IM-2 (500 mg, crude trifluoroacetate) as a black-brown solid. LCMS: m / z = 286.2 [M+H + ].

[0101] Key intermediate IM-3:

[0102]

[0103] First step:

[0104]

[0105] Dissolve 4-(2-bromoacetyl)piperidine-1-carboxylic acid tert-butyl ester (25.0 g, 81.6 mmol) and methyl 2-amino-5-bromoisonicotinate (18.8 g, 81.6 mmol) in acetonitrile (150 mL) and toluene (100 mL), add sodium bicarbonate (13.6 g, 163 mmol) to the mixture at 25 °C, heat the reaction mixture to 90 °C and stir at 90 °C for 12 h. TLC shows the reaction is complete. Pour the reaction mixture into ice water (500 mL) and stir for 10 min. Extract the aqueous phase with ethyl acetate (300 mL x 3). Wash the combined organic phase with brine (500 mL), dry over anhydrous sodium sulfate, filter and concentrate in vacuo. Purify by column chromatography (silica gel, petroleum ether / ethyl acetate, volume ratio = 100 / 1 to 0 / 1) to give compound IM-3a as a black brown solid (20.0 g).

[0106] Second step:

[0107]

[0108] Dissolve compound IM-3a (20.0 g, 45.6 mmol) and 6-(trifluoromethyl)pyridine-2- carboxamide (26.0 g, 136 mmol) in dioxane (200.0 mL), add cesium carbonate (29.7 g, 90.7 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.5 g, 18.2 mmol) and palladium acetate (2.04 g, 9.13 mmol) to the reaction mixture at 25 °C under nitrogen protection. Warm the reaction mixture to 100 °C and stir at 100 °C for 12 h. Cool the reaction mixture to 25 °C and concentrate in vacuo. Pour the residue into ice water (300 mL) and stir for 5 min. Extract the aqueous phase with ethyl acetate (300 mL x 3), wash the combined organic phase with brine (500 mL), dry over anhydrous sodium sulfate, filter and concentrate in vacuo. Purify the residue by column chromatography (silica gel, petroleum ether / ethyl acetate, volume ratio = 100 / 1 to 0 / 1) to give compound IM-3b as a yellow solid (10.0 g).

[0109] Third step:

[0110]

[0111] Compound IM-3b (10.0 g, 18.1 mmol) was dissolved in tetrahydrofuran (100 mL), the reaction mixture was cooled to 0 °C, methyl magnesium bromide (3 M, 36.5 mL) was added slowly dropwise, after the addition was completed, the system was slowly warmed to 25 °C and stirred at 25 °C for 3 hours. The reaction was quenched with aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (3 x 100 mL), the combined organic layers were dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo. The residue was purified by column chromatography (silica gel, petroleum ether / ethyl acetate = 100 / 1 to 0 / 1 by volume) to give compound IM-3c as a white solid (4.00 g, crude).

[0112] Fourth step:

[0113]

[0114] Compound IM-3c (4.00 g, 7.32 mmol) was dissolved in dioxane (40.0 mL), the system was cooled to 0 °C, hydrochloric acid-dioxane (4.00 M, 2.00 equivalents) was slowly added to the system. After the addition was completed, the system was slowly warmed to 25 °C and stirred at 25 °C for 3 hours. The reaction mixture was concentrated in vacuo. Compound IM-3 was obtained as a white solid (3.00 g, crude, hydrochloride).

[0115] Synthesis of key intermediate IM-4

[0116]

[0117] First step: synthesis of IM-4a

[0118]

[0119] tert-Butyl 4-(2-bromoacetyl)piperidine-1 -carboxylate (15.0 g, 48.9 mmol, 1.00 eq), 5-bromo-4-methoxypyridin-2-amine (9.95 g, 48.9 mmol, 1.00 eq) were dissolved in a mixture of toluene (100 mL) and acetonitrile (100 mL), sodium bicarbonate (8.23 g, 97.9 mmol, 2.00 eq) was added to the system. After the addition was completed, the resulting mixture was warmed to 90 °C and stirred for 12 hours. The reaction mixture was quenched by adding 200 mL of ice water at 0 °C, then extracted with 500 mL of ethyl acetate three times. The combined organic layers were washed with aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give compound IM-4a as a white solid (15.0 g).

[0120] MS (ES+): m / z = 410.0 [M+H + ].

[0121] Second Step: Synthesis of IM-4b

[0122]

[0123] Compound IM-4a (5.00 g, 12.1 mmol, 1.00 eq), 6-(trifluoromethyl)pyridine-2- carboxamide (6.95 g, 36.5 mmol, 3.00 eq) were dissolved in 1,4 dioxane (90.0 mL), and cesium carbonate (7.94 g, 24.3 mmol, 2.00 eq), 4,5-bis(diphenylphosphino)-9,9- dimethylxantphos (2.82 g, 4.87 mmol, 0.40 eq) and palladium acetate (547 mg, 2.44 mmol, 0.20 eq) were added successively. After the addition, the resulting mixture was warmed to 100 °C and stirred for 12 hours. The reaction mixture was quenched by adding 100 mL of water at 25 °C, and then extracted with 100 mL of ethyl acetate for three times. The combined organic layer was washed with sodium chloride aqueous solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to give compound IM-4b (3.90 g) as a yellow solid. MS (ES+): m / z = 520.2 [M+H + ].

[0124] Third Step: Synthesis of IM-4

[0125]

[0126] Compound IM-4b (4.00 g, 7.70 mmol, 1.00 eq) was dissolved in 1,4 dioxane (40.0 mL), and hydrochloric acid / 1,4 dioxane (4 M, 40.0 mL) was added slowly dropwise at 25 °C. The mixture was stirred at 25 °C for 12 hours. The mixture was concentrated in vacuum to give compound IM-4 as a white solid (4.00 g, hydrochloride salt).

[0127] MS (ES+): m / z = 420.1 [M+H + ].

[0128] Synthesis of Key Intermediate IM-5

[0129]

[0130] First Step: Synthesis of IM-5a

[0131]

[0132] Compound IM-3a (5.00 g, 12.1 mmol, 1.00 eq), compound IM-5a (3.55 g, 17.1 mmol, 1.50 eq) were dissolved in 1,4-dioxane (50.0 mL), cesium carbonate (7.43 g, 22.8 mmol, 2.00 eq), Xantphos (2.64 g, 4.56 mmol, 0.40 eq) and palladium acetate (512 mg, 2.28 mmol, 0.20 eq) were added to the system at 25 °C. After the addition was completed, the resulting mixture was warmed to 100 °C and stirred for 12 hours. The mixture was filtered and concentrated under reduced pressure to obtain compound IM-5b crude as a yellow solid (5.00 g). MS (ES+): m / z 565.2 [M+H

[0133] MS (ES+): m / z 208.1 [M+H + ]。

[0134] Second step: synthesis of IM-5b

[0135]

[0136] Compound IM-3a (5.00 g, 12.1 mmol, 1.00 eq), compound IM-5a (3.55 g, 17.1 mmol, 1.50 eq) were dissolved in 1,4-dioxane (50.0 mL), cesium carbonate (7.43 g, 22.8 mmol, 2.00 eq), Xantphos (2.64 g, 4.56 mmol, 0.40 eq) and palladium acetate (512 mg, 2.28 mmol, 0.20 eq) were added to the system at 25 °C. After the addition was completed, the resulting mixture was warmed to 100 °C and stirred for 12 hours. The mixture was filtered and concentrated under reduced pressure to obtain compound IM-5b crude as a yellow solid (5.00 g). MS (ES+): m / z 565.2 [M+H + ]。

[0137] Third step: synthesis of IM-5c

[0138]

[0139] Compound IM-5b (2.00 g, 3.54 mmol, 1.00 eq) was dissolved in tetrahydrofuran (15.0 mL), methyl magnesium bromide (3 M, 9.45 mL, 8.00 eq) was slowly added dropwise at 0 °C. Then the mixture was stirred at 25 °C for 3 hours. 20.0 mL of aqueous ammonium chloride solution was added to the reaction mixture at 25 °C for quenching, then extracted with dichloromethane (15.0 mL*3). The combined organic layer was washed with aqueous sodium chloride solution (5.00 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to obtain compound IM-5c as a yellow solid (500 mg). MS (ES+): m / z 565.2 [M+H+ ]。

[0140] Fourth Step: Synthesis of IM-5

[0141]

[0142] Compound IM-5c (500 mg, 885 μmol, 1.00 eq) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (1.24 g, 10.6 mmol, 805 μL, 12 eq) was added dropwise slowly at 25 °C. The mixture was stirred at 25 °C for 4 hours, and then concentrated in vacuum to give compound IM-5 as a white solid (500 mg, trifluoroacetate salt).

[0143] MS (ES+): m / z 465.3 [M+H + ]。

[0144] Synthesis of Key Intermediate IM-6

[0145]

[0146] First Step: Synthesis of IM-6a

[0147]

[0148] 6-fluoropyridine-2-carboxamide (10.0 g, 71.2 mmol, 1.00 eq) and (1R,4R)-2-oxa-5- azabicyclo[2.2.1]heptane hydrochloride (14.5 g, 106 mmol, 1.50 eq) were dissolved in N,N- dimethylformamide (70.0 mL). Potassium carbonate (29.6 g, 214 mmol, 3.00 eq) was added to the reaction system at 25 °C, and after the addition was completed, the resulting mixture was warmed to 100 °C and stirred for 12 hours. The reaction mixture was cooled to 25 °C, poured into 100 mL of water to quench, and then extracted with 300 mL (100 mL*3) of ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. Column chromatography (eluent, petroleum ether: ethyl acetate = 100:1 to 0:1) was used for separation and purification to give compound IM-6a as a white solid (13.0 g). LCMS: m / z 166.0 [M+H + ]。

[0149] Second Step: Synthesis of IM-6b

[0150]

[0151] Compound IM-6a (6.00 g, 13.7 mmol, 1.00 eq) and compound IM-3a (4.50 g, 20.5 mmol, 1.50 eq) were dissolved in 1,4-dioxane (42.0 mL), and potassium carbonate (29.6 g, 214 mmol, 3.00 eq), palladium acetate (614 mg, 2.74 mmol, 0.20 eq), and Xantphos (3.17 g, 5.48 mmol, 0.40 eq) were added to the reaction system in turn at 25 °C. After addition, the resulting mixture was replaced with nitrogen three times, and the mixture was warmed to 100 °C and stirred for 12 h. The reaction mixture was cooled to 25 °C, poured into 100 mL of water to quench, and then extracted with ethyl acetate (100 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Column chromatography (eluent, petroleum ether: ethyl acetate = 100:1 to 0:1) was used for separation and purification to obtain compound IM-6b as a white solid (5.20 g).

[0152] LCMS: m / z 577.3 [M+H + ].

[0153] Step 3: Synthesis of IM-6c

[0154]

[0155] Compound IM-6b (4.00 g, 6.94 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL), and methyl magnesium bromide (3.00 M, 11.6 mL, 5.00 eq) was added to the reaction system at 0 °C. After addition, the resulting mixture was warmed to 25 °C and stirred for 1 h. The reaction solution was slowly poured into 30.0 mL of saturated aqueous ammonium chloride solution in batches to quench, and then extracted with ethyl acetate (15.0 mL*3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Column chromatography (eluent, petroleum ether: ethyl acetate = 100:1 to 0:1) was used for separation and purification to obtain compound IM-6c as a yellow oil (3.80 g). LCMS: m / z 577.3 [M+H + ].

[0156] Step 4: Synthesis of IM-6

[0157]

[0158] Compound IM-6c (2.00 g, 3.47 mmol, 1.00 eq) was dissolved in dichloromethane (20.0 mL), and trifluoroacetic acid (4.75 g, 41.2 mmol, 3.09 mL, 12.0 eq) was added to the reaction system at 0 °C. After the addition was completed, the resulting mixture was warmed to 25 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound IM-6 as a brown oil (1.60 g, trifluoroacetate salt). LCMS: m / z 477.3 [M+H + ].

[0159] Key intermediate IM-7

[0160]

[0161] First step: synthesis of IM-7a

[0162]

[0163] Methyl 1H-indazole-6-carboxylate (50.0 g, 283 mmol, 1.00 eq) was dissolved in concentrated sulfuric acid (300 mL). Concentrated nitric acid (49.9 g, 554 mmol, 35.6 mL) was added dropwise at 0 °C, and then the reaction solution was stirred at 0 °C for 3 hours. The reaction solution was slowly dropped into ice water (600 mL) for quenching, filtered, and the filter cake was washed with aqueous sodium bicarbonate solution three times, and the filter cake was dried to obtain compound IM-7a as a yellow solid (40.0 g). LCMS: m / z = 222.0 [M+H + ].

[0164] Second step: synthesis of IM-7b

[0165]

[0166] Compound IM-7a (5.00 g, 22.6 mmol, 1.00 eq) was dissolved in N,N-dimethylformamide (40.0 mL). Cesium carbonate (14.7 g, 45.2 mmol, 2.00 eq) and tert-butyl 4-(p-toluenesulfonyloxy)piperidine-1-carboxylate (8.04 g, 22.6 mmol, 1.00 eq) were added at room temperature, and then the reaction solution was stirred at 80 °C for 12 hours. Three reaction solutions of parallel crystal forms were combined and diluted with water (150 mL). The aqueous layer was extracted with ethyl acetate (80 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain IM-7b as a yellow solid compound (8.00 g). LCMS: m / z = 349.1 [M+H + ].

[0167] Third step: synthesis of IM-7c

[0168]

[0169] Compound IM-7b (8.00 g, 19.7 mmol, 1.00 eq) was dissolved in ethanol (40.0 mL) and water (20.0 mL), and iron powder (5.52 g, 98.9 mmol, 5.00 eq) and calcium chloride (6.59 g, 59.3 mmol, 3.00 eq) were added at 25 °C, and then the reaction mixture was stirred at 80 °C for 12 hours. The reaction mixture was diluted with water (40 mL), extracted with ethyl acetate (40 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain IM-7c as a yellow solid (3.80 g). LCMS: m / z = 375.1 [M+H + ].

[0170] Fourth Step: Synthesis of IM-7d

[0171]

[0172] 6-Trifluoromethylpyridine-2-carboxylic acid (1.94 g, 10.1 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL), and triethylamine (3.08 g, 30.4 mmol, 4.24 mL, 3.00 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (5.79 g, 15.2 mmol, 1.50 eq) were slowly added, and then compound IM-7c (3.80 g, 10.1 mmol, 1.00 eq) was added. The reaction mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20.0 mL x 3), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain compound IM-7d as a yellow oil (1.50 g). LCMS: m / z = 548.2 [M+H + ].

[0173] Fifth Step: Synthesis of IM-7e

[0174]

[0175] Compound IM-7d (1.6 g, 2.92 mmol, 1.00 eq) was dissolved in tetrahydrofuran (10.0 mL), methyl magnesium bromide (3 M, 4.87 mL, 5.00 eq) was added dropwise at 0 °C, then the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was poured into saturated ammonium chloride (10 mL), extracted with ethyl acetate (10 mL x 3). The organic phases were combined. Washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give IM-7e as a yellow solid (800 mg), which was used directly in the next step without purification. LCMS: m / z = 548.3 [M+H + ].

[0176] Sixth step: synthesis of IM-7

[0177]

[0178] Compound IM-7e (1.23 g, 2.25 mmol, 1.00 eq) was dissolved in dioxane (10.0 mL), hydrochloric acid / dioxane (4 M, 12.30 mL, 21.9 eq) was added at 25 °C. The reaction mixture was stirred for 2 hours, then concentrated under reduced pressure to give compound IM-7 as a yellow solid (600 mg, hydrochloride salt), which was used directly in the next step without purification. LCMS: m / z = 448.2 [M+H + ]

[0179] Key intermediate IM-8

[0180]

[0181] First step: synthesis of IM-8a

[0182]

[0183] 4-Hydroxybutan-2-one (5.00 g, 56.7 mmol, 1.00 eq) was dissolved in methanol (100 mL), bromine (9.07 g, 56.7 mmol, 1.00 eq) was added slowly dropwise at 0 °C, the mixture was stirred at 25 °C for 2 hours, then hydrochloric acid (2 M, 56.7 mL, 2.00 eq) was added slowly dropwise. After the addition was completed, the resulting mixture was stirred at 25 °C for 12 hours. The two reactions carried out in parallel were combined, 200 mL of water was added at 5 °C to quench the reaction, then extracted with dichloromethane (150 mL*3). The combined organic layers were washed with aqueous sodium chloride solution (50 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give compound IM-8a as a yellow oil (7.00 g).

[0184] Second Step: Synthesis of IM-8b

[0185]

[0186] Compound IM-8a (3.00 g, 17.9 mmol, 1.00 eq) was dissolved in a mixture of toluene (50.0 mL) and acetonitrile (50.0 mL), and methyl 2-amino-5-bromopyridine-4-carboxylate (4.15 g, 17.9 mmol, 1.00 eq) and sodium bicarbonate (3.02 g, 35.9 mmol, 2.00 eq) were added successively. The mixture was warmed to 90 °C and stirred at 90 °C for 12 h. Two parallel reactions were combined and concentrated by filtration under reduced pressure. The resulting residue was purified by silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give compound IM-8b as a yellow solid (2.50 g).

[0187] Third Step: Synthesis of IM-8c

[0188]

[0189] Compound IM-8b (2.00 g, 6.69 mmol, 1.00 eq) was dissolved in N,N-dimethylformamide (20.0 mL), and imidazole (1.14 g, 16.7 mmol, 2.50 eq) was added slowly at 0 °C. The mixture was warmed to 25 °C, and tert-butyldiphenylsilyl chloride (2.76 g, 10.0 mmol, 1.50 eq) was added. The mixture was warmed to 40 °C and stirred for 12 h. The mixture was concentrated under reduced pressure to give compound IM-8c as a white solid (2.60 g).

[0190] Fourth Step: Synthesis of IM-8d

[0191]

[0192] Compound IM-8d (1.30 g, 2.01 mmol, 1.00 eq) was dissolved in tetrahydrofuran (10.0 mL), methyl magnesium bromide (3 M, 3.35 mL, 5.00 eq) was added slowly dropwise at 0 °C, the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by adding 20.0 mL of water at 5 °C, then extracted with dichloromethane (15.0 mL*3). The organic layers were combined, washed with aqueous sodium chloride solution (5.00 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give compound IM-8e as a yellow solid (500 mg).

[0193] Fifth step: synthesis of IM-8e

[0194]

[0195] Compound IM-8d (1.30 g, 2.01 mmol, 1.00 eq) was dissolved in tetrahydrofuran (10.0 mL), methyl magnesium bromide (3 M, 3.35 mL, 5.00 eq) was added slowly dropwise at 0 °C, the reaction mixture was stirred at 25 °C for 3 h. The reaction mixture was quenched by adding 20.0 mL of water at 5 °C, then extracted with dichloromethane (15.0 mL*3). The organic layers were combined, washed with aqueous sodium chloride solution (5.00 mL*3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give compound IM-8e as a yellow solid (500 mg).

[0196] 1 H NMR: (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 9.54 (s, 1H), 8.35-8.48 (m, 2H), 8.16-8.21 (m, 1H), 7.78 (s, 1H), 7.56-7.59 (m, 4H), 7.38-7.44 (m, 7H), 6.15 (s, 1H), 3.94-3.99 (m, 2H), 2.95 (br t, J = 6.9 Hz, 2H), 1.59 (s, 6H), 0.98 (s, 9H).

[0197] Sixth step: synthesis of IM-8

[0198]

[0199] Compound IM-8e (400 mg, 618 pmol, 1.00 eq) was dissolved in tetrahydrofuran (5.00 mL), and tetrabutylammonium fluoride (1 M, 3.09 mL, 5.00 eq) was added. The reaction mixture was stirred at 25 °C for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (S1O2, petroleum ether / ethyl acetate = 100 / 1 to 10 / 1) to give compound IM-8 as a white solid (200 mg).

[0200] Example 1:

[0201]

[0202] First step:

[0203]

[0204] Compound IM-3 (1.00 g, 2.23 mmol) and 2-bromo-1,1 -diethoxyethane (880 mg, 4.47 mmol) were dissolved in acetone (2.00 mL), and then potassium carbonate (926 mg, 6.70 mmol) and potassium iodide (185 mg, 1.12 mmol) were added in turn. The resulting mixture was warmed to 80 °C and stirred for 12 hours. The mixture was concentrated to dryness under reduced pressure to give intermediate 1a as a yellow solid (300 mg).

[0205] Second step:

[0206]

[0207] Compound 1a (300 mg, 532 pmol) was dissolved in water (3.00 mL), and hydrochloric acid / 1,4-dioxane (4 M, 3.00 mL) was slowly added dropwise to the system at 25 °C. The mixture was stirred at 60 °C for 12 hours, and then concentrated to dryness in vacuo to give intermediate 1b as a white solid (430 mg).

[0208] Third step:

[0209]

[0210] Compound IM-1 (50.0 mg, 148 μmol, 1.00 eq) was dissolved in N,N- dimethylformamide (1.00 mL) and 1,2-dichloroethane (1.00 mL), triethylamine (45.2 mg, 446 μmol, 62.1 μL, 3.00 eq) was added to the reaction system at 25 °C, and the reaction was stirred at 25 °C for 30 min. Then compound 1b (72.9 mg, 148 μmol, 1.00 eq), sodium triacetoxyborohydride (63.1 mg, 297 μmol, 2.00 eq) and glacial acetic acid (8.94 mg, 148 μmol, 8.53 μL, 1.00 eq) were added to the reaction system. The reaction was stirred at 25 °C for 2.5 h. The reaction mixture was quenched by adding 3.00 mL of water, then extracted with ethyl acetate (5 mL*3). The combined organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a residue. The residue was purified by pre-high performance liquid chromatography (formic acid condition) to give compound 1 as a yellow solid (12.0 mg).

[0211] 1 H NMR: (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 11.12 (s, 1H), 9.54 (s, 1H), 8.43-8.48 (m, 1H), 8.35-8.42 (m, 1H), 8.15-8.22 (m, 2H), 7.80 (s, 2H), 7.41 (s, 1H), 6.14 (br s, 1H), 5.13 (dd, J = 5.4, 12.9 Hz, 1H), 4.02 (s, 4H), 3.03 (br d, J = 11.1 Hz, 2H), 2.83-2.92 (m, 3H), 2.53-2.71 (m, 5H), 2.17 (br t, J = 10.9 Hz, 2H), 1.94-2.10 (m, 3H), 1.66-1.78 (m, 2H), 1.60 (s, 6H).

[0212] Example 2:

[0213]

[0214] Compound IM2 (150 mg, 525 pmol, 1.00 eq) and compound 1b (257 mg, 525 pmol, 1.00 eq) were dissolved in N,N-dimethylformamide (1.00 mL) and tetrahydrofuran (1.00 mL), anhydrous sodium acetate (129. mg, 1.58 mmol, 3.00 eq) was added to the reaction system at 25 °C, and the reaction was stirred at 25 °C for 30 min. Then sodium triacetoxyborohydride (334 mg, 1.58 mmol, 3.00 eq) and glacial acetic acid (31.5 mg, 525 pmol, 30.10 pL, 1.00 eq) were added to the reaction system. The reaction was stirred at 25 °C for 11.5 h. The reaction mixture was filtered and concentrated to give the crude product. Purification was performed by high performance liquid chromatography (formic acid system) to give compound 2 as a yellow solid (15.0 mg).

[0215] 1 H NMR: (400 MHz, DMSO-d6) d 12.22 (s, 1H), 10.97 (brs, 1H), 9.54 (s, 1H), 8.42-8.49 (m, 1H), 8.34-8.42 (m, 1H), 8.19 (d, J = 7.6 Hz, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 7.43 (d, J = 15.0 Hz, 2H), 6.14 (s, 1H), 5.10 (dd, J = 5.1, 13.3 Hz, 1H), 4.22-4.48 (m, 2H), 3.94 (brd, J = 7.3 Hz, 4H), 3.00 (brd, J = 10.9 Hz, 2H), 2.85 (brt, J = 6.7 Hz, 3H), 2.54-2.70 (m, 4H), 2.32-2.41 (m, 1H), 2.12 (brt, J = 10.8 Hz, 2H), 1.92-2.05 (m, 3H), 1.69 (brd, J = 10.4 Hz, 2H), 1.60 (s, 6H).

[0216] LCMS: m / z = 759.3 [M+H + ]。

[0217] Example 3:

[0218]

[0219] First step:

[0220]

[0221] Compound IM-3 (1.00 g, 2.23 mmol, 1.00 eq), 3-bromopropanal dimethyl acetal (449 mg, 2.46 mmol, 335 μL, 1.10 eq) were dissolved in N,N dimethylformamide (10.0 mL), potassium carbonate (926 mg, 6.70 mmol, 3.00 eq), potassium iodide (185 mg, 1.12 mmol, 0.50 eq) were added successively to the system. After addition, the resulting mixture was warmed to 80 °C and stirred for 12 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (20.0 ml) and extracted with ethyl acetate (3 x 20.0 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Compound 3a was obtained as a yellow solid (200 mg).

[0222] 1 H NMR: (400 MHz, CHLOROFORM-d6) δ 12.25 (s, 1H), 9.55 (s, 1H), 8.43-8.51 (m, 2H), 8.13 (t, J = 7.8 Hz, 1H), 7.86 (d, J = 7.8 Hz, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 4.82 (brs, 1H), 3.30-3.38 (m, 8H), 2.93 (brt, J = 10.8 Hz, 1H), 2.77-2.87 (m, 2H), 2.58 (brs, 2H), 2.16-2.28 (m, 2H), 1.95-2.12 (m, 4H), 1.72 (s, 6H).

[0223] LCMS: m / z 550.3 [M+H + ].

[0224] Second Step:

[0225]

[0226] Compound 3a (200 mg, 363 μmol, 1.00 eq) was dissolved in anhydrous formic acid (5.00 mL), the mixture was stirred at 25 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 3b crude (200 mg), which was used directly in the next step without purification.

[0227] LCMS: m / z 504.2 [M+H + ].

[0228] Third Step:

[0229]

[0230] IM-1 (71.3 mg, 238 pmol, 1.20 eq) was dissolved in tetrahydrofuran (0.50 mL) and N,N dimethylformamide (0.50 mL), sodium acetate (24.4 mg, 297 pmol, 1.50 eq) was added at 25 °C, then stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (126 mg, 595 pmol, 3.00 eq) and compound 3b (100 mg, 198 pmol, 1.00 eq) were added at 25 °C, then stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the product which was purified by preparative high performance liquid chromatography (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 25% - 60% B for 8.0 min) to give compound 3 as a white solid (12.0 mg). 1 H NMR: (400 MHz, DMSO-d6) d 12.22 (s, 1H), 11.11 (s, 1H), 9.54 (s, 1H), 8.44-8.47 (m, 1H), 8.39 (t, J = 7.8 Hz, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.79 (s, 3H), 7.41 (s, 1H), 6.14 (s, 1H), 5.13 (dd, J = 5.3, 12.9 Hz, 1H), 3.97 (s, 4H), 2.81-3.01 (m, 4H), 2.63-2.75 (m, 4H), 2.39 (br t, J = 7.1 Hz, 2H), 2.28-2.34 (m, 1H), 2.04-2.08 (m, 2H), 1.97 (br d, J = 11.0 Hz, 2H), 1.70 (br dd, J = 8.9, 12.3 Hz, 4H), 1.60 (s, 6H).

[0231] LCMS: m / z = 787.3 [M+H + ]。

[0232] Example 4:

[0233]

[0234] Compound 3b (100 mg, 350 pmol, 1.00 eq) was dissolved in N,N- dimethylformamide (1.00 mL) and tetrahydrofuran (1.00 mL), anhydrous sodium acetate (86.2 mg, 1.05 mmol, 3.00 eq) was added to the reaction system at 0 °C, the reaction was stirred at 0 °C for 30 min. Then triacetoxyborohydride sodium (222 mg, 1.05 mmol, 3.00 eq), glacial acetic acid (42.1 mg, 701 pmol, 40.1 pL, 2.00 eq) and compound IM-2 (176 mg, 350 pmol, 1.00 eq) were added to the reaction system at 0 °C, the reaction was allowed to warm to room temperature and stirred for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by high performance liquid chromatography (column: Phenomenex Gemini-NX 150*30mm*5um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 30% - 55% B over 20.0 min). Compound 4 was obtained as a white solid (13.3 mg).

[0235] 1 H NMR: (400 MHz, DMSO-d6) d 12.22 (s, 1H), 10.97 (br s, 1H), 9.54 (s, 1H), 8.34 - 8.49 (m, 2H), 8.19 (d, J = 7.6 Hz, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.43 (d, J = 14.1 Hz, 2H), 6.15 (s, 1H), 5.10 (dd, J = 5.1, 13.2 Hz, 1H), 4.22 - 4.46 (m, 2H), 3.90 (br d, J = 5.5 Hz, 4H), 2.85 - 3.00 (m, 3H), 2.57 - 2.76 (m, 4H), 2.32 - 2.45 (m, 3H), 1.92 - 2.07 (m, 5H), 1.64 - 1.77 (m, 4H), 1.60 (s, 6H).

[0236] LCMS: m / z = 773.4 [M+H + ]。

[0237] Example 5:

[0238]

[0239] First step:

[0240]

[0241] Compound IM-4 (1.00 g, 2.38 mmol, 1.00 eq) was dissolved in acetone (10.0 mL), potassium carbonate (1.65 g, 11.9 mmol, 5.00 eq), potassium iodide (197 mg, 1.19 mmol, 0.50 eq) were added to the system successively, the resulting mixture was warmed to 80 °C and stirred for 12 hours. The mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex Gemini NX-C18 (75*30 mm*3 um); mobile phase: [H2O (0.05% NH3H2O + 10 mM NH4HCO3) - ACN]; gradient: 20% - 50% B, 8.0 min) to give compound 5a (340 mg) as a white solid. LCMS purity: 88.8%.

[0242] MS (ES+): m / z = 536.2 [M+H + ]。

[0243] Second step:

[0244]

[0245] Compound 5a (100 mg, 186 µmol, 1.00 eq) was dissolved in water (2.00 mL), hydrochloric acid / dioxane (4 M, 2.00 mL) was slowly added to the system at 25 °C, the mixture was stirred at 50 °C for 2 hours. The mixture was concentrated in vacuum to give compound 5b (100 mg) as a white solid.

[0246] Third step:

[0247]

[0248] Compound IM-1 (64.8 mg, 216 μmol, 1.00 eq) was dissolved in 1,2 dichloroethane (1.00 mL) and N,N dimethylformamide (1.00 mL), N,N-diisopropylethylamine (84.0 mg, 650 μmol, 3.00 eq) was added at 25 °C, then stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (137 mg, 650 μmol, 3.00 eq), compound 5b (100 mg, 216 μmol, 1.00 eq) and acetic acid (19.5 mg, 325 μmol, 1.50 eq) were added at 0 °C, then stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure, the obtained residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 1% - 35% B for 8.0 min). The obtained product was purified again by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [H2O (10 mM NH4HC03) - ACN]; gradient: 30% - 65% B for 8.0 min) to give compound 5 as a white solid (7.00 mg).

[0249] 1 H NMR: (400 MHz, DMSO-d6) δ 11.11 (br s, 1H), 10.19 (s, 1H), 9.35 (s, 1H), 8.39-8.47 (m, 2H), 8.24 (d, J = 7.6 Hz, 1H), 7.79 (s, 2H), 7.65 (s, 1H), 7.08 (s, 1H), 5.13 (dd, J = 5.4, 12.7 Hz, 1H), 3.95-4.06 (m, 7H), 2.80-3.02 (m, 5H), 2.53-2.64 (m, 4H), 2.02-2.16 (m, 3H), 1.94-1.99 (m, 2H), 1.59-1.75 (m, 2H), 1.15-1.25 (m, 1H).

[0250] MS (ES+): m / z = 745.3 [M+H + ]。

[0251] Example 6:

[0252]

[0253] First step:

[0254]

[0255] Compound IM-2 (123 mg, 432 μmol, 1.00 eq) was dissolved in N,N- dimethylformamide (1.00 mL) and tetrahydrofuran (1.00 mL), anhydrous sodium acetate (106 mg, 1.29 mmol, 3.00 eq) was added to the reaction system at 25 °C, then glacial acetic acid (51.8 mg, 864 μmol, 49.4 μL, 2.00 eq), sodium triacetoxyborohydride (274 mg, 1.29 mmol, 3.00 eq) and compound 5b (200 mg, 432 μmol, 1.00 eq) were added to the reaction system, the reaction was stirred at 25 °C for 12 hours. The mixture was filtered and concentrated in vacuum to obtain a residue. Purification by high performance liquid chromatography to obtain compound 6 (5.70 mg) as a white solid.

[0256] 1 HNMR: (400 MHz, DMSO-d6) δ 10.97 (br d, J = 3.1 Hz, 1H), 10.19 (s, 1H), 9.35 (s, 1H), 8.34-8.51 (m, 2H), 8.23 (d, J = 7.5 Hz, 1H), 7.51-7.70 (m, 2H), 7.45 (s, 1H), 7.07 (s, 1H), 5.09 (br dd, J = 5.1, 13.4 Hz, 1H), 4.38-4.56 (m, 1H), 4.22-4.33 (m, 1H), 3.98 (s, 3H), 3.94 (br d, J = 6.9 Hz, 3H), 3.00 (br d, J = 11.0 Hz, 2H), 2.80-2.93 (m, 3H), 2.55-2.68 (m, 3H), 2.39 (br dd, J = 4.1, 12.9 Hz, 1H), 2.11 (br t, J = 10.9 Hz, 2H), 1.93-2.02 (m, 3H), 1.61-1.75 (m, 2H), 1.23 (br s, 2H). LCMS: m / z = 731.3 [M+H + ]。

[0257] Example 7

[0258]

[0259] First step:

[0260]

[0261] Compound IM-5 (500 mg, 864 pmol, 1.00 eq), 2-bromo-l,l-diethoxyethane (187 mg, 950 pmol, 143 pL, 1.10 eq) were dissolved in N,N dimethylformamide (10.0 mL), diisopropylethylamine (335 mg, 2.59 mmol, 451 pL, 3.00 eq) was added to the system at 25 °C, after the addition was completed, the resulting mixture was warmed to 100 °C and stirred for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative high performance liquid chromatography (formic acid system) to obtain compound 7a as a white solid (170 mg).

[0262] MS (ES+): m / z 581.3 [M+H + ].

[0263] Second step:

[0264]

[0265] Compound 7a (170 mg, 292 pmol, 1.00 eq) was slowly dropped with formic acid (4.22 mg, 86.1 pmol, 0.10 mL, 98.0% purity, 5.00 eq) to the system at 25 °C, the reaction mixture was stirred at 60 °C for 12 hours. The mixture was concentrated in vacuum to obtain compound 7b as a white solid (100 mg). MS (ES+): m / z 507.3 [M+H + ].

[0266] Third step:

[0267]

[0268] Compound IM-2 (61.9 mg, 217 μmol, 1.10 eq) was dissolved in tetrahydrofuran (1.00 mL) and N,N dimethylformamide (1.00 mL), sodium acetate (48.5 mg, 592 μmol, 3.00 eq) was added at 0 °C, then stirred at 0 °C for 0.5 h. Sodium triacetoxyborohydride (125 mg, 592 μmol, 3.00 eq), compound 7b (100 mg, 197 μmol, 1.00 eq) and acetic acid (48.58 mg, 592.19 μmol, 3.00 eq) were added at 0 °C, then stirred at 25 °C for 3.5 h. The mixture was concentrated under reduced pressure, the obtained residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 15% - 55% B over 8.0 min). The obtained product was purified again by prep-HPLC (column: Phenomenex Gemini-NX 80*40mm*3um; mobile phase: [H2O (10 mM NH4HCO3) - ACN]; gradient: 20% - 60% B over 20.0 min) to give compound 7 as a white solid (6.94 mg).

[0269] 1 H NMR: (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.81 - 11.13 (m, 1H), 9.56 (s, 1H), 7.68 - 7.81 (m, 2H), 7.57 (s, 1H), 7.42 - 7.49 (m, 2H), 7.39 (s, 1H), 7.10 (d, J = 8.5 Hz, 1H), 5.98 - 6.26 (m, 1H), 5.09 (dd, J = 4.9, 13.3 Hz, 1H), 4.41 (br d, J = 17.6 Hz, 1H), 4.28 (d, J = 17.1 Hz, 1H), 3.94 (br d, J = 7.1 Hz, 4H), 3.72 (br d, J = 4.5 Hz, 4H), 3.65 (br d, J = 4.8 Hz, 4H), 3.00 (br d, J = 10.9 Hz, 3H), 2.80 - 2.91 (m, 3H), 2.65 (br d, J = 12.3 Hz, 2H), 2.29 - 2.42 (m, 2H), 2.12 (br t, J = 10.9 Hz, 2H), 1.93 - 2.01 (m, 3H), 1.65 - 1.71 (m, 2H), 1.60 (s, 6H).

[0270] MS (ES+): m / z 776.3 [M+H + ].

[0271] Example 8:

[0272]

[0273] First Step:

[0274]

[0275] Compound IM-6 (1.00 g, 2.10 mmol, 1.00 eq) and 2-bromo-1,1-diethoxyethane (1.65 g, 8.39 mmol, 1.26 mL, 4.00 eq) were dissolved in N,N-dimethylformamide (10.0 mL), N,N-diisopropylethylamine (2.71 g, 20.9 mmol, 3.65 mL, 10.0 eq) was added to the reaction system at 25 °C, and after the addition was completed, the resulting mixture was warmed to 100 °C and stirred for 12 hours. The reaction liquid was poured into 10 mL of water to quench, and then extracted with ethyl acetate (10.0 mL*3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Column chromatography was used for separation and purification (eluent, petroleum ether: ethyl acetate = 100:1 to 0:1). Compound 8a was obtained as a yellow oil (500 mg).

[0276] LCMS: m / z 593.4 [M+H + ].

[0277] Second Step:

[0278]

[0279] Compound 8a (100 mg, 168.71 μmol, 1.00 eq) was added to formic acid (1.00 mL) at 25 °C, and the reaction mixture was stirred at 60 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to obtain compound 8b as a yellow oil (170 mg, crude), which was directly used in the next step without further purification.

[0280] LCMS: m / z 519.3 [M+H + ].

[0281] Third Step:

[0282]

[0283] Compound IM-2 (124 mg, 385 μmol, 1.00 eq, HC1) was dissolved in a mixed solution of tetrahydrofuran (2.00 mL) and N,N-dimethylformamide (2.00 mL), sodium acetate (63.2 mg, 771 μmol, 2.00 eq) was added to the reaction system at 25 °C, and after the addition was completed, the resulting mixture was stirred at 25 °C for 0.5 h. Then sodium triacetoxyborohydride (245 mg, 1.16 mmol, 3.00 eq), glacial acetic acid (69.4 mg, 1.16 mmol, 66.2 μL, 3.00 eq) and compound 8b (200 mg, 385 μmol, 1.00 eq) were added, and the resulting mixture was stirred at 25 °C for 11.5 h. The reaction solution was poured into water (4.00 mL) for quenching, and then extracted with ethyl acetate (2.00 mL*3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Concentration under reduced pressure, and then high performance liquid chromatography separation were used to obtain compound 8 as a white solid (8.60 mg).

[0284] 1 HNMR (400 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.60 - 11.32 (m, 1H), 9.59 (s, 1H), 7.71 - 7.76 (m, 2H), 7.57 (s, 1H), 7.45 (s, 1H), 7.41 - 7.38 (m, 2H), 6.76 (br d, J = 8.0 Hz, 1H), 5.09 (dd, J = 5.1, 13.0 Hz, 1H), 4.70 (s, 1H), 4.38 - 4.45 (m, 1H), 4.21 - 4.37 (m, 1H), 3.94 (br d, J = 6.9 Hz, 4H), 3.82 (d, J = 7.4 Hz, 1H), 3.69 (d, J = 7.4 Hz, 1H), 3.55 (br d, J = 9.9 Hz, 1H), 3.00 (br d, J = 11.1 Hz, 2H), 2.88 - 2.95 (m, 1H), 2.85 (br t, J = 6.9 Hz, 2H), 2.56 - 2.69 (m, 6H), 2.32 - 2.41 (m, 2H), 2.12 (br t, J = 10.6 Hz, 2H), 1.88 - 1.99 (m, 5H), 1.66 - 1.73 (m, 2H), 1.64 (s, 3H), 1.58 (s, 3H). LCMS m / z 788.4 [M+H + ]。

[0285] Example 9:

[0286]

[0287] First Step:

[0288]

[0289] Compound 9a (20.0 g, 88.6 mmol, 1.00 eq) was dissolved in acetonitrile (100 mL) at room temperature, morpholine (11.5 g, 132 mmol, 11.7 mL, 1.50 eq) was added, and finally N,N-diisopropylethylamine (22.9 g, 177 mmol, 30.8 mL, 2.00 eq) was added. The reaction was stirred at 60 °C for 12 h. The reaction was concentrated into solid under reduced pressure, which was slurried with methyl tert-butyl ether (80.0 mL) to give compound 9b as a white solid (15.0 g).

[0290] LCMS: m / z = 277.1 [M+H + ].

[0291] Second step:

[0292]

[0293] Compound 9b (15.0 g, 54.2 mmol, 1.00 eq) was dissolved in methanol (75.0 mL) and water (15.0 mL) at room temperature, and lithium hydroxide (6.50 g, 271 mmol, 5.00 eq) was added slowly. The reaction was stirred at 60 °C for 12 h. The reaction was adjusted to pH = 3-4 with 1.00 M hydrochloric acid, and the methanol was concentrated under reduced pressure. The filter cake was washed with water (30.0 mL) and dried under vacuum to give 9c as a white compound (8.00 g).

[0294] LCMS: m / z = 249.1 [M+H + ].

[0295] Third step:

[0296]

[0297] Ammonium chloride (5.17 g, 96.6 mmol, 3.00 eq) was dissolved in N,N- dimethylformamide (80.0 mL), N,N-diisopropylethylamine (12.5 g, 96.6 mmol, 16.8 mL, 3.00 eq) was added at 25 °C, then O-(7-azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate (HATU, 18.3 g, 48.3 mmol, 1.50 eq) and compound 9c (8.00 g, 32.2 mmol, 1.00 eq) were added, and the reaction solution was stirred at 25 °C for 12 h. Water (40.0 mL) was added to dilute the reaction mixture, which was extracted with ethyl acetate (40 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography to obtain yellow solid 9d (3.80 g).

[0298] 1 H NMR: (400 MHz, DMSO-d6) δ 8.76 (d, J = 7.9 Hz, 1H), 8.16 (s, 1H), 7.11-7.27 (m, 2H), 6.84 (d, J = 7.9 Hz, 1H), 3.71 (s, 8H).

[0299] LCMS: m / z = 248.1 [M+H + ]。

[0300] Fourth step:

[0301]

[0302] Compound 3a (3.00 g, 6.84 mmol, 1.00 eq) and compound 9d (1.86 g, 7.53 mmol, 1.10 eq) were dissolved in 1,4-dioxane (30.0 mL), and 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (850 mg, 1.47 mmol, 0.40 eq), cesium carbonate (2.40 g, 7.35 mmol, 2.00 eq) and palladium acetate (165 mg, 735 μmol, 0.20 eq) were added under nitrogen protection at 25 °C, and the reaction solution was stirred at 100 °C for 12 h. The reaction mixture was cooled to room temperature, poured into water (30.0 mL), and extracted with ethyl acetate (50.0 mL x 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to obtain 9e as a yellow solid (1.20 g). LCMS: m / z = 605.3 [M+H + ]。

[0303] Fifth step:

[0304]

[0305] Compound 9e (1.70 g, 2.81 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL), methyl magnesium bromide (4.00 M, 6.00 mL, 8.54 eq) was added dropwise at 0 °C, the reaction solution was stirred at 25 °C for 3 hours. The reaction mixture was diluted with ammonium chloride (20.0 mL), extracted with ethyl acetate (40 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by high performance liquid chromatography to obtain compound 9f (300 mg) as a white solid.

[0306] 1 H NMR: (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.67 (s, 1H), 8.20 (s, 1H), 7.67 (d, J = 16.0 Hz, 2H), 7.37 (s, 1H), 4.25-4.36 (m, 1H), 3.84-4.03 (m, 2H), 3.76-3.90 (m, 2H), 3.57-3.69 (m, 6H), 3.14-3.26 (m, 1H), 2.91-2.97 (m, 1H), 2.79-2.91 (m, 3H), 2.65-2.75 (m, 1H), 1.91-1.99 (m, 2H), 1.60 (s, 1H), 1.50 (br d, J = 5.9 Hz, 6H), 1.41 (s, 9H).

[0307] LCMS: m / z = 605.3 [M+H + ].

[0308] Sixth step:

[0309]

[0310] Compound 9f (300 mg, 496 μmol, 1.00 eq) was dissolved in dichloromethane (3.00 mL), trifluoroacetic acid (565 mg, 4.96 mmol, 368 μL, 10.0 eq) was slowly added at room temperature, the reaction solution was stirred at 25 °C for 12 hours. The reaction solution was concentrated to obtain compound 9g as a yellow solid (300 mg, trifluoroacetate salt), which was used directly in the next step without further purification.

[0311] LCMS: m / z = 505.2 [M+H + ].

[0312] Seventh step:

[0313]

[0314] Compound 9g (300 mg, 594 pmol, 1.00 eq) was dissolved in N,N- dimethylformamide, potassium carbonate (410 mg, 2.97 mmol, 5.00 eq), bromoacetaldehyde diethyl acetal (140 mg, 713 pmol, 107 pL, 1.20 eq) and potassium iodide (49.3 mg, 297 pmol, 0.5 eq) were added, and the reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to a solid, which was purified by high performance liquid chromatography to give compound 9h as a yellow solid (60.0 mg, crude). LCMS: m / z = 621.3 [M+H + ].

[0315] Eighth step:

[0316]

[0317] Compound 9h (60.0 mg, 96.6 pmol, 1.00 eq) was dissolved in water (1.00 mL) and hydrochloric acid (1.00 mL), and the reaction was stirred at 50 °C for 12 h. The reaction mixture was concentrated to give compound 9i as a yellow solid (40.0 mg), which was used directly in the next step without further purification. LCMS: m / z = 547.4 [M+H + ].

[0318] Ninth step:

[0319]

[0320] Compound IM-2 (26.1 mg, 91.4 pmol, 1.00 eq) was dissolved in N,N- dimethylformamide (1.00 mL) and tetrahydrofuran (1.00 mL), sodium acetate (15.0 mg, 182 pmol, 2.00 eq) was added at room temperature, followed by acetic acid (16.4 mg, 274 pmol, 15.7 pL, 3.00 eq), sodium borohydride in acetic acid (58.1 mg, 274 pmol, 3.00 eq) and compound 9i (50.0 mg, 91.4 pmol, 1.00 eq), and the reaction was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to a solid, which was purified by high performance liquid chromatography to give compound 9 as a white solid (10.0 mg).

[0321] 1H NMR: (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 8.68-8.89 (m, 2H), 8.29 (s, 1H), 7.60-7.71 (m, 1H), 7.37 (s, 1H), 6.87 (d, J = 7.9 Hz, 1H), 3.94 (br d, J = 8.8 Hz, 3H), 3.78 (br s, 5H), 3.69 (br d, J = 4.3 Hz, 4H), 2.94 - 3.05 (m, 3H), 2.77-2.87 (m, 3H), 1.89 - 2.19 (m, 8H), 1.61 - 1.76 (m, 3H), 1.51 (s, 6H).

[0322] LCMS: m / z = 816.3 [M+H + ].

[0323] Example 10

[0324]

[0325] First Step:

[0326]

[0327] Compound 10a (23.0 g, 101 mmol, 1.00 eq) and morpholine (13.3 g, 152 mmol, 13.4 mL, 1.50 eq) were dissolved in N,N-dimethylformamide (115 mL), and potassium carbonate (42.2 g, 305 mmol, 3.00 eq) was added to the reaction system at 25 °C. After the addition was completed, the resulting mixture was warmed to 100 °C and stirred for 12 hours. The reaction mixture was cooled to 25 °C, and the reaction solution was poured into 100 mL of water to quench, and then extracted with dichloromethane (100 mL*2). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Column chromatography was used for separation and purification (eluent, petroleum ether: ethyl acetate = 100:1 to 0:1). Compound 10b (18.0 g) was obtained as a yellow solid.

[0328] LCMS: m / z 277.1 [M+H + ].

[0329] Second Step:

[0330]

[0331] Compound 10b (16.0 g, 57.9 mmol, 1.00 eq) was dissolved in methanol (90.0 mL) and water (18.0 mL), and lithium hydroxide monohydrate (4.86 g, 115 mmol, 2.00 eq) was added to the reaction system at 25 °C. After the addition was completed, the resulting mixture was warmed to 60 °C and stirred for 3 hours. The reaction mixture was cooled to 25 °C, and the pH of the reaction solution was adjusted to 4 with 1.00 M hydrochloric acid. White solids were precipitated, filtered, and concentrated under reduced pressure to obtain compound 10c as a white solid (12.0 g).

[0332] LCMS: m / z 249.0 [M+H + ]。

[0333] Step 3:

[0334]

[0335] Compound 10c (10.0 g, 40.2 mmol, 1.00 eq) was dissolved in N,N- dimethylformamide (50.0 mL), and N,N-diisopropylethylamine (15.6 g, 120 mmol, 21.0 mL, 3.00 eq), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (22.9 g, 60.4 mmol, 1.50 eq), and ammonium chloride (6.46 g, 120 mmol, 3.00 eq) were added to the reaction system at 25 °C. After the addition was completed, the resulting mixture was stirred at 25 °C for 12 hours. The reaction mixture was cooled to 25 °C and quenched by pouring into 100 mL of water, and then extracted with ethyl acetate (100 mL*3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. Column chromatography was used for separation and purification (eluent, petroleum ether: ethyl acetate = 100 / 1 to 0 / 1). Compound 10d was obtained as a white solid (5.20 g).

[0336] 1H NMR: (400 MHz, DMSO-d6) δ 7.99-8.09 (m, 2H), 7.80-7.99 (m, 2H), 7.37 (d, J = 10.0 Hz, 1H), 3.73-3.79 (m, 4H), 3.47-3.52 (m, 4H).

[0337] Step 4:

[0338]

[0339] Compound 10d (3.20 g, 12.9 mmol, 1.00 eq) and compound IM-3a (5.38 g, 12.3 mmol, 0.95 eq) were dissolved in 1,4-dioxane (20.0 mL), and palladium acetate (581 mg, 2.59 mmol, 0.20 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (3.00 g, 5.18 mmol, 0.40 eq) and cesium carbonate (12.7 g, 38.8 mmol, 3.00 eq) were added to the reaction system at 25 °C, and the resulting mixture was warmed to 100 °C and stirred for 12 hours. The reaction mixture was quenched by pouring into 20.0 mL of an aqueous solution of saturated ammonium chloride, and then extracted with ethyl acetate (15.0 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent, petroleum ether: ethyl acetate = 100 / 1 to 0 / 1). Compound 10e was obtained as a white solid (4.00 g).

[0340] 1 HNMR: (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.27-9.32 (m, 1H), 8.13-8.19 (m, 2H), 8.09 (d, J = 10.0 Hz, 1H), 8.00-8.04 (m, 1H), 7.43 (d, J = 10.0 Hz, 1H), 3.84 (s, 3H), 3.72-3.76 (m, 4H), 3.58-3.62 (m, 4H), 1.41 (s, 9H).

[0341] Fifth step:

[0342]

[0343] Compound 10e (4.00 g, 6.62 mmol, 1.00 eq) was dissolved in tetrahydrofuran (20.0 mL), and methylmagnesium bromide (3.00 M, 28.6 mL, 13.0 eq) was added to the reaction system at 0 °C, and the resulting mixture was warmed to 25 °C and stirred for 3 hours. The reaction mixture was quenched by pouring into 20.0 mL of a saturated aqueous solution of ammonium chloride, and then extracted with ethyl acetate (20.0 mL*3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a residue. The residue was concentrated under reduced pressure and separated by high performance liquid chromatography to obtain compound 10f as a yellow solid (2.00 g).

[0344] Sixth step:

[0345]

[0346] Compound 10f (1.20 g, 1.98 mmol, 1.00 eq) was added into dichloromethane (10.0 mL), trifluoroacetic acid (3.39 g, 29.7 mmol, 2.21 mL, 15.0 eq) was added into the reaction system at 25 °C, the mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure to obtain compound 10g as a brown oil (1.05 g, crude product), which was directly used in the next step without further purification.

[0347] Seventh step:

[0348]

[0349] Compound 10g (1.00 g, 1.98 mmol, 1.00 eq) and bromoacetaldehyde diethyl acetal (1.56 g, 7.93 mmol, 4.00 eq) were dissolved in N,N-dimethylformamide (10.0 mL), potassium iodide (164 mg, 990 μmol, 0.50 eq) was added into the reaction system at 25 °C, after the addition of potassium carbonate (821 mg, 5.95 mmol, 3.00 eq) was completed, the obtained mixture was warmed to 100 °C and stirred for 4 h. The reaction mixture was cooled to 25 °C and the reaction mixture was poured into 10 mL of water to quench, then extracted with ethyl acetate (5 mL*3). The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 10h as a white solid (700 mg).

[0350]

[0351] Compound 10h (1.20 g, 1.98 mmol, 1.00 eq) was added into hydrochloric acid (6 M, 5.00 mL, 37.2 eq) at 25 °C, the mixture was warmed to 50 °C and stirred at 50 °C for 4 h. The pH value of the reaction solution was adjusted to 7 with saturated aqueous sodium bicarbonate solution. The reaction solution after adjustment was freeze-dried to obtain compound 10i as a brown solid (200 mg, crude product).

[0352] Ninth step:

[0353]

[0354] Compound IM-2 (104 mg, 365 μmol, 1.00 eq) was dissolved in a mixed solution of tetrahydrofuran (2.00 mL) and N,N-dimethylformamide (2.00 mL), sodium acetate (60.0 mg, 731 μmol, 2.00 eq) was added to the reaction system at 25 °C, and after the addition was completed, the resulting mixture was stirred at 25 °C for 30 minutes. Sodium triacetoxyborohydride (232 mg, 1.10 mmol, 3.00 eq), glacial acetic acid (65.92 mg, 1.10 mmol, 62.8 μL, 3.00 eq) and compound 10i (200 mg, 365 μmol, 1.00 eq) were added to the reaction system, and the resulting mixture was stirred at 25 °C for 11.5 hours. The reaction mixture was poured into water (2 mL) for quenching, and then extracted with ethyl acetate (2 mL*3). The organic layer was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated by high performance liquid chromatography to obtain compound 10 (13.0 mg) as a yellow solid.

[0355] 1 HNMR: (400 MHz, DMSO-d6) δ 10.71 (br s, 1H), 8.77 (s, 1H), 8.12 (s, 1H), 8.08 (d, J = 10.1 Hz, 1H), 7.69 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.41 (t, J = 5.1 Hz, 2H), 5.10 (dd, J = 5.1, 13.2 Hz, 1H), 4.36-4.46 (m, 1H), 4.21-4.34 (m, 1H), 3.94 (br d, J = 7.4 Hz, 4H), 3.69-3.73 (m, 4H), 3.52-3.56 (m, 4H), 2.78-3.07 (m, 6H), 2.57-2.74 (m, 3H), 2.31-2.46 (m, 2H), 2.13 (br t, J = 10.4 Hz, 2H), 1.87-2.06 (m, 4H), 1.64-1.73 (m, 2H), 1.50 (s, 6H).

[0356] LCMS: m / z 816.5 [M+H + ]。

[0357] Example 11:

[0358]

[0359] First step:

[0360]

[0361] Compound IM-8 (200 mg, 489 pmol, 1 eq) was dissolved in tetrahydrofuran (5.00 mL), triethylamine (123 mg, 1.22 mmol, 170 pL, 2.50 eq) and methanesulfonic anhydride (127 mg, 734 pmol, 1.50 eq) were added successively. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was quenched by adding 2.00 mL of water at 0 °C, then extracted with dichloromethane (5 mL*3), the organic layer was washed with sodium chloride aqueous solution (5 mL*3), dried over sodium sulfate, filtered and concentrated under reduced pressure to give compound 11a as a white solid (200 mg).

[0362] Second step:

[0363]

[0364] Compound 11a (120 mg, 246 pmol, 1.00 eq) was dissolved in N,N dimethylformamide (5.00 mL), piperidin-4-one hydrochloride (36.7 mg, 271 pmol, 1.10 eq), sodium iodide (73.9 mg, 493 pmol, 2.00 eq) and potassium carbonate (102 mg, 740 pmol, 3.00 eq) were added successively, the mixture was warmed to 80 °C and stirred for 12 h. The reaction mixture was concentrated under reduced pressure to give compound 11b as a yellow solid (30 mg).

[0365] Third step:

[0366]

[0367] Compound IM-1 (21.4 mg, 71.5 pmol, 1.00 eq), N,N-diisopropylethylamine (36.9 mg, 286 pmol, 4.00 eq) were dissolved in 1,2 dichloroethane (1.00 mL) and N,N dimethylformamide (1.00 mL), stirred at 25 °C for 0.5 h. Sodium triacetoxyborohydride (45.4 mg, 214 pmol, 3.00 eq), compound 11b (35.0 mg, 71.5 pmol, 1.00 eq) and acetic acid (4.29 mg, 71.5 pmol, 1.00 eq) were added successively, then stirred at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give the product which was purified by preparative HPLC (column: Phenomenex luna C18 100*40mm*5um; mobile phase: [H2O (0.2% FA) - ACN]; gradient: 1% - 40% B over 8.0 min]; gradient: 20% - 65% B over 8.0 min) to give compound 11 as a white solid (7.00 mg).

[0368] 1 H NMR: (400 MHz, DMSO-d6) δ 12.21 (s, 1H), 11.11 (s, 1H), 9.54 (s, 1H), 8.43-8.46 (m, 1H), 8.39 (t, J = 7.8 Hz, 1H), 8.11-8.24 (m, 2H), 7.73-7.83 (m, 3H), 7.40 (s, 1H), 6.14 (s, 1H), 5.13 (dd, J = 5.3, 12.9 Hz, 1H), 4.01 (s, 4H), 2.82-2.99 (m, 5H), 2.53-2.71 (m, 4H), 2.00-2.17 (m, 3H), 1.90 (br d, J = 9.3 Hz, 2H), 1.60 (s, 6H), 1.50 (q, J = 10.3 Hz, 2H).

[0369] Example 12:

[0370]

[0371] First step:

[0372]

[0373] Compound IM-7 (500 mg, 1.12 mmol, 1.00 eq) and bromoacetaldehyde diethyl acetal (440 mg, 2.23 mmol, 336 μL, 2.00 eq) were dissolved in N,N-dimethylformamide (5.00 mL), N,N-diisopropylethylamine (144 mg, 1.12 mmol, 194 μL, 1.00 eq) was added at 25 °C. The reaction was warmed to 100 °C and stirred for 12 h. The reaction mixture was added to ammonium chloride (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography to give compound 12a as a yellow solid (150 mg). LCMS: m / z = 564.2 [M+H + ].

[0374] Second step:

[0375]

[0376] Compound 12a (50.0 mg, 88.7 μmol, 1.00 eq) was dissolved in dioxane (1.00 mL) and water (1.00 mL), hydrochloric acid / dioxane (4 M, 1.00 mL, 45.0 eq) was added slowly at room temperature, the reaction was stirred at 50 °C for 1 h. The reaction mixture was concentrated to give compound 12b as a yellow solid (40.0 mg), which was used directly in the next step without further purification.

[0377] LCMS: m / z = 508.1 [M+18].

[0378] Third step:

[0379]

[0380] Compound IM-2 (29.0 mg, 102 μmol, 1.00 eq) was dissolved in N,N- dimethylformamide (1.00 mL) and tetrahydrofuran (1.00 mL), sodium acetate (25. mg, 306 μmol, 3.00 eq) was added at 0 °C, the reaction was stirred at 0 °C for 30 min, sodium borohydride acetic acid (43.3 mg, 204 μmol, 2.00 eq), acetic acid (18.4 mg, 306 μmol, 17 μL, 3.00 eq) and compound 12b (50.0 mg, 102 μmol, 1.00 eq) were added at 0 °C, the reaction was stirred at 25 °C for 1.5 h. The reaction was concentrated into solid under reduced pressure, the crude product was purified by high performance liquid chromatography to give compound 12 as a white solid (11.4 mg).

[0381] 1 H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 10.97 (br s, 1H), 8.72 (s, 1H), 8.31 - 8.48 (m, 3H), 8.16 (d, J = 7.8 Hz, 1H), 7.58 (d, J = 2.4 Hz, 2H), 7.46 (s, 1H), 5.95 (s, 1H), 5.10 (dd, J = 5.1, 13.3 Hz, 1H), 4.42 (br d, J = 17.4 Hz, 2H), 4.23 - 4.33 (m, 1H), 3.96 (br d, J = 7.0 Hz, 4H), 3.09 (br d, J = 10.5 Hz, 2H), 2.87 (br t, J = 6.7 Hz, 3H), 2.56 - 2.65 (m, 3H), 2.39 (br dd, J = 4.6, 13.1 Hz, 1H), 2.18 - 2.27 (m, 2H), 2.06 - 2.17 (m, 4H), 1.96 - 2.04 (m, 1H), 1.62 (s, 6H).

[0382] LCMS: m / z = 759.3 [M+H + ].

[0383] Example 13:

[0384]

[0385] Compound IM-7 (200 mg, 446 µmol, 1.00 eq) was dissolved in N,N- dimethylformamide (2.00 mL) and dichloroethane (2.00 mL), N,N- diisopropylethylamine (115 mg, 893 µmol, 155 µL, 2.00 eq) was added, then compound 13a (152 mg, 446 µmol, 1.00 eq), sodium triacetoxyborohydride (284 mg, 1.34 mmol, 3.00 eq) and acetic acid (80.5 mg, 1.34 mmol, 76.7 µL, 3.00 eq) were added. The reaction was stirred at 25 °C for 12 h. The mixture was filtered and concentrated under reduced pressure. The obtained residue was purified by high performance liquid chromatography (ammonium bicarbonate system) to give compound 13 as a yellow solid (5.00 mg).

[0386] 1 HNMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 10.98 - 11.23 (m, 1H), 8.72 (s, 1H), 8.31 - 8.53 (m, 3H), 8.16 (d, J = 7.6 Hz, 1H), 7.80 (s, 2H), 7.58 (s, 1H), 5.94 (s, 1H), 5.05 - 5.24 (m, 1H), 4.37 - 4.54 (m, 1H), 4.03 (s, 4H), 3.09 (br d, J = 10.5 Hz, 2H), 2.83 - 2.95 (m, 3H), 2.53 - 2.60 (m, 3H), 2.02 - 2.31 (m, 8H), 1.62 (s, 6H).

[0387] IRAK4 protein degradation experiment was performed on the compound prepared in the examples, and the experimental process was as follows:

[0388] HiBiT-based THP1-HIBiT-IRAK4 intracellular degradation experiment

[0389] THP1-HIBiT-IRAK4 cells (wild-type cells purchased from ATCC, HIBiT tag inserted at the C-terminal of IRAK4 by CRISPR-Cas9 technology) were cultured in RPMI1640 medium supplemented with 10% fetal bovine serum (FBS), 1% penicillin-streptomycin (PS) (37 °C, 5% CO2).

[0390] a) THP1-HIBiT-IRAK4 cells were seeded in a 384-well plate at 5000 cells / 40 μL / well.

[0391] b) Dilute the compound to 10 mM, 3.33 mM, 1.11 mM, 0.37 mM, 0.12 mM, 0.04 mM, 0.013 mM, 0.005 mM, 0.002 mM, 0 mM stock solutions with DMSO, ready for use.

[0392] c) Add the above diluted compound to the wells at 40 nL / well, and incubate at 37 °C, 5% CO2 for 24 h.

[0393] d) Add HiBiT lysis detection reagent to the wells, incubate the plate at room temperature for 30 min, then read the luminescence values on Envision.

[0394] Degradation rate (%) = (luminescence value of compound well / average of luminescence value of DMSO wells) x 100

[0395] DC of the compound is obtained using XLFIT software with the following non-linear fitting equation 50 (Half maximal degradation concentration):

[0396] Y = Bottom + (Top-bottom) / (1 + 10^((LogDC 50 -X) * HillSlope))

[0397] X: log value of compound concentration;

[0398] Y: degradation rate

[0399] Bottom: baseline value

[0400] Top: maximum response value

[0401] HillSlope: curve slope value fitted by XLFIT software.

[0402] IRAK4 protein degradation DC 50 The value results are shown in Table 1. The experimental results show that the compounds of Examples 1-8 and Examples 11-13 have significant degradation activity on IRAK4 protein, while the compounds of Example 9 and Example 10 have no IRAK4 protein degradation activity (DC 50 >10000 nM).

[0403] Table 1

[0404]

[0405]

[0406]

[0407] Determination of IRAK4 degradation by Western blotting

[0408] (1) Compound treatment and lysate preparation

[0409] a) On day 1, OCI-LY10 cells (cells purchased from Nanjing Kebai Biotechnology Co., Ltd., Kebai CBP60558) were seeded into a 12-well plate at 1.5 x 10 6 cells / mL / well, and the test compound was diluted with DMSO, and 1 uL of the diluted compound solution was added to the cell supernatant, which was incubated overnight in a 37-degree, 5% CO2 incubator.

[0410] b) On day 2, the cells were harvested and transferred to a 1.5 mL centrifuge tube and centrifuged at 3000 rpm for 5 minutes.

[0411] c) The cells were washed once with ice-cold PBS and centrifuged at 3000 rpm for 5 minutes at 4°C.

[0412] d) To 20 mL of cell lysate, add one piece of protease inhibitor and one piece of phosphatase inhibitor, and mix gently until completely dissolved. Take the above prepared cell lysate, 50ul / tube, and add it to the centrifuge tube, and lyse the cells on ice for 30 minutes.

[0413] e) Centrifuge at 13,000 rpm for 15 minutes at 4°C.

[0414] f) Transfer the supernatant to a new tube and determine the protein concentration by BCA kit.

[0415] (2) Western blotting experiment

[0416] a) Add the sample to a 4-12% BT Midi protein gel (1 mm, 26 wells) at 20 ug / well, and electrophorese at a constant voltage of 120 V for 5 minutes, and at a constant voltage of 150 V for 55 minutes.

[0417] b) Use a Bio-Rad wet transfer apparatus to transfer the sample to a PVDF membrane at 300 mA for 90 minutes.

[0418] c) Block the membrane with 1xTBS-T containing 5% BSA at room temperature for 1 hour.

[0419] d) Incubate the membrane with the corresponding primary antibody solution (rabbit anti-IRAK4 and mouse anti-GAPDH) overnight at 4°C.

[0420] e) Wash the membrane with 1xTBST 3x7 minutes, and incubate the membrane with the secondary antibody solution (HRP-labeled anti-mouse antibody and HRP-labeled anti-rabbit antibody) at room temperature for 60 minutes.

[0421] f) Wash the membrane with 1xTBST 3x7 minutes.

[0422] g) Add an enhanced chemiluminescence (ECL) substrate and scan it using an IBright CL1500 imaging system.

[0423] Experimental results are as follows Figures 1-13 As shown in Table 2, the corresponding tables are listed. Figures 1-13 The correlation between the compounds showed that all compounds in the examples exhibited significant IRAK4 protein degradation activity at concentrations of 100 nM and 1000 nM.

[0424] Table 2

[0425]

[0426]

[0427]

[0428] The applicant declares that the above embodiments illustrate the compounds of the present invention, their preparation, and applications; however, the present invention is not limited to the above embodiments, i.e., it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials used in the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A tricyclic compound, stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof, characterized in that, The tricyclic compound has the following structure of formula I: wherein: represents a single or double bond, provided that the valency requirements are met; Ring A is or , the wavy line represents the point of attachment of the group; B is substituted or unsubstituted C2-C4alkylene, substituted or unsubstituted 4-10 membered cycloalkylene, or substituted or unsubstituted 4-10 membered heterocycloalkylene; C is substituted or unsubstituted C2-C4alkylene, substituted or unsubstituted 4-10 membered cycloalkylene, or substituted or unsubstituted 4-10 membered heterocycloalkylene; one of X and Y is a nitrogen atom, and the other is a carbon atom; Z is CH2or C=O; R a each independently is selected from hydrogen, halogen, cyano, substituted or unsubstituted C1-C4alkyl, substituted or unsubstituted C1-C4alkoxy, di(C1-C4alkyl)amino, 5-10 membered cycloalkyl, 5-10 membered heterocycloalkyl; m is an integer from 0 to 5; R b selected from C1-C4alkoxy, C3-C6cycloalkyloxy or R1and R2are each independently selected from C1-C4alkyl, the wavy line represents the point of attachment of the group; the substituents in the substituted groups are selected from halogen, oxo, cyano, amino, hydroxyl, C1-C6alkyl, or -O-(C1-C6alkyl).

2. The tricyclic compound of claim 1, or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein, The B structure is , or -CH2CH2-, the wavy line represents the point of attachment of the group.

3. The tricyclic compound of claim 1, or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein, The C structure is , , , -CH2-, -CH2CH2- or -CH2CH2CH2-, the wavy line represents the point of attachment of the group.

4. The triannelated compound, stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, R a each independently is selected from hydrogen, fluoro, chloro, cyano, trifluoromethyl, trifluoromethoxy, or , the wavy line represents the point of attachment of the group.

5. The tricyclic compound of claim 1, or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein, selected from , , , or the wavy line represents the point of attachment of the group.

6. The tricyclic compound of claim 1, or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein, R b is selected from any one of methoxy, ethoxy, isopropoxy, cyclopropyloxy or , and the wavy line represents the point of attachment of the group.

7. The tricyclic compound of claim 1, or a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein The tricyclic compound is selected from any one of the following compounds having the following structures: 。 8. The triannelated compound, stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof of claim 1, wherein, The pharmaceutically acceptable salt is selected from any one of a sulfate, a pyrosulfate, a bisulfate, a sulfite, a bisulfite, a phosphate, a monohydrogen phosphate, a dihydrogen phosphate, a metaphosphate, a pyrophosphate, a chloride, a bromide, a iodide, an acetate, a propionate, a decanoate, an octanoate, an acrylate, a formate, an isobutyrate, a hexanoate, a heptanoate, a propiolate, an oxalate, a malonate, a succinate, a suberate, a sebacate, a fumarate, a maleate, a butyne-1,4-dioate, a hexyne-1,6-dioate, a benzoate, a chlorobenzoate, a methylbenzoate, a dinitrobenzoate, a hydroxybenzoate, a methoxybenzoate, a phthalate, a xylenesulfonate, a benzoic acid, a phenylacetic acid, a phenylpropionic acid, a phenylbutyric acid, a citrate, a lactate, a γ-hydroxybutyrate, a glycolate, a tartrate, a methane sulfonate, a propanesulfonate, a naphthalene-1-sulfonate, a naphthalene-2-sulfonate, or a mandelate.

9. A tricyclic IRAK4 degrader selected from the tricyclic compound, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-8.

10. A pharmaceutical composition, characterized by, The pharmaceutical composition comprises the tricyclic compound, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-8.

11. Use of the tricyclic compound, a stereoisomer, a geometric isomer, a tautomer, or a pharmaceutically acceptable salt thereof of any one of claims 1-8 in the manufacture of a medicament for treating a disease or disorder mediated by IRAK4.

12. Use according to claim 11, characterized in that, The disease is selected from an inflammatory disease, an autoimmune disease, or a tumor.

13. Use according to claim 12, characterized in that, The inflammatory disease is selected from Crohn’s disease, ulcerative colitis, asthma, graft-versus-host disease, chronic obstructive pulmonary disease, atopic dermatitis, gout, gouty arthritis, conjunctivitis, hepatitis, chronic pulmonary inflammatory disease, thyroiditis, or interstitial cystitis.

14. The use according to claim 12, characterized in that, The autoimmune disease is selected from Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus, lupus nephritis, cutaneous lupus, psoriasis, psoriatic arthritis, cryopyrin-associated periodic syndromes, TNF receptor-associated periodic syndromes, multiple sclerosis, allergic rhinitis, scleroderma, dermatomyositis, or vasculitis.

15. The use according to claim 12, characterized in that, The tumor is selected from lung cancer, breast cancer, prostate cancer, pancreatic cancer, renal cancer, liver cancer, cervical cancer, endometrial cancer, testicular cancer, colorectal cancer, laryngeal cancer, bone cancer, sarcoma, glioblastoma, melanoma, multiple myeloma, lymphoma or leukemia. The tumor is selected from lung cancer, breast cancer, prostate cancer, pancreatic cancer, renal cancer, liver cancer, cervical cancer, endometrial cancer, testicular cancer, colorectal cancer, laryngeal cancer, bone cancer, sarcoma, glioblastoma, melanoma, multiple myeloma, lymphoma or leukemia. The tumor is selected from lung cancer, breast cancer, prostate cancer, pancreatic cancer, renal cancer, liver cancer, cervical cancer, endometrial cancer, testicular cancer, colorectal cancer, laryngeal cancer, bone cancer, sarcoma, glioblastoma, melanoma, multiple myeloma, lymphoma or leukemia. The tumor is selected from lung cancer, breast cancer, prostate cancer, pancreatic cancer, renal cancer, liver cancer, cervical cancer

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