Compounds with cGAS inhibitory activity

Abstract

The invention provides a compound as shown in a formula (I). The compound inhibits cGAS in a targeted manner. The invention also includes pharmaceutical compositions comprising said compounds and methods for treating conditions associated with cGAS inhibitory activity. # imgabs0 #

Description

[0001] Citation of Related Applications

[0002] This application claims priority to Chinese patent application CN202311502238.X filed on November 10, 2023, the contents of which are incorporated by reference into this application in their entirety and for all purposes. Technical Field

[0003] The present application belongs to the field of medicinal chemistry, and specifically relates to a compound having cGAS inhibitory activity. Background Art

[0004] Cyclic GMP-AMP synthase (cGAS) (UniProtKB-Q8N884) is a recently discovered enzyme that acts as a DNA sensor to elicit immune responses to pathogens via activation of the stimulator of interferon genes (STING) receptor. Soon after its discovery in 2013, aberrant activation of cGAS by self DNA was shown to underlie debilitating and sometimes fatal autoimmune diseases such as systemic lupus erythematosus (SLE), scleroderma, and Aicardi-Goutieres Syndrome (AGS). Knockout studies in animal models have shown that inhibition of cGAS is a promising therapeutic intervention. Additionally, recent studies have shown that the cGAS-STING pathway plays a key role in the innate immune response to tumors, and stimulating this pathway is a promising strategy being tested in the clinic for cancer immunotherapy.

[0005] There are no drugs approved specifically for AGS or any other monogenic type I interferonopathy. Current treatment options are limited to intravenous or oral immunosuppressants and intravenous immunoglobulin during the acute phase, which usually only partially control exacerbations. Similarly, SLE is also treated with over-the-counter anti-inflammatory drugs, corticosteroids, and immunosuppressants (such as cyclophosphamide and methotrexate), which have serious side effects, including cancer. The only targeted therapy approved for SLE is BENLYSTA (belimumab), a monoclonal antibody (mAb) against B cell activating factor (BAFF). BENLYSTA reduces the risk of severe exacerbations and allows the use of lower doses of immunosuppressants in most patients, but is not curative.

[0006] Therefore, there is still a need for compounds that can effectively inhibit the inhibitory activity of cGAS and treat diseases caused by abnormal activation of cGAS. Summary of the invention

[0007] The purpose of the present invention is to provide a small molecule compound that targets and inhibits cGAS.

[0008] One aspect of the present disclosure provides a compound represented by formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0009]

[0010] R 1 for

[0011] R x is selected from halogen or 5-6 membered nitrogen-containing heteroaryl, wherein the heteroaryl may be further substituted with halogen, -NH2, C 1-3 Alkyl or C 1-3 haloalkyl substitution;

[0012] R y Selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl;

[0013] X1, X2 and X3 are each independently selected from CH or N; and X3 is different from X2;

[0014] m, n are selected from 0, 1, 2 or 3;

[0015] L 1 Selected from *-NH-, -CONH-*, wherein * is connected to ring A;

[0016] Ring A is selected from phenyl, cyclohexyl, benzocyclohexyl, pyridocyclohexyl;

[0017] R 1-1 is carboxyl, halogen;

[0018] Ring B is a 5-membered nitrogen-containing heterocycloalkyl group; 2 is a bond, -(CH2) s -CONH-, -O-;

[0019] Ring C is absent, pyridine, or pyridopyridine;

[0020] R 1-2 Selected from cyano, 6-membered heterocycloalkyl,

[0021] s is 0, 1, 2, or 3;

[0022] Wherein, the compound represented by formula (I) is not

[0023] When ring C is absent, R 1for

[0024] In one embodiment of the present invention, the compound represented by formula (I) is represented by formula (I-1) or formula (I-2):

[0025]

[0026] In one embodiment of the present invention, Selected from the group consisting of:

[0027]

[0028] In one embodiment of the present invention, formula (I) is as shown in formula (I-1-1), formula (I-1-2) or formula (I-2-1):

[0029]

[0030] In one embodiment of the present invention, ring A is independently The position of A is 1 connection, B is located at the same position as R 1-1 connect.

[0031] In one embodiment of the present invention, L 2 It is -(CH2)-CONH- or -O-.

[0032] In one embodiment of the present invention, formula (I) is as shown in formula (I-1-1-1), formula (I-1-1-2), formula (I-1-2-1) or formula (I-2-1-1):

[0033]

[0034] In one embodiment of the present invention, R x are independently halogen, pyridyl, or pyrazolyl, wherein the pyridyl or pyrazolyl may be further substituted with halogen, -NH2, C 1-3 Alkyl or C 1-3 Haloalkyl substitution.

[0035] In one embodiment of the present invention, R x are independently halogen, pyridyl, or pyrazolyl, wherein the pyridyl or pyrazolyl may be further substituted with -NH2 or C 1-3 Alkyl substitution.

[0036] In one embodiment of the present invention, R x are independently F, Cl, Br, I, pyridyl, pyrazolyl, wherein the pyridyl and pyrazolyl groups may be further substituted with halogen or C 1-3 Alkyl substitution.

[0037] In one embodiment of the present invention, R x are independently Cl, Br,

[0038] In one embodiment of the present invention, m is selected from 0, 1 or 2, preferably m is selected from 0 or 1. In one embodiment of the present invention, R y Independently for C 1-3 Alkyl or C 1-3 Haloalkyl, preferably R y are independently methyl, difluoromethyl or trifluoromethyl.

[0039] In one embodiment of the present invention, n is selected from 0, 1 or 2.

[0040] In one embodiment of the present invention, n is selected from 1, 2 or 3, preferably 1 or 2.

[0041] In one embodiment of the present invention, R 1-2 Selected from H, halogen, cyano, C 2-6 Alkynyl, 6-membered heterocycloalkyl,

[0042] In one embodiment of the present invention, R 1-2 Selected from C 2-4 Alkynyl, 6-membered heterocycloalkyl, the 6-membered heterocycloalkyl having 1 or 2 heteroatoms selected from N, O or S, preferably having 1 nitrogen heteroatom and 0 or 1 oxygen heteroatom.

[0043] In one embodiment of the present invention, R 1-2 Selected from ethynyl and morpholinyl.

[0044] In one embodiment of the present invention, p is selected from 1 or 2, preferably 1.

[0045] In one embodiment of the present invention, q is selected from 0, 1, 2 or 3, preferably 0, 1 or 2.

[0046] In one embodiment of the present invention, L 1 Selected from *-NH-, -CONH-*, -C(=O)-*, wherein * is connected to ring A;

[0047] In one embodiment of the present invention, R 1-2 are independently cyano,

[0048] Another aspect of the present disclosure provides a compound or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the group consisting of the following compounds in Table 1:

[0049] Table 1

[0050]

[0051]

[0052]

[0053]

[0054] Another aspect of the present disclosure provides a compound or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the group consisting of the following Table 2 compounds:

[0055] Table 2

[0056]

[0057]

[0058]

[0059] Another aspect of the present disclosure provides a compound represented by formula (II) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs,

[0060]

[0061] R 2 is selected from H, halogen or 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is optionally substituted by -NH2 or C 1-3 Preferably, the 5-6 membered heteroaryl is selected from pyridyl and pyrazolyl; More preferably, R 2 is selected from H, halogen, optionally substituted by -NH2 or C 1-3 Alkyl substituted More preferably, R 2 Selected from H, Cl,

[0062] R 3 Selected from H, C 1-3 Alkyl or C 1-3 Preferably, R 3 Selected from H, methyl, -CH2-CF3;

[0063] Ring D is selected from phenyl or 6-membered nitrogen-containing heterocycloalkyl; preferably, ring D is selected from phenyl, m1 is selected from 0, 1, 2 or 3;

[0064] Wherein the compound represented by formula (I) is not

[0065] In one embodiment of the present invention, formula (II) is as shown in formula (II-1):

[0066]

[0067] In one embodiment of the present invention, formula (II-1) is as shown in formula (II-1-1) or formula (II-1-2):

[0068]

[0069] In one embodiment of the present invention, m1 is selected from 0, 1 or 2. In one embodiment of the present invention, R 2 Selected from H or halogen.

[0070] In one embodiment of the present invention, R 3 Selected from H.

[0071] In one embodiment of the present invention, ring D is selected from phenyl.

[0072] Another aspect of the present disclosure provides a compound or its stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound, nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from the group consisting of the following Table 3 compounds:

[0073] Table 3

[0074]

[0075]

[0076] Another aspect of the present disclosure provides a composition, which includes a compound as shown in Formula I as described above, a compound as shown in Formula II as described above, stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds, nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable adjuvants, carriers or diluents.

[0077] In one embodiment of the present invention, the dosage form is selected from plain tablets, film-coated tablets, sugar-coated tablets, enteric-coated tablets, dispersible tablets, capsules, granules, oral solutions or oral suspensions.

[0078] Another aspect of the present disclosure provides a compound as shown in Formula I as described above, a compound as shown in Formula II as described above, or a group consisting of the compounds in Table 4 below, their stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds, nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions for use in the preparation of drugs for diseases or conditions associated with cGAS activation or mediated by cGAS.

[0079] Table 4

[0080]

[0081]

[0082] Another aspect of the present disclosure provides a compound as shown in Formula I as described above, a compound as shown in Formula II as described above, or a group consisting of the compounds in Table 5 below, and their stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds, nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs for use in preparing a drug for treating inflammation or autoimmune diseases.

[0083] Table 5

[0084]

[0085] In a certain embodiment of the present invention, the disease or disorder associated with cGAS activation or mediated by cGAS is selected from inflammatory diseases or autoimmune diseases.

[0086] In a certain embodiment of the present invention, the inflammatory or autoimmune disease is selected from: wherein the disease is acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, visual neovascularization and juvenile hemangioma, B-cell lymphoma, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, polyangiitis, idiopathic thrombocytopenic purpura, myasthenia gravis, allergic rhinitis, multiple sclerosis, transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, sarcoidosis, Sjogren's syndrome, peripheral neuropathy, pemphigus vulgaris and asthma.

[0087] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. The experimental methods in the following examples where specific conditions are not specified are usually based on conventional conditions.

[0088] Some representative compounds of the present invention can be prepared by the following synthesis methods. In the following reaction formulas, the reagents and conditions of each step can be selected from conventional reagents or conditions for such preparation methods in the art. After the structure of the compound of the present invention is disclosed, the above selection can be made by those skilled in the art based on the knowledge in the art. DETAILED DESCRIPTION

[0089] The inventors of the present application have conducted extensive and in-depth research and developed a cGAS targeted inhibitor for the treatment of inflammatory diseases and autoimmune diseases. Based on this, the present invention was completed.

[0090] the term

[0091] In the present invention, unless otherwise specified, the terms used have the general meanings well known to those skilled in the art.

[0092] In the present invention, the halogen is F, Cl, Br or I.

[0093] In the present invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" refers to having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on. "5-14 membered" refers to having 5-14 ring atoms, and so on.

[0094] In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety. For example, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0095] In the present invention, the term "haloalkyl" means that at least one carbon atom in the alkyl group is substituted by a halogen, such as trifluoromethyl or difluoromethyl.

[0096] In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety, for example, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl, etc. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

[0097] In the present invention, the term "heterocycloalkyl" refers to a saturated cyclic group containing at least one ring heteroatom (eg N, O or S), such as tetrahydrofuranyl, pyrrolyl, tetrahydropyridinyl or pyrrolidinyl.

[0098] In the present invention, unless otherwise specified, the alkyl, cycloalkyl, and heteroalkyl ring groups described herein are represented as unsubstituted, and the alkyl, cycloalkyl, and heteroalkyl ring groups may be substituted by substituents to form substituted alkyl, cycloalkyl, and heteroalkyl rings. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclic and aryl groups include, but are not limited to: hydroxyl, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino ... C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkylsulfoimino, arylsulfoimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, ureido, cyano, acyl, thioacyl, acyloxy, carboxyl and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl and heteroaryl groups may also be condensed with each other.

[0099] In the present invention, the substitution is mono- or poly-substitution, and the poly-substitution is di-, tri-, tetra- or penta-substitution. The di-substitution means having two substituents, and so on.

[0100] Pharmaceutically acceptable salts of the present invention can be salts formed by negatively charged groups on negatively charged ions and formula I or formula II compounds. Suitable negatively charged ions are chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, acetate, malate, toluenesulfonate, tartrate, fumarate, glutamate, glucuronide, lactate, glutarate or maleate. Similarly, salts can be formed by negatively charged groups on positively charged ions and formula I or formula II compounds. Suitable positively charged ions include sodium ions, potassium ions, magnesium ions, calcium ions and ammonium ions, such as tetramethylammonium ions.

[0101] In another preferred embodiment, "pharmaceutically acceptable salt" refers to the salts formed by the compound of formula I or formula II with an acid selected from the group consisting of hydrofluoric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, acetic acid, oxalic acid, sulfuric acid, nitric acid, methanesulfonic acid, aminosulfonic acid, salicylic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, maleic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, oxalic acid, pyruvic acid, malic acid, glutamic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, malonic acid, fumaric acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid and isethionic acid, etc.; or the sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed by the compound of formula I or formula II with an inorganic base; or the methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of general formula I with an organic base.

[0102] Example

[0103] Part Number

[0104] Compound 1: Chembridge: 6064112; Compound 2: Chembridge: 6997115; Compound 3: Chemdiv: 8017-0656; Compound 4: Enamine: Z227858320.

[0105] Example 5 Preparation of Compound 5

[0106]

[0107] Step 1: Add 5-1 (10 g, 68.04 mmol) to a solution of sodium hydride (8.16 g, 204.12 mmol) in N,N-dimethylformamide (60 mL) at 0°C under nitrogen, gradually raise the temperature to room temperature 25°C and stir for 30 minutes, cool to 0°C and slowly add 2-(trimethylsilyl)ethoxymethyl chloride (18.10 mL, 102.06 mmol), and stir the resulting mixture at room temperature for 18 hours to obtain a mixed solution. LCMS shows that the starting material is consumed and the desired product is formed. Pour the mixture into an aqueous ammonium chloride solution (200 mL) and extract with ethyl acetate (200 mL×2), wash the combined organic phases with brine (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain a crude product. The crude product is purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 2:1) to obtain intermediate 5-2. LC-MS(ESI): m / z=277.0 / 279.0[M+H]+.

[0108] Step 2: N-iodosuccinimide (11.11 g, 49.38 mmol) was added to a mixed solution of 5-3 (5.84 mL, 49.38 mmol), toluene (1000 mL) and acetic acid (28.24 mL, 493.80 mmol), and the resulting mixture was stirred at room temperature for 18 hours to obtain a mixed solution. TLC showed that the starting material was completely consumed, and spots with less polarity were observed. The mixture was poured into water (500 mL) and extracted with ethyl acetate (500 mL×2), and the combined organic phases were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 100:1 to 20:1) to obtain intermediate 5-4. 1 HNMR (400MHz, CDCl3) δ7.46 (d, J = 8.5 Hz, 1H), 6.61 (d, J = 8.5 Hz, 1H), 4.68 (s, 2H).

[0109] Step 3: Add bis(di-tert-butylchlorophosphine)palladium dichloride (374.17 mg, 0.69 mmol) to a solution of intermediate 5-4 (10 g, 34.73 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl (15.03 mL, 104.20 mmol) and triethylamine (19.26 mL, 138.93 mmol) in 1,4-dioxane (100 mL), replace with nitrogen three times, and stir at 100 ° C for 2 hours under nitrogen. A mixed solution was formed. LCMS showed that the starting material was consumed and the target product was formed. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×3), and the combined organic phases were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (eluent: 30% to 100% (v / v) acetonitrile and 0.5% aqueous ammonium bicarbonate solution) to give intermediate 5-5. LC-MS (ESI): m / z = 288.0 [M+H] +.

[0110] Step 4: 1,1'-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (38.12 mg, 0.06 mmol) was added to a solution of intermediate 5-5 (4.29 g, 14.90 mmol) and intermediate 5-2 (4.96.01 g, 17.88 mmol) and tripotassium phosphate (9.49 g, 44.69 mmol) in 1,4-dioxane (40 mL) and water (10 mL), replaced with nitrogen three times, and stirred at 100 ° C for 2 hours under nitrogen to form a mixed solution. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×3), and the combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 100: 1 to 10: 1) to obtain intermediate 5-6. LC-MS (ESI): m / z = 358.0 [M+H] +.

[0111] Step 5: To a solution of intermediate 5-6 (2.7 g, 7.53 mmol) and copper (I) bromide (2.16 g, 15.07 mmol) in acetonitrile (30 mL) was added tert-butyl nitrite (1.81 mL, 15.07 mmol), and the resulting mixture was stirred at 80°C for 2 hours to obtain a mixed solution. LCMS showed that the starting material was consumed and the target product was formed. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phase was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 2:1) to obtain intermediate 5-7. LC-MS (ESI): m / z = 420.9 / 422.9 [M+H]+.

[0112] Step 6: Add intermediate 5-7 (2.36 g, 5.58 mmol), 2-isocyano-2-methylpropane (1.27 mL, 11.17 mmol), [4-(diphenylphosphino)butyl]diphenylphosphine (476.36 mg, 1.12 mmol) and toluene (50 mL) into a microwave tube, replace the resulting mixture with nitrogen three times, add palladium acetate (250.77 mg, 1.12 mmol), then replace nitrogen three times, microwave at 120°C for 1.5 hours, then cool to room temperature. LCMS shows that the starting material is consumed and the target product is formed, and the mixture is concentrated to dryness under reduced pressure to obtain intermediate 5-8.

[0113] Step 7: Add hydrochloric acid (10 mL, 4 mol / L) to a solution of intermediate 5-8 in tetrahydrofuran (10 mL), and stir the resulting mixture at 60 ° C for 2 hours to obtain a mixed solution. LCMS shows that the starting material is consumed and the desired product is formed. The reaction mixture is alkalized to pH = 8 with aqueous sodium bicarbonate solution and extracted with ethyl acetate (30 mL × 3), and the combined organic phases are washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product is purified by preparative HPLC (eluent: 0.5% formic acid: acetonitrile = 100: 0 to 3: 1) to obtain intermediate 5-9. LC-MS (ESI): m / z = 238.9.0 [M+H] +.

[0114] Step 8: To a solution of intermediate 5-9 (350 mg, 1.46 mmol) and triethylamine (2.03 mL, 14.64 mmol) in acetonitrile (5 mL) was added 5-10 (254.77 μL, 1.76 mmol), and the resulting mixture was stirred at 30 ° C for 2 hours to obtain a mixed solution. LCMS showed that the starting material was consumed and the desired product 5-11 was formed. The reaction mixture was used for the next step without further treatment.

[0115] Step 9: To the solution of intermediate 5-11, acetonitrile (2 mL) and triethylamine (1.01 ml, 7.31 mmol) were added, and the resulting mixture was stirred at 50°C for 0.5 hours to obtain a mixed solution. LCMS showed that the starting material was consumed and the target product was formed. The crude product was filtered and purified by preparative HPLC to obtain compound 5. LC-MS (ESI): m / z=387.0 [M+H]+. 1 H NMR (400MHz, DMSO) δ7.81 (s, 1H), 7.50 (d, J = 7.5Hz, 3H), 7.40 (s, 1H), 7.08–7.00 (m, 1H).

[0116] Example 6 Preparation of Compound 6

[0117]

[0118] Step 1: To a mixed solution of 6-1 (1.00 g, 4.01 mmol) and isopropanol (10 mL) was added 2-methylpropan-2-yl 3-aminobenzoate (1.16 g, 6.01 mmol), and the resulting mixture was stirred at 80 ° C for 16 hours. After 16 hours, LCMS monitoring showed that the starting material was consumed and the desired product was formed. The mixture was filtered, and the filter cake was washed with petroleum ether (8 mL) and dried under reduced pressure to obtain intermediate 6-2. LCMS (ESI): m / z=406.0 / 408.0 [M+H]+

[0119] Step 2: To a mixture of intermediate 6-2 (100 mg, 0.25 mmol) and acetonitrile (3 mL), (3,4-dichlorophenyl) boron diol (70.44 mg, 0.37 mmol), potassium carbonate (68.03 mg, 0.49 mmol) and bis[5-(diphenylphosphino)cyclopentyl-1,3-dienyl]-λ2-iron (II) palladium chloride (18.01 mg, 0.02 mmol) were added, and the mixture was replaced with nitrogen three times and stirred at 80° C. for 16 hours under nitrogen protection. After 16 hours, LCMS monitoring showed that the starting material was consumed and the desired product was formed. The mixture was concentrated, and the crude product was separated and purified by preparative TLC (DCM: MeOH = 20: 1) and preparative HPLC (Phenomenex Gemini 150mm*25mm*10um colume) (eluent: 30% to 60% (v / v) CH3CN and H2O, containing 0.025% formic acid) to obtain intermediate 6-3. LCMS (ESI): m / z = 472.0 [M+H]+. 1 H NMR (400MHz, DMSO-d6) δ9.88(s,1H),8.57(s,1H),8.41(s,1H),8.38–8.35(m,1H),8.25(dd,J=8.0,1.2Hz,1H),7.98(d,J= 2.2Hz,1H),7.81(d,J=8.4Hz,1H),7.71(dd,J=8.4,2.2Hz,1H),7.65(d,J=7.8Hz,1H),7.53(t,J=7.8Hz,1H),1.59(s,9H).

[0120] Step 3: To a mixed solution of intermediate 6-2 (150 mg, 0.32 mmol) and dichloromethane (1.5 mL) was added trifluoroacetic acid (2 mL, 26.84 mmol), and the resulting mixture was stirred at room temperature for 1 hour. After 1 hour, LCMS monitoring showed that the starting material was consumed and the desired product was formed. The mixture was concentrated, the crude product was dissolved with methanol (20 mL), and the suspension was separated by filtration, and the filter cake was washed with methanol (20 mL) to obtain compound 6. LCMS (ESI): m / z=416.0[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ13.04(s,1H),9.84(s,1H),8.58(s,1H),8.42(d,J=6.2Hz,2H),8.27(d,J=8.0H z,1H),7.97(d,J=2.0Hz,1H),7.81(d,J=8.4Hz,1H),7.70(dd,J=8.6,2.4Hz,2H),7.54(t,J=8.0Hz,1H).

[0121] Example 7 Preparation of Compound 7

[0122]

[0123] Step 1: To a mixed solution of 7-1 (100 mg, 0.25 mmol) in acetonitrile (3 mL) were added (4-bromo-3-chlorophenyl)boranediol (86.86 mg, 0.37 mmol), potassium carbonate (68.03 mg, 0.49 mmol) and bis[5-(diphenylphosphino)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (18.01 mg, 0.02 mmol), and the resulting mixture was stirred at 80° C. for 16 hours. After 16 hours, LCMS monitoring showed that the starting material was consumed and the desired product was formed. It was separated and purified by preparative TLC (eluent: petroleum ether: ethyl acetate = 10: 1) and preparative HPLC (Phenomenex Gemini 150mm*25mm*10umcolume) (eluent: 30% to 60% (v / v) CH3CN and H2O, containing 0.025% formic acid) to obtain intermediate 7-2. LCMS (ESI): m / z = 518.0 [M+H]+. 1 HNMR (400MHz, DMSO-d6) δ9.87(s,1H),8.57(s,1H),8.42(s,1H),8.36(t,J=1.8Hz,1H),8.28–8.23(m,1H),7.97(d,J=2. 2Hz, 1H), 7.95 (d, J = 8.4Hz, 1H), 7.65 (d, J = 7.8Hz, 1H), 7.62 (dd, J = 8.4, 2.2Hz, 1H), 7.53 (t, J = 7.9Hz, 1H), 1.59 (s, 9H).

[0124] Step 2: Trifluoroacetic acid (3 mL) and dichloromethane (3 mL) were added to intermediate 7-2 (140 mg, 0.27 mmol), and the resulting mixture was stirred at room temperature for 1 hour. After 1 hour, LCMS monitoring showed that the starting material was consumed and the desired product was formed. The mixture was concentrated to dryness, the crude product was dissolved in methanol (20 mL), and the suspension was separated by filtration, the filter cake was washed with methanol (20 mL), and then dried under reduced pressure to obtain compound 7. LCMS (ESI): m / z=461.9[M+H]+. 1H NMR (400MHz, DMSO-d6) δ13.05(s,1H),9.85(s,1H),8.56(d,J=14.8Hz,1H),8.43(d,J=2.0Hz,2H),8.31–8.23( m, 1H), 7.96 (dd, J = 7.4, 5.3Hz, 2H), 7.69 (d, J = 7.8Hz, 1H), 7.62 (dd, J = 8.2, 2.3Hz, 1H), 7.54 (t, J = 7.8Hz, 1H).

[0125] Example 8 Preparation of Compound 8

[0126]

[0127] Step 1: Add bis(triphenylphosphine)palladium dichloride (49.69 mg, 0.07 mmol) to a mixed solution of compound 8-1 (0.23 mL, 1.77 mmol) and compound 8-2 (623.43 mg, 1.95 mmol) and potassium carbonate (489.23 mg, 3.54 mmol), 1,4-dioxane (3.5 mL) and water (1.5 mL), degas the mixture and purge it with nitrogen three times, and stir it at 80 ° C for 16 hours under nitrogen. LCMS shows that the starting material is consumed and the target product is formed. The mixture is poured into water (30 mL) and extracted with ethyl acetate (30 mL×3), and the combined organic phase is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product is purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain intermediate 8-3. LC-MS (ESI): m / z=349.0 / 351.0[M+H]+.

[0128] Step 2: To a mixed solution of intermediate 8-3 (356 mg, 1.02 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.40 mL, 1.53 mmol), potassium acetate (300.13 mg, 3.06 mmol) and 1,4-dioxane (3.5 mL) was added bis[5-(diphenylphosphinoyl)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (74.59 mg, 0.10 mmol), purged with nitrogen 3 times, and stirred at 85° C. for 16 hours. TLC showed that the starting material was completely consumed, and a more polar spot was observed. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 20:1 to 10:1) to obtain intermediate 8-4.

[0129] Step 3: To a mixed solution of intermediate 8-4 (100 mg, 0.25 mmol) and 8-5 (112.78 mg, 0.28 mmol), potassium carbonate (69.75 mg, 0.50 mmol), 1,4-dioxane (2 mL) and water (0.5 mL) was added bis[5-(diphenylphosphino)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (18.46 mg, 0.03 mmol), purged with nitrogen three times, and stirred at 80°C for 16 hours. TLC showed that the starting material was completely consumed, and more polar spots were observed. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether:ethyl acetate = 20:1 to 5:1) to obtain intermediate 8-6.

[0130] Step 4: Dichloromethane (3 ml) and trifluoroacetic acid (1 ml) were added to a solution of intermediate 8-6 (82 mg, 0.14 mmol), and the resulting mixture was stirred at room temperature for 1 hour. LCMS showed that the starting material was consumed and the target product was formed, which was filtered and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC to obtain compound 8. LC-MS (ESI): m / z=440.0[M+H]+. 1H NMR (400MHz, DMSO-d6) δ13.49–12.47(m,1H),9.97–9.62(m,1H),8.46(s,1H),8.40–8.35(m,1H),8.24–8.17(m,1H),7.96(s,1 H),7.83–7.77(m,1H),7.69–7.61(m,2H),7.48(s,3H),7.42–7.37(m,1H),7.26–7.20(m,1H),6.46–6.33(m,1H),6.02(s,2H).

[0131] Example 9 Preparation of Compound 9

[0132]

[0133] Step 1: Add bis(triphenylphosphine)palladium chloride (49.62 mg, 0.07 mmol) to a solution of 9-1 (0.23 mL, 1.77 mmol) and intermediate 9-2 (0.39 mL, 1.94 mmol), potassium carbonate (488.49 mg, 3.53 mmol), 1,4-dioxane (3.5 mL) and water (1.5 mL), and purge with nitrogen three times, and stir at 80 ° C for 16 hours. LCMS shows that the starting material is consumed and the target product is formed. The mixture is poured into water (30 mL) and extracted with ethyl acetate (30 mL x3), and the combined organic phase is washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product is purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10: 1-5: 1) to obtain intermediate 9-3. LC-MS (ESI): m / z=237.0 / 239.0[M+H]+.

[0134] Step 2: To a mixed solution of intermediate 9-3 (300 mg, 1.27 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (0.49 mL, 1.90 mmol), potassium acetate (372.53 mg, 3.80 mmol) and 1,4-dioxane (3 mL) was added bis[5-(diphenylphosphinoyl)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (92.58 mg, 0.13 mmol), purged with nitrogen 3 times, and stirred at 85 ° C for 16 hours. A black solution was formed. TLC showed that the starting material was completely consumed, and a more polar spot was observed. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: EtOAc = 20:1 to 5:1) to obtain intermediate 9-4.

[0135] Step 3: To a mixed solution of intermediate 9-4 (100 mg, 0.35 mmol), 2-methylpropyl-2-yl 3-[(6-bromothieno[2,3-d]pyrimidin-4-yl)amino]benzoate (157.28 mg, 0.39 mmol), potassium carbonate (97.27 mg, 0.70 mmol), 1,4-dioxane (2 mL) and water (0.5 mL) was added bis[5-(diphenylphosphino)cyclopentyl-1,3-dienyl]-λ2-iron(II)palladium chloride (25.75 mg, 0.04 mmol), purged with nitrogen 3 times, and stirred at 80°C for 16 hours. TLC showed that the starting material was completely consumed, and a more polar spot was observed. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10: 1 to 2: 1) to obtain intermediate 9-5. LC-MS (ESI): m / z = 484.0 [M+H] +.

[0136] Step 4: To a solution of intermediate 9-5 (105 mg, 0.22 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL), and the resulting mixture was stirred at room temperature for 1 hour. LCMS showed that the starting material was consumed and the target product was formed. Filtered under reduced pressure and concentrated to dryness to obtain a crude product. The crude product was purified by preparative HPLC (formic acid) to obtain compound 9. LC-MS (ESI): m / z=428.0[M+H]+. 1H NMR (400MHz, DMSO-d6) δ12.99(s,1H),9.74(s,1H),8.50(s,1H),8.38(s,1H),8.20(d,J=8.0Hz,1H),7.89(s,1H), 7.70–7.62(m,2H),7.59(dd,J=6.1,2.3Hz,2H),7.48(dt,J=12.1,4.8Hz,3H),5.92(d,J=2.2Hz,1H),3.83(s,3H).

[0137] Example 10 Preparation of Compound 10

[0138]

[0139] Step 1: To a solution of 10-1 (1.00 g, 4.01 mmol) in isopropanol (10 mL) was added tert-butyl 2-aminobenzoate (0.77 g, 4.01 mmol), and the mixture was stirred at 80°C for 19 hours. The reaction was completed by monitoring by LCMS. The reaction solution was filtered, and the filter cake was rinsed with petroleum ether (8 mL). The filter cake was concentrated under reduced pressure to obtain intermediate 10-2.

[0140] Step 2: 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborane (75.9 mg, 0.37 mmol), potassium carbonate (85.6 mg, 0.62 mmol) and DPPF palladium dichloride (23.4 mg, 0.03 mmol) were added to an acetonitrile solution (2 mL) of the intermediate 10-2 (124.3 mg, 0.31 mmol), and nitrogen was blown. The reaction was carried out in a microwave oven at 80°C for 1 hour. The reaction was completed by LCMS monitoring. The compound was concentrated under reduced pressure. The crude product was purified by a silica gel column: petroleum ether / ethyl acetate (PE:EA=50:1) gradient to obtain a compound with a purity of about 80%, and then purified by preparative HPLC (Phenomenex Gemini Purification by 150mm*25mm*10m column (eluent: 30% to 60% (v / v) acetonitrile and water, 0.025% ammonium bicarbonate) gave intermediate 10-3. LCMS (ESI): m / z=404.1[M+H]+. 1 H NMR (400MHz, DMSO) δ10.53(s,1H),8.44(s,1H),8.06–8.00(m,2H),7.89(dd,J=7.8,1.4Hz,1H),7.76(d,J=7 .4Hz,2H),7.68–7.62(m,1H),7.56(t,J=7.6Hz,2H),7.48–7.42(m,1H),7.28(t,J=7.0Hz,1H),1.38(s,9H).

[0141] Step 3: TFA (0.4 mL) was added to a dichloromethane solution (1.6 mL) of the intermediate 10-3 (75.5 mg, 0.19 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS to be complete. The mixture was concentrated to dryness under reduced pressure, the crude product was slurried with methanol (5 mL), filtered, the filter cake was rinsed with methanol (3 mL), and the filter cake was concentrated under reduced pressure to obtain compound 10. LCMS (ESI): m / z=346.0 [MH]+. 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),8.83(d,J=8.4Hz,1H),8.62(s,1H),8.06(d,J=7.8Hz,1H),7.82(s,1H),7 .77(d,J=7.6Hz,2H),7.69(t,J=7.9Hz,1H),7.55(t,J=7.6Hz,2H),7.47(t,J=7.3Hz,1H),7.19(t,J=7.6Hz,1H).

[0142] Example 11 Preparation of Compound 11

[0143]

[0144] Step 1: To a solution of 11-1 (1.5 g, 8.04 mmol) in acetonitrile (15 mL) was added benzoyl chloride (1.12 mL, 9.65 mmol), and the resulting mixture was stirred at 70 ° C for 6 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10: 1-1: 1) to obtain intermediate 11-2. LC-MS (ESI): m / z = 291.0 [M+H] +.

[0145] Step 2: Lawesson's reagent (3.04 g, 7.52 mmol) was added to a solution of intermediate 11-2 (2.19 g, 7.52 mmol) in N,N-dimethylpropylene urea (20 mL), and the resulting mixture was stirred at 150 ° C for 2.5 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 100: 0 to 10: 1) to obtain intermediate 11-3. LC-MS (ESI): m / z = 271.0 [M+H] +.

[0146] Step 3: Lithium hydroxide (442.40 mg, 10.54 mmol) was added to a mixed solution of intermediate 11-3 (950 mg, 3.51 mmol) in tetrahydrofuran (5 mL) and water (5 mL), and the resulting mixture was stirred at room temperature for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was adjusted to pH = 6 with 1 mol / L hydrochloric acid, and solids precipitated. The solids were filtered, washed with water (5 mL) and dried to obtain a crude product, which was not further treated and was used in the next step. LC-MS (ESI): M / Z = 257.0 [M+H] +.

[0147] Step 4: Intermediate 11-4 (200 mg, 0.78 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (445.11 mg, 1.17 mmol) and N,N-diisopropylethylamine (0.39 mL, 2.34 mmol) were added to N,N-dimethylformamide (3 mL), and the resulting mixture was stirred at room temperature for 20 minutes, (1R,2S)-2-aminocyclohexane-1-carboxylic acid (111.74 mg, 0.78 mmol) was added, and stirred at room temperature for 1 hour. LCMS showed that the starting material was consumed and the desired product was formed. The crude product was filtered and purified by preparative high performance liquid chromatography to obtain compound 11. LC-MS (ESI): m / z = 382.0 [M+H] +. 1 HNMR (400MHz, DMSO) δ10.09(d,J=8.6Hz,1H),8.79(d,J=4.9Hz,1H),8.31(dd,J=7.5,2.0Hz,2H),8.09(d,J= 4.9Hz,1H),7.78–7.53(m,3H),4.51(s,1H),2.89–2.72(m,1H),2.00(s,2H),1.80(s,1H),1.73–1.38(m,5H).

[0148] Example 12 Preparation of Compound 12, Compound 12C and Compound 12D

[0149]

[0150] Step 1: At 0°C, lithium bis(trimethylsilyl)amide (80.0 mL, 79.9 mmol) was slowly added to a mixed solution of 12-1 (5.61 mL, 23.79 mmol) and tetrahydrofuran (18 mL). The reaction was stirred for half an hour, and then (2S)-1-{[(2-methylpropyl-2-yl)oxy]carbonyl}-4-oxotetrahydropyrrole-2-carboxylic acid methyl ester (5.21 g, 21.4 mmol) was added under ice bath, and the reaction was allowed to proceed at room temperature for 18 hours. The reaction was completed by TLC monitoring, and the mixture was quenched with saturated ammonium chloride solution (15.0 mL). Water (150 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (150 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by column chromatography (ethyl acetate / petroleum ether (1 / 100 to 1 / 10) eluted on silica gel) to obtain intermediate 12-2. LC-MS(ESI): m / z=364.2[M+Na]+.

[0151] Step 2: Add 10% palladium on carbon (1.25 g) to a mixed solution of intermediate 12-2 (4.00 g, 11.7 mmol) and ethyl acetate (20.0 ml), replace with hydrogen 3 times, and stir at room temperature for 16 hours. LCMS monitoring reaction completion. Filter the reaction solution and elute once with ethyl acetate (20.0 mL), and concentrate the filtrate to obtain intermediate 12-3. LC-MS (ESI): m / z = 366.2 [M + Na] +.

[0152] Step 3: At room temperature, trifluoroacetic acid (3.00 mL) was slowly added to a mixed solution of intermediate 12-3 (2 g, 5.82 mmol) and dichloromethane (9.00 mL), and the reaction was stirred at room temperature for 3 hours. LCMS monitored the completion of the reaction. The reaction solution was directly concentrated to obtain the crude product intermediate 12-4. LC-MS (ESI): m / z = 188.1 [M+H] +.

[0153] Step 4: Add phenylboranediol (3.67 g, 30.0 mmol), potassium carbonate (8.31 g, 60.1 mmol) and tris(dibenzylideneacetone)dipalladium (1.84 g, 2.00 mmol) to a mixed solution of 12-6A (5.00 g, 20.04 mmol) and 1,4-dioxane (50.0 mL) at room temperature. Replace with nitrogen three times, heat to 100 °C and stir for 16 hours. LCMS monitors the completion of the reaction. The reaction solution is directly spin-dried, and the residue is separated and purified by column chromatography (ethyl acetate / petroleum ether (1 / 100 to 1 / 15) eluted on silica gel) to obtain intermediate 12-6. LC-MS (ESI): m / z = 247.1 [M+H] +.

[0154] Step 5: At room temperature, intermediate 12-6 (1.58 g, 6.41 mmol) and potassium carbonate (3.32 g, 24.0 mmol) were added to a mixed solution of intermediate 12-4 (1.50 g, 8.01 mmol) and N-methylpyrrolidone (12.0 mL), respectively. The reaction was heated to 80 ° C and stirred for 16 hours. LCMS monitored the completion of the reaction. Ethyl acetate (150 mL) was added to the reaction solution to dilute and wash with water (150 mL) 3 times. The organic phase was washed once with brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (ethyl acetate / petroleum ether (1 / 100 to 1 / 2) eluted on silica gel) to obtain intermediate 12-7. LC-MS (ESI): m / z = 398.1 [M+H] +.

[0155] Step 6: At room temperature, 4-aminopyridine (26.0 mg, 0.28 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (210 mg, 0.55 mmol) and N,N-diisopropylethylamine (0.14 mL, 0.83 mmol) were added to a mixed solution of intermediate 12-7 (110 mg, 0.28 mmol) and N,N-dimethylformamide (3.00 mL). The reaction was stirred at 25 ° C for 2 hours. LCMS monitored the completion of the reaction. Ethyl acetate (20 mL) was added to the reaction solution and diluted and washed with water (30 mL) 3 times. The organic phase was washed once with brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by HPLC (Waters-sunfire-10um-19*250mm (mobile phase: 5% to 40% (v / v) CH3CN and H2O with 0.1% FA)) to obtain intermediate 12-8. LC-MS (ESI): m / z = 474.2 [M+H]+. 1H NMR (400MHz, DMSO-d6) δ10.40(s,1H),8.45–8.38(m,2H),8.31(s,1H),7.92(s,1H),7.78(d,J=7.6Hz,2H),7.61–7.55(m,2H),7.49(dd,J=8.4,6.9 Hz,2H),7.41(t,J=7.4Hz,1H),4.74(s,1H),4.40–4.29(m,1H),3.88(s,1 H),3.65(s,3H),2.90–2.69(m,2H),2.68–2.54(m,2H),1.83–1.68(m,1H).

[0156] Step 7: At room temperature, lithium hydroxide (124 mg, 2.98 mmol) was added to a mixed solution of intermediate 12-8 (470 mg, 0.99 mmol) and tetrahydrofuran (12.0 mL), methanol (4.00 mL) and water (4.00 mL). The reaction was stirred at 25°C for 2 hours. The reaction was completed by LCMS monitoring. The reaction solution was adjusted to pH 6 with 1 molar dilute hydrochloric acid solution, extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was prepared by high performance liquid chromatography (Waters-sunfire-10um-19*250mm (mobile phase: 5% to 40% (v / v) CH3CN and H2O with 0.1% FA)) to obtain compound 12. LC-MS (ESI): m / z=460.3[M+H]+. 1 H NMR (400MHz, DMSO-d6) δ12.65(s,1H),10.40(s,1H),8.42(d,J=8.0Hz,2H),8.32(s,1H),7.92(s,1H),7.77(s,2H),7.58(d,J=4.0Hz ,2H),7.49(t,J=8.0Hz,2H),7.40(t,J=8.0Hz,1H),4.66(s,1H),4.33(d,J=8.0Hz,1H),3.87(s,1H),2.76–2.50(m,4H),1.76(s,1H).

[0157] Step 8: Compound 12 (140 mg, 0.31 mmol) was separated to obtain compound 12A (2.00 mg) and compound 12B (106 mg, 0.23 mmol). The retention time of compound 12A was 0.589 min and the retention time of compound 12B was 1.043 min;

[0158] Chiral separation conditions: Chiral column: Chiralpak AD-350A 4.6 mm ID, 3 um, mobile phase: 40% of Ethanol (0.05% DEA) in CO2, flow rate: 3 mL / min, column temp.: 35°C, ABPR: 1500 psi.

[0159] Compound 12A: LC-MS (ESI): m / z = 460.3 [M+H] +. 1 HNMR (400MHz, DMSO-d6) δ10.40(s,1H),8.42(d,J=4.0Hz,2H),8.32(s,1H),7.92(s,1H),7.77(s,2H),7.58(d,J=8.0Hz ,2H),7.49(t,J=4.0Hz,2H),7.43–7.35(m,1H),4.65(s,1H),4.32(s,1H),3.87(s,1H),2.84–2.55(m,4H),1.76(s,1H).

[0160] Compound 12B: LC-MS (ESI): m / z = 460.3 [M+H] +. 1 HNMR(400MHz,DMSO-d6)δ10.41(s,1H),8.41(d,J=8.0Hz,2H),8.31(s,1H),7.91(s,1H),7.77(s,2H),7.58(d,J =8.0Hz,2H),7.47(s,2H),7.39(s,1H),4.66(s,1H),4.31(s,1H),3.87(s,1H),2.83–2.56(m,4H),1.76(s,1H).

[0161] Compound 12C and Compound 12D are selected from Compound 12A and Compound 12B, respectively; and Compound 12C and Compound 12D are different.

[0162] Example 15 Preparation of Compound 15

[0163]

[0164] Step 1: 15-1 (5.0 g, 16.67 mmol), triphenylphosphine (5.25 g, 20.01 mmol) and 15-2 (4.91 g, 20.01 mmol) were added to tetrahydrofuran (50 mL), replaced with nitrogen three times, cooled to 0°C, and diisopropyl azodicarboxylate was added dropwise. After the addition, the mixture was returned to room temperature and stirred for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 20:1 to 5:1) to obtain intermediate 15-3. LC-MS (ESI): m / z = 471.0 / 473.0 [M-55+H]+.

[0165] Step 2: Add palladium acetate (8.52 mg, 0.04 mmol) to a toluene (10 mL) solution of intermediate 15-3 (1000 mg, 1.90 mmol), morpholine (0.18 mL, 2.09 mmol), cesium carbonate (927.12 mg, 2.85 mmol) and 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (59.06 mg, 0.09 mmol), replace the mixture with nitrogen three times, and stir at 100 ° C for 18 hours under nitrogen protection. LCMS shows that the starting material is consumed and the desired product is formed. The mixture is poured into water (20 mL) and extracted with ethyl acetate (30 mL×3), and the combined organic phases are washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product is purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain intermediate 15-4. LC-MS(ESI): m / z=486.1 / 488.1[M+H]+.

[0166] Step 3: To a solution of intermediate 15-4 (500 mg, 1.03 mmol), ethynyl [tri (propyl-2-yl)] silane (925.90 μL, 4.11 mmol) and cesium carbonate (401.95 mg, 1.23 mmol), 2-dicyclohexylphosphino-2', 4', 6'-triisopropylbiphenyl (49.01 mg, 0.10 mmol) in acetonitrile (5 ml) was added bis (acetonitrile) palladium chloride (13.34 mg, 0.05 mmol), the mixture was replaced with nitrogen three times, and stirred at 90 ° C for 5 hours under nitrogen. A black solution was formed. LCMS showed that the starting material was consumed and the target product was formed. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10: 1 to 3: 1) to obtain intermediate 15-5. LC-MS (ESI): m / z = 588.0 [M+H] +.

[0167] Step 4: Trifluoroacetic acid (4 ml) was added to a solution of intermediate 15-5 (416 mg, 0.71 mmol) in dichloromethane (4 ml), and the resulting mixture was stirred at room temperature for 1 hour to obtain a yellow solution. LCMS showed that the starting material was consumed and the target product was formed. The reaction solution was concentrated to obtain intermediate 15-6. LC-MS (ESI): m / z = 488.0 [M+H] +.

[0168] Step 5: Potassium carbonate (488.79 mg, 3.54 mmol) was added to a solution of intermediate 15-6 (345 mg, 0.71 mmol) and 4-chloro-6-phenylthieno[2,3-d]pyrimidine (174.52 mg, 0.71 mmol) in N,N-dimethylformamide (5 ml), and the resulting mixture was stirred at room temperature for 18 hours to obtain a yellow solution. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (10 mL) and extracted with dichloromethane: methanol = 5: 1 (30 mL × 3), the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10: 1 to 2: 1) to obtain intermediate 15-7. LC-MS (ESI): m / z = 698.3 [M+H] +.

[0169] Step 6: Tetrabutylammonium fluoride (0.86 ml, 0.86 mmol) was added to a solution of intermediate 15-7 (400 mg, 0.57 mmol) in tetrahydrofuran (10 ml), and the resulting mixture was stirred at room temperature for 18 hours to obtain a yellow solution. LCMS showed that the starting material was consumed and the target product was formed. The mixture was poured into water (20 mL) and extracted with dichloromethane (30 mL×3), and the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain intermediate 15-8. LC-MS (ESI): m / z = 542.2 [M+H]+.

[0170] Step 7: Lithium hydroxide (13.27 mg, 0.55 mmol) was added to a solution of intermediate 15-8 (100 mg, 0.18 mmol) in water (2 ml), and the resulting mixture was stirred at room temperature for 18 hours to obtain a yellow solution. LCMS (XT221306-333-R5) showed that the starting material was consumed and the target product was formed. The reaction mixture was acidified to pH = 6 with hydrochloric acid (1 mol / L) and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 100: 1-10: 1) to obtain compound 15. LC-MS (ESI): m / z = 528.1 [M+H]+. 1 HNMR (400MHz, DMSO) δ13.48–12.05(m,1H),8.37(s,1H),7.89(t,J=29.8Hz,4H),7.48(t,J=7.6Hz,2H),7.40(d,J=7.3Hz,1H),7.20( s,1H),5.99–5.61(m,1H),5.34–4.94(m,1H),4.80–4.46(m,1H),4.23(s,2H),3.67(d,J=4.2Hz,4H),2.95(s,5H),2.49–2.29(m,1H).

[0171] Example 16 Preparation of Compound 16

[0172]

[0173] Step 1: To a mixed solution of 16-1 (500 mg, 2.02 mmol), acetonitrile (2 mL, 38.00 mmol) and 1,4-dioxane (2 mL) was added 4 mol / L hydrochloric acid / 4-dioxane (10 mL, 40.00 mmol), and the resulting mixture was stirred at room temperature for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. Concentrate to dryness under reduced pressure to obtain a crude product. The crude product was purified by preparative HPLC (eluent: 40% to 70% (v / v) acetonitrile and 0.5% ammonium bicarbonate solution) to obtain intermediate 16-2. LC-MS (ESI): m / z = 243.0 [M+H] +.

[0174] Step 2: Phosphorus pentachloride (326.55 mg, 1.56 mmol) was added to a solution of phosphorus oxychloride (5 ml) of intermediate 16-2 (380 mg, 1.56 mmol), and the resulting mixture was stirred at 110°C for 5 hours to obtain a yellow solution. LCMS showed that the starting material was consumed and the desired product was formed. Concentrate to dryness under reduced pressure, add ice water (20 mL) to the crude product, and extract with dichloromethane (30 mL×3), wash the combined organic phases with brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 5:1) to obtain intermediate 16-3. LC-MS (ESI): m / z = 261.0 [M+H]+.

[0175] Step 3: Potassium carbonate (297.10 mg, 2.15 mmol) was added to a solution of intermediate 16-8 (209.7 mg, 0.43 mmol) and 4-chloro-6-phenylthieno[2,3-d]pyrimidine (174.52 mg, 0.71 mmol) in N,N-dimethylformamide (5 mL), and the resulting mixture was stirred at room temperature for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL×3), the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain intermediate 16-9. LC-MS (ESI): M / Z = 712.4 [M+H]+.

[0176] Step 4: Tetrabutylammonium fluoride (0.14 mL, 0.49 mmol) was added to a solution of intermediate 16-9 (232 mg, 0.33 mmol) in tetrahydrofuran (5 ml), and the resulting mixture was stirred at room temperature for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL×3), the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain intermediate 16-10. LC-MS (ESI): m / z = 556.2 [M+H]+.

[0177] Step 5: Lithium hydroxide (14.61 mg, 0.61 mmol) was added to a mixed solution of intermediate 16-10 (113 mg, 0.20 mmol), water (3 mL) and tetrahydrofuran (3 mL), and the resulting mixture was stirred at room temperature for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The reaction mixture was acidified to pH = 6 with 1 mol / L hydrochloric acid and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (dichloromethane: methanol = 100: 1 to 10: 1) to obtain compound 16. LC-MS (ESI): m / z = 542.2 [M+H] +. 1 H NMR (400MHz, DMSO) δ13.21–12.30(m,1H),7.95(d,J=1.9Hz,4H),7.46(d,J=7.7Hz,2H),7.38(d,J=7.3Hz,1H),7.20(s,1H),5.98–5.6 3(m,1H),5.30–4.93(m,1H),4.75–4.42(m,1H),4.23(s,2H),3.68(s,4H),2.96(s,4H),2.88–2.72(m,1H),2.51(s,1H),2.44(s,3H).

[0178] Example 17 Preparation of Compound 17

[0179]

[0180] Step 1: Tetrakis(triphenylphosphine)palladium (115.79 mg, 0.10 mmol) was added to a toluene (5 mL) solution of 17-1 (500 mg, 2.00 mmol) and 17-2 (0.71 mL, 2.20 mmol), and the mixture was replaced with nitrogen three times and stirred at 110°C for 18 hours. LCMS showed that the starting material was consumed and the target product was formed, which was concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography The intermediate 17-3 was obtained. LC-MS (ESI): m / z=247.9 [M+H]+.

[0181] Step 2: Potassium carbonate (306.86 mg, 2.22 mmol) was added to a solution of 17-7 (216.59 mg, 0.44 mmol) and intermediate 17-3 (110.0 mg, 0.44 mmol) in N,N-dimethylformamide (5 ml), and the resulting mixture was stirred at room temperature for 18 hours. LCMS showed that the starting material was consumed and the desired product was formed. The mixture was poured into water (10 mL) and extracted with ethyl acetate (30 mL×3), and the combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 10:1 to 1:1) to obtain intermediate 17-8.

[0182] Step 3: Tetrabutylammonium fluoride (0.37 ml, 0.37 mmol) was added to a solution of intermediate 17-8 (174 mg, 0.25 mmol) in tetrahydrofuran (5 ml), and the resulting mixture was stirred at room temperature for 18 hours. LCMS showed that the starting material was consumed and the target product was formed. The mixture was poured into water (10 mL) and extracted with dichloromethane (20 mL×3), the combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was purified by silica gel chromatography (eluent: petroleum ether: ethyl acetate = 1:1 to 1:3) to obtain intermediate 17-9.

[0183] Step 4: Lithium hydroxide (10.73 mg, 0.45 mmol) was added to a mixed solution of water (3 ml) and tetrahydrofuran (3 ml) of intermediate 17-9 (81 mg, 0.15 mmol), and the resulting mixture was stirred at room temperature for 18 hours. LCMS showed that the starting material was consumed and the target product was formed. The reaction mixture was acidified to pH = 6 with 1 mol / L hydrochloric acid and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product. The crude product was subjected to silica gel chromatography Purification gave compound 17. LC-MS (ESI): m / z = 529.1 [M+H]+. 1 H NMR (400MHz, DMSO) δ14.09–11.41(m,1H),8.67–8.49(m,1H),8.16(d,J=169.9Hz,5H),7.41–7.27(m,1H),7.25–7.14(m,1H),6.00 –5.43(m,1H),5.32–4.97(m,1H),4.78–4.47(m,1H),4.23(s,2H),3.66(s,4H),2.94(s,4H),2.86–2.70(m,1H),2.45–2.27(m,1H).

[0184] Biological evaluation

[0185] Test example: Compound inhibition experiment on hcGAS protein activity

[0186] 1. Test Purpose

[0187] In this experiment, the inhibitory effect of the compound on the hcGAS protein was detected by the Transcreener cGAMP cGAS detection kit, and the inhibitory effect of the disclosed compound on the hcGAS target was evaluated according to IC50.

[0188] 2. Experimental Methods

[0189] 1. Experimental steps

[0190] 1) Dilute the compound and positive reference compound in a 384 dilution plate as required, set 10 concentrations, and the maximum concentration is 200 μM;

[0191] 2) Use Echo to inject the diluted compound and DMSO into the 784075 plate, and centrifuge at 1000r / 1min. 3) Add 5ul of the mixture of cGAS enzyme, DNA and buffer into the plate, centrifuge at 1000r / 1min, and place in a 25℃ incubator for 60min.

[0192] 4) Add 5ul of the mixture of ATP, GTP and buffer into the plate, centrifuge at 1000r / 1min, and place in a 25℃ incubator for 120min;

[0193] 5) Add 10ul of detection reagent into the plate, centrifuge at 1000r / 1min, and place in a 25℃ incubator for 60min6) Read using Envision Ex320 / Em615 / Em665 program;

[0194] 2. Data Analysis

[0195] 1) Data stability and calculation of inhibition rate

[0196] S / B = ave G150 / ave DMSO

[0197] Z'=1-3*(STDEV DMSO+STDEV Yangshen) / (ave Yangshen-ave DMSO)

[0198] 2) Calculation of IC50

[0199] Inhibition rate = (X-ave DMSO) / (ave G150-ave DMSO)*100

[0200] X = log(compound concentration)

[0201] Y = inhibition rate

[0202] IC50 = concentration corresponding to half inhibition rate

[0203] Conclusion: The compounds of the present invention have good hcGAS inhibitory activity. The test results of some compounds are shown in Table 6.

[0204] Table 6

[0205] Compound No. <![CDATA[hcGASIC 50 ]]> Compound No. <![CDATA[hcGASIC 50 ]]> Compound No. <![CDATA[hcGASIC 50 ]]> 01 B 07 B 12A B 02 B 08 B 12B B 03 B 09 B 15 A 04 B 10 A 16 A 05 A 11 B 17 B 06 B 12 B

[0206] A means IC50≤10μM; B means IC50>10μM.

Claims

1. A compound represented by formula (I) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, R 1 for R x is selected from halogen or 5-6 membered nitrogen-containing heteroaryl, wherein, The heteroaryl group may be further substituted with halogen, -NH2, C 1-3 Alkyl or C 1-3 Haloalkyl substitution; R y Selected from halogen, C 1-3 Alkyl, C 1-3 Haloalkyl; X1, X2 and X3 are each independently selected from CH or N; and X3 is different from X2; m, n are selected from 0, 1, 2 or 3; L 1 Selected from *-NH-, -CONH-*, wherein * is connected to ring A; Ring A is selected from phenyl, cyclohexyl, benzocyclohexyl, pyridocyclohexyl; R 1-1 is carboxyl, halogen; Ring B is a 5-membered nitrogen-containing heterocycloalkyl group; L 2 is a bond, -(CH2) s -CONH-, -O-; Ring C is absent, pyridine, or pyridopyridine; R 1-2 Selected from cyano, 6-membered heterocycloalkyl, s is 0, 1, 2, or 3; Wherein, the compound represented by formula (I) is not 2. The compound of formula (I) according to claim 1, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, characterized in that: The compound represented by formula (I) is represented by formula (I-1) or formula (I-2):

3. The compound of formula (I) according to claim 1 or 2, or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, characterized in that: Selected from the group consisting of:

4. A compound of formula (I) as claimed in any one of claims 1 to 3, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: Formula (I) is shown in formula (I-1-1), formula (I-1-2) or formula (I-2-1):

5. A compound of formula (I) according to any one of claims 1 to 4, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, characterized in that: Ring A is independently The position of A is 1 The point where B is connected is the same as R 1-1 Connect the dots.

6. A compound of formula (I) according to any one of claims 1 to 5, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, characterized in that: L 2 It is -CH2-CONH- or -O-.

7. A compound of formula (I) as claimed in any one of claims 1 to 6, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: Formula (I) is shown in formula (I-1-1-1), formula (I-1-1-2), formula (I-1-2-1) or formula (I-2-1-1):

8. A compound of formula (I) according to any one of claims 1 to 7, or a stereoisomer, tautomer, diastereomer, racemate, cis-trans isomer, isotope-labeled compound (preferably deuterated), nitrogen oxide, solvate, hydrate, crystal form, ester, metabolite, pharmaceutically acceptable salt or prodrug thereof, characterized in that: R x are independently F, Cl, Br, I, pyridyl, pyrazolyl, wherein the pyridyl and pyrazolyl groups may be further substituted with halogen or C 1-3 Alkyl substituted; preferably, R x are independently Cl, Br, and / or R y Independently for C 1-3 Alkyl or C 1-3 Haloalkyl, preferably R y are independently methyl, difluoromethyl or trifluoromethyl; and / or R 1-2 are independently cyano, 9. A compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: The compound is selected from the group consisting of the following compounds: 。 10. A compound represented by formula (II) or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, R 2 is selected from H, halogen or 5-6 membered heteroaryl, wherein, The 5-6 membered heteroaryl group is optionally substituted by -NH2 or C 1-3 Preferably, the 5-6 membered heteroaryl is selected from pyridyl and pyrazolyl; More preferably, R 2 is selected from H, halogen, optionally substituted by -NH2 or C 1-3 Alkyl substituted More preferably, R 2 Selected from H, Cl, R 3 Selected from H, C 1-3 Alkyl or C 1-3 Preferably, R 3 Selected from H, methyl, -CH2-CF3; Ring D is selected from phenyl or 6-membered nitrogen-containing heterocycloalkyl; preferably, ring D is selected from phenyl, m1 is selected from 0, 1, 2 or 3; Wherein the compound represented by formula (I) is not 11. The compound as claimed in claim 10 or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds (preferably deuterated compounds), nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: Formula (II) is shown in formula (II-1): Preferably, formula (II-1) is as shown in formula (II-1-1) or formula (II-1-2):

12. A compound or its stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds, nitrogen oxides, solvates, hydrates, crystalline forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs, wherein: The compound is selected from the group consisting of the following compounds: 。 13. A composition comprising a compound as shown in formula I according to any one of claims 1 to 9, a compound as shown in formula II according to any one of claims 10 to 12, stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds, nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs thereof, and pharmaceutically acceptable adjuvants, carriers or diluents; preferably, the dosage form of the composition is selected from plain tablets, film-coated tablets, sugar-coated tablets, enteric-coated tablets, dispersible tablets, capsules, granules, oral solutions or oral suspensions.

14. Use of the compound of formula I as described in any one of claims 1 to 9, the compound of formula II as described in any one of claims 10 to 12, or the group consisting of the following compounds, their stereoisomers, tautomers, diastereomers, racemates, cis-trans isomers, isotope-labeled compounds, nitrogen oxides, solvates, hydrates, crystal forms, esters, metabolites, pharmaceutically acceptable salts or prodrugs for the preparation of a medicament for treating inflammation or autoimmune diseases; Preferably, the inflammatory or autoimmune disease is selected from the group consisting of acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, Kaposi's sarcoma, multiple myeloma, solid tumors, visual neovascularization and juvenile hemangioma, B-cell lymphoma, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, polyangiitis, idiopathic thrombocytopenic purpura, myasthenia gravis, allergic rhinitis, multiple sclerosis, transplant rejection, type I diabetes, membranous nephritis, inflammatory bowel disease, autoimmune hemolytic anemia, autoimmune thyroiditis, cold and warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura, sarcoidosis, Sjogren's syndrome, peripheral neuropathy, pemphigus vulgaris and asthma.

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