CN105753863B - Oxo-dihydroimidazopyridine compound and application thereof - Google Patents

Abstract

The invention provides a 2-oxo-1, 3-dihydroimidazopyridine compound represented by a general formula (I) and application thereof in preparing medicines for treating various diseases in which Bruton's Tyrosine Kinase (BTK) participates. Research proves that the compound disclosed by the invention can effectively inhibit the activity of BTK, and further prevent the survival, proliferation and spread of malignant hematological tumor cells by inhibiting BTK. Furthermore, inflammation and autoimmune diseases can be combated by inhibiting BTK. Therefore, the compound can be used for treating various diseases in which BTK participates, is particularly suitable for treating hematological malignancy, inflammation and autoimmune diseases, and has great application value.

Description

Oxydihydroimidazopyridine compounds and their applications

technical field

The invention relates to the field of chemistry and medicine, in particular to oxodihydroimidazopyridine compounds and applications thereof.

Background technique

Bruton's tyrosine kinase (BTK) is a key signaling molecule in the B cell receptor signaling complex and a key protein kinase for the survival and proliferation of lymphocytes. BTK plays an important role in the survival and spread of malignant B cells.

BTK inhibitors play an anti-cancer role by inhibiting BTK in tumor cells. The first BTK inhibitor Ibrutinib (Ibrutinib) is a 4'-aminopyrazolo[3,4-d]pyrimidine compound (Proc Natl Acad Sci USA,107:13075, 2010), through binding to the target protein BTK activity A site cysteine residue (Cys-481) selectively binds covalently and irreversibly inhibits BTK. Thus effectively preventing tumors from migrating from B cells to lymphoid tissues adapted to the tumor growth environment. The US FDA approved ibrutinib from 2013 to 2015 for the treatment of refractory mantle cell lymphoma (MCL), refractory chronic lymphocytic leukemia (CLL), CLL with del 17p deletion mutation and primary macroglobulin treatment of blood disorders.

In addition to ibrutinib, BTK inhibitors, AVL-292 (CC292), ONO-4059, BGB-3111 and ACP-196 have also entered the clinical development stage. For the treatment of B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, multiple myeloma, hairy cell leukemia, and adult acute lymphoblastic leukemia. Combining ibrutinib with chemotherapy drugs or other targeted anticancer drugs can increase the efficacy of these blood cancers. Drugs used in combination with BTK inhibitors in clinical trials include ituximab, lenalidomide, fludarabine; cyclophosphamide; doxorubicin, vincristine, and prednisone.

Compared with normal hematopoietic cells, about 80% of acute myeloid leukemia (AML) patients have increased BTK activity in blast cells, resulting in cells being sensitive to oral BTK inhibitor ibrutinib in vitro (Marcel Spaargaren M.LancetHeamat.2: e180 , 2015). A clinical study of ibrutinib alone or in combination with cytarabine in the treatment of acute myeloid leukemia has entered phase II clinical trials.

During normal B cell development and activation, BTK plays an important role in the B cell receptor (BCR) messenger system. Abnormal BCR signaling is associated with autoimmune diseases such as rheumatoid arthritis (RA). In addition, BTK is also expressed on myeloid cells, including monocytes, macrophages, neutrophils and mast cells. These cells infiltrate the lubricating membrane cavity and produce inflammatory cytokines that aggravate the symptoms of arthritis. BTK inhibitors can block B cell receptor-dependent cell proliferation and reduce the production of inflammatory factors (Whang J.A., Chang B.Y. Drug Discov Today. 19:1200, 2014). Preclinical studies have shown that BTK inhibitors are also effective in a variety of inflammatory and autoimmune diseases, such as rheumatoid arthritis, and in animal models. In addition to rheumatoid arthritis and lupus erythematosus, this class of drugs may be used for lupus nephritis, multiple sclerosis, Sjogren syndrome and underlying diseases such as asthma. BTK inhibitors such as CC-292 and HM71224 have entered the clinical trial stage for the treatment of autoimmune diseases (such as rheumatoid arthritis) (ClinicalTrials.gov ID: NCT01975610, NCT01765478).

The above studies all indicate that BTK inhibitors have great potential value as drugs for the prevention and treatment of tumors, various inflammatory and autoimmune diseases.

Contents of the invention

Based on this, one of the objectives of the present invention is to provide a novel BTK inhibitor oxodihydroimidazopyridine compound.

The concrete technical scheme that realizes above-mentioned purpose of the invention is as follows:

A 2-oxo 1,3-dihydroimidazopyridine compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer or a prodrug molecule thereof:

In the formula:

_X1 and _X2 are independently selected from C or N;

Ar is selected from a benzene ring or a 5-6 membered aromatic heterocycle;

L is selected from O, S, NR ₅ , CR ₅ R ₆ , OCH ₂ , CH ₂ O;

Y is selected from (CHR ₅ ) m, C=O, wherein m is selected from 0, 1, 2, 3;

Z is selected from a saturated 5-7 membered heterocycle or carbocycle;

G is selected from the following groups:

R ₁ and R ₂ are independently selected from: H, C ₁ -C ₆ alkyl, halogen, nitro, hydroxyl, C ₁ -C ₆ alkoxy, cyano, amino, C ₁ -C ₆ alkyl substituted amine group, acyl group, amido group;

R ₃ and R ₄ are independently selected from: H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cycloalkylmethyl, halogen substituted C ₁ -C ₄ alkyl, Hydroxyl substituted C ₁ -C ₄ alkyl, C ₁ -C ₃ alkoxy substituted C ₁ -C ₄ alkyl, amino substituted C ₁ -C ₄ alkyl, C ₁ -C ₃ alkylamino substituted C ₁ - C ₄ alkyl, halogen, nitro, hydroxyl, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ sulfoxide, C ₁ -C ₆ sulfone, cyano, Amino, C ₁ -C ₆ alkyl substituted amino, ester, acyl, amido, carboxyl;

When R ₃ and R ₄ are C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, OH or C ₁ -C ₆ alkyl substituted amino, and the substitution is at the adjacent position of Ar, R ₃ and R ₄ can be connected to form a carbocyclic or heterocyclic ring, selected from the following structures:

Wherein, n is selected from 0, 1, 2; Q ₁ and Q ₂ are independently selected from O, NR ₆ , CHR ₆ ;

R ₅ and R ₆ are independently selected from H, C ₁ -C ₆ alkyl;

R ₇ is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy substituted C ₁ -C ₄ alkyl, amino substituted C ₁ -C ₄ alkyl, C ₁ -C ₃ alkylamino C ₁ -C ₄ alkyl is substituted, and heterocycle is substituted for C ₁ -C ₄ alkyl.

In some of these embodiments, the compound has the structure shown in formula II:

In the formula: X ₃ , X ₄ , X ₅ , X ₆ and X ₇ are independently selected from C or N.

In some of these embodiments, X ₃ , X ₄ , X ₅ , X ₆ and X ₇ are all selected from C; or one of X ₃ , X ₄ , X ₅ , X ₆ and X ₇ is selected from N, and the rest are selected from Since C.

In some of these embodiments, G is selected from the following groups:

In some of these embodiments, _{both X1} and _X2 are C.

In some of these embodiments, L is selected from O, OCH2.

In some of these embodiments, Y is selected from (CH ₂ ) _m , wherein m is 0 or 1.

In some of these embodiments, Z is selected from the following groups:

In some of these embodiments, Z is selected from the following groups:

In some of these embodiments, R ₃ and R ₄ are independently selected from: H, halogen, hydroxyl, C ₁ -C ₆ alkoxy, hydroxyl substituted C ₁ -C ₄ alkyl, C ₁ -C ₆ alkyl substituted Amino group; when R ₃ and R ₄ are C _N1 -C ₆ alkoxyl or OH, and when substituted at the adjacent position of Ar, R ₃ and R ₄ can be connected to form a heterocyclic ring, selected from the following structures:

Wherein, n is 0 or 1.

In some of these embodiments, R _and R are _both H;

In some of these embodiments, R ₇ is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy substituted for C ₁ -C ₄ alkyl, C ₁ -C ₃ alkylamine substituted for C ₁ -C ₄ alkyl, 5-6 membered saturated nitrogen heterocycle substituted C ₁ -C ₄ alkyl.

In some of these embodiments, both X ₁ and X ₂ are C; L is selected from O, OCH ₂ ; Y is selected from (CH ₂ )m, wherein m is 0 or 1; Z is selected from R ₁ and R ₂ are both hydrogen;

_{Both R3} and _R4 are hydrogen; or one of them is hydrogen, and the other is selected from halogen or hydroxyl or _C1 - _C6 alkoxy; or when _R3 and _R4 are _C1 - _C6 alkoxy or OH , and substituted at the adjacent position of Ar, R ₃ and R ₄ can be connected to form a heterocycle, selected from the following structures:

Wherein, n is 0 or 1;

Both R ₅ and R ₆ are H; R ₇ is selected from H, C ₁ -C ₆ alkyl, C ₁ -C ₃ alkoxy substituted C ₁ -C ₄ alkyl, C ₁ -C ₃ alkylamino substituted C ₁ -C ₄ alkyl, 5-6 membered saturated nitrogen heterocycle substituted C ₁ -C ₄ alkyl.

Another object of the present invention is to provide the application of the above compounds.

The concrete technical scheme that realizes above-mentioned purpose is as follows:

Application of the above-mentioned 2-oxo 1,3-dihydroimidazopyridine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of Bruton's tyrosine kinase inhibitor.

Application of the above-mentioned 2-oxo 1,3-dihydroimidazopyridine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of drugs for preventing and treating tumors.

The application of the above-mentioned 2-oxo 1,3-dihydroimidazopyridine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule in the preparation of drugs for preventing and treating blood tumors.

In some of these embodiments, the blood tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia.

The above-mentioned 2-oxo 1,3-dihydroimidazopyridine compounds or pharmaceutically acceptable salts or stereoisomers or prodrug molecules thereof are used as Bruton's tyrosine kinase inhibitors in the preparation of anti-inflammatory or Drug use in autoimmune diseases.

In some of these embodiments, the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple sclerosis, Sjogren's syndrome and underlying disease asthma.

Another object of the present invention is to provide a pharmaceutical composition for treating diseases.

The concrete technical scheme that realizes above-mentioned purpose is as follows:

A pharmaceutical composition for treating diseases, comprising the above-mentioned 2-oxo-1,3-dihydroimidazopyridine compound or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule as an active ingredient, and a pharmaceutically acceptable carrier.

In some of these embodiments, the disease is a hematological tumor or an inflammatory or autoimmune disease associated with Bruton's tyrosine kinase.

In some of these embodiments, the blood tumor is lymphoma, myeloma, lymphocytic leukemia, acute myeloid leukemia; the inflammatory or autoimmune disease is rheumatoid arthritis, lupus erythematosus, lupus nephritis, multiple Sclerosis, Sjogren's syndrome, and underlying asthma.

The present invention provides 2-oxo 1,3-dihydroimidazopyridine compounds. The inventors have proved through a large number of experimental studies that the compounds can effectively inhibit the activity of Bruton's tyrosine kinase (BTK) , thereby preventing the survival, proliferation and spread of malignant hematological tumor cells. In addition, inflammatory and autoimmune diseases can be combated by inhibiting BTK. Therefore, the compound of the present invention can be used to treat various diseases in which BTK is involved, and is especially suitable for the treatment of hematological malignancies, inflammation and autoimmune diseases, and has great application value.

Description of drawings

Figure 1 is a graph showing the results of compound 11 in Example 40 inhibiting BTK phosphorylation in human lymphoma Jeko-1 and DOHH-2 cell lines;

Fig. 2 is a diagram showing the antitumor activity of compound 11 of Example 42 in the diffuse large B-cell lymphoma cell line TMD-8 SCID mouse model.

Detailed ways

In compounds described herein, when any variable (eg, _R1 , R, etc.) occurs more than once in any component, its definition at each occurrence is independent of its definition at each other occurrence. Also, combinations of substituents and variables are permissible only if such combinations render the compounds stable. A line drawn from a substituent into a ring system indicates that the indicated bond may be attached to any substitutable ring atom. It is understood that one of ordinary skill in the art can select substituents and substitution patterns on the compounds of the present invention to provide compounds that are chemically stable and can be readily synthesized from readily available starting materials by skill in the art and by methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms, so long as the structure is stabilized.

The term "alkyl" as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, the definition of "C ₁ -C ₆ " in "C ₁ -C ₆ alkyl" includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain. The term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example "cycloalkyl" includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl and the like.

The term "heterocycle" or "heterocyclyl" as used herein refers to an aromatic or non-aromatic heterocycle containing 1 to 4 heteroatoms selected from O, N and S, and includes bicyclic groups. "Heterocyclyl" thus includes heteroaryl, as well as dihydrogenated and tetrahydrogenated analogs thereof. Attachment of heterocyclic substituents can be via carbon atoms or via heteroatoms.

As understood by those skilled in the art, "halogen" as used herein is meant to include chlorine, fluorine, bromine and iodine.

The present invention includes free forms of compounds of formulas I-III, as well as pharmaceutically acceptable salts and stereoisomers thereof. Some specific exemplary compounds herein are protonated salts of amine compounds. The term "free form" refers to the amine compound in non-salt form. The inclusion of pharmaceutically acceptable salts includes not only the exemplary salts of the specific compounds described herein, but also typical pharmaceutically acceptable salts of all compounds of formulas I-III in free form. The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form can be regenerated by treating the salt with a suitable dilute aqueous base, such as dilute aqueous NaOH, dilute aqueous potassium carbonate, dilute aqueous ammonia, and dilute aqueous sodium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for the purposes of the invention.

The pharmaceutically acceptable salts of the present invention can be synthesized from compounds of the present invention that contain a basic or acidic moiety by conventional chemical methods. Generally, the salts of basic compounds are prepared by ion exchange chromatography or by reacting the free base with a stoichiometric amount or excess of the desired salt form of an inorganic or organic acid in a suitable solvent or combination of solvents. Similarly, salts of acidic compounds are formed by reaction with an appropriate inorganic or organic base.

Accordingly, pharmaceutically acceptable salts of the compounds of the present invention include conventional non-toxic salts of the compounds of the present invention formed by reacting a basic compound of the present invention with an inorganic or organic acid. For example, conventional nontoxic salts include those prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, as well as organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, hard acid, etc. Fatty acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl Salts prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, etc.

Where the compound of the present invention is acidic, appropriate "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Particular preference is given to ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases including salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylamine Diamine, N-ethylmorpholine, N-ethylpiperidine, Glucosamine, Glucosamine, Histidine, Hydroxocobalamin, Isopropylamine, Lysine, Methylglucamine, Morpholine, Piperazine ,Piperidine, quack, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc.

In addition to standard methods known in the literature or exemplified in experimental procedures, the compounds of the invention can be prepared using the methods outlined in the following synthetic schemes (Schemes 1-6). Combined with the following synthesis scheme, the compounds and synthesis methods described in the present invention can be better understood. The synthetic schemes describe methods that can be used to prepare the compounds described in the present invention, and the methods described are illustrative scheme descriptions for illustrative purposes only and are not intended to limit the scope of the invention.

plan 1

Scenario 2

Option 3

Option 4

Option 5

Option 6

Option 7

Option 8

The present invention will be further described below in conjunction with the examples, but the examples are not intended to limit the protection scope of the present invention.

Example 1: (R)-4-amino-1-[1-(2-butynoyl)pyrrolidin-3-yl]-3-(4-phenoxyphenyl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one ((R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4 -phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 1)

Step 1a: tert-butyl(R)-3-((2-chloro-3-nitropyridine-4-amino)pyrrole-1-carboxylate (tert-butyl(R)-3-((2-chloro -3-nitropyridin-4-yl)amino)pyrrolidine-1-carboxylate) (compound 103)

Add 2,4-dichloro-3-nitropyridine (101) (9.65g, 50.0mmol, 1.0 equivalents), tert-butyl (R)-3-aminopyrrolidine-1-carboxylate to the reaction flask (102) (9.30g, 50.0mmol, 1.0eq), triethylamine (6.56g, 65.0mmol, 1.3eq) and N,N-dimethylformamide (60ml) were reacted overnight at room temperature. The reaction solution was diluted with water (300 mL), extracted with ethyl acetate (100 mL×4), the extract was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (eluent: petroleum ether: ethyl acetate=4 : 1) tert-butyl (R)-3-((2-chloro-3-nitropyridine-4-amino)pyrrole-1-carboxylate (13.7g, yield: 80%) was obtained. Pale yellow oil material; TLC: Rf0.2 (petroleum ether: ethyl acetate = 4:1); LCMS (ESI): m/z 343[M+1] ⁺ .

Step 1b: tert-butyl (R)-3-((2-dibenzylamino-3-nitropyridine-4-amino)pyrrole-1-carboxylate (tert-butyl (R)-3-(( Preparation of 2-(dibenzylamino)-3-nitropyridin-4-yl)amino)pyrrolidine-1-carboxylate) (compound 104)

Add tert-butyl (R)-3-((2-chloro-3-nitropyridine-4-amino)pyrrole-1-carboxylate (103) (13.7g, 40.06mmol, 1.0 equivalents) to the reaction flask , dibenzylamine (8.47mL, 44.06mmol, 1.0 equivalents), triethylamine (11.15mL, 80.12mmol, 2.0 equivalents) and acetonitrile (200ml), heated and refluxed overnight. The reaction solution was spin-dried with silica gel, and the column layer Purification by analysis (eluent: petroleum ether: ethyl acetate = 4:1) to obtain tert-butyl (R)-3-((2-dibenzylamino-3-nitropyridine-4-amino)pyrrole- 1-carboxylate (20.0g, yield: 99%). Yellow oil; TLC: Rf0.4 (petroleum ether: ethyl acetate = 4:1); LCMS (ESI): m/z 504 [M+ 1] ⁺ .

Step 1c: tert-butyl (R)-3-((3-amino-2-dibenzylamino)pyridine-4-amino)pyrrole-1-carboxylate (tert-butyl (R)-3-(( Preparation of 3-amino-2-(dibenzylamino)pyridin-4-yl)amino)pyrrolidine-1-carboxylate) (compound 105)

Add tert-butyl (R)-3-((2-dibenzyl Amino-3-nitropyridine-4-amino)pyrrole-1-carboxylate (104) (20.0g, 39.71mmol, 1.0eq), heated to 50°C for 1 hour. The reaction solution was filtered with diatomaceous earth, The filtrate was spin-dried, dissolved in a mixed solvent of dichloromethane:methanol=5:1 (50ml), filtered, and the organic phase was spin-dried to obtain crude tert-butyl (R)-3-((3-amino-2-dibenzylamine Base) pyridine-4-amino)pyrrole-1-carboxylate (18.3g, yield: 97%). Pale yellow solid; TLC: Rf0.1 (petroleum ether: ethyl acetate = 4: 1); LCMS ( ESI): m/z 474[M+1] ⁺ .

Step 1d: tert-Butyl(R)-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxy (tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate ) (compound 106) preparation

Add tert-butyl (R)-3-((3-amino-2-dibenzylamino)pyridine-4-amino)pyrrole-1-carboxylate (105) (18.3g, 38.64mmol, 1.0 eq), N,N'-carbonyldiimidazole (15.7 g, 96.6 mmol, 2.5 eq) and tetrahydrofuran (200 ml), the reaction solution was heated to reflux overnight. The reaction solution was mixed with silica gel and spin-dried, and purified by column chromatography (eluent: dichloromethane:methanol=100:1) to obtain tert-butyl (R)-3-(4-dibenzylamino-2- Oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate (17.5 g, yield: 91%). Pale yellow liquid; TLC: Rf0.8 (dichloromethane:methanol=80:1); LCMS (ESI): m/z 500[M+1] ⁺ .

Step 1e: tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate ( tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate) (compound 107) preparation of

Add tert-butyl (R)-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1 to the reaction flask - carboxylate (106) (17.5g, 35.03mmol, 1.0 equivalent), palladium hydroxide (7.0g), ethanol (240ml) and ethyl acetate (60ml), the reaction solution was heated to 70 ° C, reacted in a hydrogen atmosphere overnight. The reaction mixture was filtered with celite, the filtrate was spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol=20:1) to obtain tert-butyl (R)-3-(4-amino- 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate (9.0 g, yield: 80%). Colorless solid; TLC: Rf0.1 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 320[M+1] ⁺ .

Step 1f: tert-Butyl(R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c ]pyridine)pyrrole-1-carboxylate (tert-butyl(R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5 -c] preparation of pyridin-1-yl)pyrrolidine-1-carboxylate) (compound 109-1)

tert-Butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate (107) (5.93g, 18.57mmol, 1.0eq), p-phenoxyphenylboronic acid (108-1) (5.17g, 24.14mmol, 1.3eq) and pyridine (4.5mL, 55.71mmol, 3.0eq) were dissolved in N,N- Copper acetate (3.72g, 20.43mmol, 1.1eq) and 4A molecular sieves (6.7g) were added to dimethylformamide (40mL), and reacted overnight at 50°C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (150 mL), filtered, and the filtrate was washed with half-saturated brine (70 mL×4). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by column chromatography (eluent: dichloromethane:methanol=50:1) to obtain tert-butyl (R)-3-(4-amino -2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole-1-carboxylate (2.7g, yield : 31%). Brown solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 488[M+1] ⁺ .

Step 1g: (R)-4-Amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c ]pyridin-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin -2-one) (compound 110-1) preparation

(R)-tert-butyl-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c] Pyridine) pyrrole-1-carboxylate (109-1) (2.7g, 5.54mmol, 1.0 equivalent) was dissolved in dichloromethane (25mL), and trifluoroacetic acid (5mL) was added thereto, and then reacted at room temperature 3 hours. The reaction mixture was diluted with dichloromethane (150mL), washed successively with saturated sodium carbonate solution (50mL×2) and saturated brine (60mL), then the organic layer was spin-dried with silica gel, and then washed with column layer Analysis method (eluent: dichloromethane: methanol: triethylamine=100:10:1) to obtain: (R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidine -3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (2.0 g, yield: 93%). Gray solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1); LCMS (ESI): m/z 388[M+1] ⁺ .

Step 1h: (R)-4-Amino-1-[1-(2-butynoyl)pyrrolidin-3-yl]-3-(4-phenoxyphenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridine-2-one ((R)-4-amino-1-(1-(but-2-ynoyl)pyrrolidin-3-yl)-3-(4- Preparation of phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 1)

(R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine -2-Kone (110-1) (193.5mg, 0.5mmol, 1 equivalent) was dissolved in DMF (2ml), added 2-butynoic acid (111-1) (51.5mg, 0.6mmol, 1.2 equivalent), EDCI ( 115mg, 0.6mmol, 1.2eq), HOBt (7mg, 0.05mmol, 0.1eq), react at room temperature for 1 hour. Add water (5ml) and stir, dichloromethane (2ml) extract, the organic phase is washed once more with water (10ml), dried, concentrated, and column chromatography (eluent: methanol: EA=1:10) separates and obtains white solid (R )-4-amino-1-[1-(2-butynoyl)pyrrolidin-3-yl]-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c]pyridin-2-one (163 mg, yield 70%). Melting point: 106.5-107.0℃; LCMS (ESI): m/z 454.40[M+1] ⁺ ; ¹ HNMR (600MHz, CDCl ₃ ): δ1.97(s, 1.5H), 2.03(s, 1.5H), 2.37(m,1H),2.64(m,1H),3.57(m,0.5H),3.76(m,0.5H),3.95(m,1.5H),4.11(m,3.5H),5.11(m, 1H), 6.52(d, J=5.64Hz, 0.5H), 6.58(d, J=5.58Hz, 0.5H), 7.11(m, 4H), 7.19(m, 1H), 7.40(m, 4H), 7.86 (dd, J = 18.1, 5.58 Hz, 1H).

Example 2: (R)-4-amino-3-(4-phenoxyphenyl)-1-(1-acryloylpyrrolidin-3 base)-1,3-dihydro-2H-imidazo[4 ,5-c]pyridine-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-propioloylpyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one) (compound 2) preparation

(R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine -2-Kone (110-1) (0.1g, 0.26mmol, 1.0eq), propiolic acid (111-2) (21.7mg, 0.31mmol, 1.2eq), DCC (63.9mg, 0.31mmol, 1.2eq) and DMAP (3.2mg, 0.026mmol, 0.1eq) were dissolved in dichloromethane (5mL), then reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane: methanol = 50:1) to obtain compound (R)-4-amino-3-(4-phenoxyphenyl)- 1-(1-acryloylpyrrolidin-3yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one 50 mg, yield: 44%). White solid, melting point: 141.5-143.1°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 440[M+1] ⁺ , purity: 98.587%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.89- 7.86(m,1H),7.42-7.37(m,4H),7.20-7.18(m,1H),7.13-7.09(m,4H),6.58-6.52(m,1H),5.11-5.08(m,1H ),4.19-4.14(m,3H),3.99-3.95(m,2H),3.80-3.65(m,1H),3.08(d,J＝28Hz,1H),2.76-2.65(m,1H),2.45 -2.36(m,1H).

Example 3: (R)-4-amino-1-(1-(2-pentynoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one ((R)-4-amino-1-(1-(pent-2-ynoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl )-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 3)

(R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine -2-ketone (110-1) (0.15g, 0.39mmol, 1.0 equivalent), 2-pentynoic acid (46.1mg, 0.47mmol, 1.2 equivalent), DCC (97.0mg, 0.47mmol, 1.2 equivalent) and DMAP ( 4.8mg, 0.039mmol, 0.1eq) was dissolved in dichloromethane (5mL), and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane: methanol = 50:1) to obtain compound (R)-4-amino-1-(1-(2-pentynoyl )pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (80mg, yield: 44 %). White solid, melting point: 180.1-181.6°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 468[M+1] ⁺ , purity: 99.450%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.87( dd,J＝16.0,6.0Hz,1H),7.42-7.38(m,4H),7.20-7.18(m,1H),7.14-7.09(m,4H),6.60-6.53(m,1H),5.15- 5.06(m,1H),4.23(s,2H),4.13-3.94(m,3H),3.76-3.55(m,1H),2.68-2.60(m,1H),2.40-2.32(m,3H), 1.25-1.17(m,3H).

Example 4: (R)-1-(1-acryloylpyrrolidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ 4,5-c]pyridine-2-one ((R)-1-(1-acryloylpyrrolidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ Preparation of 4,5-c]pyridin-2-one) (Compound 4)

Acryloyl chloride (202-4) (56.5mg, 0.62mmol, 1.2eq) was dissolved in dichloromethane (5mL), cooled to 0°C, and (R)-4-amino-3- (4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (110-1)(0.2 g, 0.52mmol, 1.0eq) in dichloromethane (5mL) followed by dropwise addition of N,N-diisopropylethylamine (101mg, 0.78mmol, 1.5eq) in dichloromethane (1.0mL) solution, and the mixture was reacted at 0°C for 10 minutes. The reaction solution was quenched with water (50 mL), and then extracted with dichloromethane (50 mL×2). The obtained organic layer was spin-dried with silica gel, and then purified by column chromatography (eluent: dichloromethane: methanol = 50:1) to obtain compound (R)-1-(1-acryloylpyrrole Alkyl-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.13g, rate: 57%). White solid, melting point: 119.2-120.5°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 442[M+1] ⁺ , purity: 99.019%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.87- 7.84(m,1H),7.42-7.38(m,4H),7.19-7.17(m,1H),7.13-7.09(m,4H),6.58-6.40(m,3H),5.76-5.71(m,1H ),5.16-5.08(m,1H),4.21(s,2H),4.10-3.96(m,3H),3.73-3.65(m,1H),2.80-2.65(m,1H),2.45-2.36(m ,1H).

Example 5: (R)-4-amino-1-(1-methacryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H- Imidazo[4,5-c]pyridin-2-one ((R)-4-amino-1-(1-methacryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H Preparation of -imidazo[4,5-c]pyridin-2-one) (Compound 5)

To methacryloyl chloride (202-5) (0.065g, 0.62mmol, 1.2eq) in dichloromethane solution (7ml), add dropwise (R)-4-amino-3-(4-phenoxybenzene) at 0°C Base)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (110-1) (0.200g, 0.52mmol, 1.0 equivalent) in dichloromethane (8ml), then diisopropylethylamine (0.100g, 0.78mmol, 1.5eq) in dichloromethane (1ml) was added dropwise, and reacted at 0°C for 5 minutes. The reaction solution was poured into water (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol= 40:1) to get (R)-4-amino-1-(1-methacryloylpyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-1H - Imidazo[4,5-c]pyridin-2-one (0.140 g, yield: 59%). Colorless solid, melting point: 114.6-117.5°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 456[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.86 (d, J = 5Hz, 1H), 7.41 (m, 4H), 7.20 (t, J =7.5Hz,1H),7.12(m,4H),6.57(d,J=5.5Hz,1H),5.30(s,1H),5.21(s,1H),5.08(m,1H),4.21(s ,2H), 4.03(m,3H), 3.68(m,1H), 2.64(m,1H), 2.36(m,1H), 1.99(s,3H).

Example 6: (R,E)-4-amino-1-(1-(but-2-enoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3 -Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-1-(1-(but-2-enoyl)pyrrolidin-3-yl)- Preparation of 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(Compound 6)

Add (R)-4-amino-3- (4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (110-1)(0.200 g, 0.52mmol, 1.0 equivalent) in dichloromethane (8ml), then add dropwise diisopropylethylamine (0.100g, 0.78mmol, 1.5 equivalent) in dichloromethane (1ml), at 0°C React for 5 minutes. The reaction solution was poured into water (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol= 40:1) gives (R,E)-4-amino-1-(1-(but-2-enoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1, 3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.100 g, yield: 42%). Colorless solid, melting point: 102.3-105.8°C. TLC: Rf0.4 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 456[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.86(dd,1H),7.41(m,4H),7.20(t,J=7.5Hz, 1H),7.13(m,4H),7.08(m,1H),6.58(m,1H),6.20(dd,1H),5.08(m,1H),4.23(s,2H),4.01(m,3H ), 3.69(m,1H), 2.72(m,1H), 2.41(m,1H), 1.88(dd,3H).

Example 7: (R,E)-4-amino-1-(1-(2-pentenoyl)pyrrolidin-3-yl))-3-(4-phenoxyphenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one)((R,E)-4-amino-1-(1-(pent-2-enoyl)pyrrolidin-3-yl)- Preparation of 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(Compound 7)

(R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine -2-ketone (110-1) (0.2g, 0.52mmol, 1.0eq), trans-2-pentenoic acid (67.7mg, 0.68mmol, 1.3eq), HOBT (91.9mg, 0.68mmol, 1.3eq), EDCI (130.4mg, 0.68mmol, 1.3eq) and diisopropylethylamine (0.26mL, 1.56mmol, 3.0eq) were dissolved in dichloromethane (8mL) and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane:methanol=50:1) to obtain compound (R,E)-4-amino-1-(1-(2-pentane Enyl)pyrrolidin-3-yl))-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (83mg, Yield: 34%). White solid, melting point: 221.3-222.4°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 470[M+1] ⁺ , purity: 96.527%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.86- 7.83(m,1H),7.42-7.38(m,4H),7.19-7.17(m,1H),7.13-7.09(m,4H),7.05-7.02(m,1H),6.59-6.55(m,1H ),6.16-6.06(m,1H),5.18-5.05(m,1H),4.22(s,2H),4.08-3.96(m,3H),3.75-3.58(m,1H),2.76-2.65(m ,1H), 2.45-2.22(m,3H), 1.11-1.05(m,3H).

Example 8: (R, E)-4-amino-1-(1-(4-dimethylamino-2-butenoyl)pyrrolidin-3 yl)-3-(4-phenoxyphenyl)- 1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-1-(1-(4-(dimethylamino)but-2-enoyl )pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 8)

(R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine -2-ketone (110-1) (0.5g, 1.29mmol, 1.0 equivalent), 4-bromocrotonic acid (277mg, 1.68mmol, 1.3 equivalent), DCC (347mg, 1.68mmol, 1.3 equivalent) and DMAP (16mg, 0.13mmol, 0.1eq) was dissolved in dichloromethane (15mL), and reacted at 0°C for 1.5 hours. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane: methanol = 30:1) to obtain (R, E)-4-amino-1-(3-(1-(4 -Bromo-2-butenoyl)pyrrolidine))-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.6g, yield : 88%). White solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 535[M+1] ⁺ .

The (R, E)-4-amino-1-(3-(1-(4-bromo-2-butenoyl)pyrrolidine))-3-(4-phenoxyphenyl)-1H obtained above -imidazo[4,5-c]pyridin-2(3H)-one (0.15g, 0.28mmol, 1.0eq) and dimethylamine (2M solution in tetrahydrofuran, 0.63mL, 1.26mmol, 4.5eq) were dissolved in tetrahydrofuran ( 3 mL), and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain compound (R, E)-4-amino-1-(1-(4-di Methylamino-2-butenoyl)pyrrolidin-3yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (60 mg, yield: 43%). White solid, melting point: 103.6-105.3°C. TLC: Rf 0.3 (dichloromethane:methanol=10:1); LCMS (ESI): m/z 499[M+1] ⁺ , purity: 95.928%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.87- 7.84(m,1H),7.41-7.38(m,4H),7.19-7.17(m,1H),7.13-7.09(m,4H),6.99-6.95(m,1H),6.58-6.54(m,1H ),6.41-6.28(m,1H),5.20-5.02(m,1H),4.17-3.98(m,5H),3.75-3.56(m,1H),3.17-3.10(m,2H),2.80-2.60 (m,1H), 2.43-2.38(m,1H), 2.32(s,3H), 2.28(s,3H).

Example 9: (R, E)-4-amino-1-(1-(4-methoxy-2-butenoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl) -1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-1-(1-(4-methoxybut-2-enoyl)pyrrolidin Preparation of -3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 9)

(R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine -2-ketone (110-1) (0.15g, 0.387mmol, 1.0eq), 4-methoxycrotonic acid (58.4mg, 0.503mmol, 1.3eq), DCC (103.8mg, 0.537mmol, 1.3eq) and DMAP (4.8mg, 0.039mmol, 0.1eq) was dissolved in dichloromethane (6mL) and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane: methanol = 30:1) to obtain the compound (R, E)-4-amino-1-(1-(4-methyl Oxy-2-butenoyl)pyrrolidin-3-yl)-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine-2- Ketone (60 mg, yield: 32%). White solid, melting point: 178.2-179.5°C. TLC: Rf 0.4 (dichloromethane:methanol=10:1); LCMS (ESI): m/z 486[M+1] ⁺ , purity: 98.464%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.87- 7.83(m,1H),7.40-7.37(m,4H),7.21-7.18(m,1H),7.13-7.09(m,4H),6.98-6.96(m,1H),6.57-6.54(m,1H ),6.45-6.36(m,1H),5.19-5.03(m,1H),4.24(s,2H),4.14-4.03(m,5H),3.75-3.55(m,1H),3.50-3.42(m ,3H), 2.75-2.60(m,1H), 2.45-2.30(m,1H).

Example 10: (R,E)-4-amino-3-(4-phenoxyphenyl)-1-(1-(4-(piperidin-1-yl)-2-butenoyl)pyrrolidine -3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-3-(4-phenoxyphenyl)-1- (1-(4-(piperidin-1-yl)but-2-enoyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 10) Preparation

(R)-4-amino-3-(4-phenoxyphenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridine -2-ketone (110-1) (0.16g, 0.413mmol, 1.0eq), 4-piperidinyl crotonic acid (90.1mg, 0.537mmol, 1.3eq), HATU (204.1mg, 0.537mmol, 1.3eq) and Triethylamine (125mg, 1.239mmol, 3.0eq) was dissolved in dichloromethane (5mL) and reacted at room temperature for 1 hour. After the reaction was completed, the crude product was concentrated and purified by column chromatography (eluent: dichloromethane: methanol = 20:1) to obtain the compound (R, E)-4-amino-3-(4-phenoxyphenyl )-1-(1-(4-(piperidin-1-yl)-2-butenoyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c ] Pyridin-2-one (100 mg, yield: 45%). White solid, melting point: 107.5-109.1°C. TLC: Rf 0.3 (dichloromethane:methanol=10:1); LCMS (ESI): m/z 539[M+1] ⁺ , purity: 97.356%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.88- 7.84(m,1H),7.41-7.38(m,4H),7.21-7.18(m,1H),7.13-7.09(m,4H),7.01-6.98(m,1H),6.58-6.54(m,1H ),6.50-6.25(m,1H),5.20-5.05(m,1H),4.13-3.98(m,5H),3.78-3.58(m,1H),2.49(d,J＝19.5Hz,2H), 2.80-2.60 (m, 1H), 2.58-2.30 (m, 5H), 1.78-1.56 (m, 3H), 1.52-1.40 (m, 3H).

Example 11: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo [4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 11)

Step 11a: tert-butyl(R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate ((R)-tert-butyl(R)- Preparation of 3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate) (compound 302)

Add 2,4-dichloro-3-nitropyridine (101) (5.79g, 30.0mmol, 1.0 equivalents), tert-butyl (R)-3-aminopiperidine-1-carboxylate ( 301) (6.00g, 30.0mmol, 1.0eq), triethylamine (6.06g, 60.0mmol, 2.0eq) and N,N-dimethylformamide (50ml), react overnight at room temperature. The reaction solution was diluted with ethyl acetate (250ml), washed with half-saturated brine (200ml×4), the organic phase was spin-dried with silica gel, and purified by column chromatography (eluent: petroleum ether: ethyl acetate =4:1) to obtain tert-butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (8.21g, yield: 77% ). LCMS (ESI): m/z 357[M+1] ⁺ , pale yellow oil; TLC: Rf 0.2 (petroleum ether: ethyl acetate = 4:1).

Step 11b: tert-butyl (R)-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate ((tert-butyl(R )-3-((2-(dibenzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate) (compound 303)

Add tert-butyl (R)-3-((2-chloro-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (302) (8.27g, 23.2mmol, 1.0 eq), dibenzylamine (5.94 g, 30.2 mmol, 1.3 eq), triethylamine (3.52 g, 34.8 mmol, 1.5 eq) and acetonitrile (150 ml), heated to reflux overnight. The reaction solution was mixed with silica gel and spin-dried, and purified by column chromatography (eluent: petroleum ether: ethyl acetate = 4:1) to obtain tert-butyl (R)-3-((2-(dibenzylamino )-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (10.9 g, yield: 91%). LCMS (ESI): m/z 518[M+1] ⁺ , yellow oil; TLC: Rf 0.4 (petroleum ether: ethyl acetate = 4:1).

Step 11c: tert-butyl(R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate (tert-butyl(R)- Preparation of 3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate) (compound 304)

Add tert-butyl (R)-3-((2-(di Benzylamino)-3-nitropyridin-4-yl)amino)piperidine-1-carboxylate (303) (10.9g, 21.0mmol, 1.0eq), heated to 50°C for half an hour. The reaction solution was filtered with diatomaceous earth, the filtrate was spin-dried, dissolved in dichloromethane:methanol=10:1 (100ml), filtered, and the organic phase was spin-dried to obtain crude tert-butyl (R)-3-((3-amino- tert-butyl 2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate (11.0 g, yield: 100%). LCMS (ESI): m/z 488[M+1] ⁺ , pale yellow solid; TLC: Rf 0.1 (petroleum ether: ethyl acetate = 4:1).

Step 11d: tert-Butyl(R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl ) piperidine-1-carboxylate ((tert-butyl(R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1 -yl)piperidine-1-carboxylate) (compound 305) preparation

Add tert-butyl (R)-3-((3-amino-2-(dibenzylamino)pyridin-4-yl)amino)piperidine-1-carboxylate (304) (11.0g , 22.5mmol, 1.0eq), N,N'-carbonyldiimidazole (10.9g, 67.5mmol, 3.0eq) and tetrahydrofuran (150ml), the reaction solution was heated to reflux overnight. The reaction solution was mixed with silica gel and spin-dried, and purified by column chromatography (eluent: dichloromethane:methanol=100:1) to obtain tert-butyl (R)-3-(4-(dibenzylamino)- 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (9.88 g, yield: 85%). LCMS (ESI): m/z 514[M+1] ⁺ , pale yellow liquid; TLC: Rf 0.8 (dichloromethane:methanol=80:1).

Step 11e: tert-Butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1 -Carboxylate (tert-butyl(R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate ) (compound 306) preparation

Add tert-butyl (R)-3-(4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine-1 to the reaction flask -yl) piperidine-1-carboxylate (305) (9.88g, 19.22mmol, 1.0 equivalent), palladium hydroxide (2.0g), ethanol (120ml) and ethyl acetate (30ml), the reaction solution in hydrogen Heat to 60°C overnight. The reaction mixture was filtered with celite, the filtrate was spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol=20:1) to obtain tert-butyl (R)-3-(4-amino- 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (5.28 g, yield: 83%). LCMS (ESI): m/z 334[M+1] ⁺ , colorless solid; TLC: Rf 0.1 (dichloromethane:methanol=20:1).

Step 11f: tert-Butyl(R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5- c] pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (tert-butyl(R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro Preparation of -1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-11)

Add tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask -1-carboxylate (306) (3.0g, 9.0mmol, 1.0 equivalent), p-phenoxyphenylboronic acid (108-1) (2.89g, 13.5mmol, 1.5 equivalent), copper acetate (1.82g, 9.9mmol , 1.1 equivalents), molecular sieves (3.0 g), pyridine (2.13 g, 27 mmol, 3.0 equivalents) and N,N-dimethylformamide (30 ml), and the reaction solution was heated to 40° C. in air overnight. The reaction solution was diluted with ethyl acetate (200ml), washed with half-saturated brine (150ml×3), the organic phase was spin-dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol =50:1) to obtain tert-butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate (2.23 g, yield: 49%). LCMS (ESI): m/z 502[M+1] ⁺ , yellow oil; TLC: Rf 0.7 (dichloromethane:methanol=20:1).

Step 11g: (R)-4-Amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5- c] pyridin-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c] preparation of pyridin-2-one) (compound 308-11)

Add tert-butyl (R)-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4, 5-c]pyridin-1-yl)piperidine-1-carboxylate (307-11) (2.23g, 4.45mmol, 1.0eq), dichloromethane (10ml) and trifluoroacetic acid (2.0ml), react solution at room temperature overnight. The reaction solution was poured into saturated sodium carbonate solution (100ml), extracted with dichloromethane (100ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was subjected to column chromatography (eluent: dichloromethane: Methanol: triethylamine = 10:1:0.1) to obtain (R)-4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-yl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one (1.3 g, yield: 73%). LCMS (ESI): m/z 402[M+1] ⁺ , off-white solid; TLC: Rf 0.1 (dichloromethane:methanol=20:1).

Step 11h: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ 4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[ Preparation of 4,5-c]pyridin-2-one) (Compound 11)

Add (R)-4-amino-3-(4-phenoxyphenyl) dropwise to acryloyl chloride (202-4) (0.25g, 3.89mmol, 1.2eq) in dichloromethane solution (50ml) at 0°C )-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (308-11) (1.3g, 3.24mmol, 1.0eq ) in dichloromethane (30ml), then diisopropylethylamine (0.63g, 4.86mmol, 1.5eq) in dichloromethane (5ml) was added dropwise, and reacted at 0°C for 5 minutes. The reaction solution was poured into water (100ml), extracted with dichloromethane (100ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (dichloromethane:methanol=40:1) (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4, 5-c]pyridin-2-one (0.67g, yield: 45%). Colorless solid, melting point: 89.5-91.9°C. TLC: Rf 0.5 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 456[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.84 (d, J = 5Hz, 1H), 7.41 (m, 4H), 7.20 (t, J =7.5Hz,1H),7.13(m,4H),6.64(m,2H),6.33(d,J=16.5Hz,1H),5.72(s,1H),4.82(m,1H),4.34(s ,2H),4.10(m,2H),3.85(m,0.5H),3.48(m,0.5H),3.13(m,0.5H),2.62(m,1.5H),2.11(d,J=12.5 Hz, 1H), 1.98 (d, J=13.5Hz, 1H), 1.69 (m, 1H).

Example 12: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4–(4-chlorophenoxy)phenyl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl )-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 13)

Step 12a: tert-Butyl(R)-3-(4-amino-3-(4-(4-chloro-phenoxy)phenyl)-2-oxo-2,3-dihydro-1H- Imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-(4-chlorophenoxy)phenyl) -2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-13)

2-(4–(4-chloro-phenoxy)-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxoborane (108-13) (1.78 g, 5.39mmol, 1.5 equivalents) was dissolved in methanol (10ml) and concentrated hydrochloric acid (1ml) was added to stir the reaction for 1h, washed with water, extracted with dichloromethane, dried and filtered the mother liquor for later use, and tert-butyl (R)- 3-(4-Amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (306) (1.20g , 3.59mmol, 1eq), Cu(OAc) ₂ (1.30g, 7.18mmol, 2eq), _Et3N (0.73g, 7.18mmol, 2eq) and pyridine (0.57g, 7.18mmol, 2eq), React overnight at room temperature. The reaction solution was washed with water, extracted with dichloromethane, dried, concentrated, and column chromatography with ethyl acetate/n-hexane (3:1) to obtain light yellow oil tert-butyl (R)-3-(4-amino-3 -(4-(4-Chloro-phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1 -Carboxylate (0.77g, yield 40.00%). LCMS (ESI): m/z 536.50 [M+H] ⁺ .

Step 12b: (R)-4-Amino-3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-3-yl)-1,3-dihydro-2H-imidazo [4,5-c]pyridin-2-one ((R)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro- Preparation of 2H-imidazo[4,5-c]pyridin-2-one)(compound 308-13)

The tert-butyl (R)-3-(4-amino-3-(4-(4-chloro-phenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (307-13) (0.77g, 1.44mmol, 1 equiv) was dissolved in dichloromethane (5ml), TFA (2.5ml ), react at room temperature for 1h. The reaction solution was concentrated, neutralized with saturated sodium bicarbonate until slightly alkaline, extracted with 5ml of dichloromethane, dried, concentrated, methanol/dichloromethane/triethylamine (1:10:0.3) column chromatography to obtain off-white foam (R)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[ 4,5-c]pyridin-2-one (325 mg, yield 52.08%). LCMS (ESI): m/z 436.10 [M+H] ⁺ .

Step 12c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl) Preparation of -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 13)

Acryloyl chloride (202-4) (81mg, 0.90mmol, 1.2eq) was dissolved in dichloromethane (10ml), and (R)-4-amino-3-(4-(4-chloro Phenyloxy)phenyl)-1-(pyridin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (308-13) (325mg, 0.75 mmol, 1 eq) in dichloromethane (5 ml), and finally DIEA (116 mg, 0.90 mmol, 1.2 eq) in dichloromethane (5 ml) was added and reacted for 10 minutes. Add water (40ml) and stir, extract with dichloromethane (20ml), wash the organic phase once more with water (20ml), dry, concentrate, methanol/dichloromethane (1:20) and methanol/ethyl acetate (1:20) column Chromatography twice gave white solid (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-chlorophenoxy)phenyl)-1, 3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (66mg, yield 18%), content 100%, melting point: 90-92℃; LCMS (ESI): m/z 490.05 [M+H] ⁺ ; ¹ HNMR (400MHz, CDCl ₃ ): δ2.03(d, J=30.0Hz, 1.5H), 2.10(d, J=23.7Hz, 1H), 2.60(m, 1.5H) , 3.13(s, 0.5H), 3.46(s, 1H), 3.86(d, J=37.0Hz, 0.5H), 4.10(s, 4H), 4.81(d, J=30.0Hz, 1H), 5.34( t,J=11.0Hz,0.5H), 5.73(d,J=21.6Hz,1H), 6.32(d,J=40Hz,1H), 6.63(d,J=12.6Hz,2H), 7.03(d, J=22.1Hz, 2H), 7.11(d, J=22.1Hz, 2H), 7.35(d, J=22.1Hz, 2H), 7.41(d, J=21.9Hz, 2H), 7.87(d, J= 14.0Hz,1H)

Example 13: (R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-amino-2-oxo-1,2-dihydro-3H-imidazo[ 4,5-c]pyridin-3-yl)phenoxy)benzonitrile ((R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-amino-2-oxo-1 , 2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)phenoxy)benzonitrole) (compound 15) preparation

Step 13a: tert-butyl(R)-3-(4-amino3-(4-(4-cyanophenoxy))-2oxo-2,3-dihydro-1H-imidazo[4, 5-c]pyridin-1-yl)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-(4-cyanophenoxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-15)

Add tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask -1-carboxylate (306) (1.0g, 3.0mmol, 1.0eq), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane Alk-2-yl)phenoxy)benzonitrile (108-15) (1.25g, 3.9mmol, 1.3eq), copper acetate (0.60g, 3.3mmol, 1.1eq), molecular sieves (1.0g), pyridine (0.71 g, 9.0mmol, 3.0eq) and N,N-dimethylformamide (15ml), the reaction solution was heated to 40°C in air overnight. The reaction solution was diluted with ethyl acetate (200ml), washed with half-saturated brine (100ml×3), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol =50:1) to obtain tert-butyl (R)-3-(4-amino 3-(4-(4-cyanophenoxy))-2 oxo-2,3-dihydro-1H-imidazo [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.36 g, yield: 23%). LCMS (ESI): m/z 527[M+1] ⁺ , light green oil; TLC: Rf 0.6 (dichloromethane:methanol=20:1).

Step 13b: (R)-4-(4-(4-Amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine-3(2H) -yl)phenoxy)benzonitrile ((R)-4-(4-(4-amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin- Preparation of 3(2H)-yl)phenoxy)benzonitrile) (compound 308-15)

Add tert-butyl (R)-3-(4-amino3-(4-(4-cyanophenoxy))-2oxo-2,3-dihydro-1H-imidazo[ 4,5-c]pyridin-1-yl)piperidine-1-carboxylate (307-15) (0.36g, 0.68mmol, 1.0 equiv), dichloromethane (10ml) and trifluoroacetic acid (2.0ml) , react overnight at room temperature. The reaction solution was poured into saturated sodium carbonate solution (100ml), extracted with dichloromethane (50ml×3), the organic phase was mixed with silica gel and spin-dried, and the concentrate was subjected to column chromatography (eluent: dichloromethane: Methanol: triethylamine = 10:1:0.1) purification to obtain (R)-4-(4-(4-amino-2-oxo-1-(piperidin-3-yl)-1H-imidazo[4 ,5-c]pyridin-3(2H)-yl)phenoxy)benzonitrile (0.122 g, yield: 42%). LCMS (ESI): m/z 427[M+1] ⁺ , colorless solid; TLC: Rf 0.1 (dichloromethane:methanol=20:1).

Step 13c: (R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-amino-2-oxo-1,2-dihydro-3H-imidazo[4 ,5-c]pyridin-3-yl)phenoxy)benzonitrile ((R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-amino-2-oxo-1, Preparation of 2-dihydro-3H-imidazo[4,5-c]pyridin-3-yl)phenoxy)benzonitrole) (compound 15)

Add (R)-4-(4-(4-amino-2-oxo -1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-3(2H)-yl)phenoxy)benzonitrile (308-15) (0.122g, 0.29mmol, 1.0 eq) in dichloromethane (7ml), then diisopropylethylamine (0.056g, 0.44mmol, 1.5 eq) in dichloromethane (1ml) was added dropwise, and reacted at 0°C for 5 minutes. The reaction solution was poured into water (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol= 40:1) to get (R)-4-(4-(1-(1-acryloylpiperidin-3-yl)-4-amino-2-oxo-1,2-dihydro-3H-imidazo [4,5-c]pyridin-3-yl)phenoxy)benzonitrile (0.052 g, yield: 38%). White solid, melting point: 116.1-118.7°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 481[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.89 (d, J=5Hz, 1H), 7.67 (d, J=8.5Hz, 2H), 7.49(d, J=8.5Hz, 2H), 7.22(d, J=8.5Hz, 2H), 7.12(d, J=8.5Hz, 2H), 6.66(m, 2H), 6.34(d, J=16.5 Hz,1H),5.72(s,1H),4.82(m,1H),4.16(m,4H),3.85(m,0.5H),3.48(m,0.5H),3.12(m,0.5H), 2.60(m,1.5H),2.12(m,1H),1.99(m,1H),1.65(m,1H).

Example 14: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-phenylpyridin-3-yl)-1,3-dihydro-2H- Imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloyl piperidine-3-yl)-4-amino-3-(6-phenyl pyridin-3-yl)-1 , Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 16)

Step 13a: tert-Butyl(R)-3-(4-amino-2-oxo-3-(6-phenoxypyridin-3-yl)-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate ((tert-butyl(R)-3-(4-amino-2-oxo-3-(6-phenoxypyridin-3-yl) -2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-16)

Add tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask -1-carboxylate (306) (0.666g, 2.0mmol, 1.0eq), 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopentane-2-yl)pyridine (108-16) (0.891g, 3.0mmol, 1.5 equivalents), copper acetate (0.400g, 2.2mmol, 1.1 equivalents), molecular sieves (0.500g), pyridine (0.474g, 6.0mmol, 3.0eq) and N,N-dimethylformamide (8ml), the reaction solution was heated to 40°C in air overnight. The reaction solution was diluted with ethyl acetate (100ml), washed with half-saturated brine (100ml×3), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol =60:1) to obtain tert-butyl (R)-3-(4-amino-2-oxo-3-(6-phenoxypyridin-3-yl)-2,3-dihydro-1H-imidazole [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.520 g, yield: 52%). LCMS (ESI): m/z 503 [M+1] ⁺ , yellow oil; TLC: Rf 0.7 (dichloromethane:methanol=20:1).

Step 13b: (R)-4-Amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one ((R)-4-amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (compound 308-16)

Add tert-butyl (R)-3-(4-amino-2-oxo-3-(6-phenoxypyridin-3-yl)-2,3-dihydro-1H-imidazo to the reaction flask [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.52g, 1.0mmol, 1.0 equivalent), dichloromethane (10ml) and trifluoroacetic acid (2.0ml), reaction solution room temperature overnight. The reaction solution was poured into saturated sodium carbonate solution (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was subjected to column chromatography (eluent: dichloromethane: Methanol: triethylamine=10:1:0.1) to obtain (R)-4-amino-3-(6-phenoxypyridin-3-yl)-1-(piperidin-3-yl)-1, 3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.215 g, yield: 53%). LCMS (ESI): m/z 403[M+1] ⁺ , off-white solid; TLC: Rf 0.1 (dichloromethane:methanol=20:1).

Step 13c: (R)-1-(1-Acryloylpiperidin-3-yl)-4-amino-3-(6-phenylpyridin-3-yl)-1,3-dihydro-2H-imidazole And[4,5-c]pyridin-2-one ((R)-1-(1-acryloyl piperidine-3-yl)-4-amino-3-(6-phenyl pyridin-3-yl)-1, Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 16)

Add dropwise (R)-4-amino-3-(6-phenoxypyridine- 3-yl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (308-16) (0.215g, 0.54mmol , 1.0 equivalents) in dichloromethane (7ml), then diisopropylethylamine (0.104g, 0.81mmol, 1.5 equivalents) in dichloromethane (1ml) was added dropwise, and reacted for 5 minutes at 0°C . The reaction solution was poured into water (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol= 30:1) to get (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-phenylpyridin-3-yl)-1,3-dihydro-2H - Imidazo[4,5-c]pyridin-2-one (0.083 g, yield: 34%). Colorless solid, melting point: 107.9-109.9°C. TLC: Rf0.7 (dichloromethane:methanol=20:1). LCMS(ESI): m/z 457[M+1] ⁺ , ¹ HNMR(CDCl ₃ , 500MHz): δ8.29(s, 1H), 7.89(d, 1H), 7.78(t, J=6Hz, 2H ), 7.42(m, 2H), 7.24(m, 1H), 7.18(d, J=7.5Hz, 2H), 7.05(d, J=9Hz, 1H), 6.65(m, 1H), 6.57(m, 1H), 6.30(m, 1H), 5.71(m, 1H), 4.82(m, 1H), 4.02(m, 4H), 3.85(m, 0.5H), 3.44(m, 0.5H), 3.13( m, 0.5H), 2.57(m, 1.5H), 2.11(m, 1H), 1.98(m, 1H), 1.63(m, 1H).

Example 15: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)- 1,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-( Preparation of benzo[d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 17)

Step 15a: tert-Butyl(R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c] Pyridine)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5 -c] preparation of pyridin-1-yl) piperidine-1-carboxylate) (compound 402-17)

tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxy Acid ester (306) (2.5g, 7.50mmol, 1.0 equivalent), p-iodophenylboronic acid (401-17) (2.14g, 8.62mmol, 1.3 equivalent) and pyridine (1.78g, 22.5mmol, 3.0 equivalent) were dissolved in N , N-dimethylformamide (20mL), copper acetate (1.50g, 8.25mmol, 1.1eq) and 4A molecular sieves (3.0g) were added, and reacted overnight at 50°C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with half-saturated brine (50 mL×4). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by column chromatography (eluent: dichloromethane:methanol=50:1) to obtain tert-butyl (R)-3-(4-amino -3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine-1-carboxylate (1.6g, yield : 40%). Brown solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 536[M+1] ⁺ .

Step 15b: tert-Butyl(R)-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2,3-dihydro -1H-imidazo[4,5-c]pyridine)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-(benzo[d][1, 3]dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-17) preparation

tert-butyl (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine) Piperidine-1-carboxylate (402-17) (0.8g, 1.49mmol, 1.0eq), sesamol (403-17) (0.31g, 2.24mmol, 1.5eq) and N,N-dimethylglycine Hydrochloride (39mg, 0.28mmol, 0.18eq) was dissolved in dioxane (8mL), then cuprous iodide (14.2mg, 0.075mmol, 0.05eq) and cesium carbonate (0.97g, 2.98mmol, 2.0 equivalent), and then reacted at 100° C. for 24 hours in nitrogen protection. The reaction solution was cooled to room temperature and concentrated, and the obtained crude product was purified by column chromatography (eluent: dichloromethane:methanol=40:1 to 20:1) to obtain tert-butyl (R)-3-(4- Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piper Pyridine-1-carboxylate (0.35 g, yield: 44%). Gray solid; TLC: Rf0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 546[M+1] ⁺ .

Step 15c: (R)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4 ,5-c]pyridin-2(3H)-one((R)-4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(piperidin Preparation of -3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one)(compound 308-17)

tert-Butyl (R)-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl) 2-oxo-2,3-dihydro-1H -imidazo[4,5-c]pyridine)piperidine-1-carboxylate (307-17) (0.35g, 0.64mmol, 1.0eq) was dissolved in dichloromethane (10mL), and tris Fluoroacetic acid (2 mL), then reacted at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50mL), washed successively with saturated sodium carbonate solution (30mL×2) and saturated brine (60mL), and then the organic layer was spin-dried with silica gel, followed by column chromatography (Eluent: dichloromethane: methanol: triethylamine = 100:10:1) to obtain (R)-4-amino-3-(4-(3,4-methylenedioxyphenoxy) Phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.26 g, yield: 91%). Gray solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1); LCMS (ESI): m/z 446[M+1] ⁺ .

Step 15d: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1 ,3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzo Preparation of [d][1,3]dioxol-5-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 17)

Acryloyl chloride (202-4) (0.057mL, 0.7mmol, 1.2eq) was dissolved in dichloromethane (5mL), cooled to 0°C, and (R)-4-amino-3- (4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (308-17) (0.26g, 0.584mmol, 1.0eq) in dichloromethane (5mL) followed by dropwise addition of N,N-diisopropylethylamine (0.156mL, 0.876mmol, 1.5eq) dichloromethane (1.0 mL) solution, and the mixture was reacted at 0°C for 10 minutes. The reaction solution was quenched with water (50 mL), and then extracted with dichloromethane (50 mL×2). The obtained organic layer was spin-dried with silica gel, and then purified by column chromatography (eluent: dichloromethane:methanol=50:1) to obtain compound (R)-1-(1-acryloylpiperidine- 3-yl)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c] Pyridin-2-one (0.170 g, yield: 58%). White solid, melting point: 194.5-195.6°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 500[M+1] ⁺ , purity: 97.054%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.86( d,J=5.5Hz,1H),7.37(d,J=8.5Hz,2H),7.08(d,J=9.0Hz,2H),6.80(d,J=8.5Hz,1H),6.64-6.55( m,4H),6.34-6.30(m,1H),6.00(s,2H),5.78-5.65(m,1H),4.82-4.78(m,1H),4.25-3.80(m,5H),3.17- 2.45 (m, 2H), 2.15-1.94 (m, 2H), 1.82-1.75 (m, 1H).

Example 16: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl) -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 18)

Step 16a: tert-Butyl(R)-3-(4-amino-3-(4-(4-benzyloxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H- Imidazo[4,5-c]pyridine)piperidine-1-carboxylate ((R)-tert-butyl 3-(4-amino-3-(4-(4-(benzyloxy)phenoxy)phenyl)- Preparation of 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-18)

tert-butyl (R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine) Piperidine-1-carboxylate (402-17) (0.7g, 1.31mmol, 1.0 equivalent), 4-benzyloxyphenol (403-18) (0.39g, 1.96mmol, 1.5 equivalent) and N,N- Dimethylglycine hydrochloride (34mg, 0.24mmol, 0.18eq) was dissolved in dioxane (10mL), then cuprous iodide (12.5mg, 0.066mmol, 0.05eq) and cesium carbonate (0.85g, 2.62mmol, 2.0 equivalents), and then reacted at 100°C for 20 hours under the protection of nitrogen. The reaction solution was cooled to room temperature and concentrated, and the obtained crude product was purified by column chromatography (eluent: dichloromethane:methanol=40:1 to 20:1) to obtain tert-butyl (R)-3-(4- Amino-3-(4-(4-benzyloxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine-1 -Carboxylate (0.4 g, yield: 50%). Pale yellow solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 608[M+1] ⁺ .

Step 16b: (R)-4-Amino-3-(4-(4-benzyloxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c ]pyridin-2(3H)-one ((R)-4-amino-3-(4-(4-(benzyloxy)phenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4, Preparation of 5-c]pyridin-2(3H)-one)(compound 308-18)

tert-Butyl (R)-3-(4-amino-3-(4-(4-benzyloxyphenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo [4,5-c]pyridine) piperidine-1-carboxylate (307-18) (0.40 g, 0.658 mmol, 1.0 equiv) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid ( 2 mL), and reacted at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50mL), washed successively with saturated sodium carbonate solution (30mL×2) and saturated brine (60mL), and then the organic layer was spin-dried with silica gel, followed by column chromatography (Eluent: dichloromethane: methanol: triethylamine = 100:10:1) to obtain (R)-4-amino-3-(4-(4-benzyloxyphenoxy)phenyl)- 1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.305 g, yield: 91%). Gray solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1); LCMS (ESI): m/z 508[M+1] ⁺ .

Step 16c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)- Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 18)

(R)-4-amino-3-(4-(4-benzyloxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridine -2(3H)-ketone (308-18) (0.305g, 0.6mmol, 1.0 equivalent) was dissolved in ethanol (10mL), and palladium/carbon (100mg) was added thereto, and then the React overnight. The reaction solution was cooled to room temperature and filtered, the filtrate was collected and concentrated to obtain a crude product, which was purified by column chromatography (eluent: dichloromethane: methanol = 10:1) to obtain (R)-4-amino-3-(4- (4-hydroxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.22g, yield: 88% ). Gray solid; TLC: Rf 0.2 (dichloromethane:methanol=8:1); LCMS (ESI): m/z 418[M+1] ⁺ . The (R)-4-amino-3-(4-(4-hydroxyphenoxy)phenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c] obtained above Pyridin-2(3H)-one (0.2g, 0.48mmol, 1.0eq), acrylic acid (201-18) (38mg, 0.53mmol, 1.1eq), DCC (119mg, 0.58mmol, 1.2eq) and DMAP (6mg, 0.048mmol, 0.1eq) was dissolved in dichloromethane (10mL), and reacted at 0°C for 1 hour. After the reaction was completed, the crude product was concentrated and purified by column chromatography (eluent: dichloromethane: methanol = 40:1) to obtain the compound (R)-1-(1-acryloylpiperidin-3-yl)- 4-Amino-3-(4-(4-hydroxyphenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (83mg, yield: 37%). White solid, melting point: 196.3-198.2°C. TLC: Rf0.4 (dichloromethane: methanol = 20:1); LCMS (ESI): m/z 471[M+1] ⁺ , purity: 96.893%; ¹ HNMR (CDCl ₃ , 500MHz): δ7.86 (d, J=5.0Hz, 1H), 7.35(d, J=8.5Hz, 2H), 7.03(d, J=9.0Hz, 2H), 6.94(d, J=8.5Hz, 2H), 6.81(d ,J=8.5Hz,2H),6.66-6.59(m,2H),6.34(d,J=15Hz,1H),5.75-5.73(m,1H),4.83-4.78(m,1H),4.19(s ,2H), 4.13-4.07(m,2H), 3.85-3.47(m,1H), 3.14-2.59(m,2H), 2.12-1.96(m,3H).

Example 17: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl )-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 19)

Step 17a: tert-Butyl(R)-3-(4-amino3-(4-hydroxyphenyl)-2oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine- 1-yl)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 502-19) preparation

Add tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask -1-carboxylate (306) (3.0g, 9.0mmol, 1.0 equivalent), 4-hydroxyphenylboronic acid (501-19) (1.62g, 11.7mmol, 1.3 equivalent), copper acetate (1.820g, 10mmol, 1.1 Equiv), molecular sieves (3.0g), pyridine (2.13g, 27.0mmol, 3.0eq) and N,N-dimethylformamide (30ml), the reaction solution was heated to 40°C in air overnight. The reaction solution was diluted with ethyl acetate (200ml), washed with half-saturated brine (200ml×3), the organic phase was spin-dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol =20:1) to get tert-butyl (R)-3-(4-amino3-(4-hydroxyphenyl)-2oxo-2,3-dihydro-1H-imidazo[4,5-c ]pyridin-1-yl)piperidine-1-carboxylate (0.240 g, yield: 6%). LCMS (ESI): m/z 426[M+1] ⁺ , yellow oil; TLC: Rf 0.35 (dichloromethane:methanol=20:1).

Step 17b: tert-Butyl(R)-3-(4-amino-3-(4-(4-nitrophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazole And[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (tert-butyl(R)3-(4-amino-3-(4-(4-nitrophenoxy)phenyl)- Preparation of 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-19)

Add to the reaction flask to obtain tert-butyl (R)-3-(4-amino3-(4-hydroxyphenyl)-2oxo-2,3-dihydro-1H-imidazo[4,5-c ]pyridin-1-yl)piperidine-1-carboxylate (502-19) (0.240g, 0.56mmol, 1.0 equivalent), p-fluoronitrobenzene (503-19) (0.088g, 0.62mmol, 1.1 equivalent ), potassium carbonate (0.116g, 0.84mmol, 1.5eq) and acetonitrile (15ml), the reaction solution was heated to reflux overnight. The reaction solution was spin-dried with silica gel, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol=40:1) to obtain tert-butyl (R)-3-(4-amino-3- (4-(4-nitrophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidin-1 -Carboxylate (0.270 g, yield: 89%). LCMS (ESI): m/z 547[M+1] ⁺ , yellow oil; TLC: Rf 0.5 (dichloromethane:methanol=20:1).

Step 17c: (R)-4-Amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c ]pyridin-2(3H)-one((R)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c Preparation of ]pyridin-2(3H)-one) (compound 308-19))

Add tert-butyl (R)-3-(4-amino-3-(4-(4-nitrophenoxy)phenyl)-2-oxo-2,3-dihydro-1H to the reaction flask -imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (307-19) (0.27g, 0.5mmol, 1.0eq), dichloromethane (10ml) and trifluoro Acetic acid (2.0ml) was reacted at room temperature for half an hour. The reaction solution was poured into saturated sodium carbonate solution (100ml), extracted with dichloromethane (50ml×3), the organic phase was mixed with silica gel and spin-dried, and the concentrate was subjected to column chromatography (eluent: dichloromethane: Methanol: triethylamine=10:1:0.1) purification to obtain (R)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1-(piperidin-3-yl) -1H-imidazo[4,5-c]pyridin-2(3H)-one (0.220 g, yield: 99%). LCMS (ESI): m/z 447[M+1] ⁺ , colorless solid; TLC: Rf 0.1 (dichloromethane:methanol=20:1).

Step 17d: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl) Preparation of -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 19)

Add dropwise (R)-4-amino-3-(4-(4-nitro Phenoxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (308-19) (0.220g, 0.50mmol, 1.0 equiv) in dichloromethane (7 ml), then diisopropylethylamine (0.097 g, 0.75 mmol, 1.5 equiv) in dichloromethane (1 ml) was added dropwise, and reacted at 0° C. for 5 minutes. The reaction solution was poured into water (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol= 30:1) to get (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-nitrophenoxy)phenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.170 g, yield: 68%). Yellow solid, melting point: 92.6-98.6°C. TLC: Rf 0.5 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 501[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ8.27 (d, J=9Hz, 2H), 7.89 (s, 1H), 7.52 (d, J =8.5Hz, 2H), 7.25(d, J=9Hz, 2H), 7.14(d, J=9Hz, 2H), 6.67(m, 2H), 6.34(d, J=17Hz, 1H), 5.74(d ,J＝7.5Hz,1H),4.83(m,1H),4.22(m,4H),3.86(m,0.5H),3.48(m,0.5H),3.13(m,0.5H),2.62(m , 1.5H), 2.12(d, J=12Hz, 1H), 1.99(d, J=13Hz, 1H), 1.66(m, 1H).

Example 18: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3-dihydro-2H -imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3 Preparation of -dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 24)

Step 18a: tert-Butyl(R)-3-(4-amino-3-(4-(benzyloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate ((tert-butyl(R)-3-(4-amino-3-(4-(benzyloxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 602-24)

tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxy Ester (306) (500mg, 1.5mmol, 1 equivalent) was dissolved in dichloromethane (5ml), and 4A molecular sieves (1g), copper acetate (408mg, 2.25mmol, 1.5 equivalents), benzyloxyphenylboronic acid (601 -24) (410mg, 1.8mmol, 1.2eq), pyridine (178mg, 2.25mmol, 1.5eq), Et ₃ N (227mg, 2.25mmol, 1.5eq), stirred at room temperature for 24 hours. After completion of the reaction, filter, wash the mother liquor twice with water, dry, concentrate, methanol/dichloromethane (1:40) column chromatography to obtain a yellow-brown solid tert-butyl (R)-3-(4-amino-3-(4- (Benzyloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (350mg, Yield 45.3%). LCMS (ESI): m/z 516.40 [M+1] ⁺ .

Step 18b: (R)-4-Amino-3-(4-(benzyloxy)phenyl)-1-[piperidin-3-yl]-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one((R)-4-amino-3-(4-(benzyloxy)phenyl)-1-[(piperidin-3-yl]-1,3-dihydro-imidazo[4 ,5-c]pyridin-2-one) (compound 603-24) preparation

tert-butyl(R)-3-(4-amino-3-(4-(benzyloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- c] Pyridin-1-yl)piperidine-1-carboxylate (602-24) (350mg, 0.68mmol, 1 equivalent) was dissolved in dichloromethane (1ml), TFA (2ml) was added, and reacted at room temperature for 1h. The reaction solution was concentrated, neutralized with saturated sodium bicarbonate until slightly alkaline, extracted with 5ml of dichloromethane, dried, concentrated, methanol/dichloromethane/triethylamine (1:10:0.3) column chromatography to obtain off-white foam (R)-4-amino-3-(4-(benzyloxy)phenyl)-1-[piperidin-3-yl]-1,3-dihydro-2H-imidazo[4, 5-c] Pyridin-2-one (90 mg, yield 32%). LCMS (ESI): m/z 416.40 [M+1] ⁺ .

Step 18c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3-dihydro-2H- imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyl)oxy)phenyl)-1, Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 24)

Acryloyl chloride (202-4) (24mg, 0.26mmol, 1.2eq) was dissolved in dichloromethane (4ml), and (R)-4-amino-3-(4-(benzyloxy)benzene was added under ice-cooling Base)-1-[piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (603-24) (90mg, 0.217mmol, 1 equivalent ) in dichloromethane (4ml), and finally a solution of DIEA (34mg, 0.26mmol, 1.2 eq) in dichloromethane (2ml) was added and reacted for 10 minutes. Add water (5ml) and stir, extract with dichloromethane (2ml), wash the organic phase once more with water (10ml), dry, concentrate, methanol/ethyl acetate (1:10) column chromatography to give white solid (R)-1- (1-acryloylpiperidin-3-yl)-4-amino-3-(4-(benzyloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c] Pyridin-2-one (19.4 mg, 19% yield). Melting point: 75-76°C; LCMS (ESI): m/z 470.50[M+1] ⁺ ; ¹ HNMR (600MHz, CDCl ₃ ): δ1.27 (s, 1.5H), 2.02 (m, 1.5H), 2.12(s, 1H), 2.51(d, J=10.74Hz, 0.5H), 2.63(dd, J=26.34, 11.88Hz, 1H), 3.14(t, J=11.94Hz, 0.5H), 3.49(t , J=11.46Hz, 0.5H), 3.86(t, J=10.86Hz, 0.5H), 4.08(t, J=28.56Hz, 3.5H), 4.22(s, 0.5H), 4.84(dd, J= 34.98, 10.68Hz, 1H), 5.14(s, 2H), 5.74(d, J=9.96Hz, 1H), 6.34(t, J=15.9Hz, 1H,), 6.65(m, 2H), 7.14(d , J=8.64Hz, 2H,), 7.38(t, J=8.64Hz, 3H), 7.43(q, J=7.32Hz, 2H), 7.46(d, J=7.32Hz, 2H), 7.87(s, 1H).

Example 19: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1,3 -Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4- Preparation of chlorobenzyl)oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 26)

Step 19a: tert-Butyl(R)-3-(4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-2-oxo-2,3-dihydro-1H -imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (tert-butyl(R)-3-(4-amino-3-(4-((4-chlorobenzyl) Preparation of oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 602-26)

Add tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask -1-carboxylate (306) (0.423g, 1.27mmol, 1.0 equivalent), (4-((4-chlorobenzyl)oxy)phenyl)boronic acid (601-26) (0.433g, 1.65mmol, 1.3 equivalents), copper acetate (0.254g, 1.40mmol, 1.1 equivalents), molecular sieves (0.400g), pyridine (0.301g, 3.81mmol, 3.0 equivalents) and N,N-dimethylformamide (10ml), reaction solution Heat to 40°C overnight in air. The reaction solution was diluted with ethyl acetate (100ml), washed with half-saturated brine (100ml×3), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol =60:1) to obtain tert-butyl (R)-3-(4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-2-oxo-2,3-di Hydrogen-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.200 g, yield: 29%). LCMS (ESI): m/z 551[M+1] ⁺ , yellow oil; TLC: Rf 0.7 (dichloromethane:methanol=20:1).

Step 19b: (R)-4-Amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5 -c]pyridin-2(3H)-one ((R)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[ Preparation of 4,5-c]pyridin-2(3H)-one)(compound 603-26)

Add tert-butyl (R)-3-(4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-2-oxo-2,3-dihydro to the reaction flask -1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (602-26) (0.20g, 1.0mmol, 1.0eq), dichloromethane (10ml) and tris Fluoroacetic acid (2.0ml), react at room temperature for half an hour. The reaction solution was poured into saturated sodium carbonate solution (100ml), extracted with dichloromethane (80ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was subjected to column chromatography (eluent: dichloromethane: Methanol: triethylamine=10:1:0.1) to obtain (R)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1-(piperidine-3- yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.145 g, yield: 90%). LCMS (ESI): m/z 451[M+1] ⁺ , pale yellow solid; TLC: Rf0.1 (dichloromethane:methanol=20:1).

Step 19c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-chlorobenzyl )oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 26)

Add dropwise (R)-4-amino-3-(4-((4-chloro Benzyl)oxy)phenyl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (603-26) (0.145g, 0.32 mmol, 1.0 equivalents) in dichloromethane (8ml), then diisopropylethylamine (0.062g, 0.48mmol, 1.5 equivalents) in dichloromethane (1ml) was added dropwise, and reacted at 0°C for 5 minute. The reaction solution was poured into water (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane:methanol= 40:1) to obtain (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-chlorobenzyl)oxy)phenyl)-1, 3-Dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.100 g, yield: 62%). Colorless solid, melting point: 93.1-95.9°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 504[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.83 (d, J = 5Hz, 1H), 7.37 (m, 6H), 7.09 (d, J = 8.5Hz,1H),6.62(m,2H),6.32(m,1H),5.71(m,1H),5.08(s,2H),4.80(m,1H),4.22(s,2H),4.09( m,2H),3.84(m,0.5H),3.45(m,0.5H),3.12(m,0.5),2.60(m,1.5H),2.19(m,2H),2.09(m,1H), 1.97(m,1H).

Example 20: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3-yl)-1,3-dihydro -2H-imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3- Preparation of yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 27)

Step 20a: tert-Butyl(R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridin-3-yl)-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl)piperidine-1-carboxylate ((tert-butyl(R)-3-(4-amino-3-(6-(benzyloxy)pyridin-3-yl)- Preparation of 2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate)(602-27)

Add tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask -1-carboxylate (306) (0.999g, 3.0mmol, 1.0eq), 2-benzyloxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Heterocyclopentane-2-yl)pyridine (601-27) (1.400g, 4.5mmol, 1.5 equivalents), copper acetate (0.820g, 4.5mmol, 1.5 equivalents), molecular sieves (0.500g), pyridine (0.710g, 9.0mmol, 3.0eq) and N,N-dimethylformamide (10ml), the reaction solution was heated to 40°C overnight in air. The reaction solution was diluted with ethyl acetate (100ml), washed with half-saturated brine (100ml×3), the organic phase was mixed with silica gel and spin-dried, and the concentrate was purified by column chromatography (eluent: dichloromethane: methanol =60:1) to obtain tert-butyl (R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridin-3-yl)-2,3-dihydro-1H-imidazole [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.410 g, yield: 52%). LCMS (ESI): m/z 517[M+1] ⁺ , yellow oil; TLC: Rf 0.7 (dichloromethane:methanol=20:1).

Step 20b: (R)-4-Amino-3-(6-benzyloxypyridin-3-yl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridine- 2(3H)-keto((R)-4-amino-3-(6-(benzyloxy)pyridin-3-yl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c] Preparation of pyridin-2(3H)-one)(603-27)

Add tert-butyl (R)-3-(4-amino-2-oxo-3-(6-benzyloxypyridin-3-yl)-2,3-dihydro-1H-imidazo to the reaction flask [4,5-c]pyridin-1-yl)piperidine-1-carboxylate (602-27) (0.41g, 1.0mmol, 1.0eq), dichloromethane (10ml) and trifluoroacetic acid (2.0ml ), react at room temperature for half an hour. The reaction solution was poured into saturated sodium carbonate solution (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the concentrate was subjected to column chromatography (eluent: dichloromethane: Methanol: triethylamine=10:1:0.1) to obtain (R)-4-amino-3-(6-benzyloxypyridin-3-yl)-1-(piperidin-3-yl)-1H- Imidazo[4,5-c]pyridin-2(3H)-one (0.220 g, yield: 66%). LCMS (ESI): m/z 417[M+1] ⁺ , pale yellow solid; TLC: Rf 0.1 (dichloromethane:methanol=20:1).

Step 20c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3-yl)-1,3-dihydro- 2H-imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3-yl )-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 27)

Add dropwise (R)-4-amino-3-(6-benzyloxypyridine- 3-yl)-1-(piperidin-3-yl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (603-27) (0.220g, 0.53mmol, 1.0eq) dichloromethane solution (7ml), and diisopropylethylamine (0.102g, 0.80mmol, 1.5eq) dichloromethane solution (1ml) was added dropwise, and reacted at 0°C for 5 minutes. The reaction solution was poured into water (100ml), extracted with dichloromethane (50ml×2), the organic phase was mixed with silica gel and spin-dried, and the residue was purified by column chromatography (eluent: dichloromethane:methanol= 30:1) to obtain (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(6-(benzyloxy)pyridin-3-yl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one (0.135 g, yield: 54%). Colorless solid, melting point: 107.3-109.2°C. TLC: Rf 0.5 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 471[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ8.29 (d, J=3Hz, 1H), 7.89 (d, J=5.5Hz, 1H), 7.68(q, 2H), 7.48(d, J=7Hz, 2H), 7.40(t, J=7Hz, 2H), 7.35(m, 1H), 6.96(d, J=8.5Hz, 1H), 6.60( m, 2H), 6.30(m, 1H), 5.71(m, 1H), 5.44(s, 2H), 4.82(m, 1H), 4.0-4.19(m, 4H), 3.84(m, 0.5H) , 3.45(m, 0.5H), 3.13(m, 0.5H), 2.58(m, 1.5H), 2.11(m, 1H), 1.98(m, 1H), 1.65(m, 1H).

Example 21: 1-((R)-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[3 ,2-c]pyridin-2(3H)-one(1-((R)-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo Preparation of [3,2-c]pyridin-2(3H)-one)(compound 12)

Step 21a: 2-(4-(4-fluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2-(4 -(4-fluorophenoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) (compound 108-12)

1-Bromo-4-(4-fluoro-phenoxy)benzene (2.00g, 7.54mmol, 1.0eq), biboronic acid pinacol ester (5.84g, 15.1mmol, 2.0eq), potassium acetate (1.48g , 15.1mmol, 2.0eq) and Pd(dppf)Cl ₂ (0.54g, 0.754mmol, 0.1eq) were protected with nitrogen, then dioxane (20ml) was added and reacted overnight at 90°C. The reaction solution was cooled and washed with water, extracted with dichloromethane, dried and concentrated, and column chromatography (eluent: dichloromethane: n-hexane=1:2) gave 2-(4-(4-fluoro-phenoxy)- Phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.10g, yield 46.5%), off-white solid, TLC: Rf 0.6 (dichloromethane: n-hexane=1:2)

Step 21b: ((3R)-tert-Butyl-3-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H- Pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate ((3R)-tert-butyl 3-(4-amino-3-(4-(4-fluorophenoxy)phenyl) -2-oxo-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-12)

Add tert-butyl (R)-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine to the reaction flask -1-carboxylate (306) (3.0g, 9.0mmol, 1.0eq), 2-(4-(4-fluoro-phenoxy)-phenyl]-4,4,5,5-tetramethyl – 1,3,2-dioxaborolane (108-12) (0.85g, 2.5mmol, 1.00eq), copper acetate (0.98g, 5mmol, 2eq), triethylamine (0.5g, 5mmol, 2.00 equivalent), pyridine (0.40g, 5mmol, 2.00 equivalents) and N,N-dimethylformamide (10ml), and the reaction solution was heated to 40°C in air overnight. The reaction solution was diluted with ethyl acetate (200ml) and washed with Washed with half-saturated brine (150ml×3), the organic phase was mixed with silica gel and spin-dried, and the residue was purified by column chromatography (eluent: ethyl acetate:cyclohexane=2:1) to obtain tert-butyl ( (3R)-tert-butyl-3-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-2-oxo-2,3-dihydro-1H-pyrrolo[3 ,2-c]pyridin-1-yl)piperidine-1-carboxylate (0.19g, yield: 14%). LCMS (ESI): m/z 519[M+1] ⁺ , yellow oil; TLC: Rf0.57 (ethyl acetate:cyclohexane=2:1).

Step 21c: 4-Amino-3-(4-(4-fluorophenoxy)phenyl)-1-((R)-piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridine -2(3H)-keto(4-amino-3-(4-(4-fluorophenoxy)phenyl)-1-((R)-piperidin-3-yl)-1H-pyrrolo[3,2-c]pyridin -2(3H)-one) (compound 308-12) preparation

Add tert-butyl ((3R)-tert-butyl-3-(4-amino-3-(4-(4-fluorophenoxy)phenyl)-2-oxo-2,3- Dihydro-1H-pyrrolo[3,2-c]pyridin-1-yl)piperidine-1-carboxylate (307-12) (0.19g, 0.36mmol, 1.0 equivalent), dichloromethane (5ml) and trifluoroacetic acid (1.0ml), the reaction solution was overnight at room temperature. The reaction solution was poured into saturated sodium carbonate solution (100ml), extracted with dichloromethane (10ml×2), the organic phase was spin-dried with silica gel, and the residue was Purified by column chromatography (eluent: dichloromethane: methanol: triethylamine = 10:1:0.1) to obtain 4-amino-3-(4-(4-fluorophenoxy)phenyl)-1- ((R)-piperidin-3-yl)-1H-pyrrole[3,2-c]pyridin-2(3H)-one (0.1 g, yield: 66.7%). LCMS (ESI): m/z 419 [M+1] ⁺ , yellow oil; TLC: Rf 0.1 (dichloromethane:methanol=20:1).

Step 21d: 1-((R)-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[3, 2-c]pyridine-2(3H)-one (1-((R)-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[ Preparation of 3,2-c]pyridin-2(3H)-one)(compound 12)

Add (4-amino-3-(4-(4-fluorophenoxy)phenyl)-(4-amino-3-(4-(4-fluorophenoxy)phenyl)- 1-((R)-piperidin-3-yl)-1H-pyrrole[3,2-c]pyridin-2(3H)-one (308-12) (0.1g, 0.24mmol, 1.0 equiv) di Chloromethane solution (3ml), then diisopropylethylamine (0.062g, 0.48mmol, 2.0 equivalents) dichloromethane solution (2ml) was added dropwise, and reacted for 5 minutes at 0 ° C. The reaction solution was poured into In water (10ml), extracted with dichloromethane (10mlX2), the organic phase was mixed with silica gel and spin-dried, and the residue was purified by column chromatography (dichloromethane:methanol=40:1) to obtain (1-((R )-1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[3,2-c]pyridine-2( 3H)-ketone (0.028g, yield: 24%). Off-white solid, melting point: 86-88°C. TLC: Rf 0.5 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 473[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 400MHz): δ7.87(d, J=5Hz, 1H), 7.39(d, J=8.7Hz, 2H), 7.08(m, 6H), 6.63 (d,J=5Hz,2H),6.30(d,J=17.6Hz,1H),5.72(s,1H),4.82(d,J=12Hz,1H),4.12(d,J=13.6Hz,4H ),3.85(m,0.5H),3.48(d,J=11.2Hz,0.5H),3.13(m,0.5H),2.62(m,1.5H),2.11(d,J=11.2Hz,1H) , 1.98 (d, J=14Hz, 1H), 1.60 (m, 1H).

Example 22: (R)-1-(3-(1-(acryloyl)piperidine))-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1, 3-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-(dimethylamino) Preparation of phenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 21)

Step 22a: (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-dimethylaminophenyl)-2,3-dihydro-1H-imidazo[ 4,5-c]pyridine)piperidine (tert-butyl(R)-3-(4-amino-3-(4-(4-(dimethylamino)phenoxy)phenyl)-2-oxo-2,3-dihydro Preparation of -1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-21)

(R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-hydroxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c ]pyridine) piperidine (502-19) (0.88g, 2.07mmol, 1.0 equivalent), p-dimethylaminobromobenzene (1.24g, 6.21mmol, 3.0 equivalent) and N,N-dimethylglycine hydrochloride ( 0.35g, 2.48mmol, 1.2 equivalents) was dissolved in dioxane (20mL), then added cuprous iodide (0.12g, 0.62mmol, 0.3 equivalents) and cesium carbonate (2.36g, 7.25mmol, 3.5 equivalents), Then react at 100° C. for 24 hours under the protection of nitrogen. The reaction solution was cooled to room temperature and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol=50:1) to obtain (R)-1-tert-butoxycarbonyl-3-(4-amino-2- Oxo-3-(4-dimethylaminophenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.69 g, yield: 61%). LCMS (ESI): m/z 545[M+1] ⁺ , gray solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1).

Step 22b: (R)-4-Amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1-(3-pyrrolidine)-1H-imidazo[4,5-c] Pyridine-2(3H)-one ((R)-4-amino-3-(4-(4-(dimethylamino)phenoxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H Preparation of -imidazo[4,5-c]pyridin-2-one) (compound 308-21)

((R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-dimethylaminophenyl)-2,3-dihydro-1H-imidazo[4 ,5-c]pyridine)piperidine (307-21) (0.69g, 1.27mmol, 1.0eq) was dissolved in dichloromethane (15mL), and trifluoroacetic acid (3mL) was added thereto, then reacted at room temperature 2 hours.The reaction mixture was diluted with dichloromethane (100mL), washed successively with saturated sodium carbonate solution (30mL×2) and saturated brine (60mL), then the organic layer was spin-dried with silica gel, and then washed with column Purified by chromatography (dichloromethane: methanol: triethylamine = 100:10:1) to obtain (R)-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1 -(3-pyrrolidine)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.52 g, yield: 93%). LCMS (ESI): m/z 445 [M+ 1] ⁺ , pale yellow solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1).

Step 22c: (R)-1-(3-(1-(acryloyl)piperidine))-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1,3 -2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(4-(dimethylamino)phenoxy )phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 21)

(R)-4-amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1-(3-pyrrolidine)-1H-imidazo[4,5-c]pyridine- 2(3H)-Kone (308-21) (0.2g, 0.45mmol, 1.0eq), acrylic acid (39mg, 0.54mmol, 1.2eq), DCC (111mg, 0.54mmol, 1.2eq) and DMAP (5.5mg, 0.045 mmol, 0.1 equiv) was dissolved in dichloromethane (10 mL), and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=50:1) to obtain compound (R)-1-(3-(1-(acryloyl)piperidine))-4- Amino-3-(4-(4-dimethylaminophenoxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (60mg, yield: 27%) . White solid, melting point: 92.3-97.6°C. TLC: Rf 0.5 (dichloromethane:methanol=15:1). LCMS (ESI): m/z 499[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.85(s, 1H), 7.35(d, J=9.0Hz, 2H), 7.04(d, J＝9.0Hz, 2H), 7.01(d, J＝2.5Hz, 2H), 6.75(d, J＝6.5Hz, 2H), 6.70-6.51(m, 2H), 6.33-6.30(m, 1H), 5.71 (s, 1H), 4.83-4.81 (m, 1H), 4.25-4.10 (m, 4H), 3.84-3.46 (m, 1H).

Example 23: (3R)-1-[1-(1-acryloyl)piperidin-3-yl]-4-amino-3-[4-(4-trifluoromethylphenoxy-phenyl )]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((3R)-1-(1-Acryloyl-piperidin-3-yl)-4-amino-3 - Preparation of [4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (compound 22)

Step 23a: (3R)-3-[4-Amino-2-oxo-3-[4-(4-trifluoromethylphenoxy-phenyl)]-2,3-dihydro-1H-imidazole [4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (3-{4-Amino-2-oxo-3-[4-(4-trifluoromethyl-phenoxy)-phenyl] -2,3-dihydro-imidazo[4,5-c]pyridin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester) (compound 307-22)

(3R)-3-(4-Amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester (306) (1.17g, 3.52mmol, 1 eq) was dissolved in DMF (15ml), and added successively Molecular sieves (2g), copper acetate (0.96g, 5.28mmol, 1.5 equivalents), 4-trifluoromethylphenoxyphenylboronic acid (108-22) (1.19g, 4.22mmol, 1.1 equivalents), pyridine (0.417g, 5.28mmol, 1.5 equivalents), stirred overnight at room temperature. The reaction was completed, filtered, the mother liquor was washed twice with water, dried, concentrated, methanol/DCM (1:40) column chromatography to obtain brown syrup (3R)-3-[4-amino-2-oxo-3-[4 -(4-Trifluoromethylphenoxy-phenyl)]-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (0.55g, yield 27.5%); TLC: Rf 0.7 (dichloromethane:methanol=20:1); LCMS (ESI): m/z 570[M+1] ⁺¹ .

Step 23b: (3R)-4-Amino-1-[piperidin-3-yl]-3-[4-(4-trifluoromethylphenoxy)-phenyl]1,3-2H-imidazo [4,5-c]pyridin-2-one (4-Amino-1-piperidin-3-yl-3-[4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo[4 ,5-c]pyridin-2-one) (compound 308-22) preparation

(3R)-3-[4-Amino-2-oxo-3-[4-(4-trifluoromethylphenoxy-phenyl)]-2,3-dihydro-1H-imidazo [4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (307-22) (0.55 g, 0.97 mmol, 1 equiv) was dissolved in DCM (2 ml), TFA (2 ml) was added, Reaction at room temperature for 1h. The reaction solution was concentrated, then neutralized with saturated sodium bicarbonate until slightly alkaline, extracted with 5ml of DCM, dried, concentrated, methanol/DCM/triethylamine (1:10:0.1) column chromatography to obtain off-white foamy solid ( 3R)-4-amino-1-[piperidin-3-yl]-3-[4-(4-trifluoromethylphenoxy)-phenyl]1,3-2H-imidazo[4,5 -c]pyridin-2-one (0.408g, yield 90%); TLC: Rf 0.2 (dichloromethane:methanol=10:1); LCMS (ESI): m/z 470[M+1] ⁺¹ .

Step 23c: (3R)-1-[1-(1-acryloyl)piperidin-3-yl]-4-amino-3-[4-(4-trifluoromethylphenoxy-phenyl) ]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ((3R)-1-(1-Acryloyl-piperidin-3-yl)-4-amino-3- Preparation of [4-(4-trifluoromethyl-phenoxy)-phenyl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one)(compound 22)

4-Amino-3-[4-(4-trifluoromethylphenoxy-phenyl)]-1-[(3R)-piperidin-3-yl]-1,3-dihydro-2H -Imidazolo[4,5-c]pyridin-2-one (308-22) (67 mg, 0.143 mmol, 1 equiv), acrylic acid (12 mg, 0.171 mmol, 1.2 equiv) were dissolved in DCM (5 ml), and HATU ( 71mg, 0.186mmol, 1.3eq) and Et ₃ N (22mg, 0.215mmol, 1.5eq), react under ice bath for 0.5 hours. The reaction was completed, concentrated, and purified by column chromatography (eluent: methanol: dichloromethane = 1:20) to obtain a white solid (3R)-1-[1-(1-acryloyl)piperidin-3-yl]- 4-Amino-3-[4-(4-trifluoromethylphenoxy-phenyl)]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one ( 20mg, yield 20%); purity 95.1%; TLC: Rf 0.4 (dichloromethane:methanol=20:1); melting point: 64～65°C; LCMS (ESI): m/z 524[M+1] ^{+ 1} ; ¹ HNMR (400MHz, CDCl ₃ ): δ1.64 (m, 1H), 1.99 (m, 3H), 2.64 (m, 1.5H), 3.13 (t, 0.5H, J=12.36Hz), 3.47 ( t,0.5H,J＝11.34Hz),3.86(s,0.5H),4.11(m,1.5H),4.21(s,0.5H),4.31(s,1H),4.83(dd,1H, ^1J ＝10.08Hz, ² J＝8.34Hz), 5.75(d, 1H, J＝9.66Hz), 6.35(d, 1H, J＝16.2Hz), 6.62(m, 2H), 7.18(dd, 4H, ¹ J =8.64Hz, ^2J =8.4Hz), 7.46(d, 2H, J=8.52Hz), 7.65(d, 2H, J=8.4Hz), 7.86(s, 1H).

Example 24: (3R)-1-(1-acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethylphenoxy)-phenyl]-1,3- 2H-Imidazol[4,5-c]pyridin-2-one (1-(1-Acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]- Preparation of 1,3-dihydro-imidazo[4,5-c]pyridin-2-one)(compound 23)

Step 24a: (3R)-3-[4-Amino-2-oxo-3-(4-hydroxymethylphenoxy-phenyl)-2,3-dihydro-1H-imidazo[4, 5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (3-{4-Amino-2-oxo-3-(4-hydroxy methylphenoxy-phenoxy)-2,3-dihydro-1- Preparation of H-imidazo[4,5-c]pyridin-1-yl}-piperidine-1-carboxylic acid tert-butyl ester) (compound 307-23)

Add (3R)-3-[4-amino-2-oxo-3-(4-hydroxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine to the flask -1-yl]piperidine-1-carboxylic acid tert-butyl ester (502-19) (737mg, 1.73mmol, 1eq), _Cs2CO3 (1.13g, 3.46mmol, 2eq), _add NMP (10ml) and stir As a brown suspension, 4-fluorobenzaldehyde (258mg, 2.076mmol, 1.2eq) was added and reacted overnight at 80°C. The reaction system was cooled, filtered, 20ml of water was added to the mother liquor and acetic acid was added to adjust the pH to partial acidity, DCM (10ml) was extracted twice, the organic phase was finally washed twice with water (20ml), concentrated, and column chromatography (methanol: DCM = 1:40) to obtain (3R)-3-[4-amino-2-oxo-3-(4-formaldehyde phenoxy-phenyl)-2,3-dihydro-1H-imidazo[4 ,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (500mg, yield 55%), TLC: Rf 0.4 (methanol:dichloromethane=1:40), light brown syrup , LCMS (ESI): m/z 530 [M+1] ⁺ . The above compound (500mg, 0.945mmol, 1 equivalent) was dissolved in methanol/tetrahydrofuran (3ml/3ml), and sodium borohydride (179mg, 4.73mmol, 5 equivalents) and lithium chloride (200mg, 4.73mmol, 5 equivalents) were added . Added water (20ml) and stirred, extracted with DCM (10ml x 2), concentrated, and column chromatography (methanol:DCM=1:40) gave (3R)-3-[4-amino-2-oxo-3-( 4-Hydroxymethylphenoxy-phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (220 mg, yield 44%), TLC: Rf 0.3 (methanol:dichloromethane=1:40), light yellow syrup, LCMS (ESI): m/z 532[M+1] ⁺ .

Step 24b: (3R)-4-Amino-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1-piperidin-3-yl-1,3-2H-imidazo[ 4,5-c]pyridin-2-one (4-Amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1-piperidin-3-yl-1,3-dihydro-imidazo[4, Preparation of 5-c]pyridin-2-one) (compound 308-23)

Add (3R)-3-[4-amino-2-oxo-3-[4-(4-hydroxymethylphenoxy-phenyl)]-2,3-dihydro-1H- Imidazo[4,5-c]pyridin-1-yl]piperidine-1-carboxylic acid tert-butyl ester (307-23) (0.22 g, 0.41 mmol, 1 equiv), dissolved in DCM (2 ml), added TFA ( 1ml), react at room temperature for 1h. The reaction solution was concentrated, then neutralized with saturated sodium bicarbonate until slightly alkaline, extracted with 5ml DCM, dried, concentrated, and column chromatography of methanol/DCM/triethylamine (1:10:0.1) gave (3R)-4 -Amino-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1-piperidin-3-yl-1,3-2H-imidazo[4,5-c]pyridine- 2-Kone (0.092g, yield 52%), off-white oil, TLC: Rf 0.2 (dichloromethane: methanol = 10:1); LCMS (ESI): m/z 432[M+1] ⁺¹ .

Step 24c: (3R)-1-(1-Acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethylphenoxy)-phenyl]-1,3-2H -Imidazol[4,5-c]pyridin-2-one(1-(1-Acryloyl-piperidin-3-yl)-4-amino-3-[4-(4-hydroxymethyl-phenoxy)-phenyl]-1 , Preparation of 3-dihydro-imidazo[4,5-c]pyridin-2-one) (compound 23)

Add (3R)-4-amino-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1-piperidin-3-yl-1,3-2H-imidazo to the flask [4,5-c]pyridin-2-one (308-23) (80mg, 0.1854mmol, 1 equiv), dissolved in DCM (2ml)/Et3N (56mg), added acrylic acid (15mg, 0.2039mmol, 1.1 equiv) and HATU (92 mg, 0.241 mmol, 1.3 equiv), reacted for 0.5 hours. After the reaction was completed, column chromatography purification (eluent: methanol: dichloromethane = 1:20) gave white solid 4-amino-1-[(3R)-1-(2-butenoyl)dimethylamine- 3-yl]-3-[4-(4-hydroxymethylphenoxy-phenyl)]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (20mg , yield 22%); purity 95.3%; TLC: Rf 0.4 (dichloromethane:methanol=20:1); melting point: 99～100°C; LCMS (ESI): m/z 486[M+1] ⁺¹ ; ¹ HNMR (600MHz, CDCl3): δ1.64 (m, 1H), 1.89 (m, 2H), 2.10 (s, 1H), 2.64 (m, 1.5H), 3.12 (t, 0.5H, J = 12.12 Hz),3.46(t,0.5H,J＝11.04Hz),3.85(s,0.5H),4.21(m,4H),4.82(dd,1H, ¹ J＝8.04Hz, ² J＝11.22Hz), 5.74(d, 1H, J＝9.84Hz), 6.34(m, 1H), 6.62(m, 2H), 7.11(dd, 4H, ¹ J＝8.52Hz, ² J＝8.34Hz), 7.39(t, 4H , J=6.36Hz), 7.86(s, 1H).

Example 25: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-1,3-2H -imidazo[4,5-c]pyridin-2-one((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-fluorobenzyl)oxy)phenyl )-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 25)

Step 25a: Preparation of 4-(4-fluorobenzyloxy)phenylboronic acid ((4-((4-fluorobenzyl)oxy)phenyl)boronicacid) (compound 601-25)

Add p-bromophenol (3.0g, 17.34mmol, 1.0 equivalents), p-fluorobenzyl bromide (3.93g, 20.81mmol, 1.2 equivalents), potassium carbonate (4.79g, 34.68mmol, 2.0 equivalents) and N,N -Dimethylformamide (20ml), react overnight at room temperature. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL×3), the extract was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 4-(4-fluorobenzyloxy)bromobenzene (4.48 g, yield: 92%). LCMS (ESI): m/z 281[M+1] ⁺ , white solid; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 10:1). The compound obtained above (3.16g, 11.24mmol, 1.0 equivalent) was dissolved in anhydrous tetrahydrofuran (40mL), cooled to -78°C with a dry ice acetone bath, and then slowly added dropwise n-butyl lithium (2.5M, 5.4mL , 13.49mmol, 1.2 equivalents), after the dropwise addition was completed, it was stirred at -78°C for 1 hour. Trimethyl borate (2.55 mL, 22.48 mmol, 2.0 equiv) was added then slowly warmed to room temperature and stirred overnight. 2N Aqueous hydrochloric acid (20 mL) was added and stirred for 2 hours. The aqueous layer was extracted with ethyl acetate (50mL×3), the combined organic layers were dried over anhydrous sodium sulfate, concentrated, and the obtained crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 4 -(4-fluorobenzyloxy)phenylboronic acid (0.92 g, yield: 33%). LCMS (ESI): m/z 247[M+1] ⁺ , white solid; TLC: Rf 0.2 (petroleum ether: ethyl acetate = 2:1).

Step 25b: (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyridine)piperidine (tert-butyl(R)-3-(4-amino-3-(4-((4-fluorobenzyl)oxy)phenyl)-2-oxo- Preparation of 2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 602-25)

(R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.85g, 2.55mmol, 1.0eq), 4-(4-fluorobenzyloxy)phenylboronic acid (0.82g, 3.32mmol, 1.3eq) and pyridine (0.62mL, 7.65mmol, 3.0eq) were dissolved in N,N-dimethyl In formamide (8mL), add copper acetate (0.51g, 2.81mmol, 1.1 equivalent) and Molecular sieves (1 g), then react overnight at 50°C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with half-saturated brine (50 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol=50:1) to obtain (R)-1-tert-butoxycarbonyl-3-(4-amino -3-(4-(4-fluorobenzyloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.27g, rate: 32%). LCMS (ESI): m/z 534[M+1] ⁺ , brown solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1).

Step 25c: (R)-4-Amino-3-(4-(4-fluorobenzyloxy)phenyl)-1-(3-piperidinyl)-1,3-2H-imidazo[4,5 -c]pyridin-2-one((R)-4-amino-3-(4-((4-fluorobenzyl)oxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H Preparation of -imidazo[4,5-c]pyridin-2-one) (compound 603-25)

(R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-2-oxo-2,3-dihydro-1H- Imidazo[4,5-c]pyridine)piperidine (602-25) (0.27g, 0.51mmol, 1.0eq) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (2mL) was added thereto, then The reaction was carried out at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50mL), washed successively with saturated sodium carbonate solution (30mL×2) and saturated brine (30mL), then the organic layer was spin-dried with silica gel, and then purified by column chromatography. (Dichloromethane: Methanol: Triethylamine = 100:10:1) to obtain (R)-4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-1-(3-piper Pyridyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (0.20 g, yield: 90%). LCMS (ESI): m/z 434[M+1] ⁺ , pale yellow solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1).

Step 25d: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-1,3-2H- Imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((4-fluorobenzyl)oxy)phenyl) Preparation of -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 25)

(R)-4-amino-3-(4-(4-fluorobenzyloxy)phenyl)-1-(3-piperidinyl)-1,3-2H-imidazo[4,5-c ]pyridin-2-one (603-25) (0.20g, 0.46mmol, 1.0eq), acrylic acid (43mg, 0.60mmol, 1.3eq), DCC (124mg, 0.60mmol, 1.3eq) and DMAP (5.6mg, 0.046 mmol, 0.1 equiv) was dissolved in dichloromethane (10 mL), and reacted at 0°C for 1 hour. After the reaction was completed, the crude product was concentrated and purified by column chromatography (dichloromethane:methanol=50:1) to obtain compound 6-7 (110 mg, yield: 49%). White solid, melting point: 69.7-71.7°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1). LCMS(ESI): m/z 488[M+1] ⁺ , ¹ HNMR(CDCl ₃ , 500MHz): δ7.86(s,1H),7.44-7.41(m,2H),7.38-7.35(m,2H ),7.11-7.08(m,4H),6.64-6.57(m,2H),6.34-6.30(m,1H),5.72(s,1H),5.08(s,2H),4.90-4.82(m,1H ),4.25-4.05(m,4H),3.90-3.46(m,1H),3.16-2.50(m,2H),2.18-2.10(m,1H),2.02-1.95(m,1H),1.70-1.60 (m,1H).

Example 26: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(2-pyridyloxy)phenyl)-1,3-2H- Imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-2-yloxy)phenyl)- Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 28)

Step 26a: Preparation of 4-(2-pyridinyloxy)phenylboronic acid ((4-(pyridin-2-yloxy)phenyl)boronic acid) (compound 108-28)

Add p-bromophenol (3.0g, 17.34mmol, 1.0 equivalents), 2-fluoropyridine (2.02g, 20.81mmol, 1.2 equivalents), potassium carbonate (4.79g, 34.68mmol, 2.0 equivalents) and N,N -Dimethylformamide (20ml), react overnight at 120°C. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL×3), the extract was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain 2-(4-Bromophenoxy)pyridine (1.2 g, yield: 28%). LCMS (ESI): m/z 250[M+1] ⁺ , pale yellow oily liquid; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 4:1). The compound obtained above (1.17g, 4.68mmol, 1.0 equivalent) and bis-linked pinacol borate (1.54g, 6.08mmol, 1.3 equivalent) were dissolved in dioxane (15mL), and then potassium acetate (1.38 g, 14.04 mmol, 3.0 equiv) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.34 g, 0.47 mmol, 0.1 equiv). Replaced with nitrogen three times and reacted overnight at 100°C. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain 4-(2-pyridyloxy) phenylboronic acid pinacol ester (1.1 g, yield: 79 %). LCMS (ESI): m/z 298 [M+1] ⁺ , colorless oily liquid; TLC: Rf 0.5 (petroleum ether: ethyl acetate = 10:1). The compound obtained above (1.0g, 3.37mmol, 1.0eq) was dissolved in tetrahydrofuran (10mL), then sodium periodate (1.08g, 5.05mmol, 1.5eq) and 1N hydrochloric acid solution (10mL) were added, and React for 3 hours. After the reaction is completed, solid sodium bicarbonate is added to adjust the pH value of the solution to 6-7. The aqueous layer was extracted with dichloromethane (30mL×3), the organic layer was mixed and washed with saturated brine (30mL×1), dried over anhydrous sodium sulfate, and concentrated to obtain 4-(2-pyridyloxy)phenylboronic acid (0.62 g, yield: 86%). LCMS (ESI): m/z 216[M+1] ⁺ , white solid; TLC: Rf 0.1 (petroleum ether: ethyl acetate = 4:1).

Step 26b: (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl)-2,3-dihydro-1H -imidazo[4,5-c]pyridine)piperidine (tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-2-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-28)

(R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (306)( 0.74g, 2.22mmol, 1.0 equivalent), 4-(2-pyridyloxy) phenylboronic acid (108-28) (0.62g, 2.89mmol, 1.3 equivalent) and pyridine (0.54mL, 6.66mmol, 3.0 equivalent) were dissolved in In N,N-dimethylformamide (10mL), add copper acetate (0.44g, 2.44mmol, 1.1 equivalent) and Molecular sieves (1 g), then react overnight at 50°C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with half-saturated brine (50 mL×2). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol=50:1) to obtain (R)-1-tert-butoxycarbonyl-3-(4-amino -2-oxo-3-(4-(2-pyridyloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.228g, yield : 20%). LCMS (ESI): m/z 503[M+1] ⁺ , brown solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1).

Step 26c: (R)-4-Amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5- c] Pyridin-2-one ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-2-yloxy)phenyl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (compound 308-28)

(R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl)-2,3-dihydro-1H-imidazole And[4,5-c]pyridine)piperidine (307-28) (0.228g, 0.454mmol, 1.0 equivalent) was dissolved in dichloromethane (10mL), and trifluoroacetic acid (2mL) was added thereto, and then in The reaction was carried out at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50mL), washed successively with saturated sodium carbonate solution (30mL×2) and saturated brine (30mL), then the organic layer was spin-dried with silica gel, and then purified by column chromatography. (Dichloromethane: Methanol: Triethylamine = 100:10:1) to obtain (R)-4-amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)benzene yl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (0.17 g, yield: 93%). LCMS (ESI): m/z 403[M+1] ⁺ , pale yellow solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1).

Step 26d: (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino-3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazole And[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-2-yloxy)phenyl)-1 , Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 28)

(R)-4-amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5-c] Pyridin-2-one (308-28) (0.17g, 0.422mmol, 1.0eq), acrylic acid (40mg, 0.549mmol, 1.3eq), DCC (113mg, 0.549mmol, 1.3eq) and DMAP (5.2mg, 0.042mmol , 0.1 eq) was dissolved in dichloromethane (10 mL), and reacted at 0° C. for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=50:1) to obtain compound (R)-1-(3-(1-acryloyl)piperidinyl)-4-amino -3-(4-(2-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (115 mg, yield: 60%). White solid, melting point: 211.2-213.3°C. TLC: Rf0.4 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 457[M+1] ⁺ , ¹ HNMR (CDCl ₃ -d ₁ , 500MHz): δ8.23-8.22 (m, 1H), 7.88 (d, J = 5.0Hz, 1H) ,7.76-7.73(m,1H),7.46(d,J=8.5Hz,2H),7.30(d,J=8.5Hz,2H),7.08-7.06(m,1H),6.99(d,J=8.5 Hz,1H),6.64-6.55(m,2H),6.35-6.32(m,1H),5.75-5.73(m,1H),4.85-4.76(m,1H),4.18(s,2H),4.15- 4.07(m,2H),3.86-3.49(m,1H),3.13-2.61(m,2H),2.51-2.08(m,1H),2.01-1.95(m,1H),1.86-1.82(m,1H ).

Example 27: (R)-1-(3-(1-acryloyl)piperidine)-4-amino-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazole And[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1 , Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 29)

Step 27a: (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H -imidazo[4,5-c]pyridine)piperidine (tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-3-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-29)

(R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- c] pyridine) piperidine (402-17) (0.8g, 1.49mmol, 1.0eq), 3-hydroxypyridine (403-29) (0.21g, 2.24mmol, 1.5eq) and N,N-dimethylglycine Hydrochloride (39mg, 0.28mmol, 0.18eq) was dissolved in dioxane (8mL), then cuprous iodide (14.2mg, 0.075mmol, 0.05eq) and cesium carbonate (0.97g, 2.98mmol, 2.0 equivalent), and then reacted at 100° C. for 60 hours in nitrogen protection. The reaction solution was cooled to room temperature and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol=40:1 to 20:1) to obtain (R)-1-tert-butoxycarbonyl-3-(4- Amino-2-oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (0.24g, rate: 32%). LCMS (ESI): m/z 503[M+1] ⁺ , pale yellow solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1).

Step 27b: (R)-4-Amino-1-(3-piperidinyl)-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5- c] Pyridin-2-one ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-3-yloxy)phenyl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (compound 308-29)

The synthesis method is as in step 26c of Example 26, except that (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl) )-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (307-28) was replaced by (R)-1-tert-butoxycarbonyl-3-(4-amino-2 -Oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (307-29) (0.24g , 0.48mmol, 1.0 equivalents), to obtain (R)-4-amino-1-(3-piperidinyl)-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazole De[4,5-c]pyridin-2-one (0.18 g, yield: 93%). LCMS (ESI): m/z 403[M+1] ⁺ , pale yellow solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1).

Step 27c: (R)-1-(3-(1-acryloyl)piperidine)-4-amino-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazo [4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-3-yloxy)phenyl)-1, Preparation of 3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 29)

The synthesis method is as in step 26d of Example 26, except that (R)-4-amino-1-(3-piperidinyl)-3-(4-(2-pyridyloxy)phenyl)-1,3 -2H-imidazo[4,5-c]pyridin-2-one (308-28) was replaced by (R)-4-amino-1-(3-piperidinyl)-3-(4-(3- Pyridyloxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (308-29) (0.18g, 0.45mmol, 1.0eq) to give (R)-1 -(3-(1-acryloyl)piperidine)-4-amino-3-(4-(3-pyridyloxy)phenyl)-1,3-2H-imidazo[4,5-c]pyridine -2-one (0.18 g, yield: 93%). White solid, melting point: 80.5-83.8°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1). LCMS(ESI): m/z 457[M+1] ⁺ , ¹ HNMR(CDCl ₃ , 500MHz): δ8.49(d, J=2.5Hz, 1H), 8.45(d, J=4.0Hz, 1H) ,7.88(d,J=5.5Hz,1H),7.45-7.39(m,3H),7.35-7.32(m,1H),7.16(d,J=8.5Hz,2H),6.65-6.58(m,2H ),6.34-6.31(m,1H),5.72(s,1H),4.83-4.79(m,1H),4.20-4.11(m,4H),3.92-3.47(m,1H),3.15-2.52(m ,2H), 2.12-1.96(m,2H), 1.70-1.60(m,1H).

Example 28: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-di Hydrogen-2H-imidazo[4,5c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl )-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 30)

Step 28a: (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(3-pyridyloxy)phenyl)-2,3-dihydro-1H -imidazo[4,5-c]pyridine)piperidine (tert-butyl(R)-3-(4-amino-2-oxo-3-(4-(pyridin-3-yloxy)phenyl)-2, Preparation of 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate) (compound 307-30)

The synthesis method is as in Example 26 step 26b, except that 4-(2-pyridyloxy)phenylboronic acid (108-28) is replaced by (4-(pyridin-4-yloxy)phenyl)boronic acid (108- 30) (0.645g, 3.0mmol, 1.0 equiv), yielding (R)-3-(4-amino-2-oxo-3-(4-(pyridin-4-yloxy)phenyl)-2, tert-butyl 3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate (0.21 g, yield: 14%). LCMS (ESI): m/z 503[M+1] ⁺ , off-white solid; TLC: Rf 0.5 (dichloromethane:methanol=20:1).

Step 28b: (R)-4-Amino-1-(piperidin-3-yl)-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazole And[4,5-c]pyridin-2-one ((R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-4-yloxy)phenyl)-1,3 Preparation of -dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 308-30)

The synthesis method is as in step 26c of Example 26, except that (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(2-pyridyloxy)phenyl) )-2,3-dihydro-1H-imidazo[4,5-c]pyridine)piperidine (307-28) was replaced by (R)-3-(4-amino-2-oxo-3-( 4-(pyridin-4-yloxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylic acid tert-butyl ester ( 307-30) (0.21g, 0.42mmol, 1.0 equivalents), to obtain (R)-4-amino-1-(piperidin-3-yl)-3-(4-(pyridin-4-yloxy)benzene yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (0.158 g, yield: 94%). LCMS (ESI): m/z 403[M+1] ⁺ , colorless solid; TLC: Rf 0.1 (dichloromethane:methanol=20:1).

Step 28c: (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro -2H-imidazo[4,5c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl) Preparation of -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 30)

(R)-4-amino-1-(piperidin-3-yl)-3-( 4-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (308-30) (0.158g, 0.39mmol, 1.0 equiv) in dichloromethane (10 ml), then diisopropylethylamine (0.075 g, 0.59 mmol, 1.5 equiv) in dichloromethane (1 ml) was added dropwise, and reacted at 0° C. for 10 minutes. The reaction solution was poured into water (100ml), extracted with dichloromethane (100ml×2), the organic phase was mixed with silica gel and spin-dried, and the residue was purified by column chromatography (dichloromethane:methanol=20:1) Obtaining (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(pyridin-4-yloxy)phenyl)-1,3-dihydro-2H - Imidazo[4,5c]pyridin-2-one (0.050 g, yield: 28%). Colorless solid, melting point: 79.6-81.7°C. TLC: Rf 0.5 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 457[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ8.51 (d, J=6Hz, 2H), 7.89 (d, J=5Hz, 1H), 7.51 (d,J=8.5Hz,2H),7.27(d,J=8.5Hz,2H),6.94(d,J=6Hz,2H),6.67(s,1H),6.60(d,J=9.5Hz, 1H), 6.34(d, J=16.5Hz, 1H), 5.72(s, 1H), 4.84(m, 1H), 4.31-4.11(m, 4H), 3.86(m, 0.5H), 3.48(m, 0.5H), 3.13(m, 0.5H), 2.63(m, 1.5H), 2.11(d, J=12Hz, 1H), 1.98(d, J=13.5Hz, 1H), 1.69(m, 1H).

Example 29: (R)-4-amino-3-(4-phenoxyphenyl)-1-(3-(1-propioloylpiperidine))-1,3-2H-imidazo[4, 5-c]pyridin-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-propioloylpiperidin-3-yl)-1,3-dihydro-2H-imidazo[4, Preparation of 5-c]pyridin-2-one) (compound 32)

(R)-4-amino-3-(4-phenoxyphenyl)-1-(3-piperidinyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one ( 308-11) (0.20g, 0.50mmol, 1.0 equivalent), propiolic acid (42mg, 0.60mmol, 1.2 equivalent), DCC (123mg, 0.60mmol, 1.2 equivalent) and DMAP (6mg, 0.05mmol, 0.1 equivalent) in dichloromethane (10 mL), then react at 0° C. for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=50:1) to obtain compound (R)-4-amino-3-(4-phenoxyphenyl)-1-(3 -(1-propioloylpiperidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one (80 mg, yield: 35%). White solid, melting point: 89.3-95.6°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 454[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.90-7.86(m, 1H), 7.41-7.38(m, 4H), 7.20-7.17(m ,1H),7.14-7.09(m,4H),6.64-6.60(m,1H),4.79-4.63(m,1H),4.58-4.45(m,1H),4.20-4.05(m,3H),3.95 -3.52(m,1H),3.20-2.70(m,2H),2.68-2.53(m,1H),2.15-1.95(m,2H),1.73-1.65(m,1H).

Example 30: (R)-4-Amino-1-(3-(1-(2-butynoyl))piperidinyl)-3-(4-phenoxyphenyl)-1,3-2H- Imidazo[4,5-c]pyridin-2-one((R)-4-amino-1-(1-(but-2-ynoyl)piperidin-3-yl)-3-(4-phenoxyphenyl)- Preparation of 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 33)

The synthesis method is as in Example 29, except that propynoic acid is replaced by 2-butynoic acid (52 mg, 0.62 mmol, 1.3 equivalents) to obtain (R)-4-amino-1-(3-(1-(2 -butynoyl))piperidinyl)-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (60mg, yield: 27% ). White solid, melting point: 84.6-89.4°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 468[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.89-7.85(m,1H),7.41-7.37(m,4H),7.21-7.18(m, 1H),7.14-7.08(m,4H),6.66-6.60(m,1H),4.77-4.65(m,1H),4.55-4.45(m,1H),4.28-4.05(m,3H),3.90- 3.47 (m, 1H), 3.10-2.62 (m, 1H), 2.60-2.50 (m, 1H), 2.15-1.95 (m, 5H), 1.75-1.60 (m, 1H).

Example 31: 1-(3-(1-acryloyl)piperidinylmethyl)-4-amino-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c ]pyridin-2-one (1-((1-acryloylpiperidin-3-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c] preparation of pyridin-2-one) (compound 35)

Step 31a: 1-tert-butoxycarbonyl-3-(4-(2-chloro-3-nitro)pyridineaminomethyl)piperidine (tert-butyl 3-(((2-chloro-3-nitropyridin-4 Preparation of -yl)amino)methyl)piperidine-1-carboxylate) (compound 702-35)

Add 2,4-dichloro-3-nitropyridine (101) (1.0g, 5.18mmol, 1.0 equivalents), 1-tert-butoxycarbonyl-3-aminomethylpiperidine (701-35) into the reaction flask (1.11g, 5.18mmol, 1.0eq), triethylamine (1.4mL, 10.36mmol, 2.0eq) and N,N-dimethylformamide (10ml), react overnight at room temperature. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (30 mL×3), the extract was dried over anhydrous sodium sulfate, concentrated, and then purified by column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain 1-tert-butoxycarbonyl-3-(4-(2-chloro-3-nitro)pyridineaminomethyl)piperidine (1.66 g, yield: 86%). LCMS (ESI): m/z 371[M+1] ⁺ , pale yellow oil; TLC: Rf 0.2 (petroleum ether: ethyl acetate = 4:1).

Step 31b: 1-tert-butoxycarbonyl-3-(4-(2-dibenzylamino-3-nitro)pyridineaminomethyl)piperidine (tert-butyl 3-(((2-(dibenzylamino)- Preparation of 3-nitropyridin-4-yl)amino)methyl)piperidine-1-carboxylate) (compound 703-35)

Add 1-tert-butoxycarbonyl-3-(4-(2-chloro-3-nitro)pyridineaminomethyl)piperidine (702-35) (1.66g, 4.48mmol, 1.0 equivalents) into the reaction flask, Dibenzylamine (0.95mL, 4.92mmol, 1.1eq), triethylamine (1.24mL, 8.96mmol, 2.0eq) and acetonitrile (25ml) were heated to reflux overnight. The reaction solution was mixed with silica gel and spin-dried, and purified by column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain 1-tert-butoxycarbonyl-3-(4-(2-dibenzylamino-3- Nitro)pyridineaminomethyl)piperidine (2.13 g, yield: 90%). LCMS (ESI): m/z 532[M+1] ⁺ , yellow oil; TLC: Rf 0.4 (petroleum ether: ethyl acetate = 3:1).

Step 31c: 1-tert-butoxycarbonyl-3-(4-(3-amino-2-dibenzylamino)pyridineaminomethyl)piperidine (tert-butyl 3-(((3-amino-2-( Preparation of dibenzylamino) pyridin-4-yl) amino) methyl) piperidine-1-carboxylate) (compound 704-35)

Add 1-tert-butoxycarbonyl-3-(4-(2- Dibenzylamino-3-nitro)pyridineaminomethyl)piperidine (703-35) (2.13g, 4.01mmol, 1.0eq), heated to 50°C for 1 hour. The reaction solution was filtered with diatomaceous earth, the filtrate was spin-dried, dissolved in dichloromethane:methanol=5:1 (50ml), filtered, and the organic phase was spin-dried to obtain the crude product 1-tert-butoxycarbonyl-3-(4-(3- Amino-2-dibenzylamino)pyridineaminomethyl)piperidine (2.10 g, yield: 100%). LCMS (ESI): m/z 502[M+1] ⁺ , gray solid; TLC: Rf 0.1 (petroleum ether: ethyl acetate = 1:1).

Step 31d: 1-tert-butoxycarbonyl-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine ( tert-butyl 3-((4-(dibenzylamino)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)piperidine-1-carboxylate) (compound 705 -35) Preparation

Add 1-tert-butoxycarbonyl-3-(4-(3-amino-2-dibenzylamino)pyridineaminomethyl)piperidine (704-35) (2.10g, 4.19mmol, 1.0eq ), N,N'-carbonyldiimidazole (1.70g, 10.46mmol, 2.5eq) and tetrahydrofuran (30ml), the reaction solution was heated to reflux overnight. The reaction solution was mixed with silica gel and spin-dried, and purified by column chromatography (dichloromethane:methanol=100:1) to obtain 1-tert-butoxycarbonyl-3-(4-dibenzylamino-2-oxo-2 , 3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (1.87 g, yield: 85%). LCMS (ESI): m/z 528[M+1] ⁺ , pale yellow solid; TLC: Rf0.4 (dichloromethane:methanol=80:1).

Step 31e: 1-tert-butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (tert-butyl Preparation of 3-((4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)methyl)piperidine-1-carboxylate)(compound 706-35)

Add 1-tert-butoxycarbonyl-3-(4-dibenzylamino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperene into the reaction flask Pyridine (705-35) (1.87g, 3.54mmol, 1.0eq), palladium hydroxide (1.6g), ethanol (40ml) and ethyl acetate (10ml), the reaction solution was heated to 70°C overnight in a hydrogen atmosphere. The reaction mixture was filtered with celite, the filtrate was spin-dried, and the residue was purified by column chromatography (dichloromethane:methanol=20:1) to obtain 1-tert-butoxycarbonyl-3-(4-amino-2-oxo -2,3-Dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (0.8 g, yield: 65%). LCMS (ESI): m/z 348[M+1] ⁺ , white solid; TLC: Rf 0.2 (dichloromethane:methanol=20:1).

Step 31f: 1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c ]pyridylmethyl)piperidine (tert-butyl 3-((4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1 -yl)methyl)piperidine-1-carboxylate) (compound 707-35) preparation

1-tert-butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (706-35) ( 0.8g, 2.30mmol, 1.0 equivalent), p-phenoxyphenylboronic acid (0.64g, 2.99mmol, 1.3 equivalent) and pyridine (0.55g, 6.90mmol, 3.0 equivalent) were dissolved in N,N-dimethylformamide ( 10mL), add copper acetate (0.46g, 2.53mmol, 1.1 equivalent) and Molecular sieves (1 g), then react overnight at 50°C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (100 mL), filtered, and the filtrate was washed with half-saturated brine (30 mL×3). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol=50:1) to obtain 1-tert-butoxycarbonyl-3-(4-amino-2-oxo Subo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridylmethyl)piperidine (0.45 g, yield: 38%). LCMS (ESI): m/z 516[M+1] ⁺ , pale yellow solid; TLC: Rf0.4 (dichloromethane:methanol=20:1).

Step 31g: 4-Amino-3-(4-phenoxyphenyl)-1-(3-piperidinylmethyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one ( 4-amino-3-(4-phenoxyphenyl)-1-(piperidin-3-ylmethyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 708-35) preparation of

1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine Methyl)piperidine (707-35) (0.45g, 0.87mmol, 1.0eq) was dissolved in dichloromethane (15mL), and trifluoroacetic acid (3mL) was added thereto, followed by reaction at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (50mL), washed successively with saturated sodium carbonate solution (30mL×2) and saturated brine (30mL), then the organic layer was spin-dried with silica gel, and then purified by column chromatography. (Dichloromethane: Methanol: Triethylamine = 100:10:1) to obtain 4-amino-3-(4-phenoxyphenyl)-1-(3-piperidinylmethyl)-1,3-2H - Imidazo[4,5-c]pyridin-2-one (0.34 g, yield: 93%). LCMS (ESI): m/z 416[M+1] ⁺ , pale yellow solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1).

Step 31h: 1-(3-(1-acryloyl)piperidinylmethyl)-4-amino-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c] Pyridin-2-one (1-((1-acryloylpiperidin-3-yl)methyl)-4-amino-3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin -2-one) (compound 35) preparation

4-amino-3-(4-phenoxyphenyl)-1-(3-piperidinylmethyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (708- 35) (0.17g, 0.41mmol, 1.0eq), acrylic acid (38mg, 0.53mmol, 1.3eq), DCC (110mg, 0.53mmol, 1.3eq) and DMAP (5.0mg, 0.041mmol, 0.1eq) were dissolved in dichloro Methane (10 mL), then reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=50:1) to obtain the compound 1-(3-(1-acryloyl)piperidinylmethyl)-4-amino-3- (4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (55 mg, yield: 29%). White solid, melting point: 68.5-70.7°C. TLC: Rf 0.4 (dichloromethane:methanol=20:1). LCMS (ESI): m/z 470[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.86 (d, J=4.0Hz, 1H), 7.41-7.38 (m, 4H), 7.20- 7.17(m,1H),7.13-7.09(m,4H),6.58-6.50(m,2H),6.26-6.23(m,1H),5.68-5.66(m,1H),4.51-4.41(m,1H ),4.19(s,2H),3.83-3.78(m,3H),3.20-3.03(m,1H),2.88-2.75(m,1H),2.20-2.12(m,1H),1.95-1.75(m ,2H), 1.59-1.42(m,2H).

Example 32: (R, E)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino-2-butane Enyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one((R,E)-4-amino-1-(1-(4-(dimethylamino) but-2-enoyl)pyrrolidin-3-yl)-3-(4-(4-methoxyphenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 44) Preparation

Step 32a: (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4, 5-c]pyridine)pyrrolidine (tert-butyl(R)-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c ]pyridin-1-yl)pyrrolidine-1-carboxylate) (compound 801-44) preparation

(R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (107)( 4.5g, 14.09mmol, 1.0eq), p-iodophenylboronic acid (401-17) (4.54g, 18.32mmol, 1.3eq) and pyridine (3.4mL, 42.27mmol, 3.0eq) were dissolved in N,N-dimethyl In formamide (40mL), add copper acetate (2.82g, 15.50mmol, 1.1 equivalent) and Molecular sieves (5 g), then react overnight at 50°C in air. The reaction solution was cooled to room temperature and diluted with ethyl acetate (200 mL), filtered, and the filtrate was washed with half-saturated brine (50 mL×4). The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol=50:1) to obtain (R)-1-tert-butoxycarbonyl-3-(4-amino -3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (3.05 g, yield: 41%). LCMS (ESI): m/z 522[M+1] ⁺ , brown solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1).

Step 32b: (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)2-oxo-2,3-dihydro- 1H-imidazo[4,5-c]pyrrolidine (tert-butyl(R)-3-(4-amino-3-(4-(4-methoxyphenoxy)phenyl)-2-oxo-2,3 -dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate) (compound 109-44)

(R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5- c] pyridine) pyrrolidine (801-44) (2.0g, 3.84mmol, 1.0eq), p-methoxyphenol (403-44) (1.19g, 9.59mmol, 2.5eq) and N,N-dimethyl Glycine hydrochloride (1.07g, 7.68mmol, 2.0eq) was dissolved in dioxane (20mL), then copper iodide (0.37g, 1.92mmol, 0.5eq) and cesium carbonate (7.51g, 23.04mmol , 6.0 equivalents), and then reacted at 100°C for 20 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol=40:1 to 20:1) to obtain ((R)-1-tert-butoxycarbonyl-3-(4 -Amino-3-(4-(4-methoxyphenoxy)phenyl)2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (0.61 g, yield: 31%). LCMS (ESI): m/z 518[M+1] ⁺ , gray solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1).

Step 32c: (R)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-pyrrolidine)-1H-imidazo[4,5-c]pyridine -2(3H)-ketone((R)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4 ,5-c]pyridin-2-one) (compound 110-44) preparation

(R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(4-methoxyphenoxy)phenyl)-2,3-dihydro-1H -imidazo[4,5-c]pyridine)pyrrolidine (109-44) (0.61 g, 1.18 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (3 mL) was added thereto, Then react at room temperature for 2 hours. The reaction mixture was diluted with dichloromethane (100mL), washed successively with saturated sodium carbonate solution (30mL×2) and saturated brine (60mL), and then the organic layer was spin-dried with silica gel, followed by column chromatography (Dichloromethane: Methanol: Triethylamine = 100:10:1) to obtain (R)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3- Pyrrolidine)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.45 g, yield: 92%). LCMS (ESI): m/z 418[M+1] ⁺ , pale yellow solid; TLC: Rf0.2 (dichloromethane:methanol=10:1).

Step 32d: (R,E)-4-Amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino-2-butene Acyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one((R,E)-4-amino-1-(1-(4-(dimethylamino)but -2-enoyl)pyrrolidin-3-yl)-3-(4-(4-methoxyphenoxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(Compound 44 ) preparation

(R)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-pyrrolidine)-1H-imidazo[4,5-c]pyridine-2 (3H)-ketone (110-44) (0.28g, 0.671mmol, 1.0eq), 4-dimethylaminocroton hydrochloride (144mg, 0.872mmol, 1.3eq), HATU (332mg, 0.872mmol, 1.3eq ) and triethylamine (0.28mL, 2.013mmol, 3.0eq) were dissolved in dichloromethane (5mL), and reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=20:1) to obtain the compound (R, E)-4-amino-3-(4-(4-methoxyphenoxy )Phenyl)-1-(3-(1-(4-Dimethylamino-2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridine-2- Ketone (70 mg, yield: 20%). White solid, melting point: 50.4-55.9°C. TLC: Rf 0.2 (dichloromethane:methanol=10:1). LCMS (ESI): m/z 529[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.86-7.83 (m, 1H), 7.35 (d, J=9.0Hz, 2H), 7.07- 7.04(m,4H),6.94-6.91(m,3H),6.57-6.43(m,2H),5.12-5.06(m,1H),4.21(s,2H),4.12-4.02(m,3H), 3.83(s,3H), 3.75-3.73(m,1H), 3.31-3.23(m,2H), 2.75-2.71(m,2H), 2.44(s,3H), 2.38(s,3H).

Example 33: (R, E)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-dimethyl Amino-2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-3-(4-( benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1,3-dihydro-2H- Preparation of imidazo[4,5-c]pyridin-2-one) (compound 45)

Step 33a: (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2, 3-Dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (tert-butyl(R)-3-(4-amino-3-(4-(benzo[d][1,3] Preparation of dioxol-5-yloxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)pyrrolidine-1-carboxylate) (compound 109-45)

The synthesis method is as in step 32b of Example 32, except that p-methoxyphenol (403-44) is replaced by sesamol (403-45) (1.21g, 8.78mmol, 1.5 equivalents) to obtain (R)-1- tert-butoxycarbonyl-3-(4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)2-oxo-2,3-dihydro-1H-imidazo [4,5-c]pyridine)pyrrolidine (1.0 g, yield: 39%). LCMS (ESI): m/z 532[M+1] ⁺ , gray solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1).

Step 33b: (R)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-pyrrolidine)-1H-imidazo[4, 5-c]pyridine-2(3H)-one ((R)-4-amino-3-(4-(benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(pyrrolidin- Preparation of 3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 110-45)

The synthesis method is as in step 32c of Example 32, except that (R)-1-tert-butoxycarbonyl-3-(4-amino-2-oxo-3-(4-(4-methoxyphenoxy) Phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrolidine (109-44) was replaced by (R)-1-tert-butoxycarbonyl-3-(4-amino -2-Oxo-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-2,3-dihydro-1H-imidazo[4,5-c]pyridine)pyrrole Alkane(109-45) (1.0g, 1.88mmol, 1.0eq) to give (R)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1 -(3-Pyrrolidine)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.76 g, yield: 94%). LCMS (ESI): m/z 432[M+1] ⁺ , pale yellow solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1).

Step 33c: (R,E)-4-Amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino -2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-3-(4-(benzo [d][1,3]dioxol-5-yloxy)phenyl)-1-(1-(4-(dimethylamino)but-2-enoyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo Preparation of [4,5-c]pyridin-2-one) (Compound 45)

The synthesis method is as in step 32d of Example 32, except that (R)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-pyrrolidine)-1H- Imidazo[4,5-c]pyridin-2(3H)-one (110-44) was replaced by (R)-4-amino-3-(4-(3,4-methylenedioxyphenoxy )phenyl)-1-(3-pyrrolidine)-1H-imidazo[4,5-c]pyridin-2(3H)-one (110-45) (0.20g, 0.464mmol, 1.0 equiv), to obtain Compound (R, E)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-dimethylamino-2 -Crotenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one (38 mg, yield: 15%). White solid, melting point: 186.3-188.5°C. TLC: Rf 0.2 (dichloromethane:methanol=10:1). LCMS (ESI): m/z 543[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.86-7.83 (m, 1H), 7.36 (d, J=7.0Hz, 2H), 7.09- 7.07(m,2H),6.98-6.94(m,1H),6.80(d,J=8.5Hz,1H),6.63(d,J=2.0Hz,1H),6.57-6.54(m,2H),6.45 -6.31(m,1H),6.00(s,2H),5.13-5.07(m,1H),4.20(s,2H),4.10-1.00(m,3H),3.73-3.71(m,1H),3.21 -3.14(m,2H),2.79-2.63(m,1H),2.45-2.38(m,1H),2.35(s,3H),2.31(s,3H).

Example 34: (R, E)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-piperidinyl-2-butane Enyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one((R,E)-4-amino-3-(4-(4-methoxyphenoxy)phenyl )-1-(1-(4-(piperidin-1-yl)but-2-enoyl)pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2- one) (Compound 46)

The synthesis method was as in step 32d of Example 32, except that 4-dimethylaminocroton hydrochloride was replaced with 4-piperidinyl croton hydrochloride (109mg, 0.529mmol, 1.3 equivalents) to obtain compound (R, E)-4-amino-3-(4-(4-methoxyphenoxy)phenyl)-1-(3-(1-(4-piperidinyl-2-butenoyl)pyrrolidine)) -1,3-2H-imidazo[4,5-c]pyridin-2-one (45 mg, yield: 19%). White solid, melting point: 79.9-82.4°C. TLC: Rf 0.2 (dichloromethane:methanol=10:1). LCMS (ESI): m/z569[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.87-7.83 (m, 1H), 7.35 (d, J=9.0Hz, 2H), 7.06-7.03 (m,4H),6.94-6.91(m,3H),6.61-6.57(m,1H),6.47-6.35(m,1H),5.15-5.06(m,1H),4.15-4.01(m,5H) ,3.82(s,3H),3.75-3.62(m,1H),3.37-3.29(m,2H),2.69-2.61(m,5H),2.42-2.36(m,1H),1.70-1.66(m, 4H), 1.50-1.49 (m, 2H).

Example 35: (R, E)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-piperidine Base-2-butenoyl)pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one ((R,E)-4-amino-3-(4-( benzo[d][1,3]dioxol-5-yloxy)phenyl)-1-(1-(4-(piperidin-1-yl)but-2-enoyl)pyrrolidin-3-yl)-1,3- Preparation of dihydro-2H-imidazo[4,5-c]pyridin-2-one) (compound 47)

The synthesis method was as in step 33c of Example 33, except that 4-dimethylaminocroton hydrochloride was replaced with 4-piperidinylcroton hydrochloride (112mg, 0.542mmol, 1.3 equivalents) to obtain compound (R, E)-4-amino-3-(4-(3,4-methylenedioxyphenoxy)phenyl)-1-(3-(1-(4-piperidinyl-2-butenoyl) )pyrrolidine))-1,3-2H-imidazo[4,5-c]pyridin-2-one (70 mg, yield: 29%). White solid, melting point: 125.2-128.3°C. TLC: Rf 0.2 (dichloromethane:methanol=10:1). LCMS (ESI): m/z 583[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.85-7.83 (m, 1H), 7.36 (d, J=8.5Hz, 2H), 7.08( d,J=2.5Hz,2H),6.95-6.90(m,1H),6.80(d,J=8.0Hz,1H),6.72-6.54(m,4H),6.00(s,2H),5.10-5.04 (m,1H),4.17-4.01(m,5H),3.78-3.55(m,1H),3.52-3.36(m,2H),2.95-2.60(m,6H),2.42-2.33(m,2H) ,1.88-1.83(m,4H).

Example 36: 4-Amino-1-[(3R)-1-(2-butenoyl)piperidin-3-yl]-3-(4-phenoxyphenyl)-1,3-di Hydrogen-2H-imidazo[4,5-c]pyridin-2-one (4-Amino-3-(4-phenoxy-phenyl)-1-[1-(4-piperidin-1-yl-but-2 Preparation of -enoyl)-piperidin-3-yl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (Compound 48)

4-Amino-3-(4-phenoxyphenyl)-1-[(3R)-piperidin-3-yl]-1,3-dihydro-2H-imidazo[4,5-c ]pyridin-2-one (308-11) (80 mg, 0.2 mmol, 1 equiv), 4-(piperidinamine)-2-butene hydrochloride (49 mg, 0.24 mmol, 1.2 equiv) were dissolved in DCM ( 5ml), HATU (99mg, 0.26mmol, 1.3eq) and Et ₃ N (61mg, 0.6mmol, 3eq) were added, and reacted under ice bath for 1 hour. The reaction was completed, concentrated, methanol/ethyl acetate (1:20) column chromatography gave white solid 4-amino-1-[(3R)-1-(2-butenoyl)piperidin-3-yl]- 3-(4-phenoxyphenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (16 mg, yield 15%); purity 96.7%; TLC: Rf 0.5 (dichloromethane:methanol=10:1); melting point: 85.2～86.0℃; LC-MS: 553[M+1] ⁺ ; ¹ HNMR (400MHz, CDCl ₃ ): δ1.48(s, 3.5H ),1.70(s,1H),1.98(m,2.5H),2.10(d,1.5H,J＝11.56Hz),2.21(t,0.5H,J＝7.51Hz),2.57(s,5.5H) ,3.12(t,1H,J=10.84Hz),3.27(s,2H),3.48(t,1H,J=10.76Hz),3.84(s,0.5H),4.15(s,4H),4.80(d ,1H,J=24.72Hz),6.63(m,2H),6.90(m,1H),7.10(m,4H),7.18(t,1H,J=7.4Hz),7.40(m,4H),7.87 (d, 1H, J = 5.44 Hz).

Example 37: 4-amino-1-[(3R)-1-(2-butenoyl)dimethylamino-3-yl]-3-(4-phenoxyphenyl)-1,3- Dihydro-2H-imidazo[4,5-c]pyridin-2-one (4-Amino-3-(4-phenoxy-phenyl)-1-[1-(4-piperidin-1-yl-but- Preparation of 2-enoyl)-dimethylamino-3-yl]-1,3-dihydro-imidazo[4,5-c]pyridin-2-one) (compound 49)

The synthesis method was as in Example 36, except that 4-(piperidinamine)-2-butene hydrochloride was replaced by 4-(dimethylamine)-2-butene hydrochloride (49mg, 0.24 mmol, 1.2 equivalents), to obtain white solid 4-amino-1-[(3R)-1-(2-butenoyl)dimethylamino-3-yl]-3-(4-phenoxyphenyl) -1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (20mg, yield 20%); purity 95.5%; TLC: Rf 0.4 (dichloromethane:methanol=10: 1); Melting point: 67～68℃; LC-MS: 513[M+1] ⁺ ; ¹ HNMR (400MHz, CDCl ₃ ): δ1.65(m, 0.5H), 1.98(m, 0.5H), 2.11 (d, 1.5H, J=12.64Hz), 2.21(t, 0.5H, J=7.52Hz), 2.37(d, 6H, 17.8Hz), 2.62(m, 1.5H), 3.21(m, 2.5H) ,3.46(m,0.5H),3.83(d,0.5H,J＝10.12Hz),4.15(s,4H),4.80(m,1H),6.60(m,2H),6.87(m,1H), 7.10 (m, 4H), 7.18 (t, 1H, J = 7.36Hz), 7.40 (m, 4H), 7.86 (d, 1H, J = 5.6Hz).

Example 38: (R)-1-(3-(1-acryloylpiperidine))-4-amino-3-(4-(1,4-benzodioxane-6-oxyl)phenyl )-1,3-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-(( 2,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 52) preparation of

Step 38a: (R)-1-tert-butoxycarbonyl-3-(4-amino-3-(1,4-benzodioxan-6-oxyl)phenyl)-2-oxo-2, 3-Dihydro-1H-imidazo[4,5-c]pyridyl)piperidine (tert-butyl(R)-3-(4-amino-3-(4-((2,3-dihydrobenzo[b ][1,4]dioxin-6-yl)oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridin-1-yl)piperidine-1-carboxylate)( Compound 307-52) Preparation

1-tert-butoxycarbonyl-3-(4-amino-3-(4-iodophenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridyl ) piperidine (402-17) (0.65g, 1.214mmol, 1.0eq), 1,4-benzodioxane-6-ol (403-52) (0.28g, 1.821mmol, 1.5eq) and N, N-Dimethylglycine hydrochloride (67.8mg, 0.486mmol, 0.4eq) was dissolved in dioxane (8mL), then copper iodide (23mg, 0.121mmol, 0.1eq) and cesium carbonate (1.19 g, 3.642mmol, 3.0 equivalents), and then reacted at 100°C for 20 hours under nitrogen protection. The reaction solution was cooled to room temperature and concentrated, and the obtained crude product was purified by column chromatography (dichloromethane:methanol=40:1 to 20:1) to obtain (R)-1-tert-butoxycarbonyl-3-(4- Amino-3-(1,4-benzodioxan-6-oxy)phenyl)-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]pyridyl) Piperidine (0.26 g, yield: 39%). LCMS (ESI): m/z 560[M+1] ⁺ , brown solid; TLC: Rf 0.4 (dichloromethane:methanol=20:1).

Step 38b: (R)-4-Amino-3-(4-(1,4-benzodioxan-6-oxyl)phenyl)-1-(3-piperidinyl)-1H-imidazo [4,5-c]pyridin-2(3H)-one ((R)-4-amino-3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl) Preparation of oxy)phenyl)-1-(piperidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one)(compound 308-52)

(R)-1-tert-butoxycarbonyl-3-(4-amino-3-(1,4-benzodioxan-6-oxyl)phenyl)-2-oxo-2,3- Dihydro-1H-imidazo[4,5-c]pyridyl)piperidine (307-52) (0.26g, 0.472mmol, 1.0eq) was dissolved in dichloromethane (10mL), and trifluoro Acetic acid (2 mL), followed by reaction at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (100mL), washed successively with saturated sodium carbonate solution (30mL×2) and saturated brine (60mL), and then the organic layer was spin-dried with silica gel, followed by column chromatography (Dichloromethane: Methanol: Triethylamine = 100:10:1) to obtain (R)-1-(3-piperidinyl)-4-amino-3-(4-(1,4-benzobis Oxan-6-oxy)phenyl)-1H-imidazo[4,5-c]pyridin-2(3H)-one (0.195 g, yield: 90%). LCMS (ESI): m/z 460[M+1] ⁺ , white solid; TLC: Rf 0.2 (dichloromethane:methanol=10:1).

Step 38c: (R)-1-(3-(1-acryloylpiperidine))-4-amino-3-(4-(1,4-benzodioxane-6-oxyl)phenyl) -1,3-2H-imidazo[4,5-c]pyridin-2-one ((R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-((2 ,3-dihydrobenzo[b][1,4]dioxin-6-yl)oxy)phenyl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one) (Compound 52) preparation

(R)-1-(3-piperidinyl)-4-amino-3-(4-(1,4-benzodioxane-6-oxyl)phenyl)-1H-imidazo[4 ,5-c]pyridin-2(3H)-one (308-52) (0.195g, 0.424mmol, 1.0eq), acrylic acid (40mg, 0.552mmol, 1.3eq), DCC (114mg, 0.522mmol, 1.3eq) and DMAP (5.1 mg, 0.042 mmol, 0.1 eq) were dissolved in dichloromethane (8 mL), then reacted at room temperature for 1 hour. After the reaction was completed, it was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=20:1) to obtain compound (R)-1-(3-(1-acryloylpiperidine))-4-amino- 3-(4-(1,4-Benzodioxane-6-oxyl)phenyl)-1,3-2H-imidazo[4,5-c]pyridin-2-one (62mg, yield : 28%). White solid, melting point: 235.0-236.7°C. TLC: Rf 0.5 (dichloromethane:methanol=10:1). LCMS (ESI): m/z 514[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.86 (d, J = 5.0Hz, 1H), 7.36 (d, J = 9.0Hz, 2H) ,7.08(d,J=9.0Hz,2H),6.87(d,J=9.0Hz,1H),6.65-6.58(m,4H),6.33-6.30(m,1H),5.71(s,1H), 4.83-4.78(m,1H),4.28(s,4H),4.27-4.01(m,4H),3.84-3.48(m,2H),3.12-2.52(m,2H),2.11-2.08(m,1H ), 1.98-1.95(m,1H).

Example 39: (R)-4-amino-3-(4-phenoxyphenyl)-1-(3-(1-vinylsulfonyl)piperidine))-1,3-2H-imidazo[4 ,5-c]pyridin-2-one ((R)-4-amino-3-(4-phenoxyphenyl)-1-(1-(vinylsulfonyl)piperidin-3-yl)-1,3-dihydro-2H- Preparation of imidazo[4,5-c]pyridin-2-one) (compound 55)

(R)-4-amino-1-(3-piperidinyl)-3-(4-phenoxyphenyl)-1,3-2H-imidazo[4,5-c]pyridine-2- Ketone (308-11) (0.26g, 0.648mmol, 1.0eq) and triethylamine (0.18mL, 1.296mmol, 2.0eq) were dissolved in dichloromethane (20mL), cooled to -60°C with a dry ice-acetone bath , then chloroethylsulfonyl chloride (158 mg, 0.971 mmol, 1.5 equiv) was dissolved in dichloromethane (5 mL) and added dropwise. The reaction solution was reacted at -60°C for 30 minutes and then slowly raised to room temperature. The solvent was removed by rotary evaporation to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=50:1) to obtain compound 6-53 (100 mg, yield: 31%). White solid, melting point: 86.3-89.4°C. TLC: Rf 0.5 (dichloromethane:methanol=15:1). LCMS (ESI): m/z 492[M+1] ⁺ , ¹ HNMR (CDCl ₃ , 500MHz): δ7.88 (d, J=5.5Hz, 1H), 7.41-7.37 (m, 4H), 7.20- 7.17(m,1H),7.13-7.08(m,4H),6.62(d,J=5.5Hz,1H),6.48-6.42(m,1H),6.27-6.23(m,1H),6.04(d, J=9.5Hz, 1H), 4.32-4.26(m, 1H), 4.16(s, 2H), 3.86-3.83(m, 2H), 3.48-3.44(m, 1H), 2.66-2.65(m, 1H) ,2.46-2.44(m,1H),2.03-1.98(m,2H),1.89-1.82(m,1H).

Embodiment 40 biological activity test

1. BTK enzyme activity inhibition experiment

1. Experimental method

Caliper mobility shift assay was used to measure BTK protein kinase activity (see J Biomol Screen 14:31, 2009). The compound obtained above was dissolved in DMSO and diluted 10 times with kinase buffer (50 mM HEPES-pH 7.5, 0.0015% Brij-35, 10 mM MgCl ₂ , 2 mM DTT), and 5 μl of 10% DMSO dissolved in 384-well plate was added. Compounds at 5 times the final concentration of the reaction, 5 μl of 10% DMSO in the control wells without compound and in the control wells without enzyme activity. Add 10 μl of BTK enzyme solution (BTK, Cat.No.08-080, Carna) at 2.5 times the final concentration of the reaction, and incubate with the compound at room temperature for 10 minutes, and add 10 μl of kinase buffer to the control well without enzyme activity. Then 10 μl of the substrate solution of FAM-labeled SRCtide peptide (Biochem, Cat. No. 112394) and ATP (90 μM) at 2.5 times the final concentration of the reaction was added to initiate the reaction. Then incubate at room temperature for 10 minutes. After incubation at 28° C. for 1 hour, 25 μl of stop solution (100 mM HEPES, pH 7.5, 0.015% Brij-35, 0.2% Coating Reagent#3, 50 mM EDTA) was added to terminate the reaction. Conversion data were read on a Caliper EZ Reader II (CaliperLife Sciences). Calculate the inhibition rate, and the calculation formula is inhibition rate%=(max-transformation)/(max-min)×100%.

2. Experimental results

These compounds can potently inhibit BTK activity, which is equal or better than the positive control compounds Ibrutinib and ONO-4059. Table 1 lists the activities of representative compounds described in the present invention in the BTK assay. In these assays, the following scales were used: I > 200 nM, 200 nM > II > 100 nM, 100 nM > III > 50 nM, 50 nM > IV > 10 nM, V < 10 nM for IC50.

Table 1 Inhibition results of BTK enzyme activity

Note: Compound numbers in the table correspond to those of Examples 1-39.

2. Tumor cell proliferation inhibition experiment

1. Experimental method

Cell viability was assessed by measuring the content of adenosine triphosphate (ATP) using the CellTiter-Glo Luminescent Cell Viability Assay Kit (Promega, #G7572, Madison, WI). Diffuse large B-cell lymphoma cell line TMD-8 and large B-cell lymphoma cell line SU-DHL-16 were purchased from Shanghai Fudan IBS Cell Resource Center and American Type Culture Collection (ATCC). The cells were digested from the cell culture dish with trypsin and resuspended in DPBS medium, and counted to determine the cell density with a Scepter automatic cell counter (Millipore, #PHCC00000). Cells were diluted to a solution containing 44,000 cells per milliliter. The density-adjusted cell solution was added to the cell experiment plate at 90 μl per well. The orifice plate was placed in a 37° C., 5% CO ₂ incubator for 24 hours, and then different concentrations of the test compound were added. Cells were incubated with compounds for 72 hours in the presence of 10% fetal calf serum. use Luminescent Cell ViabilityAssay kit (see manufacturer's instructions) measures ATP content to evaluate cell growth inhibition. Briefly, add 30 μl to each well The reagents were shaken for 10 minutes to induce cell lysis, and the fluorescence signal was detected and recorded with a fluorescence/chemiluminescence analyzer Fluoroskan Ascent FL (ThermoScientific Fluoroskan Ascent FL). Maximum signal values were obtained from cells treated with dimethylsulfoxide (DMSO) for 72 or 120 hours. The minimum signal value obtained from medium alone (zero cell number) was defined as 0. Inhibition rate %=(maximum signal value-compound signal value)/(maximum signal value-minimum signal value)×100%. Data were processed using GraphPad Prism V5.0 (GraphPad Software, San Diego, CA) software. IC50 values were calculated by sigmoidal dose-response curve fitting.

2. Experimental results

This type of compound has strong anti-cell proliferation activity on tumor cells such as TMD-8, SU-DHL-16, etc., which is equivalent or better than the activity of the positive control compound Ibrutinib and ONO-4059, listed in the following table 2 The anti-cell proliferation activity of representative compounds described in the present invention in cell-based assays was demonstrated. In these assays the following scales were used: I>1uM, 1uM>II>0.1uM, 0.1uM>III>0.05uM, 0.05uM>IV>0.01uM, V<0.01uM for IC50.

Table 2 Inhibition results of tumor cell proliferation

Note: Compound numbers in the table correspond to those of Examples 1-39.

3. Western Blot experiment

1. Experimental method

ATCC human mantle cell lymphoma cells Jeko-1 and DOHH-2 were purchased from Shanghai Baili Biotechnology Co., Ltd. and grown in suspension culture. After adding the test compound or reference compound and culturing for 1 hour, the cells were collected by low-speed centrifugation (1200rpm; 4min). Cells were then resuspended in serum-free medium. Add GoatF(ab')2Anti-Human IgM (10ug/ml), after 2min, wash twice with pre-cooled PBS, collect the cells, homogenize 3 times with a biological sample homogenizer, centrifuge at 12,000rpm at 4°C for 10min, Take the supernatant. The protein concentration was determined by the Branfor method, adding loading buffer (Beyotime, #P0015L) and cooking at 100°C for 4 minutes, separating the protein by 10% SDS-PAGE electrophoresis and transferring it to a PVDF membrane, and then using 5% bovine serum albumin (BSA ) (Beiyuntian; CATNo.ST023) in TBST solution for blocking for 1 hour, add primary antibody β-actin mAb (CST, #4970), BTK (D3H5) mAb (CST, #8547) or phospho-BTK (Try223) mAb ( CST, #5802) was incubated overnight at 4°C, and then the membrane was washed with TBST solution for 3×10 min. After incubating with the fluorescent secondary antibody IRDye@680CW Goat (polyclonal) Anti-Rabbit IgG (H+L), Highly Cross Adsorbed (LI-COR, #926-68071) in the dark for 2 hours at room temperature, the membrane was washed under the same washing conditions as above. Finally, the membrane was placed on the LI-COR Odyssey infrared fluorescence scanning imaging system for detection and imaging.

2. Experimental results

Compound 11 prepared in Example 11 and the reference substance Ibrutinib strongly inhibited the phosphorylation of BTK protein in Jeko-1 and DOHH-2 lymphoma cells, and significantly decreased the expression of p-BTK in Jeko-1 and DOHH-2 cells under IgM stimulation (the results are shown in Fig. 1). It can be seen from Figure 1 that compound 11 provided by the present invention acts on Jeko-1 and DOHH-2 human lymphoma cells, and can effectively reduce the phosphorylation of BTK.

Embodiment 41 Pharmacokinetics (PK) experiment

1. Experimental method

Male SD rats, weighing 250-300 grams, fasted overnight before the test. The compound to be tested was dissolved in 30% sulfobutyl-β-cyclodextrin (SBE-β-CD), and administered by intragastric administration at 20 mg/kg. 15 minutes, 30 minutes and 1, 2, 3, 4, 6, 8, and 24 hours after administration, blood was collected from the tail end, about 0.3ml at each time point, placed in a centrifuge tube containing K ₂ -EDTA, and centrifuged (2,000g, 10 minutes, 4°C) Plasma was collected and stored in an ultra-low temperature freezer at -80°C. 50 μL of plasma samples were mixed with 5 μL of internal standard (IS) and extracted with ethyl acetate. After drying in vacuo the residue was redissolved in acetonitrile. Samples were filtered and injected for LC-MS/MS analysis.

2. Experimental results

Compound 1 prepared in Example 1 and Compound 11 prepared in Example 11 were absorbed well after intragastric administration, and the blood exposure dose was high. Cmax were 544.3 and 2776.7 ng/ml, respectively. Compound 11 had a shorter half-life (1.2 hours), but a higher AUC (4985.5 ng/ml*h) (Table 3). In the table, Tmax refers to the peak time, Cmax refers to the maximum blood concentration, T1/2 refers to the half-life, AUC _0-24 refers to the area under the 0-24 hour time-concentration curve, AUC _inf refers to the 0-Inf time-concentration area under the curve.

Table 3. Pharmacokinetic data of intragastric administration (20mg/kg)

Embodiment 42 pharmacodynamic experiment

1. Experimental method

SCAD mice with severe immunodeficiency were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., and were raised in the SPF animal room. When the human diffuse large B-cell lymphoma cell line TMD-8 reaches a sufficient number in the culture dish, the cells are collected and washed twice with DPBS. Finally, cells were inoculated in suspension with serum-free RPMI1640 medium and Matrigel (1:1, v/v). Only single cell suspensions with greater than 90% viability (trypan blue exclusion) were used for injection. Using a 1ml syringe and a 25G syringe needle, inject 5 million cells suspended in 0.2ml of serum-free medium and Matrigel (1:1, v/v) into the subcutaneous area of the right flank of each mouse and carefully avoid Open blood vessels. Tumor size can be measured within about a week of implantation. Measure the size of the tumor using calipers. And the tumor volume was calculated with the following formula: tumor volume=(length×width ² )/2.

When the tumor volume reaches about ^100-300mm3 , the mice are divided into 3 intragastric administration groups, i.e. vehicle control group, Ibrutinib intragastric administration group (50mg/kg, 1 time/day) and Example 11 The prepared compound 11 was administered orally to the group (25 mg/kg, 2 times/day). 6 animals per group. Dissolve Ibrutinib or Compound 11 in 30% sulfobutyl-β-cyclodextrin (SBE-β-CD) and 1.0 molar equivalent of hydrochloric acid (pH 3-4), and administer by intragastric administration at 10ml/kg, continuously Administration for 14 days.

2. Experimental results

Compound 11 and Ibrutinib have extremely high antitumor activity in the TMD-8 transplanted tumor model. Oral administration of compound 11 (dose 25 mg/kg, bid) can significantly inhibit the growth of diffuse large B-cell lymphoma cell line TMD-8, and after 14 days of administration, the transplanted tumor TMD-8 shrinks to disappear. Compared with before administration, there was no significant weight loss in each administration group (Fig. 2).

The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, should be considered as within the scope of this specification.

The above-mentioned embodiments only express several implementation modes of the present invention, and the descriptions thereof are relatively specific and detailed, but should not be construed as limiting the patent scope of the invention. It should be pointed out that those skilled in the art can make several modifications and improvements without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.

Claims (18)

1. the 2- oxo 1,3- glyoxalidine with formula (I) structure and pyridine compounds and their or its pharmaceutically acceptable salt：

In formula：

X₁And X₂It is selected from C；

Ar is selected from phenyl ring；

L is selected from O, OCH₂；

Y is selected from (CHR₅)_m, C=O, wherein m are selected from 0,1；

Z is selected from：

G is selected from following group：

R₁And R₂It is respectively and independently selected from：H, C₁-C₆Alkyl, halogen, nitro, hydroxyl, C₁-C₆Alkoxy, cyano, amino, C₁-C₆Alkane Base substituted amido, acyl group, amide groups；

R₃And R₄It is respectively and independently selected from：H, C₁-C₆Alkyl, C₃-C₆Naphthenic base, C₃-C₆Methyl cycloalkyl, halogen replace C₁-C₄Alkyl, Hydroxyl replaces C₁-C₄Alkyl, C₁-C₃Alkoxy replaces C₁-C₄Alkyl, amino replace C₁-C₄Alkyl, C₁-C₃Alkyl amine group replaces C₁- C₄Alkyl, halogen, nitro, hydroxyl, C₁-C₆Alkoxy, C₁-C₆Alkylthio group, C₁-C₆Sulfoxide group, C₁-C₆Sulfuryl, cyano, amino, C₁-C₆Alkyl substituted amido, ester group, acyl group, amide groups, carboxyl；And R₃And R₄It is asynchronously hydrogen；

Work as R₃And R₄It is C₁-C₆Alkyl, C₁-C₆Alkoxy, OH or C₁-C₆Alkyl substituted amido, and it is substituted in the adjacent position of Ar When, R₃And R₄One carbocyclic ring of connectable composition or heterocycle are selected from having structure：

Wherein, n is selected from 0,1,2；Q₁And Q₂It is respectively and independently selected from O, NR₆, CHR₆；

R₅、R₆It is respectively and independently selected from H, C₁-C₆Alkyl；

R₇Selected from H, C₁-C₆Alkyl, C₁-C₃Alkoxy replaces C₁-C₄Alkyl, amino replace C₁-C₄Alkyl, C₁-C₃Alkyl amine group takes For C₁-C₄Alkyl, heterocyclic substituted C₁-C₄Alkyl.

2. 2- oxos 1,3- glyoxalidine according to claim 1 and pyridine compounds and their or its is pharmaceutically acceptable Salt, which is characterized in that G is selected from following group：

3. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that Y is selected from (CH₂)_m, wherein m is 0 or 1.

4. 2- oxos 1,3- glyoxalidine according to claim 1 or 2 and pyridine compounds and their or its is pharmaceutically acceptable Salt, which is characterized in that Z be selected from following group：

5. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that R₃And R₄It is respectively and independently selected from：H, halogen, hydroxyl, C₁-C₆Alkoxy, hydroxyl replace C₁-C₄Alkane Base, C₁-C₆Alkyl substituted amido；And R₃And R₄It is asynchronously hydrogen；

Work as R₃And R₄It is C₁-C₆Alkoxy or when OH, and when being substituted in the adjacent position of Ar, R₃And R₄Connectable composition one is miscellaneous Ring is selected from having structure：

Wherein, n is 0 or 1.

6. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that R₅And R₆It is H.

7. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that R₇Selected from H, C₁-C₆Alkyl, C₁-C₃Alkoxy replaces C₁-C₄Alkyl, C₁-C₃Alkyl amine group replaces C₁-C₄Alkyl, 5-6 members are saturated azacyclo- and replace C₁-C₄Alkyl.

8. according to claim 1-2 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its pharmaceutically may be used The salt of receiving, which is characterized in that

X₁And X₂It is C；

L is selected from O, OCH₂；

Y is selected from (CH₂)_m, wherein m is 0 or 1；

Z is selected fromOr

R₁And R₂It is hydrogen；

R₃And R₄In one be hydrogen, another is selected from halogen or hydroxyl or C₁-C₆Alkoxy；Or work as R₃And R₄For C₁-C₆Alcoxyl Base or when OH, and it is substituted in the adjacent position of Ar, R₃And R₄One heterocycle of connectable composition is selected from having structure：

Wherein, n is 0 or 1；

R₅And R₆It is H；

R₇Selected from H, C₁-C₆Alkyl, C₁-C₃Alkoxy replaces C₁-C₄Alkyl, C₁-C₃Alkyl amine group replaces C₁-C₄Alkyl, 5-6 members are full Replace C with azacyclo-₁-C₄Alkyl.

9. 2- oxos 1,3- glyoxalidine according to claim 1 and pyridine compounds and their or its is pharmaceutically acceptable Salt, which is characterized in that the compound is selected from：

10. claim 1-9 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its can pharmaceutically connect Application of the salt received in preparing bruton's tyrosine kinase inhibitor.

11. claim 1-9 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its can pharmaceutically connect Application of the salt received in the drug for preparing anti-curing oncoma.

12. claim 1-9 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its can pharmaceutically connect Application of the salt received in the drug for preparing prevention neoplastic hematologic disorder.

13. application according to claim 12, which is characterized in that the neoplastic hematologic disorder is that lymthoma, myeloma, lymph are thin Born of the same parents' leukaemia or acute myeloid leukemia.

14. claim 1-9 any one of them 2- oxo 1,3- glyoxalidine and pyridine compounds and their or its can pharmaceutically connect Application of the salt received as bruton's tyrosine kinase inhibitor in preparing the drug of prevention inflammation or autoimmune disease.

15. application according to claim 14, which is characterized in that the inflammation or autoimmune disease are closed for rheumatoid Save inflammation, lupus erythematosus, lupus nephritis, multiple sclerosis, gren's syndrome and potential disease asthma.

16. a kind of pharmaceutical composition for treating disease, which is characterized in that include as active constituent claim 1-9 it is any 2- oxos 1 described in, 3- glyoxalidine and pyridine compounds and their or its pharmaceutically acceptable salt and pharmaceutically acceptable Carrier.

17. pharmaceutical composition according to claim 16, which is characterized in that the disease is neoplastic hematologic disorder or and Bu Ludun The relevant inflammation of tyrosine kinase or autoimmune disease.

18. pharmaceutical composition according to claim 17, which is characterized in that the neoplastic hematologic disorder be lymthoma, myeloma, Lymphocytic leukemia, acute myeloid leukemia；The inflammation or autoimmune disease are rheumatoid arthritis, erythema wolf Sore, lupus nephritis, multiple sclerosis, gren's syndrome and potential disease asthma.