Tricyclic compound, preparation method therefor, pharmaceutical composition thereof and use thereof

Abstract

Provided in the present invention are a tricyclic compound, a preparation method therefor, a pharmaceutical composition thereof, and the use thereof. Specifically provided in the present invention are a compound represented by formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of the pharmaceutically acceptable salt thereof. The compound of the present invention has good inhibitory activity on TYK2, and can significantly inhibit the proliferation of cells carrying TYK2-E957D mutations.

Description

Tricyclic compounds, methods of making, pharmaceutical compositions thereof, and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 2024113200404, filed on September 20, 2024. This application incorporates the entirety of the aforementioned Chinese Patent Application. TECHNICAL FIELD

[0002] The present application relates to tricyclic compounds, methods of making, pharmaceutical compositions thereof, and uses thereof. BACKGROUND

[0003] Tyrosine kinase 2 (TYK2) is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases, the JAK proteins, including TYK2, are integral parts of cytokine signal transduction. TYK2 associates with the cytoplasmic domains of type I and type II cytokine receptors and type I and type III interferon receptors and is activated by these receptors upon cytokine binding. Cytokines associated with TYK2 activation include interferons and interleukins. Upon activation of the TYK2 signaling pathway by cytokines, signal transducer and activator of transcription (STAT) proteins are phosphorylated and activated, and STATs enter the nucleus to participate in the production of specific proteins. This pathway is involved in TH17, TH1, B cell, and myeloid cell functions, which play a key role in the pathophysiology of autoimmune diseases such as psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, allergic dermatitis, and the like.

[0004] Meanwhile, TYK2 has been shown to play an important role in maintaining tumor surveillance, TYK2 knockout mice show impaired cytotoxic T cell responses and accelerated tumor development. Studies on T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 through TYK2, maintaining cancer cell survival through STAT-mediated signaling, through upregulation of the anti-apoptotic protein BCL2. Knockdown of TYK2 (but not other JAK family members) reduced cell growth. TYK2-specific activating mutations that promote cancer cell survival include mutations in the FERM domain (G36D, S47N, and R425H), the JH2 domain (V73II), and the kinase domain (E957D and R1027H). However, it was also found that the kinase function of TYK2 is required for increased cancer cell survival, as TYK2 enzymes have kinase-dead mutations (M978Y or M978F) in addition to activating mutations (E957D) that result in transformation failure.

[0005] In a 2024 report (bioRxiv [Preprint]. 2024 Jun 6: 2024.06.04.595773. doi: 10.1101 / 2024.06.04.595773.), a team from Harvard Medical School found that TYK2 has potential as a therapeutic target for neuroinflammation in Alzheimer's disease. TYK2 also has potential for treating many neurodegenerative diseases, including multiple sclerosis (European Journal of Human Genetics, 2009, 17, 1309-1313), amyotrophic lateral sclerosis (Sci Transl Med. 2021; 13(601): eaaz4699), and Parkinson's disease (Neuronal Signal. 2023 Dec 4; 7(4): NS20220063), etc.

[0006] TYK2 inhibitors reported in the prior art include Deucravacitinib and Zasocitinib, and the types are still relatively limited. Considering that TYK2 plays an important role in the pathological process of many diseases, it is still necessary to provide more new compounds that inhibit TYK2 to meet the needs of disease treatment. SUMMARY

[0007] The technical problem to be solved by the present application is to provide a novel tricyclic compound, its preparation method, its pharmaceutical composition and its application to overcome the lack of TYK2 inhibitors in the prior art. The tricyclic compound of the present application has good inhibitory activity on TYK2 and can significantly inhibit the proliferation of cells carrying the TYK2-E957D mutation.

[0008] The present application solves the above technical problems by the following technical solutions.

[0009] The present application provides a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

[0010] wherein,

[0011] represents a single bond or a double bond, which satisfies the valence theory;

[0012] "*" indicates that the S atom marked is in R configuration, S configuration or a mixture thereof;

[0013] R 1 is O, NR 1-1 or C1-C6 alkyl;

[0014] R 1-1hydrogen, cyano or Ci-C6alkyl;

[0015] R 2 Ci-C6alkyl or Ci-C6alkyl substituted by one or more R 2-1 Ci-C6alkyl;

[0016] R 2-1 independently deuterium;

[0017] X 3 and X 4 are each independently C or N;

[0018] ring A is a 5-6 membered heteroaromatic ring, wherein the kind of heteroatom(s) is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3;

[0019] R 5 deuterium, halogen, Ci-C6alkyl or Ci-C6alkyl substituted by one or more R 5-1 Ci-C6alkyl;

[0020] R 5-1 independently deuterium or halogen;

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

[0022] X 2 is CH or N;

[0023] R 3 Ci-C6alkyl, NR 3-1 R 3-2 Ci-C6alkyl or Ci-C6alkyl substituted by one or more R 3-3 Ci-C6alkyl;

[0024] R 3-1 and R 3-2 are each independently hydrogen, Ci-C6alkyl or Ci-C6alkyl substituted by one or more R 1a Ci-C6alkyl;

[0025] R 1a and R 3-3 are each independently deuterium;

[0026] X 1 is CH or N;

[0027] R 4 C3-C 12 cycloalkyl.

[0028] In certain preferred embodiments of the application, certain groups in the compounds of formula (I), the pharmaceutically acceptable salts thereof, the solvates thereof, or the solvates of the pharmaceutically acceptable salts of the compounds of formula (I) are defined as follows, and the groups not mentioned are as described in any of the schemes of the application (simply referred to as "in a scheme of the application").

[0029] In a scheme of the application, each "C1-C6alkyl" is independently of the other(s) methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl, for example methyl or ethyl.

[0030] In a scheme of the application, each "5-6 membered heteroaromatic ring" is independently of the other(s) a 5-6 membered heteroaromatic ring having 2 or 3 heteroatoms, the kind of the heteroatoms being N and / or S, for example a pyrazole ring, a thiazole ring, a triazole ring, or a pyrazine ring, further for example

[0031] In a scheme of the application, each "halogen" is independently of the other(s) F, Cl, Br, or I, for example Cl.

[0032] In a scheme of the application, each "C3-C 12 cycloalkyl" is independently of the other(s) C3-C6cycloalkyl, for example

[0033] In a scheme of the application, the compound of formula (I) is any one of the following compounds: further for example preferably

[0034] In a scheme of the application, R 2 is -CH3, -CH2CH3, or -CD3.

[0035] In a scheme of the application, R is for example

[0036] In a scheme of the application, R 3 is NHR 3-2 or C1-C6alkyl substituted by one or more deuterium; for example

[0037] In a scheme of the application, R 4 is

[0038] In a scheme of the application, the compound of formula (I) is any one of the following compounds:

[0039] The present application also provides a pharmaceutical composition comprising the compound as shown in formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof or the solvate of the pharmaceutically acceptable salt thereof according to any one of the above-mentioned schemes, and a pharmaceutically acceptable adjuvant.

[0040] The present application also provides the use of the compound as shown in formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition according to any one of the above-mentioned schemes in the preparation of a drug for preventing and / or treating a disease related to TYK2; preferably, the disease related to TYK2 is a disease related to TYK2-E957D.

[0041] In one scheme of the present application, the disease related to TYK2 is selected from one or more of psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, allergic dermatitis, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease.

[0042] The present application also provides the use of the compound as shown in formula (I), the pharmaceutically acceptable salt thereof, the solvate thereof, the solvate of the pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition according to any one of the above-mentioned schemes in the preparation of a drug for preventing and / or treating a disease, wherein the disease is selected from one or more of psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, allergic dermatitis, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease.

[0043] Explanation of terms

[0044] The term "alkyl" refers to a straight-chain or branched-chain alkyl group having a specified number of carbon atoms (e.g., C1-C6). Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, sec-butyl, n-pentyl, n-hexyl and the like.

[0045] The term "heteroaromatic ring" refers to a cyclic aromatic group having a specified number of ring atoms (e.g., 5-6 membered), a specified number of heteroatoms (e.g., 1, 2 or 3), a specified type of heteroatom (one or more of N, O and S), which satisfies either of the following conditions: 1, linked to the rest of the molecule by two or more single bonds; 2, shares two atoms and one bond with the rest of the molecule. Heteroaromatic rings include, but are not limited to: , etc.

[0046] The term "halogen" refers to F, Cl, Br, I.

[0047] The term "cycloalkyl" refers to saturated monocyclic, bridged ring, or spirocyclic ring radical having the number of ring carbon atoms specified (e.g., C3-C6), the ring atoms consisting solely of carbon atoms. Monocycloalkyl groups include, but are not limited to etc.

[0048] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain preferred embodiments of the present application.

[0049] The reagents and starting materials used in the present application are commercially available.

[0050] The positive progress effect of the present application is that the compound of the present application has excellent inhibitory activity on TYK2-E957D, and can significantly inhibit the proliferation activity of cells carrying TYK2-E957D mutation. DETAILED DESCRIPTION

[0051] The present application will be further described by way of examples, but the present application is not limited to the scope of the examples. The experimental methods in the following examples, if no specific conditions are indicated, are selected according to conventional methods and conditions, or according to the instructions of the products.

[0052] Example D01

[0053] Step 1: Synthesis of compound 2

[0054] Dissolve 1 (2.48 g, 11.46 mmol) and t-BuOK (1.41 g, 12.6 mmol) in THF (10 mL), cool to 0°C, and add deuterated methyl iodide (1.83 g, 12.6 mmol) under nitrogen protection. Stir the mixture at room temperature for 3 h. After the raw material is completely reacted, quench and dilute the reaction solution with H2O. Extract the mixture with dichloromethane, combine the organic phases, and concentrate under reduced pressure. Obtain 2 (2.5 g, yield 93.6%).

[0055] Step 2: Synthesis of compound 4

[0056] Dissolve 2 (2.5 g, 10.7 mmol) in anhydrous toluene (7 mL), add 3 (2.25 g, 10.7 mmol), magnesium chloride (1 g, 10.7 mmol) and TEA (2.2 g, 21.4 mmol). Replace the reaction system with nitrogen three times, heat the mixture to 50 °C and stir for 4 h. After the reaction is completed, quench the reaction by adding 10 mL of H2O to the reaction solution. Extract the mixture with EtOAc (30 mL x 3). Combine all the organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter the resulting organic phase under reduced pressure, concentrate under vacuum, and purify the crude product by column chromatography on silica gel (PE:EtOAc = 40:1) to obtain the target 4 (3.5 g, yield 78.6%). HRMS m / z: 407.1205 [M+H] + .

[0057] Step 3: Synthesis of compound 5

[0058] Dissolve 4 (3.5 g, 8.6 mmol), concentrated sulfuric acid (1 mL), H2O (10 mL) in acetic acid (10 mL), and replace with nitrogen three times. Stir the mixture at 110 °C for 8 h. After the reaction is completed, quench the reaction by adding water to the reaction solution, and extract the mixture with EtOAc (30 mL x 3). Combine the resulting organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter the resulting organic phase under reduced pressure, concentrate under vacuum, and purify the crude product by column chromatography on silica gel (PE:EtOAc = 40:1) to obtain 5 (0.8 g, yield 46%).

[0059] Step 4: Synthesis of compound INT01

[0060] Dissolve 5 (2.3 g, 11.1 mmol), cyclopropylcarboxamide (1.1 g, 13.3 mmol), potassium carbonate (3.8 g, 27.8 mmol), dppf (0.3 g, 0.55 mmol) in 1,4-dioxane (15 mL), replace with nitrogen three times, add Pd2(dba)3 (0.3 g, 0.3 mmol), and replace with nitrogen three times. Stir the mixture at 80 °C overnight. After the reaction is completed, quench the reaction by adding water to the reaction solution, and extract the mixture with EtOAc (20 mL x 3). Combine the resulting organic phases, wash with saturated brine, and dry over anhydrous sodium sulfate. Filter the resulting organic phase under reduced pressure, concentrate under vacuum, and purify the crude product by column chromatography on silica gel (PE:EtOAc = 20:1) to obtain INT01 (2.2 g, yield 79%).

[0061] Step 5: Synthesis of compound 1-2

[0062] Dissolve 1-1 (1 g, 6.21 mmol) in chlorosulfonic acid (2 mL), the mixture is stirred at 100 °C for 1 h. Add sulphurous chloride (2 mL), the mixture is stirred at 80 °C for 5 h. The reaction is slowly dropped into ice water to quench, the aqueous phase is extracted with dichloromethane for three times (20 mL x 3). The combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude 1-2 (1 g, yield 62%) is used for the next step directly.

[0063] Step 6: Synthesis of compound 1-3

[0064] Dissolve 1-2 (100 mg, 0.39 mmol) in dichloromethane (1 mL), slowly drop in methylamine solution (0.5 mL, 2M in THF), the mixture is stirred at room temperature for 30 min. The reaction is concentrated in vacuum, the crude is purified by silica gel plate (DCM:MeOH = 30:1-20:1) to give 1-3 (50 mg, yield 51%). MS m / z: 254.20 [M+H] + .

[0065] Step 7: Synthesis of compound 1-5

[0066] Dissolve 1-3 (350 mg, 1.37 mmol) in 1,4-dioxane (5 mL), replace with nitrogen for three times. Add 2-fluoro-3-nitrophenylboronic acid pinacol ester (750 mg, 2.75 mmol), potassium carbonate (575 mg, 4.13 mmol) and triphenylphosphine (145 mg, 0.55 mmol), replace with nitrogen for three times. Add palladium acetate (34 mg, 0.15 mmol), replace with nitrogen for three times. The mixture is heated to 50 °C and stirred for 8 h. The reaction is quenched by adding water (10 mL), the aqueous phase is extracted with ethyl acetate for three times (30 mL x 3), the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude is purified by silica gel plate (PE:EtOAc = 1:1) to give 1-5 (130 mg, yield 32%). MS m / z: 295.35 [M+H] + .

[0067] Step 8: Synthesis of compound 1-6

[0068] Dissolve 1-5 (120 mg) in methanol (5 mL), replace with nitrogen for three times. Add a catalytic amount of Pd / C (5 mg), replace with hydrogen for three times. The mixture is stirred at room temperature for 16 h. The reaction is filtered under reduced pressure, concentrated in vacuum, the crude is purified by silica gel plate (PE:EtOAc = 1:1) to give 1-6 (24 mg, yield 22.4%). MS m / z: 265.35 [M+H] + .

[0069] Step 9: Synthesis of compound D01

[0070] Dissolve 1-6 (18 mg, 0.07 mmol) in isopropanol (7 mL), add INT01 (17 mg, 0.07 mmol) and concentrated hydrochloric acid (2.5 mg, 0.07 mmol), the reaction solution is stirred at 75 °C overnight. The reaction solution is added with sodium bicarbonate to adjust the pH to 7, the aqueous phase is extracted with dichloromethane for three times (8 mL x 3), the combined organic phase is washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuum. The crude product is purified by silica gel plate (PE: EOtAc = 1: 1-DCM: MeOH = 30: 1) to obtain D01 (15 mg, yield 45%). MS m / z: 484.55 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.99 (s, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 8.20 (s, 1H), 7.72 (dd, J = 7.6, 1.4 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 4.05 (s, 3H), 3.14 (s, 2H), 2.82 (s, 3H), 2.08 - 1.96 (m, 1H), 0.83 - 0.76 (m, 4H).

[0071] Example D02

[0072] Step 1: Synthesis of compound 2-2

[0073] Dissolve 2-1 (same as 1-2, 100 mg, 0.39 mmol) in dichloromethane (2 mL), slowly drop in ethylamine (260 mg, 5.8 mmol), the mixture is stirred at room temperature for 30 min. The reaction solution is concentrated in vacuum, the crude product is purified by silica gel plate (DCM: MeOH = 25: 1) to obtain 2-2 (50 mg, yield 49%). MS m / z: 268.20, 270.20 [M+H] + .

[0074] Step 2: Synthesis of compound 2-3

[0075] Dissolve 2-2 (50 mg, 0.19 mmol) in 1,4-dioxane (5 mL), add 2-fluoro-3-nitrophenylboronic acid pinacol ester (99 mg, 0.37 mmol) and potassium phosphate (119 mg, 0.56 mmol), and replace with nitrogen three times. Add Pd(dppf)2Cl2(15 mg, 0.02 mmol), and replace with nitrogen three times. Stir the mixture at 50 °C for 8 h. Add water (10 mL) to quench the reaction, and extract the aqueous phase with dichloromethane three times (30 mL x 3). Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify the crude product on a silica gel plate (PE:EtOAc = 1:1) to obtain 2-3 (25 mg, yield 44%). MS m / z: 309.20 [M+H] + .

[0076] Step 3: Synthesis of compound 2-4

[0077] Synthesis of 2-4 is the same as the corresponding step scheme of Example D01, using the product of hydrogenation of 2-3. MS m / z: 279.30 [M+H] + .

[0078] Step 4: Synthesis of compound D02

[0079] Synthesis of D02 is the same as the corresponding step scheme of Example D01, using the product of coupling of 2-4 with INT01. MS m / z: 498.45 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 10.99 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 8.17 (s, 1H), 7.73 (dd, J = 7.6, 1.4 Hz, 1H), 7.64 (dd, J = 8.1, 1.4 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 4.04 (s, 3H), 3.39 (q, J = 7.1 Hz, 2H), 3.13 (s, 2H), 2.07 - 1.97 (m, 1H), 0.88 - 0.77 (m, 4H), 0.71 (t, J = 7.1 Hz, 3H).

[0080] Example D03

[0081] Step 1: Synthesis of compound 3-2

[0082] Dissolve 3-1 (same as 1-2, 500 mg, 1.93 mmol) in dichloromethane (5 mL), replace with nitrogen for three times. Add deuterated methylamine hydrochloride (272 mg, 3.85 mmol) and triethylamine (1 g, 9.6 mmol), stir the mixture at room temperature for 30 min. Concentrate the reaction under reduced pressure, concentrate in vacuum. Purify the crude product on silica gel plate (DCM:MeOH = 20:1) to get 3-2 (380 mg, yield 77%). MS m / z: 257.10, 259.10 [M+H] + .

[0083] Step 2: Synthesis of compound 3-3

[0084] The synthesis of 3-3 is the same as the corresponding step in Example D02, using the coupling of 3-2 with 2-fluoro-3-nitrophenylboronic acid pinacol ester. MS m / z: 298.30 [M+H] + .

[0085] Step 3: Synthesis of compound 3-4

[0086] The synthesis of 3-4 is the same as the corresponding step in Example D01, using the hydrogenation of 3-3. MS m / z: 268.35 [M+H] + .

[0087] Step 4: Synthesis of compound D03

[0088] The synthesis of D03 is the same as the corresponding step in Example D01, using the coupling of 3-4 with INT01. MS m / z: 487.35 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.99 (s, 1H), 8.94 (s, 1H), 8.64 (s, 1H), 8.20 (s, 1H), 7.72 (d, J = 7.3 Hz, 1H), 7.65 (d, J = 8.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 4.05 (s, 3H), 3.14 (s, 2H), 2.08 - 1.96 (m, 1H), 0.83 - 0.76 (m, 4H).

[0089] Example D04

[0090] Step 1: Synthesis of compound 4-2

[0091] Dissolve 4-1 (500 mg, 2.77 mmol) in dichloromethane (5 mL), replace with nitrogen for three times. Add (2M in THF) methylamine solution (2.77 ml, 5.54 mmol), stir the mixture at room temperature for 30 min. Concentrate the reaction under reduced pressure, purify the crude product by silica gel plate (DCM:MeOH = 20:1) to give 4-2 (320 mg, yield 66%). MS m / z: 176.25 [M+H] + .

[0092] Step 2: Synthesis of compound 4-3

[0093] Dissolve 4-2 (160 mg, 0.86 mmol) in tetrahydrofuran (5 mL), replace with nitrogen for three times. Add 2-fluoro-3-bromonitrobenzene (245 mg, 1.1 mmol) and cesium carbonate (560 mg, 1.72 mmol), replace with nitrogen for three times. Stir the mixture at 75 °C for 3 h. Add water (10 mL) to quench the reaction, extract the aqueous phase with dichloromethane for three times (30 mL x 3), combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under vacuum. Purify the crude product by silica gel plate (PE:EtOAc = 1:1) to give 4-3 (100 mg, yield 29%). MS m / z: 375.20 [M+H] + .

[0094] Step 3: Synthesis of compound 4-4

[0095] Dissolve 4-3 (50 mg, 0.133 mmol) in tetrahydrofuran (5 mL), replace with nitrogen for three times. Add NaHMDS (1M in THF, 0.66 mL, 0.66 mmol) and hexachloroethane (188 mg, 0.8 mmol), replace with nitrogen for three times. Stir the mixture at room temperature for 3 h. Add saturated ammonium chloride solution (10 mL) to quench the reaction, extract the aqueous phase with dichloromethane for three times (30 mL x 3), combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under vacuum. Purify the crude product by silica gel plate (PE:EtOAc = 2:1) to give 4-4 (30 mg, yield 55%). MS m / z: 411.00 [M+H] + .

[0096] Step 4: Synthesis of compound 4-5

[0097] Dissolve 4-4 (30 mg, 0.07 mmol) in N,N-dimethylformamide (5 mL), replace with nitrogen for three times. Add sodium carbonate (11 mg, 0.1 mmol) and palladium acetate (1.6 mg, 0.007 mmol), replace with nitrogen for three times. Stir the mixture at 90 °C for 3 h. Quench the reaction by adding water (10 mL) to the reaction mixture, extract the aqueous phase with dichloromethane for three times (30 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 2:1) to give the target 4-5 (110 mg, yield 83%). MS m / z: 329.15 [M+H] + .

[0098] Step 5: Synthesis of compound 4-6

[0099] Dissolve 4-5 (20 mg, 0.06 mmol) in methanol (3 mL) and acetic acid (1.5 mL), replace with nitrogen for three times. Add iron powder (17 mg, 0.3 mmol), replace with nitrogen for three times. Stir the mixture at room temperature for 6 h. Filter the reaction mixture through celite under reduced pressure, concentrate in vacuum, and purify the crude product on silica gel plate (PE:EtOAc = 1:1) to give 4-6 (10 mg, yield 55.5%). MS m / z: 299.10 [M+H] + .

[0100] Step 6: Synthesis of compound D04

[0101] Synthesis of D04 is carried out according to the same procedure as the corresponding step of Example D01, using 4-6 coupled with INT01. MS m / z: 518.15 [M+H] + 1H NMR (400 MHz, DMSO-d6) d 11.27 (s, 1H), 11.00 (s, 1H), 8.94 (s, 1H), 8.19 (s, 1H), 7.70 (ddd, J = 12.1, 7.9, 1.4 Hz, 2H), 7.57 (t, J = 7.9 Hz, 1H), 4.00 (s, 3H), 3.14 (s, 2H), 2.87 (s, 3H), 2.03 (p, J = 6.5 Hz, 1H), 0.87 - 0.77 (m, 4H).

[0102] Example D05

[0103] Step 1: Synthesis of compound 5-2

[0104] Dissolve 5-1 (same as 3-3, 200 mg, 0.68 mmol) in tetrahydrofuran (20 mL), replace with nitrogen for three times. Add lithium bis(trimethylsilyl)amide solution (2M in THF) (1.36 mL, 1.36 mmol) dropwise, stir the mixture at room temperature for 30 min. Add deuterium water (3.6 mL) to the reaction, stir the mixture at room temperature for 2 h. Adjust the pH of the reaction to 7 by adding saturated ammonium chloride solution, extract the aqueous phase with ethyl acetate for three times (20 mL x 3), combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuum. Obtain crude 5-2 (159 mg) for direct use in the next step. HRMS m / z: 296.0553 [M+H] + .

[0105] Step 2: Synthesis of compound 5-3

[0106] Dissolve 5-2 (159 mg, 0.54 mmol) in methanol (10 mL), replace with nitrogen for three times, add Pd / C (6 mg, 0.05 mmol), replace with hydrogen for three times. Stir the reaction at room temperature for 2 h. Filter the reaction under reduced pressure, concentrate in vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 1:1) to obtain 5-3 (88 mg, yield 62%). HRMS m / z: 266.0805 [M+H] + .

[0107] Step 3: Synthesis of compound D05

[0108] Synthesis of D05 is the same as the corresponding step scheme of Example D01, using 5-3 to couple with INT01. MS m / z: 485.10 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.99 (s, 1H), 8.94 (s, 1H), 8.20 (s, 1H), 7.76-7.69 (m, 1H), 7.65 (dd, J = 8.0, 1.4 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 4.05 (s, 3H), 3.14 (s, 2H), 2.82 (s, 3H), 2.03 (p, J = 6.4 Hz, 1H), 0.84-0.73 (m, 4H).

[0109] Example D06

[0110] Step 1: Synthesis of compound 6-2

[0111] Dissolve 6-1 (250 mg, 1.28 mmol) in dichloromethane (5 mL), replace with nitrogen for three times. Add (2M in THF) methylamine solution (1.28 ml, 2.57 mmol), stir the mixture at room temperature for 30 min. Concentrate the reaction under reduced pressure, purify the crude product by silica gel plate (DCM:MeOH = 20:1) to get 6-2 (200 mg, yield 82.3%). MS m / z: 190.25 [M+H] + .

[0112] Step 2: Synthesis of compound 6-3

[0113] Dissolve 6-2 (200 mg, 1.06 mmol) in tetrahydrofuran (5 mL), replace with nitrogen for three times. Add 2-fluoro-3-bromonitrobenzene (301 mg, 1.37 mmol) and cesium carbonate (689 mg, 2.1 mmol), replace with nitrogen for three times, stir the mixture at 75 °C for 3 h. Add water (10 mL) to quench the reaction, extract the aqueous phase with dichloromethane for three times (30 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under vacuum. Purify the crude product by silica gel plate (PE:EtOAc = 1:1) to get 6-3 (180 mg, yield 44%). MS m / z: 388.90 [M+H] + .

[0114] Step 3: Synthesis of compound 6-4

[0115] Dissolve 6-3 (180 mg, 0.46 mmol) in N,N-dimethylformamide (5 mL), replace with nitrogen for three times. Add sodium carbonate (74 mg, 0.7 mmol) and palladium acetate (12 mg, 0.05 mmol), replace with nitrogen for three times. Stir the mixture at 90 °C for 3 h. Add water (10 mL) to quench the reaction, extract the aqueous phase with dichloromethane for three times (30 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under vacuum. Purify the crude product by silica gel plate (PE:EtOAc = 1:1) to get 6-4 (110 mg, yield 78%). MS m / z: 309.05 [M+H] + .

[0116] Step 4: Synthesis of compound 6-5

[0117] Dissolve 6-4 (30 mg, 0.1 mmol) in methanol (3 mL) and acetic acid (1.5 mL), nitrogen replacement three times. Add iron powder (45 mg, 0.81 mmol), nitrogen replacement three times. The mixture was stirred at room temperature for 6 h. The reaction was filtered through celite under reduced pressure, concentrated in vacuo, and the crude product was purified by silica gel plate (PE:EtOAc = 1:1) to give 6-5 (15 mg, yield 54%). MS m / z: 279.15 [M+H] + .

[0118] Step 5: Synthesis of compound D06

[0119] The synthesis method of D06 is the same as the corresponding step scheme of Example DOl, using 6-5 coupled with INT01. MS m / z: 498.20 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ 11.28 (s, 1H), 11.04 (s, 1H), 8.98 (s, 1H), 8.24 (s, 1H), 7.74 (dd, J = 7.6, 1.3 Hz, 1H), 7.68 (dd, J = 8.2, 1.4 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 3.98 (s, 3H), 3.19 (s, 2H), 2.86 (s, 3H), 2.58 (s, 3H), 2.08 (p, J = 6.4 Hz, 1H), 0.90 - 0.82 (m, 4H).

[0120] Examples D07 & D08

[0121] Step 1: Synthesis of compound 7-2

[0122] Dissolve 7-1 (209 mg, 1.07 mmol) in dichloromethane (5 mL), add (2M in THF) methylamine solution (1.1 mL, 2.15 mmol), and stir the mixture at room temperature for 30 min. The reaction was filtered under reduced pressure, concentrated in vacuo to give crude 7-2 (235 mg) which was used directly for the next step. MS m / z: 190.10 [M+H] + .

[0123] Step 2: Synthesis of compound 7-3

[0124] Dissolve 7-2 (235 mg, 1.24 mmol) in tetrahydrofuran (8 mL), replace with nitrogen for three times. Add 2-fluoro-3-bromonitrobenzene (236 mg, 1.07 mmol) and cesium carbonate (700 mg, 2.15 mmol), replace with nitrogen for three times. Stir the mixture at 80 °C for 2 h. Concentrate the reaction under vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 1:1) to give 7-3 (392 mg, yield 94%). MS m / z: 389.00, 391.00 [M+H] + .

[0125] Step 3: Synthesis of compound 7-4

[0126] Dissolve 7-3 (392 mg, 1.01 mmol) in tetrahydrofuran (20 mL), replace with nitrogen for three times. Add hexachloroethane (1.43 g, 6.06 mmol), replace with nitrogen for three times. Add lithium bis(trimethylsilyl)amide solution (2.02 mL, 2M in THF, 2.02 mmol) dropwise. Stir the mixture at room temperature. Dilute the reaction with saturated ammonium chloride solution (10 mL) and wash, extract the aqueous phase with ethyl acetate three times (20 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate and concentrate under vacuum. Obtain the crude product 7-4 directly for the next step. MS m / z: 422.80, 424.80 [M+H] + .

[0127] Step 4: Synthesis of compound 7-5

[0128] Dissolve 7-4 in N,N-dimethylformamide (5 mL), replace with nitrogen for three times. Add potassium carbonate (215.9 mg, 1.52 mmol) and palladium acetate (23.4 mg, 0.1 mmol), replace with nitrogen for three times. Stir the mixture at 90 °C. Dilute the reaction with water, extract the aqueous phase with ethyl acetate three times (15 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate and concentrate under vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 2:1) to give 7-5 (137.4 mg, yield 43%). HRMS m / z: 343.0258, 345.0226 [M+H] + .

[0129] Step 5: Synthesis of compound 7-6

[0130] Dissolve 7-5 (47.4 mg, 0.14 mmol) in methanol (6 mL), replace with nitrogen for three times, add Pd / C (5 mg), replace with hydrogen for three times. Stir the reaction solution at room temperature for 2 h. Filter the reaction solution under reduced pressure, concentrate in vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 2.5:1) to give 7-6 (24 mg, yield 53%). HRMS m / z: 313.0526, 315.0681 [M+H] + .

[0131] Step 6: Synthesis of compound D07

[0132] Synthesis of D07 is the same as the corresponding step scheme of Example D01, using 7-6 coupled with INT01. MS m / z: 532.15 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 11.00 (s, 1H), 8.94 (s, 1H), 8.18 (s, 1H), 7.74 (dd, J = 7.7, 1.4 Hz, 1H), 7.69 (dd, J = 8.3, 1.4 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 4.36 (q, J = 7.3 Hz, 2H), 3.14 (s, 2H), 2.88 (s, 3H), 2.02 (q, J = 6.3 Hz, 1H), 1.47 (t, J = 7.2 Hz, 3H), 0.84 - 0.77 (m, 4H).

[0133] Step 7: Synthesis of compound 8-1

[0134] Dissolve 7-6 (50 mg, 0.16 mmol) in methanol (15 mL), replace with nitrogen for three times, add Pd / C (3 mg), replace with hydrogen for three times. Stir the reaction solution at room temperature for 18 h under 1.8 MPa hydrogen pressure. Filter the reaction solution under reduced pressure, concentrate in vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 2.5:1) to give 8-1 (11 mg, yield 25%). MS m / z: 279.15 [M+H] + .

[0135] Step 8: Synthesis of compound D08

[0136] The same as the corresponding step scheme of Example D01. MS m / z: 498.20 [M+H] +1H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.99 (s, 1H), 8.94 (s, 1H), 8.71 (s, 1H), 8.19 (s, 1H), 7.78 - 7.68 (m, 1H), 7.65 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 7.9 Hz, 1H), 4.35 (q, J = 7.3 Hz, 2H), 3.14 (s, 2H), 2.82 (s, 3H), 2.09 - 1.98 (m, 1H), 1.50 (t, J = 7.3 Hz, 3H), 0.83 - 0.77 (m, 4H).

[0137] Example D09

[0138] Step 1: Synthesis of compound 9-2

[0139] Dissolve 9-1 (400 mg, 1.74 mmol) in 1,4-dioxane (10 mL), replace with nitrogen for three times. Add p-tert-butylbenzyl mercaptan (628.8 mg, 3.49 mmol) and N,N- diisopropylethylamine (225.4 mg, 3.49 mmol), replace with nitrogen for three times. Add Xantphos Pd G4 (160 mg, 0.17 mmol), replace with nitrogen for three times. Stir the mixture at 90 °C overnight. Concentrate the reaction under vacuum, purify the crude product on silica gel plate (PE:EtOAc = 20:1) to get 9-2 (284 mg, yield 51.3%). MS m / z: 340.30, 342.30 [M+H] + .

[0140] Step 2: Synthesis of compound 9-3

[0141] Dissolve 9-2 (190 mg, 0.56 mmol) in 1,4-dioxane (5 mL) and water (1 mL), replace with nitrogen for three times. Add 2-fluoro-3-nitrobenzeneboronic acid pinacol ester (224.5 mg, 0.84 mmol) and sodium carbonate (194.5 mg, 1.40 mmol), replace with nitrogen for three times. Add tetrakis(triphenylphosphine)palladium (64.76 mg, 0.06 mmol), replace with nitrogen for three times. Stir the mixture at 50 °C overnight. Filter the reaction under reduced pressure, concentrate under vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 4:1) to get 9-3 (108 mg, yield 48%). MS m / z: 401.35 [M+H] + .

[0142] Step 3: Synthesis of compound 9-4

[0143] Dissolve 9-3 (108 mg, 0.27 mmol) in acetic acid (4 mL) and water (2 mL), stir the mixture at -20 °C. Add N-chlorosuccinimide (144 mg, 1.08 mmol), let the system gradually rise to room temperature, stir the mixture at room temperature overnight. Concentrate the reaction under vacuum to obtain crude 9-4 directly for the next step.

[0144] Step 4: Synthesis of compound 9-5

[0145] Dissolve 9-4 from the previous step in dichloromethane (4 mL) and tetrahydrofuran (4 mL), add (2M in THF) methylamine (0.2 mL). Stir the mixture at room temperature for 3 h. Concentrate the reaction under vacuum, purify the crude product on a silica gel plate (PE:EtOAc = 1:1) to obtain 9-5 (130 mg). MS m / z: 316.25 [M+H] + .

[0146] Step 5: Synthesis of compound 9-6

[0147] Dissolve 9-5 (85 mg, 0.27 mmol) in dichloromethane (10 mL), replace with nitrogen three times. Add potassium carbonate (74.9 mg, 0.54 mmol), stir the mixture at 30 °C overnight. Filter the reaction under reduced pressure, concentrate under vacuum to obtain crude 9-6 directly for the next step. MS m / z: 296.25 [M+H] + .

[0148] Step 6: Synthesis of compound 9-7

[0149] Dissolve 9-6 from the previous step in methanol (3 mL), replace with nitrogen three times. Add Pd / C (4 mg), replace with hydrogen three times. Stir the mixture at room temperature for 2 h, filter the reaction under reduced pressure, concentrate under vacuum to obtain crude 9-7 (40 mg, yield 56%) directly for the next step. MS m / z: 266.25 [M+H] + .

[0150] Step 7: Synthesis of compound D09

[0151] The synthesis method of D09 is the same as the corresponding step scheme of Example D01, using the coupling of 9-7 with INT01. MS m / z: 485.40 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.31 (s, 1H), 11.01 (s, 1H), 8.95 (s, 1H), 8.19 (s, 1H), 7.81 - 7.68 (m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 5.76 (s, 1H), 4.43 (s, 3H), 3.15 (s, 2H), 2.92 (s, 3H), 2.03 (dt, J = 13.5, 6.9 Hz, 1H), 0.85 - 0.75 (m, 4H).

[0152] Example D10

[0153] Step 1: Synthesis of compound 10-2

[0154] Dissolve 10-1 (100 mg, 0.56 mmol) in 1,4-dioxane (8 mL), add and p- tert- butylbenzyl mercaptan (212.7 mg, 1.18 mmol) and N,N-diisopropylethylamine (152.4 mg, 1.18 mmol), replace with nitrogen for three times. Add XantPhos Pd G4 (54 mg, 0.06 mmol), replace with nitrogen for three times. Stir the mixture at 90 °C overnight. Concentrate the reaction under vacuum, the crude product is purified by silica gel plate (PE:EtOAc = 30:1) to give 10-2 (110 mg, yield 70.7%). MS m / z: 278.20 [M+H] + .

[0155] Step 2: Synthesis of compound 10-3

[0156] Dissolve 10-2 (110 mg, 0.40 mmol) in acetic acid (4 mL) and water (2 mL), add N- chlorosuccinimide (212 mg, 1.59 mmol), stir the mixture at room temperature for 2 h. Concentrate the reaction under vacuum to give crude 10-3 which is used directly for the next step.

[0157] Step 3: Synthesis of compound 10-4

[0158] Dissolve 10-3 from the previous step in dichloromethane (3 mL), add (2M in THF) methylamine solution (0.4 mL, 0.79 mmol), stir the mixture at room temperature for 2 h. Concentrate the reaction under vacuum, the crude product is purified by silica gel plate (PE:EtOAc = 2:1) to give 10-5 (129 mg). MS m / z: 193.15 [M+H] + .

[0159] Step 4: Synthesis of compound 10-5

[0160] Dissolve 10-4 (88 mg, 0.46 mmol) in N,N-dimethylformamide (6 mL), add 2-fluoro-3-bromonitrobenzene (105.9 mg, 0.48 mmol), cesium carbonate (373 mg, 1.14 mmol), stir the mixture at 60 °C for 30 min. Filter the reaction under reduced pressure, concentrate in vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 2:1) to give 10-5 (150 mg, yield 83.7%). HRMS m / z: 391.9360, 393.9337 [M+H] + .

[0161] Step 5: Synthesis of compound 10-6

[0162] Dissolve 10-5 (120 mg, 0.31 mmol) in N,N-dimethylformamide (6 mL), replace with nitrogen for three times. Add sodium carbonate (48.8 mg, 0.46 mmol) and palladium acetate (6.95 mg, 0.03 mmol), replace with nitrogen for three times, stir the mixture at 90 °C for 6 hours. Filter the reaction under reduced pressure, dilute with water (15 mL), extract the aqueous phase with ethyl acetate for three times (20 mL x 3), combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 2:1) to give 10-6 (50 mg, 53%). MS m / z: 312.10 [M+H] + .

[0163] Step 6: Synthesis of compound 10-7

[0164] Dissolve 10-6 (51 mg, 0.16 mmol) in methanol (5 mL), replace with nitrogen for three times. Add Pd / C (5 mg), replace with hydrogen for three times, stir at room temperature for 1 h. Filter the reaction under reduced pressure, concentrate in vacuum, purify the crude product on silica gel plate (PE:EtOAc = 2:1) to give 10-7 (28 mg, yield 61%). MS m / z: 282.15 [M+H] + .

[0165] Step 7: Synthesis of compound D10

[0166] Synthesis of D10 is the same as the corresponding step scheme of Example DOl, using 10-7 to couple with INT01. MS m / z: 501.35 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 11.01 (s, 1H), 8.95 (s, 1H), 8.18 (s, 1H), 7.91 (dd, J = 7.8, 1.4 Hz, 1H), 7.72 (dd, J = 8.1, 1.4 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 3.15 (s, 2H), 2.93 (s, 3H), 2.90 (s, 3H), 2.03 (p, J = 6.4 Hz, 1H), 0.85 - 0.77 (m, 4H).

[0167] Example D11

[0168] Step 1: Synthesis of compound 11-2

[0169] Dissolve 11-1 (220 mg, 1.48 mmol) and p-tert-butylbenzyl mercaptan (186 mg, 1.03 mmol) in dimethyl sulfoxide (1.5 mL), add cesium carbonate (722 mg, 2.22 mmol), stir the mixture at 60 °C for 4 h. Filter the reaction solution under reduced pressure. Dilute the reaction solution with water (10 mL), extract the aqueous phase with dichloromethane three times (15 mL x 3), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Purify the crude product on a silica gel plate (PE:EtOAc = 10:1) to give 11-2 (364 mg, yield 84%). HRMS m / z: 293.0863, 295.0833 [M+H] + .

[0170] Step 2: Synthesis of compound 11-3

[0171] Dissolve 11-2 (165 mg, 0.56 mmol) in 1,4-dioxane (4 mL) and water (1 mL), replace with nitrogen three times. Add 2-fluoro-3-nitrophenylboronic acid pinacol ester (226 mg, 0.85 mmol) and potassium carbonate (157 mg, 1.13 mmol), replace with nitrogen three times. Add palladium acetate (13 mg, 0.06 mmol) and triphenylphosphine (59 mg, 0.22 mmol), replace with nitrogen three times. Stir the mixture at 50 °C overnight. Filter the reaction solution under reduced pressure, concentrate in vacuo. Purify the crude product on a silica gel plate (PE:EtOAc = 5:1) to give 11-3 (142 mg, yield 63%). HRMS m / z: 398.1281 [M+H] + .

[0172] Step 3: Synthesis of compound 11-4

[0173] Dissolve 11-3 (142 mg, 0.36 mmol) in dichloromethane (5 mL), the mixture is stirred in ice bath. Add acetic acid (2d) and water (4d), add 1,3-dichloro-5,5-dimethylhydantoin (141 mg, 0.72 mmol), the mixture is stirred at room temperature for 1.5 h. Dilute the reaction solution with water (8 mL), the aqueous phase is extracted with dichloromethane three times (10 mL x 3), combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuum. The crude product 11-4 is directly used in the next step.

[0174] Step 4: Synthesis of compound 11-5

[0175] Dissolve 11-4 in dichloromethane (3 mL), add (2M in THF) methylamine solution (0.5 mL, 1 mmol). The mixture is stirred at room temperature for 30 min. The reaction solution is filtered under reduced pressure, concentrated in vacuum to obtain the crude product 11-5 which is directly used in the next step. MS m / z: 313.25 [M+H] + .

[0176] Step 5: Synthesis of compound 11-6

[0177] Dissolve 11-5 in dichloromethane (5 mL) and tetrahydrofuran (5 mL), add potassium carbonate (99 mg, 0.71 mmol), the mixture is stirred at 50°C for 3 h. The reaction solution is filtered under reduced pressure, concentrated in vacuum to obtain the crude product 11-6 which is directly used in the next step. MS m / z: 293.25 [M+H] + .

[0178] Step 6: Synthesis of compound 11-7

[0179] Dissolve 11-6 in methanol (3 mL), replace with nitrogen three times, add Pd / C (10 mg), replace with hydrogen three times. The reaction solution is stirred at room temperature for 2 h. The reaction solution is filtered under reduced pressure, concentrated in vacuum, the crude product is purified by silica gel plate (PE:EtOAc = 1:1) to obtain 11-7 (19.5 mg, yield 21%). MS m / z: 263.30 [M+H] + .

[0180] Step 7: Synthesis of compound D11

[0181] The synthesis method of D11 is the same as the corresponding step scheme of Example DOl, using 11-7 to couple with INT01. MS m / z: 482.30 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 11.01 (s, 1H), 9.19 (d, J = 2.4 Hz, 1H), 9.01 - 8.85 (m, 2H), 8.23 (dd, J = 7.8, 1.3 Hz, 1H), 8.16 (s, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.69 (t, J = 8.0 Hz, 1H), 3.16 (s, 2H), 3.00 (s, 3H), 2.10 - 1.95 (m, 1H), 0.84 - 0.75 (m, 4H).

[0182] Example D12

[0183] Step 1: Synthesis of compound 12-2

[0184] Dissolve 12-1 (1 g, 6.8 mmol) in tetrahydrofuran (15 mL), replace with nitrogen for three times, cool the reaction to 0 °C. Add 60% sodium hydride (408 mg, 10.2 mmol), stir the mixture at room temperature for 30 min. Add deuterated methyl iodide (1.18 g, 8.2 mmol) to the reaction at 0 °C, stir the mixture at room temperature for 2 h. Dilute the reaction with water (10 mL), extract the aqueous phase with ethyl acetate for three times (20 mL x 3). Combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate in vacuum. Get the crude 12-2 (958 mg, yield 87%) directly for the next step. MS m / z: 164.20, 166.20 [M+H] + .

[0185] Step 2: Synthesis of compound 12-3

[0186] Dissolve 12-2 (203 mg, 1.24 mmol) in tert-butyl alcohol (8 mL), replace with nitrogen for three times. Add p-tert-butylbenzyl mercaptan (449 mg, 2.49 mmol) and triethylamine (252 mg, 2.49 mmol), replace with nitrogen for three times. Add t-BuBrettPhos Pd G6 TES (11 mg. 0.01 mmol), replace with nitrogen for three times. Stir the mixture at 50 °C overnight. Filter the reaction under reduced pressure, concentrate in vacuum. Purify the crude on silica gel plate (PE:EtOAc = 3:1) to get 12-3 (122 mg, yield 37%). HRMS m / z: 264.1613 [M+H] + .

[0187] Step 3: Synthesis of compound 12-4

[0188] Dissolve 12-3 (122 mg, 0.46 mmol) in acetic acid (5 mL) and water (2.5 mL), and replace with nitrogen for three times. Add N-chlorosuccinimide (248 mg, 1.85 mmol), and stir the mixture at room temperature for 2 h. Dilute the reaction with water (10 mL), and extract the aqueous phase with dichloromethane (10 mL x 3) three times. Combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Obtain the crude 12-4 directly for the next step.

[0189] Step 4: Synthesis of compound 12-5

[0190] Dissolve 12-4 in dichloromethane (5 mL), and add a solution of methylamine (2 M in THF) (3 mL). Stir the mixture at room temperature for 30 min. Concentrate the reaction in vacuo. Obtain the crude 12-5 (194 mg). MS m / z: 179.25 [M+H] + .

[0191] Step 5: Synthesis of compound 12-6

[0192] Dissolve 12-5 (194 mg) in N,N-dimethylformamide (10 mL), and replace with nitrogen for three times. Add 2-fluoro-3-bromonitrobenzene (240 mg, 1.09 mmol) and cesium carbonate (710 mg, 2.18 mmol), and replace with nitrogen for three times. Stir the mixture at 80 °C for 2 h. Concentrate the reaction in vacuo. Purify the crude product on a silica gel plate (PE:EtOAc = 1:1) to obtain 12-6 (44 mg, yield 25%). MS m / z: 378.00, 380.00 [M+H] + .

[0193] Step 6: Synthesis of compound 12-7

[0194] Dissolve 12-6 (44 mg, 0.12 mmol) in tetrahydrofuran (10 mL), and replace with nitrogen for three times. Add hexachloroethane (166 mg, 0.7 mmol), and replace with nitrogen for three times. Add a solution of lithium bis(trimethylsilyl)amide (1 M in THF) (0.23 mL, 0.23 mmol) dropwise. Stir the mixture at room temperature for 2 h. Wash the reaction with saturated ammonium chloride solution (10 mL), extract the aqueous phase with ethyl acetate (15 mL x 3) three times, combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuo. Obtain the crude 12-7 (65.6 mg) directly for the next step. MS m / z: 412.00, 414.00 [M+H] + .

[0195] Step 7: Synthesis of compound 12-8

[0196] Dissolve 12-7 (65.6 mg, 0.16 mmol) in N,N-dimethylformamide (5 mL), replace with nitrogen for three times. Add sodium carbonate (25.4 mg, 0.24 mmol) and palladium acetate (3.6 mg, 0.02 mmol), replace with nitrogen for three times. Stir the mixture at 90 °C. Dilute the reaction solution with water, extract the aqueous phase with ethyl acetate for three times (15 mL x 3), combine the organic phase, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate in vacuum. Obtain the crude 12-8 (60 mg). MS m / z: 332.15 [M+H] + .

[0197] Step 8: Synthesis of compound 12-9

[0198] Dissolve 12-8 (60 mg, 0.18 mmol) in methanol (8 mL), replace with nitrogen for three times, add Pd / C (6 mg), replace with hydrogen for three times, stir the reaction solution at room temperature for 2 h. Add triethylamine (22 mg, 0.22 mmol), stir the reaction solution at room temperature for 1 h. Filter the reaction solution under reduced pressure, concentrate in vacuum. Purify the crude product on silica gel plate (PE:EtOAc = 1.5:1) to obtain 12-9 (13 mg, yield 28%). MS m / z: 268.25 [M+H] + .

[0199] Step 9: Synthesis of compound D12

[0200] Synthesis of D12 is the same as the corresponding step scheme of Example D01, using 12-9 to couple with INT01. MS m / z: 487.20 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.26 (s, 1H), 10.99 (s, 1H), 8.93 (s, 1H), 8.63 (s, 1H), 8.20 (s, 1H), 7.71 (dd, J = 7.6, 1.3 Hz, 1H), 7.65 (dd, J = 8.2, 1.4 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 3.14 (s, 2H), 2.81 (s, 3H), 2.07 - 1.97 (m, 1H), 0.88 - 0.77 (m, 4H).

[0201] Example D13

[0202] Step 1: Synthesis of compound 13-2

[0203] Dissolve 13-1 (same as 6-2, 129 mg, 0.68 mmol) in N,N-dimethylformamide (5 mL), nitrogen substitution for three times. Add 2-chloro-3-fluoro-4-iodopyridine (193 mg, 0.75 mmol) and cesium carbonate (556 mg, 1.71 mmol), nitrogen substitution for three times. The mixture was stirred at 70 °C for 2 h. The reaction was filtered under reduced pressure, concentrated in vacuum. The crude product was purified by silica gel plate (DCM:MeOH = 30:1) to give 13-2 (123 mg, yield 42%). HRMS m / z: 426.9496, 428.9465 [M+H] + .

[0204] Step 2: Synthesis of compound 13-3

[0205] Dissolve 13-2 (73 mg, 0.17 mmol) in N,N-dimethylformamide (5 mL), nitrogen substitution for three times. Add sodium carbonate (27 mg, 0.26 mmol) and palladium acetate (3.8 mg, 0.02 mmol), nitrogen substitution for three times. The mixture was stirred at 90 °C for 16 h. The reaction was diluted with water, the aqueous phase was extracted with ethyl acetate for three times (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The crude product was purified by silica gel plate (DCM:MeOH = 50:1) to give 13-3 (36 mg, yield 71%). MS m / z: 299.15 [M+H] + .

[0206] Step 3: Synthesis of compound 13-4

[0207] Dissolve 13-3 (71 mg, 0.24 mmol) in toluene (5 mL), nitrogen substitution for three times. Add BocNH2 (84 mg, 0.71 mmol) and sodium tert-butoxide (57 mg, 0.6 mmol), nitrogen substitution for three times. Add Pd2(dba)3 (5.5 mg, 0.006 mmol) and t-Bu XPhos (10 mg, 0.02 mmol), nitrogen substitution for three times. The mixture was stirred at 100 °C overnight. The reaction was filtered under reduced pressure, concentrated in vacuum. The crude product was purified by silica gel plate (DCM:MeOH = 30:1) to give 13-4 (13.7 mg, yield 21%). MS m / z: 280.20 [M+H] + .

[0208] Step 4: Synthesis of compound D13

[0209] D13 (3 mg, 13% yield) was obtained by dissolving 13-4 (13 mg, 0.05 mmol) in 1,4-dioxane (5 mL) and replacing with nitrogen for three times. INT01 (12 mg, 0.05 mmol) and cesium carbonate (30 mg, 0.09 mmol) were added and replaced with nitrogen for three times. Pd2(dba)3(4.3 mg, 0.005 mmol) and BINAP (5.8 mg, 0.009 mmol) were added and replaced with nitrogen for three times. The mixture was stirred at 110 °C overnight. The reaction was filtered under reduced pressure and concentrated in vacuum. The crude product was purified by silica gel plate (DCM:MeOH = 20:1) to give D13 (3 mg, 13% yield). MS m / z: 499.20 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 10.98 (s, 1H), 9.69 (s, 1H), 9.00 (s, 1H), 8.39 (d, J = 5.1 Hz, 1H), 7.46 (d, J = 5.0 Hz, 1H), 3.96 (s, 3H), 3.16 (s, 2H), 2.95 (s, 3H), 2.55 (s, 3H), 0.86 (dd, J = 8.0, 5.9 Hz, 5H). 2.06 - 1.96 (m, 1H), 0.90 - 0.78 (m, 4H).

[0210] Example D14

[0211] Step 1: Synthesis of compound 14-2

[0212] Dissolve 14-1 (718 mg, 3.64 mmol) in acetonitrile (5 mL), drop ammonia water in ice bath until the reaction is complete. First concentrate the reaction in vacuum, then filter under reduced pressure, and finally concentrate in vacuum. The crude product was purified by silica gel plate (DCM:MeOH = 15:1) to give the target product 14-2 (383 mg, yield 59%). MS m / z: 163.35 [M+H] + .

[0213] Step 2: Synthesis of compound 14-3

[0214] Add 14-2 (67 mg, 1 eq), dichloromethane (5 mL) and triethylamine (127 mg, 3 eq) into the reaction bottle, and stir it in ice bath for 30 min. Add TBSOTf (120 mg, 1.1 eq), continue to stir the system in ice bath for 30 min, monitor the reaction completion by TLC plate, and use the crude compound 14-3 directly for the next step.

[0215] Step 3: Synthesis of compound 14-4

[0216] PPh3(146 mg, 1.8 eq), dry dichloromethane (5 mL) and C2Cl6(176 mg, 1.35 eq) were added into the reaction flask. The system was stirred at 40 °C for 30 min. Triethylamine (126 mg, 3 eq) was added, and after stirring at room temperature for 30 min, the temperature was lowered to 0 °C, and 14-3 reaction solution was added dropwise. The mixture was stirred at 0 °C for 30 min. (S)-(-)-1-(4-methoxyphenyl)ethylamine (69 mg, 1.1 eq) was added, and the reaction was stirred in an ice bath. The reaction solution was filtered under reduced pressure, and concentrated under vacuum. The crude product was purified by silica gel plate (PE:EtOAc = 2:1) to obtain compound 14-4 (50 mg, yield: 30%). MS m / z: 410.50 [M+H] + .

[0217] Step 4: Synthesis of compound 14-5

[0218] 14-4 (50 mg, 0.12 mmol), dichloromethane (10 mL) and tetrabutylammonium fluoride (0.24 mL, 0.24 mmol, 1M in THF) were added into the reaction flask, and the system was stirred at 25 °C for 2 h. The reaction solution was diluted with dichloromethane and extracted into water until no product was detected in water. The organic phase solvent was evaporated under reduced pressure to obtain the crude product of 14-5 (48 mg). MS m / z: 296.35 [M+H] + .

[0219] Step 5: Synthesis of compound 14-7

[0220] The reaction flask was replaced with nitrogen, and 14-5 (36 mg, 1 eq), 14-6 (27 mg, 1 eq), Cs2CO3(80 mg, 2 eq) and DMF (3 mL) were added. The system was warmed to 80 °C for 4 h. The reaction solution was diluted with dichloromethane and extracted with water (10 mL x 3), and the organic phase was combined and concentrated under vacuum. The crude product was purified by silica gel plate (PE:EtOAc = 3:1) to obtain 14-7 (27 mg, yield 45%). MS m / z: 495.25, 497.25 [M+H] + .

[0221] Step 6: Synthesis of compound 14-8

[0222] A mixture of 14-7 (27 mg, 0.05 mmol), K2CO3(17 mg, 0.12 mmol), MeI (15.5 mg, 0.11 mmol) and DMF (2 mL) was stirred at 80 °C for 8 h. The reaction was diluted with dichloromethane, extracted with water (10 mL x 3), the organic phases were combined and concentrated in vacuo. The crude product was purified by silica gel plate (PE:EtOAc = 3:1) to give compound 14-8 (14 mg, yield 51%). MS m / z: 509.25, 511.25 [M+H] + .

[0223] Step 7: Synthesis of compound 14-9

[0224] A mixture of 14-8 (28 mg, 0.06 mmol), Cs2CO3(36 mg, 0.11 mmol), Pd(OAc)2(1.24 mg, 0.006 mmol) and DMF (4 mL) was added to a reaction vial, which was replaced with nitrogen. The mixture was stirred at 90 °C for 8 h. The reaction was diluted with dichloromethane, extracted with water (10 mL x 3), the organic phases were combined and concentrated in vacuo. The crude product was purified by silica gel plate (PE:EtOAc = 3:1) to give compound 14-9 (20 mg, yield 85%). MS m / z: 429.35 [M+H] + .

[0225] Step 8: Synthesis of compound 14-10

[0226] The synthesis of 14-10 was carried out in the same manner as the corresponding step in Example D10 to give compound 14-10 (19 mg, yield 98%). MS m / z: 399 [M+H] + .

[0227] Step 9: Synthesis of compound 14-11

[0228] The synthesis of 14-11 was carried out in the same manner as the corresponding step in Example D10 to give compound 14-11 (10 mg, yield 51%). MS m / z: 618.50 [M+H] + .

[0229] Step 10: Synthesis of compound D14

[0230] Compound 14-11 (10 mg, 1 eq), BCI3(0.05 mL, 3 eq, 1 M in THF) and DCM (3 mL) were added into a single-neck flask, the mixture was stirred at 25 °C for 1 h. The system was added dropwise into an ice water solution of K2CO3(286 mg, 9 eq), the pH was adjusted to basic, followed by extraction operation, the organic phase was concentrated in vacuum. The crude product was purified by silica gel plate (DCM:MeOH=10:1) to obtain the target product D14 (5 mg, yield 64%). MS m / z: 484.45 [M+H] + .

[0231] Bioexample 1: Cell proliferation inhibition activity of the compound was determined by CTG (CELLTITER-GLO) luminescence method

[0232] Test principle: Promega's CellTiter-Glo TM Luminescence kit was used, which used luciferase as the detector, and the participation of ATP was required in the luminescence process. The respiration and other life activities of metabolically active cells could produce ATP. An equal volume of CellTiter-Glo TM reagent was added to the cell culture medium, the luminescence value was measured, and the light signal was proportional to the amount of ATP in the system. ATP and the number of living cells were positively correlated, so it was used for the detection of the inhibition of the proliferation activity of the compound on the cells.

[0233] Test method: Prepare complete medium (RPMI 1640 + 10% FBS + 1% P / S) to resuscitate Ba / F3-FL-TYK2-E957D cells (Hefei Priserise), pass two generations or so, centrifuge to collect logarithmic growth phase cells and count, resuspend the cells to the appropriate concentration, inoculate the cell suspension into a 96-well plate, add 95 μL of cell suspension to each well, the seeding density is 2000 cells / well, the test compound is prepared into a stock solution with DMSO, with 1 mM as the highest concentration, gradually 3-fold dilution with DMSO, 10 concentration gradients are obtained; dilute the test compound 50 times with medium, take 5 μL into the 96-well cell plate containing 95 μL of cells, add 5 μL of DMSO-cell culture medium mixture (DMSO final concentration is 0.1%) to the Min control well without cells (containing 0.1% DMSO), 37°C, 5%, relative humidity above 90% carbon dioxide incubator, incubate for 72h. Add 50 μL / well CellTiter Glo to terminate the reaction, incubate at room temperature for 30 min in the dark, gently shake and detect in Envision. Read the fluorescence value RLU of each well, calculate the cell inhibition rate according to the formula cell growth inhibition rate % = (1-As / Ac) x 100. Wherein As: RLU sample (cells + CTG + test compound) - RLU Min (culture medium without cells), Ac: RLU normal growth cell control (cells + CTG + DMSO) - RLU Min (culture medium without cells). Enter the inhibition rate Inh% (Y) corresponding to each concentration (X) in EXCEL, and calculate the half inhibition concentration IC 50 value of each compound according to the built-in four-parameter fitting formula Y = Bottom + (Top-Bottom) / (1+(IC50 / X)*HillSlope) using Graphpad Prism 8 software. The specific effect data is shown in Table 1.

[0234] The data of representative molecules of the application tested by the test method described in Biological Example 1 are listed in Table 3 below. In Table 3, "A" represents IC 50 value less than 10 nM; "B" represents IC 50 value greater than or equal to 10 nM and less than 100 nM; "C" represents IC 50 value greater than or equal to 100 nM and less than 1000 nM. Control compounds Deucravacitinib (J. Med. Chem. 2019, 20, 8973-8995) and Zasocitinib (J. Med. Chem. 2023, 66, 10473-10496) were also tested.

[0235] Table 1 Cell proliferation inhibition test data

[0236] By the above tests, it was confirmed that the compound of the present application has an inhibitory effect on TYK2-E957D activity.

[0237] Although the specific embodiments of the present application are described above, it should be understood by those skilled in the art that these are only illustrative, and various changes or modifications can be made to these embodiments without departing from the principles and essence of the present application. Therefore, the scope of protection of the present application is defined by the appended claims.

Claims

1. A compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof: wherein, represents a single bond or a double bond, the definition of which satisfies the valence theory; "*" represents that the S atom marked thereby is in R configuration, S configuration or a mixture thereof; R 1 is O, NR 1-1 or C1-C6 alkyl; R 1-1 R is hydrogen, cyano or Ci-C6alkyl; R 2 C1-C6alkyl or C1-C6alkyl substituted by one or more R 2-1 substituted C1-C6alkyl; R 2-1 independently deuterium; X 3 and X 4 each independently C or N; ring A is a 5-6 membered heteroaromatic ring, in which the type of heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2 or 3; R 5 halo, C1-C6alkyl, or C1-C6alkyl substituted with one or more R 5-1 halo, C1-C6alkyl, or C1-C6alkyl substituted with one or more R R 5-1 independently deuterium or halogen; n is 0, 1, 2 or 3; X 2 is CH or N; R 3 C1-C6alkyl, NR 3-1 R 3-2 C1-C6alkyl substituted by one or more R 3-3 C1-C6alkyl; R 3-1 and R 3-2 each independently is hydrogen, C1-C6alkyl or C1-C6alkyl substituted with one or more R 1a substituted C1-C6alkyl; R 1a and R 3-3 each independently is deuterium; X 1 is CH or N; R 4 is C3-C 12 cycloalkyl.

2. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, one or more of the following conditions are satisfied: (1) each "C1-C6 alkyl" is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl or t-butyl, for example methyl or ethyl; (2) each "5-6 membered heteroaromatic ring" is independently a 5-6 membered heteroaromatic ring having 2 or 3 heteroatoms, the kind of which is N and / or S, for example a pyrazole ring, a thiazole ring, a triazole ring or a pyrazine ring, further for example (3) each "halogen" is independently F, Cl, Br or I, for example Cl; (4) Each "C3-C" 12 Each "cycloalkyl" is independently a C3-C6 cycloalkyl group, for example...

3. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, one or more of the following conditions are satisfied: (1) For (2) R 3 is NHR 3-2 or C1-C6 alkyl substituted with one or more deuterium.

4. The compound of formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof according to at least one of claims 1 to 3, wherein one or more of the following conditions are satisfied: (1) is any one of the following: For example Further examples Preferably (2) R 2 is -CH3, -CH2CH3, or -CD3; (3) For (4) R 3 To (5) R 4 For 5. The compound of formula (I) as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, or a solvate of a pharmaceutically acceptable salt thereof, characterized in that, The compound as shown in formula (I) is any one of the following compounds:

6. A pharmaceutical composition comprising a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof, as claimed in at least one of claims 1-5, and a pharmaceutically acceptable adjuvant.

7. Use of a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, as claimed in at least one of claims 1-5, or a pharmaceutical composition as claimed in claim 6, for the preparation of a medicament for the prevention and / or treatment of a TYK2-related disease; preferably, the TYK2-related disease is a TYK2-E957D-related disease; more preferably, the TYK2-related disease is selected from one or more of psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, allergic dermatitis, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease.

8. Use of a compound as shown in formula (I), a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of a pharmaceutically acceptable salt thereof, as claimed in at least one of claims 1-5, or a pharmaceutical composition as claimed in claim 6, for the preparation of a medicament for the prevention and / or treatment of a disease selected from one or more of psoriasis, psoriatic arthritis, inflammatory bowel disease, lupus erythematosus, allergic dermatitis, multiple sclerosis, Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease.

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