Compound combined with CRBN protein and degradation agent of protein

Abstract

The invention belongs to the technical field of medical chemistry, particularly relates to a compound capable of being combined with CRBN protein and a composition of the compound, and further relates to a protein degradation agent based on the CRBN protein and application of the protein degradation agent. The invention belongs to the technical field of chemical engineering, and particularly discloses a compound capable of being combined with CRBN protein, the compound is composed of a substructure unit A and a substructure unit B, the substructure A and the substructure B are formed by connecting Y of the substructure A with one of C2 (carbon 2 position), 4 (fourth position), 5 (fifth position), 6 (sixth position) and 7 (seventh position) of the substructure B through chemical single bonds, and the compound is shown as a formula I; the compound can be used as a structural unit of an E3 ubiquitin ligase ligand in a PROTAC technology, and provides more treatment means for cancers or diseases such as prostatic cancer, breast cancer, non-small cell lung cancer, Alzheimer's disease, neuroblastoma, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, malignant rhabdomyoma, oral squamous cell carcinoma and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical chemistry, and specifically relates to a compound capable of binding to CRBN protein and a composition thereof, and also relates to a protein degrader based on CRBN protein and an application thereof. Background Art

[0002] CRBN (Cereblon) is a substrate receptor protein of the E3 ubiquitin ligase complex of the CRL4CRBN subtype. It, together with DDB1 protein (Damage-specific DNA Binding protein 1), zinc finger domain protein RBX1, and Cullin4 (Cul4) scaffold protein, forms the DDB1–Cul4–Rbx1–CRBN E3 ubiquitin ligase complex and determines the substrate specificity of the CRL4 E3 ubiquitin ligase. It is widely expressed in the cytoplasm, nucleus, and peripheral membrane of the prostate, liver, pancreas, placenta, kidney, lung, peripheral blood leukocytes, and brain. E3 ubiquitin ligase can specifically recognize substrate proteins and induce polyubiquitination of substrate proteins, thereby causing the degradation of ubiquitinated substrate proteins through the ubiquitin-proteasome pathway, thereby affecting various physiological activities of cells, such as energy metabolism, membrane potential regulation, and transcription factor degradation.

[0003] In 2010, Ito et al. first confirmed that the direct target of thalidomide is a substrate receptor protein of E3 ubiquitin ligase, CRBN. After thalidomide and other immunomodulators bind to CRBN, they activate the activity of E3 ubiquitin ligase, prompting E3 ubiquitin ligase to recruit substrate protein IKZF1 / IKZF3 (Ikaros / Aiolos is a zinc finger transcription factor that plays an important role in blood cell differentiation). After that, E3 ubiquitin ligase, substrate protein IKZF1 / IKZF3 and immunomodulator will form a stable ternary complex, thereby transferring ubiquitin to substrate protein IKZF1 / IKZF3, resulting in IKZF1 / IKZF3 being degraded by 26S proteasome. IKZF1 and IKZF3 are transcriptional regulatory factors essential for the proliferation and development of B cells and T cells [John LB, Ward A C. The ikaros gene family: transcriptional regulators of hematopoiesis and immunity [J]. Molecular immunology, 2011, 48 (9): 1272-1278. and Dijon M, Bardin F, Murati A, et al. The role of ikaros in human erythroid differentiation [J]. Blood, 2008, 111 (3): 1138-1146]. Under normal circumstances, IKZF3 inhibits the gene encoding IL-2 in T cells and stimulates the expression of IRF4 (a transcription factor that has a stress effect on infection). Therefore, the degradation of IKZF1 and IKZF3 directly reduces the expression of transcription factors such as IRF4 and Myc, thereby producing cytotoxic effects on myeloma cells; on the other hand, the degradation of IKZF1 and IKZF3 increases the expression of IL-2 in T cells, thereby activating the immune response of T cells and inhibiting the function of B cells, achieving tumor killing and tumor proliferation inhibition; at the same time, it reduces the expression of tumor necrosis factor TNF and promotes the secretion of anti-inflammatory factor IL-10 by human peripheral blood mononuclear cells. This imbalance leads to apoptosis of multiple myeloma cells. Based on this, in recent years, protein degradation targeted chimeras (PROTACs) designed using the chemical structure of thalidomide, lenalidomide, pomalidomide and other amine-type immunomodulators have emerged.

[0004] PROTAC, Proteolysis Targeting Chimera, protein degradation targeting chimera, is a bifunctional molecule, which consists of three parts: an E3 ligand structural unit that can bind to a specific E3 ubiquitin ligase, a target protein ligand structural unit that can bind to a target protein, and a linker connecting the above two ligands. PROTAC can recruit a specific E3 ubiquitin ligase, bind to a specific target protein to form a [E3 ubiquitin ligase-PROTAC-target protein] ternary complex, induce the target protein to be polyubiquitinated by the recruited E3 ubiquitin ligase, and then cause the degradation of the target protein by the ubiquitin-proteasome pathway.

[0005] Currently, more than 100 proteins have been successfully degraded by PROTAC. These targets include (1) kinases, such as RIPK2, BCR-ABL, EGFR, HER2, c-Met, TBK1, CDK2 / 4 / 6 / 9, ALK, Akt, CK2, ERK1 / 2, FLT3, PI3K, BTK, Fak, etc.; (2) BET proteins, such as BRD2 / 4 / 6 / 9; (3) nuclear receptors, such as AR, ER, etc.; (4) other proteins, such as MetAp-2, Bcl-xL, Sirt2, HDAC6, Pirin, SMAD3, ARNT, PCAF / GCN5, Tau, FRS2, etc. Even the transcription factor regulatory protein pirin, epigenetic-related protein PCAF / GCN5, KRAS-G12C, etc., which are considered "undruggable targets", are included. Therefore, PROTAC technology may become a potential method for responding to and treating diseases related to the above target proteins, such as prostate cancer, breast cancer, non-small cell lung cancer, chronic myeloid leukemia, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, Alzheimer's disease, gout, autoimmune diseases, inflammatory bowel disease, B-cell lymphoma, androgenic alopecia, acne, synovial sarcoma, solid tumors, lung cancer, multiple myeloma, lymphoma, tumor metastasis, cervical cancer, neuroblastoma, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, malignant rhabdoid tumor, oral squamous cell carcinoma and other cancers or diseases. Summary of the invention

[0006] The CRBN protein showed different degrees of inhibition on the binding of CRBN to its immunomodulator thalidomide, indicating that this compound that can bind to the CRBN protein can potentially serve as an alternative structure of thalidomide and bind to CRBN. Therefore, the series of compounds of the present invention can be used as structural units of E3 ubiquitin ligase ligands in PROTAC technology. PROTACs designed based on the series of compounds of the present invention can select specific inhibitors of target proteins that need to be degraded or other small molecule compounds as target protein ligands to achieve the degradation of target proteins that depend on CRBN-type E3 ubiquitin ligases, providing more treatment methods for the above diseases.

[0007] In a first aspect, the present invention provides a compound that can bind to a CRBN protein, the compound consisting of two substructure units A and B, the two substructures A and B are connected by a chemical single bond from Y of the A substructure to one of C2 (carbon 2 position), 4 (4th position), 5 (5th position), 6 (6th position) and 7 (7th position) of the B substructure, and the compound is as shown in Formula I;

[0008]

[0009] In formula I, the A substructure comprises the following A 1 , A 2 , A 3 Three types:

[0010]

[0011] In Formula I, when Y is one of CH, C-alkyl, CF or CD (carbon deuterium), the substructure A is a glutarimide (G) skeleton A 1 , at this time A 1 R 5 is one of H, alkyl, F or D (deuterium);

[0012] In formula I, when Y is N, the substructure A can be a dihydrouracil (DHU) skeleton A 2 or uracil (U) backbone A 3 , at this time A 3 R 6 is one of H, alkyl (alkyl) or halo (halogen);

[0013] The A substructure in formula I, wherein A 1 , A 2 and A 3 Three types of R 4 It is one of H, alkyl, Boc, Cbz, Bn, or aryl.

[0014] In Formula I, the substructure B comprises the following B 1 , B 2a～d , B 3a～b , B 4a～c or B 5 Five types:

[0015]

[0016] W of the B substructure in Formula I 1 It can only be one of N, CH or CR (R is a substituent).

[0017] W of the B substructure in Formula I 2 It can only be one of N, CH or CR (R is a substituent).

[0018] W of the B substructure in Formula I 3 It can only be one of N, CH or CR (R is a substituent).

[0019] W of the B substructure in Formula I 4 It can only be one of N, CH or CR (R is a substituent).

[0020] W of the B substructure in Formula I 1 , W 2 , W 3 and W 4 When both are not N, the substructure B is the benzimidazole skeleton B 1 , at this time, the A substructure and B 1 The substructure consists of A's Y and B 1 One of the positions C2 (carbon 2 position), 4 (carbon 4 position), 5 (carbon 5 position), 6 (carbon 6 position) or 7 (carbon 7 position) is connected by a CC single bond or a CN single bond.

[0021] W of the B substructure in Formula I 1 is N, and W 2 , W 3 and W 4 When both are not N, the substructure B is B of pyrrolo[3,2-b]pyridine 2a Type, A substructure and B 2a The substructure consists of A's Y and B 2a One of the positions C2 (carbon 2 position), 5 (carbon 5 position), 6 (carbon 6 position) or 7 (carbon 7 position) is connected by a CC single bond or a CN single bond.

[0022] W of the B substructure in Formula I 2 is N, and W 1 , W 3 and W 4When both are not N, the substructure B is B of pyrrolo[3,2-c]pyridine 2b Type, A substructure and B 2b The substructure consists of A's Y and B 2b One of the positions C2 (carbon 2 position), 4 (carbon 4 position), 6 (carbon 6 position) or 7 (carbon 7 position) is connected by a CC single bond or a CN single bond.

[0023] W of the B substructure in Formula I 3 is N, and W 1 , W 2 and W 4 When both are not N, the substructure B is B of pyrrolo[2,3-c]pyridine 2c Type, A substructure and B 2c The substructure consists of A's Y and B 2c One of the positions C2 (carbon 2 position), 4 (carbon 4 position), 5 (carbon 5 position) or 7 (carbon 7 position) is connected by a CC single bond or a CN single bond.

[0024] W of the B substructure in Formula I 4 is N, and W 1 , W 2 and W 3 When both are not N, the substructure B is B of pyrrolo[2,3-b]pyridine 2d Type, A substructure and B 2d The substructure consists of A's Y and B 2d One of the positions C2 (carbon 2 position), 4 (carbon 4 position), 5 (carbon 5 position) or 6 (carbon 6 position) is connected by a CC single bond or a CN single bond.

[0025] W of the B substructure in Formula I 2 and W 4 is N, and W 1 and W 3 When both are not N, the substructure B is B of pyrrolo[2,3-d]pyrimidine 3a Type, A substructure and B 3a The substructure consists of A's Y and B 3a One of the C2 (carbon 2 position), 4 (4th position) or 6 (6th position) positions is connected by a CC single bond or a CN single bond.

[0026] W of the B substructure in Formula I 1 and W 3 is N, and W 2 and W 4 When both are not N, the substructure B is B of pyrrolo[3,2-d]pyrimidine 3b Type, A substructure and B 3b The substructure consists of A's Y and B 3bOne of the C2, 5 or 7 positions is connected via a CC single bond or a CN single bond.

[0027] W of the B substructure in Formula I 3 and W 4 is N, and W 1 and W 2 When both are not N, the substructure B is the B of pyrrolo[2,3-c]pyridazine 4a Type, A substructure and B 4a The substructure consists of A's Y and B 4a One of the C2 (carbon 2 position), 4 (4th position) or 5 (5th position) positions is connected by a CC single bond or a CN single bond.

[0028] W of the B substructure in Formula I 2 and W 3 is N, and W 1 and W 4 When both are not N, the substructure B is the B of pyrrolo[2,3-d]pyridazine 4b Type, A substructure and B 4b The substructure consists of A's Y and B 4b One of the C2 (carbon 2 position), 4 (4th position) or 7 (7th position) is connected by a CC single bond or a CN single bond.

[0029] W of the B substructure in Formula I 1 and W 2 is N, and W 3 and W 4 When both are not N, the substructure B is the B of pyrrolo[3,2-c]pyridazine 4c Type, A substructure and B 4c The substructure consists of A's Y and B 4c One of the positions, C2 (carbon 2 position), 6 (carbon 6 position) or 7 (carbon 7 position), is connected by a CC single bond or a CN single bond.

[0030] W of the B substructure in Formula I 1 and W 4 is N, and W 2 and W 3 When both are not N, the substructure B is the B of pyrrolo[2,3-b]pyrazine 5 Type, A substructure and B 5 The substructure consists of A's Y and B 5 One of the C2 (carbon 2 position), 5 (5th position) or 6 (6th position) of the molecule is connected by a CC single bond or a CN single bond;

[0031] The compound structure is as follows:

[0032]

[0033] Among them, R in the compound structure 1 Select one of the following structures

[0034]

[0035] In the structure of the compound, R 2 , R 3 , R 7 , R 8 , R 9 , and R 10 One of the following structures

[0036]

[0037] Among them, A in the compound structure 1 / 2 / 3 A 1 or A 2 or A 3 , A 1 / 3 Representative A 1 or A 3 , A 2 / 3 Representative A 2 or A 3 .

[0038] In a second aspect, the present invention also provides a pharmaceutically acceptable salt of the compound (Formula I) described in the first aspect.

[0039] Furthermore, the pharmaceutically acceptable salt refers to a salt prepared from the parent compound by addition of a non-toxic acid or base.

[0040] In a third aspect, the present invention provides a protein degrader having a structure of: target protein ligand (POI ligand) + linker (Linker) + CRBN protein ligand; wherein the CRBN protein ligand is the compound described in the first aspect of the present invention.

[0041] The structural formula of the protein degradation agent of the present invention is shown in Formula II:

[0042]

[0043] The linker is shown in Formula II, wherein L of the linker substructure 1It can be connected to one of the positions N1 (nitrogen position 1), C2 (carbon position 2), C3 (carbon position 3), 4 (4th position), 5 (5th position), 6 (6th position) or 7 (7th position) on the B substructure of the structure represented by Formula I through one of the chemical single bonds of CC chemical single bond, CN chemical single bond, NC chemical single bond or OC chemical single bond.

[0044] The specific connection mode is as follows: Indicates the B substructure and L 1 The attachment site is selected from one of the following:

[0045]

[0046]

[0047]

[0048]

[0049] The Linker substructure L 1 , L 3 and L 5 One or more structures can be selected;

[0050]

[0051] Among them, R a One or more selected from H, alkyl, SO2-alkyl or SO2-aryl;

[0052] The Linker substructure L 2 , and L 4 Selected from

[0053]

[0054] One of;

[0055] Wherein, the target protein ligand is a ligand of the target protein that causes the relevant disease.

[0056] Furthermore, the diseases include but are not limited to prostate cancer, breast cancer, non-small cell lung cancer, chronic myeloid leukemia, acute myeloid leukemia, T-cell acute lymphoblastic leukemia, Alzheimer's disease, gout, autoimmune diseases, inflammatory bowel disease, B-cell lymphoma, androgenic alopecia, acne, synovial sarcoma, solid tumors, lung cancer, multiple myeloma, lymphoma, tumor metastasis, cervical cancer, neuroblastoma, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, malignant rhabdomyosarcoma, oral squamous cell carcinoma and other cancers or diseases.

[0057] Furthermore, the target protein ligand, i.e., the POI ligand in Formula II, can be selected from one or more of the following structures:

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067] Further, in some embodiments of the present invention, the specific structure of the protein degradation agent is as follows:

[0068]

[0069]

[0070] In a fourth aspect, the present invention provides a pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof according to the first aspect and a pharmaceutically acceptable diluent or carrier.

[0071] Furthermore, the pharmaceutical composition may also comprise an enantiomer, a diastereomer, a stereoisomer or a pharmaceutically acceptable salt of the compound of formula (I) and a pharmaceutically acceptable diluent or carrier.

[0072] In a fifth aspect, the present invention provides a pharmaceutical composition for targeted protein degradation, the pharmaceutical composition comprising the protein degrader (Formula II) described in the second aspect of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

[0073] Furthermore, the pharmaceutical composition for targeted protein degradation may also include its enantiomer, diastereomer, stereoisomer or pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier.

[0074] In a sixth aspect, the present invention provides a regulator for regulating a transcriptional regulatory factor, wherein the regulator contains a compound of formula (I) or a pharmaceutically acceptable salt thereof or a protein degrading agent (II) or a pharmaceutically acceptable salt thereof, hydrate, solvate, prodrug, stereoisomer or tautomer.

[0075] Furthermore, the transcriptional regulatory factor is a regulatory factor essential for the proliferation and development of B cells and T cells.

[0076] Furthermore, the regulation may be positive regulation and / or negative regulation.

[0077] Furthermore, the transcription factors include but are not limited to IRF4 and Myc.

[0078] In the seventh aspect, the present invention provides a method for treating or preventing pathological conditions or symptoms of diseases caused by limiting or inhibiting the expression of IRF4 and Myc, comprising administering an effective amount of at least one compound of Formula I or Formula II or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof to a patient in need of treatment.

[0079] Furthermore, the pathological conditions or symptoms include, but are not limited to, bone marrow failure, anemia, immunoparesis and infection, bone fractures and bone pain, high calcium levels and renal failure. BRIEF DESCRIPTION OF THE DRAWINGS DETAILED DESCRIPTION

[0080] The specific embodiments of the present invention are further described below. It should be noted that the description of these embodiments is used to help understand the present invention, but does not constitute a limitation of the present invention. In addition, the technical features involved in the embodiments described below can be combined with each other as long as they do not conflict with each other.

[0081] The terms "C2 (carbon 2), 4 (4), 5 (5), 6 (6) and 7 (7)" etc. described herein refer to the position number of a specific element, substituent or functional group on the core skeleton of a compound, that is, used to describe the connection mode of specific atoms or groups of the compound; in the present invention, as shown in the following formula I-α, the N position of the five-membered ring is called the N1 position (nitrogen 1 position), in a counterclockwise direction, the carbon position where the five-membered ring R2 substituent is located is called the C2 position (carbon 2), the carbon position where the five-membered ring R3 substituent is located is called the C3 position (carbon 3), and the six-membered ring W1, W2, W3, W4 positions are respectively called the 4th, 5th, 6th, and 7th positions of the specific element, substituent or functional group on the core skeleton of the compound; the element at the specific position may be C or N or other elements, as shown by the specific compounds herein.

[0082]

[0083] As used herein, the terms "CD" and "D" refer to deuterium, the isotope of H.

[0084] The term "stereoisomer" as used herein refers to compounds that have identical chemical constitution but differ in the arrangement of atoms or groups in space, and includes "diastereomers" and "enantiomers".

[0085] The term "diastereomer" as used herein refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other, and diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics and reactivity. In the presence of a resolving agent or chromatographic column, a mixture of diastereomers can be separated under high-resolution analytical steps such as electrophoresis and crystallization using, for example, a chiral HPLC column.

[0086] The term "enantiomers" as used herein refers to two stereoisomers of a compound that are non-superimposable mirror images of each other. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in chemical reactions or processes without stereoselectivity or stereospecificity.

[0087] The terms "pharmaceutically acceptable salts" and "salts of compounds" as used herein are interchangeable and are derivatives of the disclosed compounds, wherein the parent compound is prepared by adding non-toxic acids or bases; examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition salts: salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, alkyls having 1 to 6 carbon atoms, sulfonates and arylsulfonates, where appropriate.

[0088] Table 1 Structures of exemplary compounds that bind to CRBN protein

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114] Table 2 Exemplary compound structures of PROTAC protein degraders

[0115]

[0116]

[0117]

[0118] The experimental methods in the following examples are conventional methods unless otherwise specified, and the experimental materials used in the following examples are commercially available unless otherwise specified. In the following examples, compounds A1 and E1 are commercially available compounds.

[0119] Example 1 Synthesis of Compound A4

[0120] RouteA:

[0121]

[0122] In a flask dried in an oven and replaced with argon, add the bromoindole starting material A2 (1.0 equiv.), 2,6-bis(benzyloxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (A1, 1.2 equiv.), Pd(dppf)Cl2 (10 mol%), replace the gas with argon, add a mixture of dry 1,4-dioxane-pre-deoxygenated saturated sodium bicarbonate aqueous solution (3:1, v:v, 0.1 M), replace the gas with argon, and heat the reaction mixture in an oil bath at 85°C overnight. TLC monitoring shows that no bromoindole raw material remains. After the reaction system is cooled to room temperature, water and EtOAc are added to dilute it. The resulting aqueous phase is extracted with EtOAc, and the combined organic phases are washed with saturated brine and dried over anhydrous sodium sulfate. After suction filtration and vacuum removal of the solvent, the intermediate A3 is purified by silica gel flash column chromatography.

[0123] In a flask dried in an oven and replaced with argon, add intermediate A3, MeOH-THF (0.2M, 1:1, v / v), and 10% Pd / C (20wt%), and replace hydrogen during vigorous stirring. The reaction solution is vigorously stirred for 8 hours under the pressure of a hydrogen balloon. TLC monitoring shows that there is no residual raw material, and LC-MS monitoring shows that there is no unreacted intermediate. The reaction solution is filtered through a silica gel cake and dried under reduced pressure to obtain a crude product A4. A4 as the target final product needs to be purified by preparative HPLC (MeCN / H2O) to obtain a pure product. A4 as an intermediate does not need to be purified and is directly used in the next step of the reaction.

[0124] Example 2 Synthesis of Compound 5-bromo-3-fluoro-1-methyl-1H-indole

[0125]

[0126] In a flask dried in an oven and replaced with argon three times, DCE (4 mL), distilled water (2 mL), Selectfluor (708 mg, 2.00 mmol, 2.0 equiv.), and Li2CO3 (296 mg, 4.00 mmol, 4.0 equiv.) were added. 5-bromo-1-methyl-1H-indole-3-carboxylic acid (254 mg, 1.00 mmol, 1.0 equiv.) was added to the above mixture at 0°C. The reaction mixture was stirred for 24 h under argon atmosphere at the same temperature. TLC monitoring showed that there was no residual raw material. Water and DCM were added to dilute the solution. The aqueous phase was extracted with DCM (3×10 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and decompression, the solvent was removed and purified by silica gel flash column chromatography to obtain 123 mg of the intermediate 5-bromo-3-fluoro-1-methyl-1H-indole with a yield of 54%.

[0127] 1 H NMR (400MHz, Chloroform-d) δ7.96 (dt, J = 5.1, 1.5 Hz, 1H), 7.44 (d, J = 1.5 Hz, 2H), 6.95 (d, J = 8.2 Hz, 1H), 3.82 (s, 3H) ppm. 19 F NMR (376MHz, Chloroform-d) δ-175.5ppm.

[0128] Example 3 Compound 5-bromo-1-methyl-3-(trifluoromethyl)-1H-indole

[0129] Route B:

[0130]

[0131] In a flask dried in an oven and replaced with argon, the starting material 4-bromo-2-iodoaniline (500 mg, 1.68 mmol, 1.0 equiv.) and dry DCM (10 mL) were added, and the reaction system was placed in an ice-water bath at 0°C, followed by the addition of pyridine (159 mg, 2.01 mmol, 1.2 equiv.) and p-toluenesulfonyl chloride (384 mg, 2.01 mmol, 1.2 equiv.), and the reaction system was stirred overnight at room temperature. TLC detected that there was no residual starting material, and water was added to quench the reaction. The aqueous phase was extracted with DCM (3×10 mL), and the organic phases were combined, washed with saturated sodium chloride solution (1×20 mL), and dried over anhydrous sodium sulfate. After filtration and decompression, the solvent was removed by flash column chromatography on silica gel to obtain 725 mg of intermediate B1 with a yield of 95%, MS (ESI) m / z 451.9.

[0132] In an oven-dried, argon-displaced flask, intermediate B1 (700 mg, 1.55 mmol, 1.0 equiv.), (3,3,3-trifluoroprop-1-en-2-yl)boronic acid (260 mg, 1.86 mmol, 1.2 equiv.), Na2CO3 (328 mg, 3.10 mmol, 2.0 equiv.), PdCl2(PPh3)2 (22 mg, 0.03 mmol, 0.02 equiv.) were added. The mixture was replaced with argon, and dry THF and pre-degassed distilled water were injected. The reaction system was heated to reflux in an oil bath and stirred for 20 h. TLC detected that there was no residual raw material. After the reaction system was cooled to room temperature, water and EtOAc were added to dilute it, and the aqueous phase was extracted with EtOAc (3×10 mL). The organic phases were combined, washed with saturated sodium chloride solution (1×20 mL), and dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, the product was purified by silica gel flash column chromatography to obtain 423 mg of intermediate B2 with a yield of 65% and MS (ESI) m / z 420.0.

[0133] Add intermediate B2 (80 mg, 0.19 mmol, 1.0 equiv.), t-BuOH (2 mL), and ammonium cerium nitrate (314 mg, 0.57 mmol, 3.0 equiv.) to a microwave reaction tube, cover the rubber stopper, and react the reaction system at 100 ° C for 5 min under microwave radiation (60 W). Turn off the microwave reaction radiation, wait for the reaction system to cool to room temperature, and TLC detection shows that there is no residual raw material. Add water and EtOAc to dilute the reaction system, extract the aqueous phase with EtOAc (3×4 mL), combine the organic phases, wash with saturated sodium chloride solution (1×5 mL), and dry over anhydrous sodium sulfate. After suction filtration and decompression, the solvent is removed by flash column chromatography on silica gel to obtain 85 mg of intermediate B3, with a yield of 65%, MS (ESI) m / z 418.0.

[0134] To an anhydrous DMF solution (2 mL) of intermediate B3 (200 mg, 0.48 mmol, 1.0 equiv.), lithium hydroxide monohydrate (80 mg, 1.92 mmol, 4.0 equiv.) and thioglycolic acid (53 mg, 0.57 mmol, 1.2 equiv.) were added, and the reaction mixture was stirred for 4 h under an argon atmosphere. TLC showed that no starting material remained. Water and EtOAc were added to the reaction system for dilution, and the aqueous phase was extracted with EtOAc (3×4 mL). The combined organic phases were washed with saturated sodium chloride solution (1×5 mL) and dried over anhydrous sodium sulfate. After filtration and decompression of the solvent, the target intermediate 5-bromo-3-(trifluoromethyl)-1H-indole was obtained by flash column chromatography on silica gel with a yield of 85%.

[0135] 1 H NMR (400MHz, Chloroform-d) δ8.13–8.08(m,1H),7.97–7.91(m,1H),7.88(d,J=6.2Hz,1H),7.33–7.24(m,2H)ppm. 19 F NMR (376MHz, Chloroform-d) δ-58.9ppm.

[0136] Anhydrous potassium carbonate (84 mg, 0.60 mmol, 2.0 equiv.) and iodomethane (64 mg, 0.45 mmol, 1.5 equiv.) were added to an anhydrous DMF solution (2 mL) of the intermediate 5-bromo-3-(trifluoromethyl)-1H-indole (80 mg, 0.30 mmol, 1.0 equiv.), and the reaction mixture was stirred for 5 h under an argon atmosphere. TLC showed that no starting material remained. Water and EtOAc were added to the reaction system for dilution, and the aqueous phase was extracted with EtOAc (3×4 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and decompression of the solvent, the target intermediate 5-bromo-1-methyl-3-(trifluoromethyl)-1H-indole was obtained by flash column chromatography on silica gel with a yield of 85%.

[0137] 1 H NMR (400MHz, Chloroform-d) δ7.94 (s, 1H), 7.81 (s, 1H), 7.45 (d, J = 1.2Hz, 2H), 3.84 (s, 3H) ppm. 19 F NMR (376MHz, Chloroform-d) δ-58.8ppm.

[0138] Example 4 Synthesis of Compounds C7-12

[0139] Route C:

[0140]

[0141] CF3SO2Na (2.0 equiv.), K2S2O8 (1.5 equiv.), and glucose (0.6 equiv.) were added to an anhydrous DMSO solution (0.5 M) of the starting material C1-6 (1.0 equiv.), and the reaction mixture was stirred for 8 h under an argon atmosphere. TLC detected that there was no residual starting material, and water and EtOAc were added to the reaction system for dilution. The aqueous phase was extracted with EtOAc (3×4 mL), and the combined organic phases were washed with a saturated sodium chloride solution (3×4 mL) and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the target intermediate C7-12 was obtained by purification by silica gel flash column chromatography.

[0142] Example 5 Synthesis of compounds methyl 2-bromo-1H-indole-5-carboxylate and methyl2-bromo-1-methyl-1H-indole-5-carboxylate

[0143] Route D:

[0144]

[0145] To a solution of methyl 3-formyl-4-nitrobenzoate (500 mg, 2.39 mmol, 1.0 equiv.) and CBr4 (1.59 g, 4.78 mmol, 2.0 equiv.) in anhydrous DCM (10 mL) was added dropwise at 0°C. After the addition, the reaction mixture was stirred for 30 min at the same temperature and then for 2 h at room temperature. TLC detected that there was no residual starting material. Water and DCM were added to the reaction system for dilution. The aqueous phase was extracted with DCM (3×15 mL). The combined organic phases were washed with saturated sodium chloride solution (1×25 mL) and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the mixture was purified by silica gel flash column chromatography to obtain 653 mg of intermediate D1 with a yield of 75%.

[0146] Intermediate D1 (600 mg, 1.64 mmol, 1.0 equiv.) was dissolved in absolute ethanol (20 mL), and SnCl2·2H2O (1.85 g, 8.20 mmol, 5.0 equiv.) was added thereto, and the reaction mixture was stirred under reflux for 2 h. After the reaction system was cooled to room temperature, TLC detected that no raw material remained, water and EtOAc were added to the reaction system for dilution, and the aqueous phase was extracted with EtOAc (3×15 mL), and the organic phases were combined and washed with saturated sodium chloride solution (1×25 mL) and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, it was purified by silica gel flash column chromatography to obtain 518 mg of intermediate D2 with a yield of 94%.

[0147] In a round-bottom flask dried in an oven and replaced with argon three times, intermediate D2 (450 mg, 1.34 mmol, 1.0 equiv.), Pd(OAc)2 (15 mg, 0.07 mmol, 5 mol%), P(t-Bu)3HBF4 (23 mg, 0.08 mmol, 6 mol%), K2CO3 (371 mg, 2.69 mmol, 2.0 equiv.) were added, the mixture was replaced with argon three times, and dry 1.4-dioxane (6 mL) was injected, and the reaction system was heated to 100 ° C in an oil bath and stirred for 12 h. TLC detected that there was no residual starting material, and the reaction system was cooled to room temperature and diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc (3×10 mL), and the organic phases were combined, washed with saturated sodium chloride solution (1×20 mL), and dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, the product was purified by silica gel flash column chromatography to obtain 293 mg of the intermediate methyl 2-bromo-1H-indole-5-carboxylate with a yield of 86%.

[0148] 1 H NMR (400MHz, Chloroform-d) δ9.71(s,1H),8.19(t,J=1.9Hz,1H),7.88(dd,J=7.2,1.6Hz,1H),7.55(d,J=7.3Hz,1H),7.19(d,J=2.2Hz,1H),3.89(s,3H)ppm.

[0149] To a dry DMF solution (5 mL) of methyl 2-bromo-1H-indole-5-carboxylate (120 mg, 0.47 mmol, 1.0 equiv.) was added NaH (28 mg, 60 wt%, 0.71 mmol, 1.5 equiv.), the reaction mixture was stirred at room temperature for 30 min, iodomethane (80 mg, 0.57 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred for 4 h under argon atmosphere. TLC showed that no starting material remained, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc (3×4 mL), the organic phases were combined, washed with saturated sodium chloride solution (1×5 mL), and dried over anhydrous sodium sulfate. After filtration and decompression, the solvent was removed by flash column chromatography on silica gel to obtain 111 mg of the target intermediate methyl2-bromo-1-methyl-1H-indole-5-carboxylate, with a yield of 88%.

[0150] 1H NMR (400MHz, Chloroform-d) δ8.18–8.13(m,1H),7.89(dd,J=7.7,1.5Hz,1H),7.67–7.61(m,1H),6.45(d,J=2.2Hz,1H),3.89(s,3H),3.69(s,3H)ppm.

[0151] Example 6 Synthesis of Compounds E7 and E8

[0152] Route E:

[0153]

[0154] In a flask dried in an oven and replaced with argon, add intermediate E1 (1.0 equiv.) and dry DCM (0.2 M), add pyridine (2.0 equiv.) and p-toluenesulfonyl chloride (1.2 equiv.) to the solution under stirring at 0°C, and continue stirring the reaction system overnight at room temperature. TLC detection shows that there is no residual raw material, add water and DCM to dilute, extract the aqueous phase with DCM, combine the organic phases, wash with saturated sodium chloride solution, and dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure, then purify by silica gel flash column chromatography to obtain intermediate E2.

[0155] In a flask dried in an oven and replaced with argon, add halogenated indole or halogenated azaindole (1.0 equiv.) and dry DMF (0.2 M), add NaH (1.5 equiv.) to the solution under stirring at 0°C, stir the reaction mixture at room temperature for 30 min, add a dry DMF solution of intermediate E2 (1.2 equiv.), and stir the reaction system at room temperature for 15 h. TLC detection shows that there is no residual raw material, add water and EtOAc to dilute the reaction system, extract the aqueous phase with EtOAc, combine the organic phases, wash with saturated sodium chloride solution, and dry over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure, and purify by silica gel flash column chromatography to obtain intermediate E3.

[0156] Intermediates E3 and A1 were synthesized by referring to the first and second steps of Route A to obtain intermediates E4 and E5. Intermediate E5 (1.0 equiv.) was dissolved in dry DCM (0.2 M), and a dioxane solution of HCl (4 M, 8.0 equiv.) was added to the solution under stirring at 0°C, and the reaction system was stirred at room temperature for 2 h. TLC detection showed that no starting material remained, and the solvent was removed under reduced pressure to obtain intermediate E6.

[0157] AcOH (1.15 equiv.), NaOAc (1.15 equiv.), NaBH(OAc)3 (2.5 equiv.) were added to a DCE solution (0.3 M) of the intermediate E6 (1.0 equiv.) under stirring at 0°C, and an aqueous formaldehyde solution (37%, 2.0 equiv.) or benzaldehyde (2.0 equiv.) was added, and the reaction mixture was stirred at room temperature for 8 to 18 hours. No raw material remained after LC-MS monitoring, a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 6 to 7, and the mixture was extracted with a mixed solvent of DCM-MeOH (3:1), the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and then purified by preparative HPLC to obtain the target product E7 or E8.

[0158] Example 7 Synthesis of Compounds F5 and F6

[0159] Route F:

[0160]

[0161] Halogenated indole or halogenated azaindole (1.0 equiv.) and A1 (1.2 equiv.) were synthesized to obtain intermediate F1 according to the first step of Route A. In a round-bottom flask dried in an oven and replaced with argon three times, intermediate F1 (1.0 equiv.), Pd2(dba)3 (10 mol%), XPhos (20 mol%), tert-butyl4-bromo-3,6-dihydropyridine-1(2H)-carboxylate (1.2 equiv.), and NaOt-Bu (1.5 equiv.) were added. After replacing argon three times, dry dioxane (0.2 M) was added, and the reaction system was stirred at 100°C for 12 to 20 h under argon atmosphere. TLC detected that there was no residual raw material. After the reaction system was cooled to room temperature, water and EtOAc were added to dilute it, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and removal of the solvent under reduced pressure, the intermediate F2 was purified by silica gel flash column chromatography.

[0162] Referring to the fourth and fifth steps of Route E, F3 is synthesized from intermediate F2, and F4 is synthesized from F3. Referring to the sixth and seventh steps of Route E, target compounds F5 and F6 are synthesized.

[0163] Example 8 Synthesis of Compounds G5, G6, G7, and G8

[0164] Route G:

[0165]

[0166] NaH (1.5 equiv.) was added to a dry DMF (0.2 M) solution of halogenated indole or halogenated azaindole (1.0 equiv.), and the reaction mixture was stirred at room temperature for 30 min, and then methyl 2-bromoacetate (1.3 equiv.) was slowly added dropwise thereto, and the reaction system was stirred at room temperature for 15 h. TLC detection showed that there was no residual raw material, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate G1 was purified by silica gel flash column chromatography.

[0167] Intermediate G1 (1.0 equiv.) and A1 (1.2 equiv.) were synthesized with reference to the first step of Route A to obtain intermediate G2. Intermediate G2 (1.0 equiv.) was dissolved in dry DCM (0.2 M), and DIBAL-H (1.0 Min hexanes, 1.2 equiv.) was added dropwise to the solution at -78°C, and the reaction mixture was stirred at the same temperature for 2 h. TLC detected that there was no residual raw material, methanol was added to quench the reaction, water and saturated sodium potassium tartrate solution were added, and stirred at room temperature for 30 min, the aqueous phase was extracted with EtOAc, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate G3 was purified by silica gel flash column chromatography.

[0168] AcOH (1.15 equiv.), NaBH(OAc)3 (2.5 equiv.), and secondary amine (2.0 equiv.) were added to a DCE solution (0.3 M) of the intermediate G3 (1.0 equiv.) under stirring at 0°C, and the reaction mixture was stirred at room temperature for 8 to 18 hours. No raw material remained after LC-MS monitoring, saturated sodium bicarbonate aqueous solution was added to adjust the pH to 6 to 7, and the mixture was extracted with a DCM-MeOH (3:1) mixed solvent, and the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to obtain the target product G4.

[0169] Referring to the third, fourth, fifth and sixth steps of Route F, G5, G6, G7 and G8 were synthesized from intermediate G4.

[0170] Example 9 Synthesis of Compound H4

[0171] Route H:

[0172]

[0173] To a solution of compound 1 (150 mg, 0.66 mmol, 1.0 equiv.) in dry DMF (3 mL) was added NaH (29 mg, 0.72 mmol, 1.1 equiv.) under stirring at 0°C. The reaction mixture was stirred at room temperature for 15 min, and then (2-(chloromethoxy)ethyl)trimethylsilane (120 mg, 0.72 mmol, 1.1 equiv.) was slowly added dropwise thereto. The reaction system was stirred at room temperature for 1 h. TLC detected that no starting material remained. Water and EtOAc were added to the reaction system for dilution. The aqueous phase was extracted with EtOAc, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate H1 (154 mg) was purified by silica gel flash column chromatography with a yield of 65%.

[0174] NaH (16 mg, 0.40 mmol, 1.2 equiv.) was added to a dry DMF (0.2 M) solution of intermediate H1 (120 mg, 0.33 mmol, 1.0 equiv.) under stirring at 0°C. The reaction mixture was stirred at room temperature for 15 min, and then 4-(bromomethyl)benzaldehyde (80 mg, 0.40 mmol, 1.2 equiv.) was added thereto, and the reaction system was stirred at room temperature for 2 h. TLC detected that there was no residual starting material, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate H2 was purified by silica gel flash column chromatography to obtain 106 mg, with a yield of 66%.

[0175] Referring to step 7 of Route E, intermediate H2 reacts with secondary amine HNRR through reductive amination to synthesize intermediate H3.

[0176] TFA (1 / 2 volume of DCM) was added dropwise to a solution of intermediate H3 (1.0 equiv.) in dry DCM (0.1 M) under stirring at 0°C, and the reaction system was stirred at room temperature for 1 h. LC-MS monitoring showed that no starting material remained, and the solvent was removed under reduced pressure and purified by preparative HPLC to obtain the target product H4.

[0177] Example 10 Synthesis of Compounds J1-5

[0178] Route J:

[0179]

[0180] Potassiumbromomethyl trifluoroborate (1.0 equiv.) was added to a solution of a secondary amine (1.0 equiv.) in dry THF (0.2 M) under stirring, and the reaction mixture was stirred at 80°C for 2-4 hours, and then the solvent was removed by vortexing under reduced pressure. The residue was dissolved in acetone (0.02 M), and then potassium carbonate (1.0 equiv.) was added, and the reaction system was stirred at room temperature for 30 minutes. The filtrate was filtered, and the solvent was removed by vortexing under reduced pressure, and then dissolved in a minimum amount of hot acetone-ether (2:1) mixed solvent, and then n-pentane was added dropwise thereto, and the resulting precipitate was collected by filtration and dried under vacuum to obtain the target products J1-5.

[0181] Example 11 Synthesis of Compound K8

[0182] Route K:

[0183]

[0184] NaH (1.2 equiv.) was added to a dry THF (0.2 M) solution of halogenated indole or halogenated azaindole (1.0 equiv.) under stirring at 0°C, and the reaction mixture was stirred at room temperature for 15 min, followed by the addition of benzenesulfonylchloride (1.2 equiv.), and the reaction system was stirred at room temperature for 2 h. TLC detected that there was no residual raw material, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed with a saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate K1 was purified by silica gel flash column chromatography.

[0185] To a solution of intermediate K1 (1.0 equiv.) in dry THF (0.2 M) was added LDA (1.1 equiv.) dropwise under stirring at -78°C, followed by a solution of TMEDA (1.1 equiv.) in dry THF (1 M), and the reaction mixture was stirred at the same temperature for 1 h. To the upper reaction solution was added a solution of I2 (1.1 equiv.) in dry THF (1 M) at the same temperature, the reaction system was automatically warmed to room temperature and continued to stir overnight. TLC detected that there was no residual raw material, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed with saturated sodium thiosulfate solution and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate K2 was purified by silica gel flash column chromatography.

[0186] The intermediate K2 (1.0 equiv.) was dissolved in anhydrous ethanol (0.2 M), and a 3N NaOH aqueous solution (3 / 4 volume of EtOH) was added. The reaction mixture was refluxed for 5 h under an argon atmosphere. TLC detected that there was no residual raw material. After the reaction system was cooled to room temperature, water and EtOAc were added to dilute it. The aqueous phase was extracted with EtOAc, and the organic phases were combined and washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. After suction filtration and decompression, the solvent was removed and purified by silica gel flash column chromatography to obtain the intermediate K3.

[0187] NaH (1.2 equiv.) was added to a solution of intermediate K3 (1.0 equiv.) in dry DMF (0.2 M) at 0°C with stirring, and the reaction mixture was stirred at room temperature for 15 min, followed by the addition of dimethyl sulfate (1.2 equiv.), and the reaction system was stirred at room temperature for 2 h. TLC detected that no raw material remained, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate K4 was purified by silica gel flash column chromatography.

[0188] NIS (1.05 equiv.) was added to a DMSO (0.2 M) solution of halogenated N-methylindole or halogenated aza-N-methylindole (1.0 equiv.), and the reaction mixture was stirred at room temperature for 30 min, followed by the addition of benzenesulfonylchloride (1.2 equiv.), and the reaction system was stirred at room temperature for 2 h. TLC detected that there was no residual raw material, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc, the combined organic phases were washed with saturated sodium thiosulfate solution and saturated sodium chloride solution in turn, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate K5 was purified by silica gel flash column chromatography.

[0189] In a round-bottom flask dried in an oven and replaced with argon three times, intermediate K4 or K5 (1.0 equiv.), J1 or J2 or J3 or J4 or J5 (1.1 equiv.), Cs2CO3 (3.0 equiv.), Pd(OAc)2 (0.10 equiv.), XPhos (0.20 equiv.) were added, the mixture was replaced with argon three times, and dry THF and pre-degassed distilled water (THF:H2O, 10:1, v:v, 0.2M) were injected. The reaction system was heated to 80°C in an oil bath and stirred for 20 hours under argon atmosphere. TLC detected that there was no residual raw material. After the reaction system was cooled to room temperature, water and EtOAc were added to dilute it, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and vacuum removal of the solvent, the intermediate K6 was purified by silica gel flash column chromatography.

[0190] According to the first step of RouteA, intermediate K6 and A1 are synthesized by Suzuki reaction to obtain intermediate K7; according to the second step of RouteA, intermediate K7 is synthesized by catalytic hydrogenation reaction to obtain the target final product K8.

[0191] Example 12 Synthesis of Compound L3

[0192] Route L:

[0193]

[0194] According to the first step of Route A, intermediate K4 and A1 are synthesized by Suzuki reaction to obtain intermediate L1; according to the sixth step of Route K, intermediate L1 and J1 are synthesized by Suzuki reaction to obtain intermediate L2; according to the second step of Route A, intermediate L2 is synthesized by catalytic hydrogenation reaction to obtain the target final product L3.

[0195] Example 13 Synthesis of Compound M3

[0196] Route M:

[0197]

[0198] In an oven-dried flask replaced with argon, 1-methyl-4-methylenepiperidine (1.1 equiv.) and dry THF (0.4 M) were added, and 9-BBN (0.5 M in THF, 1.15 equiv.) was added dropwise to the solution under stirring at 0°C. After the addition, the reaction system was heated under reflux for 1 h in an argon atmosphere. In another oven-dried flask replaced with argon, Pd(dppf)Cl2·CH2Cl2 (0.1 equiv.), K2CO3 (2.0 equiv.), and intermediate K4 or K5 (1.0 equiv.) were added. After the argon atmosphere was replaced, dry DMF and pre-degassed distilled water (DMF:H2O, 16:1, v:v, 0.4 M) were injected. Then, the THF reaction solution containing 9-BBN adduct was introduced into the reaction system through a double-ended needle. The reaction system was heated to 70°C in an oil bath and stirred for 4 h in an argon atmosphere. TLC detected that there was no residual raw material. After the reaction system was cooled to room temperature, water was added to dilute it, and the pH was adjusted to about 11 with 2NNaOH aqueous solution. The aqueous phase was extracted with EtOAc, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression, the solvent was removed by rotation and purification by silica gel flash column chromatography to obtain intermediate M1.

[0199] According to the first step of RouteA, intermediate M1 and A1 are synthesized by Suzuki reaction to obtain intermediate M2; according to the second step of RouteA, intermediate M2 is synthesized by catalytic hydrogenation reaction to obtain the target final product M3.

[0200] Example 14 Synthesis of Compound P10

[0201] Route P:

[0202]

[0203] Referring to the second step of Route K, intermediate P5 is synthesized from raw material P1 or P2 or P3 or P4. TBAF (1.0M in THF, 1.1equiv.) is added dropwise to a dry THF (0.2M) solution of intermediate P5 (1.0equiv.), and the reaction mixture is stirred at 70°C for 2h. TLC detection shows that there is no residual raw material. Water and EtOAc are added to the reaction system for dilution, the aqueous phase is extracted with EtOAc, the organic phases are combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate P6 is purified by silica gel flash column chromatography.

[0204] Referring to the fourth step of Route K, intermediate P7 was synthesized from intermediate P6. According to the first step of Route A, intermediate P7 and A1 were synthesized by Suzuki reaction to obtain intermediate P8. Intermediate P8 (1.0 equiv.) was dissolved in anhydrous methanol (0.2 M), and NaOMe (5.4 M in MeOH, 3.0 equiv.) was added dropwise at 0°C. The reaction mixture was heated to reflux for 2 h under an argon atmosphere. After cooling to room temperature, TLC detected that there was no residual raw material. AcOH was added to quench the reaction. After dilution with water, the aqueous phase was extracted with EtOAc, and the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression, the solvent was removed and purified by silica gel flash column chromatography to obtain intermediate P9.

[0205] According to the second step of Route A, the intermediate P9 is synthesized by catalytic hydrogenation to obtain the target final product P10.

[0206] Example 15 Synthesis of Compound 1-33

[0207]

[0208] According to the synthetic route of Route A, compound 1 was synthesized from 5-bromo-1H-indole as the starting material. 1 H NMR (400MHz, DMSO-d6) δ11.309(d,J=6.6Hz,1H),10.784(s,1H),7.718(t,J=1.8Hz,1H),7.370(d,1H),7.201(d,1H),7.173(dd,J=7.3,1.8 Hz,1H),6.409(dd,J=3.2,1.8Hz,1H),3.933–3.860(m,1H),2.484(dd,J=8.3,5.5Hz,2H),1.991(ddt,J=23.5,8.4,5.7Hz,2H).MS(ESI)m / z 229.1.

[0209]

[0210] According to the synthetic route of Route A, compound 2 was synthesized from 5-bromo-1-methyl-1H-indole as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.795(s,1H),7.366(d,1H),7.305(d,J=3.0Hz,1H),6.996(dd,J=8.4,1.8Hz,1H),6.380(dd,J=3.1,0.8Hz,1H),3. 887(dd,J=10.7,5.0Hz,1H),3.773(s,3H),2.724–2.595(m,1H),2.496–2.412(m,1H),2.294–2.150(m,1H),2.143–2.026(m,1H).MS(ESI)m / z 243.1.

[0211]

[0212] According to the synthetic route of Route A, compound 3 was synthesized from 5-bromo-1-ethyl-1H-indole as the starting material. 1 H NMR(400MHz,DMSO-d6)δ10.769(s,1H),7.394(d,1H),7.346(d,1H),7.337(d,1 H),6.954(dd,J=8.5,1.7Hz,1H),6.360(dd,J=3.1,0.8Hz,1H),4.166(q,J=7.2H z,2H),3.856(dd,J=10.8,5.0Hz,1H),2.703–2.574(m,1H),2.474–2.406(m,0H) ,2.271–2.127(m,1H),2.119–2.003(m,1H),1.324(t,J=7.2Hz,3H).MS(ESI)m / z 257.1.

[0213]

[0214] According to the synthetic route of Route A, compound 3 was synthesized starting from 5-bromo-3-fluoro-1-methyl-1H-indole. 1H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.943(s,1H),7.809–7.758(m,1H),7.419(dd,J=7.9,0.7Hz,1H),7.230–7.159(m,1H) ),3.994–3.917(m,1H),3.809(s,3H),2.484(dd,J=8.3,5.5Hz,2H),1.991(ddt,J=23.5,8.4,5.7Hz,2H).MS(ESI)m / z261.1.

[0215]

[0216] According to the synthetic route of Route A, compound 5 was synthesized from 5-bromo-3-methyl-1H-indole as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.753(s,1H),10.658(d,J=2.2Hz,1H),7.242(d,J= 2.0Hz,1H),7.218(d,1H),7.051(dd,J=2.3,1.2Hz,1H),6.861(dd,J=8.3,1. 8Hz,1H),3.835(dd,J=10.9,4.9Hz,1H),2.667–2.566(m,1H),2.457–2.389( m,1H),2.270–2.192(m,1H),2.187(s,3H),2.097–1.909(m,1H).MS(ESI)m / z 243.1.

[0217]

[0218] According to the synthetic route of Route A, compound 6 was synthesized from 5-bromo-1,3-dimethyl-1H-indole as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.737(s,1H),7.263(d,0H),7.240(d,1H),7.005(d,J=1.3Hz,1H),6.911(dd,J=8.4,1.8Hz,1H),3.832(dd, J=11.1,4.9Hz,1H),3.640(s,3H),2.670–2.540(m,1H),2.439–2.372(m,2H),2.182–2.137(m,1H),2.071–1.907(m,2H).MS(ESI)m / z 257.1.

[0219]

[0220] According to the synthetic route of Route A, compound 7 was synthesized from 5-bromo-1H-indole-3-carbonitrile as the starting material. 1 H NMR (400MHz, DMSO-d6) δ12.238–12.023(m,1H),10.808(s,1H),8.206(d,J=3.0Hz,1H),7.467(d,J=8.5Hz,1H),7.444(d,1H),7.103(dd,J=8.5 ,1.7Hz,1H),3.953(dd,J=11.7,4.9Hz,1H),2.654–2.579(m,1H),2.525–2.470(m,1H),2.329–2.180(m,1H),2.090–1.976(m,1H).MS(ESI)m / z 254.1.

[0221]

[0222] According to the synthetic route of Route A, compound 8 was synthesized from 5-bromo-1-methyl-1H-indole-3-carbonitrile as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.992(d,J=2.0Hz,1H),7.926(s,1H),7.506(d,J=7.9Hz,1H),7.247(dd,J=7.9,2.2,0.7Hz,1H) ,3.992–3.919(m,1H),3.855(s,3H),2.516–2.485(m,1H),2.484–2.443(m,1H),2.056–1.993(m,1H),1.992–1.929(m,1H).MS(ESI)m / z 268.1.

[0223]

[0224] According to the synthetic route of Route A, compound 9 was synthesized from methyl 5-bromo-1H-indole-3-carboxylate as the starting material. 1HNMR(400MHz,DMSO-d6)δ11.888(d,J=2.9Hz,1H),10.799(s,1H),8.049(d, J=3.0Hz,1H),7.814(d,J=1.7Hz,1H),7.409(d,1H),7.036(dd,J=8.4,1.8H z,1H),3.938(dd,J=11.2,5.0Hz,1H),3.771(s,3H),2.736–2.606(m,1H),2 .518–2.430(m,1H),2.277–2.131(m,1H),2.127–2.012(m,1H).MS(ESI)m / z 287.1.

[0225]

[0226] According to the synthetic route of Route A, compound 10 was synthesized from methyl 5-bromo-1-methyl-1H-indole-3-carboxylate as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),8.011(s,1H),7.812(d,1H),7.530(d,J=7.9Hz,1H),7.208(dd,J=7.9,2.2,0.7Hz,1H),3.9 94–3.917(m,1H),3.868(s,3H),2.514–2.484(m,1H),2.483–2.457(m,1H),2.052–1.992(m,1H),1.992–1.932(m,1H).MS(ESI)m / z 301.1.

[0227]

[0228] According to the synthetic route of Route A, compound 11 was synthesized from 5-bromo-3-isopropyl-1H-indole as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.784(s,1H),8.702(d,J=6.6Hz,1H),7.780(d,J=2.4Hz,1H ),7.397(d,1H),7.290(d,1H),7.154(dd,1H),3.956(dd,J=6.1,5.3Hz,1H),3.527–3 .398(m,1H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.055–1.993(m,1H),1. 993–1.931(m,1H),1.492(d,J=6.6Hz,3H),1.442(d,J=6.6Hz,3H).MS(ESI)m / z271.1.

[0229]

[0230] According to the synthetic route of Route A, compound 12 was synthesized from 5-bromo-3-isopropyl-1-methyl-1H-indole as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.748(d,J=2.3Hz,1H),7.468(d,J=7.9Hz, 1H),7.391(s,1H),7.199(dd,1H),3.992–3.919(m,1H),3.860(s,3H),3.406–3.298 (m,1H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.065–1.992(m,1H),1.99 1–1.917(m,1H),1.435(d,J=6.3Hz,3H),1.385(d,J=6.4Hz,3H).MS(ESI)m / z285.2.

[0231]

[0232] According to the synthetic route of Route A, compound 13 was synthesized from 5-bromo-N,N-dimethyl-1H-indole-3-carboxamide as the starting material. 1H NMR (400MHz, DMSO-d6) δ11.157(d,J=7.5Hz,1H),10.784(s,1H),8.067(d,J=7.4Hz,1H),7.878(d,1H),7.412(d,J=7.2Hz,1H),7.178(dd,1H ),3.994–3.917(m,1H),3.000(s,6H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.6Hz,1H),2.054–1.992(m,1H),1.992–1.927(m,1H).MS(ESI)m / z 300.1.

[0233]

[0234]

[0235] According to the synthetic route of Route A, compound 14 was synthesized from 5-bromo-N,N,1-trimethyl-1H-indole-3-carboxamide as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.908(s,1H),7.830(d,J=2.3Hz,1H),7.487(d,J=7.9Hz,1H),7.227(dd,1H),3.994–3.9 17(m,1H),3.857(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.054–1.992(m,1H),1.992–1.924(m,1H).MS(ESI)m / z 314.2.

[0236]

[0237] According to the synthetic route of Route A, compound 15 was synthesized from 1-(5-bromo-1H-indol-3-yl)-N,N-dimethylmethanamine as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.841(d,J=7.0Hz,1H),10.784(s,1H),7.479(d,J=2.1 Hz,1H),7.348(d,J=7.5Hz,1H),7.257(d,J=7.0Hz,1H),7.157(dd,1H),3.955(dd ,J=6.0,5.3Hz,1H),3.852(d,J=1.5Hz,2H),2.494(d,J=5.5Hz,1H),2.473(d,J= 5.5Hz,1H),2.326(s,6H),2.066–1.992(m,1H),1.992–1.926(m,1H).MS(ESI)m / z 286.2.

[0238]

[0239] According to the synthetic route of Route A, compound 16 was synthesized from 1-(5-bromo-1-methyl-1H-indol-3-yl)-N,N-dimethylmethanamine as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.497(d,J=2.1Hz,1H),7.417(d,J =7.9Hz,1H),7.213–7.179(m,1H),7.177(s,1H),3.994–3.917(m,1H),3.83 1(s,3H),3.749(d,J=1.5Hz,2H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz ,1H),2.326(s,6H),2.059–1.991(m,1H),1.991–1.924(m,1H).MS(ESI)m / z 300.2.

[0240]

[0241] According to the synthetic route of Route A, compound 17 was synthesized from 1-(5-bromo-1-methyl-1H-indol-3-yl)-N,N-dimethylmethanamine as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.784(s,1H),8.268(d,J=5.9Hz,1H),8.048(d,1H),7.946(d,1H),7.374(d,1H),7.150(dd,J=7.5,2.2Hz ,1H),3.994–3.917(m,1H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.062–1.991(m,1H),1.991–1.919(m,1H).MS(ESI)m / z 297.1.

[0242]

[0243] According to the synthetic route of Route A, compound 18 was synthesized from 5-bromo-1-methyl-3-(trifluoromethyl)-1H-indole as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.930(d,1H),7.821(s,1H),7.475(d,J=7.9Hz,1H),7.188(dd,1H),3.994–3.917(m ,1H),3.863(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.061–1.992(m,1H),1.992–1.926(m,1H).MS(ESI)m / z 311.1.

[0244]

[0245] According to the synthetic route of Route A, compound 19 was synthesized from 5-bromo-2-methyl-1H-indole as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.700–10.655(m,1H),10.599(s,1H),7.025(d,1H),7.011(d,1H),6.632(dd,J=8.4,1.7Hz,1H),5.881(dd,J=2.0,1.1Hz, 1H),3.640(dd,J=10.4,5.0Hz,1H),2.512–2.383(m,1H),2.314–2.198(m, 2H),2.178(s,3H),2.058–1.936(m,1H),1.935–1.837(m,1H).MS(ESI)m / z 243.1.

[0246]

[0247] According to the synthetic route of Route A, compound 20 was synthesized from 5-bromo-1,2-dimethyl-1H-indole as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.386(t,J=2.0Hz,1H),7.328(d,J=7.9Hz,1H),7.168(dd,J=7.9,1.7Hz,1H),6.109(dd,1H),3.896(dd,J=6 .0,5.3Hz,1H),3.676(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz, 1H),2.263(s,3H),2.051–1.991(m,1H),1.990–1.930(m,1H).MS(ESI)m / z 257.1.

[0248]

[0249] According to the synthetic route of Route A, compound 21 was synthesized from 5-bromo-N,N-dimethyl-1H-indole-2-carboxamide as the starting material. 1H NMR (400MHz, DMSO-d6) δ11.157(d,J=7.5Hz,1H),10.784(s,1H),8.067(d,J=7.4Hz,1H),7.878(d,1H),7.412(d,J=7.2Hz,1H),7.178(dd,1H ),3.994–3.917(m,1H),3.000(s,6H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.6Hz,1H),2.057–1.991(m,1H),1.991–1.928(m,1H).MS(ESI)m / z 300.1.

[0250]

[0251] According to the synthetic route of Route A, compound 22 was synthesized from 5-bromo-N,N,1-trimethyl-1H-indole-2-carboxamide as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.908(s,1H),7.830(d,J=2.3Hz,1H),7.487(d,J=7.9Hz,1H),7.263–7.192(m,1H),3.994– 3.917(m,1H),3.857(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.054–1.991(m,1H),1.991–1.924(m,1H).MS(ESI)m / z 314.2.

[0252]

[0253] According to the synthetic route of Route A, compound 23 was synthesized starting from ethyl 5-bromo-1H-indole-2-carboxylate. 1H NMR (400MHz, DMSO-d6) δ11.595(s,1H),10.784(s,1H),7.700(t,J=1.9Hz,1H),7.47 7(d,J=2.2Hz,1H),7.429–7.364(m,1H),7.165(dd,J=7.3,1.9Hz,1H),4.316(q,J=6 .4Hz,2H),3.897(dd,J=6.1,5.3Hz,1H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz, 1H),2.063–1.994(m,1H),1.992–1.925(m,1H),1.360(t,J=6.4Hz,3H).MS(ESI)m / z 301.1.

[0254]

[0255] According to the synthetic route of Route A, compound 24 was synthesized from ethyl 5-bromo-1-methyl-1H-indole-2-carboxylate as the starting material. 1 HNMR(400MHz,DMSO-d6)δ10.784(s,1H),7.656(q,J=1.3,0.8Hz,1H),7.444(d,J=7 .9,0.9Hz,1H),7.420(d,J=2.2Hz,1H),7.208(dd,J=7.9,2.1Hz,1H),4.310(q,J=6. 4Hz, 2H), 3.897 (dd, J=6.1, 5.3Hz, 1H), 2.494 (d, J=5.5Hz, 1H), 2.473 (d, J=5.6Hz, 1H),2.062–1.991(m,1H),1.991–1.917(m,1H),1.360(t,J=6.4Hz,3H).MS(ESI)m / z 315.1.

[0256]

[0257] According to the synthetic route of Route A, compound 25 was synthesized from 5-bromo-1H-indole-2-carbonitrile as the starting material. 1H NMR (400MHz, DMSO-d6) δ11.524(s,1H),10.784(s,1H),7.727(t,J=2.0Hz,1H),7.393(d,J=7.5Hz,1H),7.244(d,J=2.2Hz,1H),7.193(dd,J=7.7, 2.0Hz,1H),3.897(dd,J=6.1,5.3Hz,1H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.069–1.992(m,1H),1.992–1.918(m,1H).MS(ESI)m / z 254.1.

[0258]

[0259] According to the synthetic route of Route A, compound 26 was synthesized from 5-bromo-1-methyl-1H-indole-2-carbonitrile as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.704(t,J=2.1Hz,1H),7.509(dd,J=7.9,0.9Hz,1H),7.247(dd,1H),6.967(d,J=2.2Hz,1H),3. 935–3.858(m,1H),3.769(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.6Hz,1H),2.057–1.992(m,1H),1.992–1.919(m,1H).MS(ESI)m / z 268.1.

[0260]

[0261] According to the synthetic route of Route A, compound 27 was synthesized starting from 5-bromo-2-(trifluoromethyl)-1H-indole. 1H NMR (400MHz, DMSO-d6) δ11.435(s,1H),10.784(s,1H),7.616(t,J=2.0Hz,1H),7.345(d,J=7.2Hz,1H),7.303(d,J=2.3Hz,1H),7.184–7.115 (m,1H),3.897(dd,J=6.1,5.3Hz,1H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.070–1.993(m,1H),1.990–1.919(m,1H).MS(ESI)m / z 297.1.

[0262]

[0263] According to the synthetic route of Route A, compound 28 was synthesized starting from 5-bromo-1-methyl-2-(trifluoromethyl)-1H-indole. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.580(t,J=2.0Hz,1H),7.445(d,J=7.9Hz,1H),7.188(dd,1H),6.725(d,1H),3.897(t,J= 5.7Hz,1H),3.865(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.6Hz,1H),2.061–1.991(m,1H),1.991–1.924(m,1H).MS(ESI)m / z 311.1.

[0264]

[0265] According to the synthetic route of Route A, compound 29 was synthesized from intermediate C7 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.951(s,1H),10.784(s,1H),7.635(d,J=2.0Hz,1H),7.393(d,J=7.2Hz,1H),7.126–7.056(m,1H),3.992– 3.917(m,1H),2.539(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.072–1.997(m,1H),1.986–1.892(m,1H).MS(ESI)m / z 311.10.

[0266]

[0267] According to the synthetic route of Route A, compound 30 was synthesized from the intermediate C8 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.606(d,J=2.2Hz,1H),7.274(d,1H),7.084(dd,J=8.0,2.1Hz,1H),3.955(t,J=5.7Hz,1H), 3.778(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.6Hz,1H),2.426(s,3H),2.063–1.991(m,1H),1.990–1.923(m,1H).MS(ESI)m / z 325.1.

[0268]

[0269] According to the synthetic route of Route A, compound 31 was synthesized using intermediate C9 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ11.176(s,1H),10.784(s,1H),7.943(d,J=2.2Hz,1H),7.436(d,J=7.2Hz,1H),7.119(dd,J=7.0,2.2Hz,1H),3.956( dd,J=6.1,5.3Hz,1H),3.799(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.6Hz,1H),2.064–1.991(m,1H),1.991–1.921(m,1H).MS(ESI)m / z 355.1.

[0270]

[0271] According to the synthetic route of Route A, compound 32 was synthesized from the intermediate C10 in Route C as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.918(d,1H),7.411(d,1H),7.137(dd,J=7.7,2.2Hz,1H),3.994–3.917(m,1H),3.834(s, 3H),3.801(s,3H),2.494(d,J=5.5Hz,1H),2.473(d,J=5.6Hz,1H),2.069–1.993(m,1H),1.991–1.923(m,1H).MS(ESI)m / z369.1.

[0272]

[0273] To a dry DMF solution (2 mL) of 5-bromo-1H-indole (100 mg, 0.51 mmol, 1.0 equiv.) was added NaH (31 mg, 60 wt%, 0.76 mmol, 1.5 equiv.), the reaction mixture was stirred at room temperature for 30 min, 1-bromo-2-(2-methoxyethoxy)ethane (112 mg, 0.61 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred for 8 h under argon atmosphere. TLC showed that no starting material remained, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc (3×4 mL), the organic phases were combined, washed with saturated sodium chloride solution (1×5 mL), and dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, the target intermediate 5-bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-indole (117 mg) was obtained by flash column chromatography on silica gel with a yield of 77%. 1 H NMR(400MHz,Chloroform-d)δ7.70(t,J=2.0Hz,1H),7.48–7.38(m,2H),7.30(dd,J=5.1,0.7Hz ,1H),6.56(dd,J=5.0,2.3Hz,1H),4.15(t,J=3.9Hz,2H),3.67–3.54(m,5H),3.37(s,3H).ppm.

[0274] According to the synthetic route of Route A, compound 33 was synthesized starting from the intermediate 5-bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-indole. 1H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.565(q,J=1.7,1.2Hz,1H),7.505(d,J=8.3Hz,1H),7.2 48(d,J=1.8Hz,1H),7.219(d,1H),6.517(dd,J=4.9,2.0Hz,1H),4.079(t,J=3.8Hz,2H),3.897( t,1H),3.642(t,J=3.9Hz,2H),3.620–3.587(m,2H),3.588–3.551(m,2H),3.364(s,3H),2.494( d,J=5.5Hz,1H),2.473(d,J=5.5Hz,1H),2.071–1.992(m,1H),1.992–1.921(m,1H).MS(ESI)m / z 331.2.

[0275] Example 16 Synthesis of Compounds 82-97

[0276]

[0277] According to the synthetic route of Route A, compound 82 was synthesized using 6-bromo-1H-indole as the starting material. 1 H NMR (400MHz, DMSO-d6) δ11.41(d,J=6.6Hz,1H),10.78(s,1H),7.72–7.65(m,1H),7.58–7.53(m,1H),7.24–7.16(m,2H),6. 51(dd,J=3.1,1.1Hz,1H),4.03–3.96(m,1H),2.48(dd,J=8.3,5.5Hz,2H),2.00(ddt,J=20.9,8.3,5.6Hz,2H).MS(ESI)m / z 229.1.

[0278]

[0279] According to the synthetic route of Route A, compound 83 was synthesized starting from 6-bromo-1-methyl-1H-indole. 1H NMR (400MHz, DMSO-d6) δ10.78(s,1H),7.72(d,J=2.5Hz,1H),7.57(dt,J=8.0,0.9Hz,1H),7.35–7.29(m,1H),7.18(dd,J=8.0,2.3 Hz,1H),6.68–6.62(m,1H),3.89–3.82(m,1H),2.48(dd,J=8.3,5.5Hz,2H),2.00(ddt,J=20.9,8.3,5.6Hz,2H).MS(ESI)m / z243.1.

[0280]

[0281] According to the synthetic route of Route A, compound 84 was synthesized using 6-bromo-1-ethyl-1H-indole as the starting material. 1 HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.67–7.59(m,2H),7.26(d,J=0.7Hz,0H),7.25(s,1H),7.20(dd,J=7.9,2.2Hz,1H),6.64–6.57(m,1H) ,3.97(q,J=5.1Hz,2H),3.89–3.82(m,1H),2.48(dd,J=8.3,5.5Hz,2H),2.00(ddt,J=20.9,8.3,5.6Hz,2H),1.33(t,J=5.1Hz,3H).MS(ESI)m / z 257.1.

[0282]

[0283] According to the synthetic route of Route A, compound 85 was synthesized from 6-bromo-1,3-dimethyl-1H-indole as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),7.66–7.59(m,1H),7.35(d,J=2.2Hz,1H),7.14(s,1H),7.07(ddd,J=7.7,2.2,0.7Hz,1H) ,3.89–3.82(m,1H),2.48(dd,J=8.3,5.5Hz,2H),2.31(d,J=0.7Hz,3H),2.00(ddt,J=20.9,8.3,5.6Hz,2H).MS(ESI)m / z257.1.

[0284]

[0285] According to the synthetic route of Route A, compound 86 was synthesized from intermediate C8 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),7.93(s,1H),7.88(d,J=7.0Hz,1H),7.66–7.61(m,1H),7.18(ddd,J=7.0, 2.2,0.7Hz,1H),3.89–3.82(m,0H),2.48(dd,J=8.3,5.5Hz,2H),2.00(ddt,J=20.9,8.3,5.6Hz,2H).MS(ESI)m / z 268.1.

[0286]

[0287] According to the synthetic route of Route A, compound 87 was synthesized from intermediate C8 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.01(s,1H),7.99(d,J=0.8Hz,0H),7.62(d,J=2.3Hz,1H),7.20–7.13(m,1 H),3.86(s,3H),3.89–3.82(m,1H),2.48(dd,J=8.3,5.5Hz,2H),2.00(ddt,J=20.9,8.3,5.6Hz,2H).MS(ESI)m / z 301.1.

[0288]

[0289] According to the synthetic route of Route A, compound 88 was synthesized from the intermediate C8 in Route C as the starting material. 1HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.75–7.68(m,1H),7.62(d,J=2.5Hz,1H ),7.39(s,1H),7.11(ddd,J=7.9,2.2,0.7Hz,1H),3.86(dd,J=11.9,0.8Hz,0H) ,3.86(s,3H),3.31(h,J=6.2Hz,1H),2.48(dd,J=8.3,5.5Hz,2H),2.00(ddt,J= 20.9,8.3,5.6Hz,2H),1.44(d,J=6.3Hz,3H),1.39(d,J=6.3Hz,3H).MS(ESI)m / z 285.2.

[0290]

[0291] According to the synthetic route of Route A, compound 89 was synthesized from intermediate C8 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.90(d,J=8.1Hz,1H),7.82(d,J=2.2Hz,1H),7.71(s,1H),7.19–7. 10(m,1H),3.86(s,3H),3.82–3.77(m,1H),2.99(s,6H),2.53–2.39(m,2H),2.07–1.93(m,2H).MS(ESI)m / z 314.2.

[0292]

[0293] According to the synthetic route of Route A, compound 90 was synthesized using intermediate C8 in Route C as the starting material. 1 HNMR(400MHz,DMSO-d6)δ10.81(s,1H),7.90–7.85(m,1H),7.70(d,J=2.2Hz,1H),7.55(s,1 H),7.14–7.09(m,1H),3.84–3.77(m,4H),2.53–2.39(m,2H),2.08–1.93(m,2H).MS(ESI)m / z 311.1.

[0294]

[0295] According to the synthetic route of Route A, compound 91 was synthesized using intermediate C8 in Route C as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.58–7.49(m,1H),7.41–7.30(m,1H),7.15(dd,J=7.9,2.2Hz,1H),6.57( q,J=1.0Hz,1H),3.85–3.77(m,1H),3.74(s,3H),2.53–2.39(m,2H),2.27(s,3H),2.08–1.93(m,2H).MS(ESI)m / z 257.1.

[0296]

[0297] According to the synthetic route of Route A, compound 92 was synthesized using intermediate C8 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.81(d,J=2.5Hz,1H),7.57(dd,J=7.9,2.0Hz,1H),7.31–7.09(m,2H ),3.91(s,3H),3.82–3.77(m,1H),3.01(s,6H),2.46(dt,J=7.7,6.0Hz,2H),2.08–1.94(m,2H).MS(ESI)m / z 314.1.

[0298]

[0299] According to the synthetic route of Route A, compound 93 was synthesized using intermediate C8 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.68–7.65(m,1H),7.63–7.59(m,1H),7.36(d,J=2.0Hz,1H),7.25–7.21(m,1H),4.28 (q,J=6.4Hz,2H),3.99(s,3H),3.85–3.75(m,1H),2.53–2.39(m,2H),2.08–1.93(m,2H),1.35(t,J=6.4Hz,3H).MS(ESI)m / z 256.1.

[0300]

[0301]

[0302] According to the synthetic route of Route A, compound 94 was synthesized using intermediate C8 in Route C as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.84–7.79(m,1H),7.66(dd,J=7.9,2.0Hz,1H),7.55(q,J=1 .0Hz,1H),7.22–7.15(m,1H),3.81-3.78(m,4H),2.54–2.39(m,2H),2.09–1.92(m,2H).MS(ESI)m / z 268.1.

[0303]

[0304] According to the synthetic route of Route A, compound 95 was synthesized using intermediate C8 in Route C as the starting material. 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.65(d,J=2.5Hz,1H),7.50(dd,J=7.9,2.0Hz,1H) ,7.21–7.12(m,2H),3.84–3.78(m,4H),2.54–2.39(m,2H),2.09–1.92(m,2H).MS(ESI)m / z 311.1.

[0305]

[0306] According to the synthetic route of Route A, compound 96 was synthesized from the intermediate C11 in Route C as the starting material. 1 HNMR(400MHz,DMSO-d6)δ10.81(s,1H),7.59–7.52(m,1H),7.36(d,J=2.5Hz,1H),7.15–7.0 8(m,1H),3.83–3.75(m,4H),2.54–2.39(m,2H),2.34(s,3H),2.09–1.92(m,2H).MS(ESI)m / z 325.1.

[0307]

[0308] According to the synthetic route of Route A, compound 97 was synthesized from the intermediate C12 in Route C as the starting material. 1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),8.12–8.05(m,1H),7.46(d,J=2.5Hz,1H),7.28 –7.21(m,1H),3.82(s,7H),2.54–2.39(m,2H),2.09–1.92(m,2H).MS(ESI)m / z369.1.

[0309] Example 17 Synthesis of Compounds 116 and 117

[0310]

[0311] According to the synthetic route of Route A, compound 116 was synthesized starting from 4-bromo-1H-indole. 1 H NMR (400MHz, DMSO-d6) δ11.41(d,J=6.6Hz,1H),10.78(s,1H),7.39(dd,J=7.7,1.5Hz,1H),7.28–7.1 5(m,3H),6.64(d,J=3.7Hz,1H),3.76–3.70(m,1H),2.57–2.42(m,2H),2.11–1.92(m,2H).MS(ESI)m / z 229.1.

[0312]

[0313] According to the synthetic route of Route A, compound 117 was synthesized starting from 4-bromo-1-methyl-1H-indole. 1 HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.51–7.42(m,1H),7.24–7.15(m,2H),7.02–6.96(m,1H),6.74–6.69( m,1H),3.98(td,J=5.8,0.7Hz,1H),3.76(d,J=0.6Hz,3H),2.57–2.42(m,2H),2.11–1.92(m,2H).MS(ESI)m / z 243.1.

[0314] Example 18 Synthesis of Compounds 122, 123, and 124

[0315]

[0316] According to the synthetic route of Route A, compound 122 was synthesized starting from 2-bromo-1-methyl-1H-indole. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.63(ddd,J=6.6,2.2,1.2Hz,1H),7.38(dd,J=8.6,1.4Hz,1H),7.31–7.23(m,1H),7.17(td, J=6.5,1.2Hz,1H),6.73–6.68(m,1H),4.10–4.03(m,1H),3.83(s,3H),2.50(dd,J=6.7,5.9Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z 243.1.

[0317]

[0318] Following the synthetic route of Route A, compound 123 was synthesized from methyl2-bromo-1-methyl-1H-indole-5-carboxylate in Route D as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.05(t,J=2.1Hz,1H),7.88(dd,J=7.9,2.0Hz,1H),7.54–7.48(m,1H),6.93–6 .88(m,1H),4.10–4.03(m,1H),3.89(s,3H),3.83(s,3H),2.50(dd,J=6.8,5.9Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z 301.1.

[0319]

[0320] According to the synthetic route of Route A, compound 124 was synthesized using methyl2-bromo-1-methyl-1H-indole-6-carboxylate synthesized by the synthetic method of Route D as the starting material. 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.10(dd,J=7.7,2.1Hz,1H),7.95–7.88(m,1H),7.85(d,J=2.0Hz,1H),6.70(d,J =2.1Hz,1H),4.10–4.03(m,1H),3.90(s,3H),3.82(s,3H),2.50(dd,J=6.8,5.9Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z 301.1.

[0321] Example 19 Synthesis of Compounds 131-140

[0322]

[0323] According to the synthetic route of Route A, compound 131 was synthesized from 2-iodo-1-methyl-1H-pyrrolo[3,2-b]pyridine as the starting material. 1 H NMR(400MHz, DMSO-d6)δ10.98(s,1H),8.68(dd,J=3.7,2.2Hz,1H),7.68–7.61(m,1H),7.29(dd,J=6.4,3.7Hz, 1H),7.00(s,1H),4.08–4.01(m,1H),3.81(s,3H),2.50(dd,J=6.8,6.0Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z 244.1.

[0324]

[0325] According to the synthetic route of Route A, compound 132 was synthesized from 5-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine as the starting material. 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.64(d,J=7.7Hz,1H),7.35–7.29(m,1H),7.09–7.03(m,1H),6.46(d ,J=5.0Hz,1H),3.94(td,J=5.7,0.7Hz,1H),3.79(s,3H),2.58–2.47(m,2H),2.19–1.97(m,2H).MS(ESI)m / z 244.1.

[0326]

[0327] According to the synthetic route of Route A, compound 133 was synthesized starting from 6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine. 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.41(d,J=2.3Hz,1H),7.74(d,J=2.3Hz,1H),7.09–7.03(m,1H),6 .50(d,J=5.0Hz,1H),3.97–3.89(m,1H),3.81(s,3H),2.54–2.40(m,2H),2.16–1.99(m,2H).MS(ESI)m / z 244.1.

[0328]

[0329] According to the synthetic route of Route A, compound 134 was synthesized starting from 7-chloro-1-methyl-1H-pyrrolo[3,2-b]pyridine. 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.51(d,J=4.2Hz,1H),7.42–7.36(m,1H),7.22(dd,J=4.2,0.7Hz,1H ),6.45(d,J=4.8Hz,1H),4.00–3.93(m,1H),3.77(s,3H),2.58–2.43(m,2H),2.11–1.92(m,2H).MS(ESI)m / z 244.1.

[0330]

[0331] According to the synthetic route of Route A, compound 135 was synthesized from 2-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.69(t,J=1.7Hz,1H),8.41(dd,J=4.1,1.7Hz,1H),7.37–7.31(m,1H),5.84( d,J=1.7Hz,1H),4.10–4.03(m,1H),3.80(s,3H),2.50(dd,J=6.7,5.9Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z244.1.

[0332]

[0333] According to the synthetic route of Route A, compound 136 was synthesized starting from 4-bromo-1-methyl-1H-pyrrolo[3,2-c]pyridine. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.38(d,J=4.6Hz,1H),7.42–7.37(m,1H),7.27(d,J=5.4Hz,1H),6. 84(d,J=5.5Hz,1H),4.04(t,J=5.8Hz,1H),3.75(s,3H),2.60–2.49(m,2H),2.19–2.01(m,2H).MS(ESI)m / z 244.1.

[0334]

[0335] According to the synthetic route of Route A, compound 137 was synthesized starting from 6-chloro-1-methyl-1H-pyrrolo[3,2-c]pyridine. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.69(d,J=2.0Hz,1H),7.54(s,1H),7.36–7.30(m,1H),6.75(dd,J =5.6,2.0Hz,1H),3.94–3.87(m,1H),3.78(s,3H),2.53(t,J=7.7Hz,2H),2.19–2.01(m,2H).MS(ESI)m / z 244.1.

[0336]

[0337] According to the synthetic route of Route A, compound 138 was synthesized starting from 2-iodo-1-methyl-1H-pyrrolo[2,3-c]pyridine. 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.67–8.61(m,2H),7.57–7.51(m,1H),5.89–5.84(m,1H) ),4.10–4.03(m,1H),3.81(s,3H),2.50(dd,J=6.7,5.9Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z 244.1.

[0338]

[0339] According to the synthetic route of Route A, compound 139 was synthesized from 5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine as the starting material. 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.76(s,1H),7.51(d,J=2.5Hz,1H),7.35–7.29(m,1H),6.49–6. 43(m,1H),3.94(td,J=5.7,0.7Hz,1H),3.74(s,3H),2.58–2.47(m,2H),2.19–1.98(m,2H).MS(ESI)m / z 244.1.

[0340]

[0341] According to the synthetic route of Route A, compound 140 was synthesized starting from 2-iodo-1-methyl-1H-pyrrolo[2,3-b]pyridine. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.38(dd,J=3.4,1.9Hz,1H),8.16(dt,J=6.8,1.8Hz,1H),7.38–7.31(m,1H),5.8 3(t,J=1.4Hz,1H),4.05(td,J=5.3,0.7Hz,1H),3.82(s,3H),2.52–2.46(m,1H),2.07–1.90(m,2H).MS(ESI)m / z244.1.

[0342] Example 20 Synthesis of Compounds 142, 144, 147, 149, and 150

[0343]

[0344] According to the synthetic route of Route A, compound 142 was synthesized starting from 2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine. 1H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.85(s,1H),7.10(d,J=5.0Hz,1H),6.51–6.45(m,1 H),4.16(t,J=5.7Hz,1H),3.80(s,3H),2.67–2.51(m,2H),2.24–2.01(m,2H).MS(ESI)m / z 245.1.

[0345]

[0346] According to the synthetic route of Route A, compound 144 was synthesized starting from 2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine. 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),9.03(d,J=2.1Hz,1H),7.46–7.40(m,1H),6.40(dd,J=6.8, 2.0Hz,1H),4.13(t,J=5.7Hz,1H),3.84(s,3H),2.67–2.51(m,2H),2.24–2.01(m,2H).MS(ESI)m / z 245.1.

[0347]

[0348] According to the synthetic route of Route A, compound 146 was synthesized from 3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazine as the starting material. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.77(s,1H),7.09(d,J=5.4Hz,1H),6.53–6.47(m,1 H),4.03(t,J=6.1Hz,1H),3.81(s,3H),2.61–2.46(m,2H),2.23–2.05(m,2H)..MS(ESI)m / z 245.1.

[0349]

[0350] According to the synthetic route of Route A, compound 147 was synthesized starting from 4-chloro-1-methyl-1H-pyrrolo[2,3-d]pyridazine. 1H NMR (400MHz, DMSO-d6) δ11.15(s,1H),9.09(s,1H),7.32(d,J=5.5Hz,1H),6.97(d,J=5.5Hz ,1H),3.75(s,3H),3.73(t,J=6.3Hz,1H),2.64–2.48(m,2H),2.25–2.06(m,2H).MS(ESI)m / z 245.1.

[0351]

[0352] According to the synthetic route of Route A, compound 149 was synthesized from 4-bromo-7-methyl-7H-pyrrolo[2,3-c]pyridazine as the starting material. 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.84(s,1H),7.35–7.28(m,1H),7.05–6. 99(m,1H),3.89–3.81(m,4H),2.58–2.42(m,2H),2.17–1.97(m,2H).MS(ESI)m / z 245.1.

[0353]

[0354] According to the synthetic route of Route A, compound 150 was synthesized starting from 3-chloro-7-methyl-7H-pyrrolo[2,3-c]pyridazine. 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),7.91(d,J=1.8Hz,1H),7.47–7.41(m,1H),6.40(dd,J=6.3 ,1.9Hz,1H),4.09–4.01(m,1H),3.83(s,3H),2.59–2.48(m,2H),2.24–2.05(m,2H).MS(ESI)m / z 245.1.

[0355] Example 21 Synthesis of Compounds 151-153, 34-37, 119-120, 160, 162, 165, 168, 170, 172

[0356]

[0357] According to the synthetic route of Route A, compound 151 was synthesized from 6-iodo-5-methyl-5H-pyrrolo[2,3-b]pyrazine as the starting material. 1 HNMR (400MHz, DMSO-d6) δ11.03(s,1H),8.57(d,J=2.9Hz,1H),8.25(d,J=2.9Hz,1H),7.22(d,J=0.6 Hz,1H),4.14–4.07(m,1H),3.90(s,3H),2.50(dd,J=6.8,5.9Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z 245.1.

[0358]

[0359] According to the synthetic route of Route A, compound 152 was synthesized starting from 2-bromo-5-methyl-5H-pyrrolo[2,3-b]pyrazine. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.45(d,J=0.6Hz,1H),7.22–7.15(m,1H),6.46(d,J=6.2 Hz,1H),4.02(t,J=6.1Hz,1H),3.82(s,3H),2.58–2.47(m,2H),2.28–2.04(m,2H).MS(ESI)m / z 245.1.

[0360]

[0361] According to the synthetic route of Route A, compound 153 was synthesized starting from 3-chloro-5-methyl-5H-pyrrolo[2,3-b]pyrazine. 1 H NMR (400MHz, DMSO-d6) δ11.07(s,1H),8.53(d,J=0.6Hz,1H),7.22–7.15(m,1H),6.56(d,J=6.4Hz ,1H),4.01(td,J=6.2,0.7Hz,1H),3.85(s,3H),2.61–2.46(m,2H),2.26–2.03(m,2H).MS(ESI)m / z 245.1.

[0362]

[0363]

[0364] Following the synthetic route of Route E, compound 34 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.562(t,J=2.2,1.2Hz,1H),7.463(dd,J=8.4,1.0Hz,1H),7.237( dd,J=8.5,2.3Hz,1H),7.178(d,1H),6.576(dd,1H),3.899(dd,1H),3.868(dd,1H),3.753(dd,J=12.5,4. 8Hz,1H),2.731(dd,J=7.9,5.0Hz,2H),2.484(dd,J=8.3,5.5Hz,2H),2.382(dd,J=7.7,5.0Hz,2H),2.213 (s,3H),2.065–1.962(m,2H),1.962–1.859(m,2H),1.777–1.717(m,2H),1.712–1.654(m,2H).MS(ESI)m / z 340.2.

[0365]

[0366] Following the synthetic route of Route E, compound 35 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.562(dt,J=2.3,1.2Hz,1H),7.463(dd,J=8.4,1.0Hz,1H),7.335–7.2 59(m,4H),7.259(dd,J=4.8,1.9Hz,1H),7.259–7.201(m,1H),7.235–7.150(m,1H),6.610–6.545(m,1H),3.93 5–3.862(m,1H),3.905–3.826(m,1H),3.753(dd,J=12.5,4.8Hz,1H),3.482(s,2H),2.741–2.661(m,2H),2.48 4(dd,J=8.3,5.5Hz,2H),2.149(dd,J=7.5,6.8Hz,2H),2.068–1.846(m,3H),1.557–1.404(m,4H).MS(ESI)m / z 416.2.

[0367]

[0368] Following the synthetic route of Route E, compound 36 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.563(dd,J=2.4,1.6Hz,1H),7.505(d,J=8.3Hz,1H),7.273–7. 190(m,2H),6.523(dd,J=5.0,2.2Hz,1H),4.012(dt,J=13.4,6.2Hz,1H),3.945–3.824(m,2H),2.721(dd ,J=8.7,5.8Hz,2H),2.484(dd,J=8.3,5.5Hz,2H),2.374(dd,J=8.7,5.8Hz,2H),2.217(s,3H),1.991(dd t,J=23.5,8.4,5.7Hz,2H),1.897–1.777(m,1H),1.748–1.633(m,5H),1.672–1.606(m,1H).MS(ESI)m / z 354.2.

[0369]

[0370] Following the synthetic route of Route E, compound 37 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.563(dd,J=2.4,1.6Hz,1H),7.505(d,J=8.4Hz,1H),7.33 5–7.190(m,7H),6.523(dd,J=5.0,2.2Hz,1H),4.012(dt,J=13.4,6.2Hz,1H),3.941–3.824(m,2H) ,3.476(s,2H),2.687(dd,J=8.1,5.3Hz,2H),2.510–2.444(m,1H),2.205(dd,J=8.1,5.3Hz,2H),1 .991(ddt,J=23.5,8.4,5.7Hz,2H),1.897–1.777(m,1H),1.767–1.605(m,6H).MS(ESI)m / z430.3.

[0371]

[0372] Following the synthetic route of Route E, compound 119 was synthesized. 1H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.56–7.46(m,1H),7.26–7.15(m,3H) ,6.77(d,J=5.4Hz,1H),4.04–3.95(m,2H),3.91(dd,J=12.6,4.7Hz,1H),2. 80(ddd,J=12.6,7.5,5.4Hz,2H),2.57–2.43(m,2H),2.38(ddd,J=12.5,7.4 ,5.5Hz,2H),2.22(s,3H),2.11–1.85(m,3H),1.79–1.62(m,4H).MS(ESI)m / z 340.2.

[0373]

[0374] Following the synthetic route of Route E, compound 120 was synthesized. 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.56–7.46(m,1H),7.26–7.16(m,3H) ,6.81(d,J=5.1Hz,1H),4.15–4.03(m,1H),4.02–3.90(m,2H),2.76(ddd,J= 12.5,8.3,6.4Hz,2H),2.54–2.43(m,2H),2.46–2.32(m,2H),2.23(s,3H),2 .11–1.92(m,2H),1.86–1.72(m,1H),1.76–1.59(m,6H).MS(ESI)m / z354.2.

[0375]

[0376] Following the synthetic route of Route E, compound 160 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.96(s,1H),8.36(d,J=4.8Hz,1H),7.38(dd,J=4.8,0.7Hz,1H),7 .09(d,J=5.9Hz,1H),6.91(d,J=5.9Hz,1H),4.07–3.95(m,2H),3.90(dd,J=12.5,4.6Hz,1H ),2.80(ddd,J=12.6,7.5,5.4Hz,2H),2.60–2.49(m,2H),2.38(ddd,J=12.5,7.4,5.5Hz,2H ),2.22(s,3H),2.19–2.01(m,2H),1.91(hept,J=5.3Hz,1H),1.79–1.62(m,4H).MS(ESI)m / z 341.2.

[0377]

[0378] Following the synthetic route of Route E, compound 162 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.71–8.65(m,1H),7.54(d,J=1.0Hz,1H),7.14(d,J= 5.7Hz,1H),6.68(dd,J=5.6,2.0Hz,1H),3.99(dd,J=12.5,4.8Hz,1H),3.95–3.86(m,2H),2 .80(ddd,J=12.6,7.5,5.4Hz,2H),2.58–2.48(m,2H),2.38(ddd,J=12.5,7.4,5.5Hz,2H),2 .22(s,3H),2.19–2.01(m,2H),1.91(dt,J=10.1,5.1Hz,1H),1.79–1.62(m,4H).MS(ESI)m / z 341.2.

[0379]

[0380]

[0381] Following the synthetic route of Route E, compound 165 was synthesized. 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),9.02(s,1H),7.43(d,J=2.5Hz,1H),7.18–7.12( m,1H),6.67–6.60(m,1H),4.01(dd,J=12.6,4.7Hz,1H),3.97–3.89(m,2H),2.80(ddd, J=12.6,7.5,5.4Hz,2H),2.58–2.48(m,2H),2.38(ddd,J=12.5,7.4,5.5Hz,2H),2.22( s,3H),2.19–1.98(m,2H),1.89(dq,J=10.2,5.1Hz,1H),1.79–1.62(m,4H).MS(ESI)m / z 341.2.

[0382]

[0383] Following the synthetic route of Route E, compound 168 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.30(s,1H),7.43(d,J=5.3Hz,1H),6.50(d d,J=5.3,0.7Hz,1H),4.16(t,J=5.7Hz,1H),4.02(d,J=4.8Hz,2H),2.80(ddd,J=1 2.6,7.5,5.4Hz,2H),2.67–2.53(m,2H),2.38(ddd,J=12.5,7.4,5.5Hz,2H),2.22 (s,3H),2.21–2.01(m,2H),1.92(p,J=5.0Hz,1H),1.79–1.62(m,4H).MS(ESI)m / z 342.2.

[0384]

[0385] Following the synthetic route of Route E, compound 170 was synthesized. 1H NMR (400MHz, DMSO-d6) δ11.15(s,1H),9.06(d,J=2.0Hz,1H),7.34(d,J=7.0Hz,1H),6.44(d d,J=7.0,2.0Hz,1H),4.13(t,J=5.7Hz,1H),4.08(dd,J=14.0,5.6Hz,1H),3.96(dd,J=14.0, 5.6Hz,1H),2.80(ddd,J=12.6,7.7,5.3Hz,2H),2.67–2.53(m,2H),2.38(ddd,J=12.5,7.6, 5.3Hz,2H),2.25–2.01(m,5H),1.95(dq,J=11.0,5.5Hz,1H),1.79–1.61(m,4H).MS(ESI)m / z 342.2.

[0386]

[0387] Following the synthetic route of Route E, compound 172 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.08 (s, 1H), 7.42 (d, J = 5.7Hz, 1H), 7.36 (s, 1H), 6. 57(d,J=5.7Hz,1H),4.09–4.00(m,2H),3.96(dd,J=12.6,4.7Hz,1H),2.80(dd d,J=12.6,7.5,5.4Hz,2H),2.58–2.48(m,2H),2.38(ddd,J=12.5,7.4,5.5Hz, 2H),2.25–2.05(m,5H),1.90(p,J=5.1Hz,1H),1.79–1.62(m,4H).MS(ESI)m / z 342.2.

[0388] Example 22 Synthesis of Compounds 38, 39, 102, 103, and 118

[0389]

[0390] Following the synthetic route of Route F, compound 38 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.784 (s, 1H), 7.628 (dd, J = 2.5, 1.8Hz, 1H), 7.579 –7.512(m,1H),7.270–7.164(m,2H),6.683–6.619(m,1H),4.272–4.193(m,1 H),3.896(dd,J=6.0,5.3Hz,1H),2.670(s,1H),2.561–2.444(m,4H),2.257( s,3H),2.068–1.915(m,4H),1.842(ddd,J=7.3,4.5,3.4Hz,2H).MS(ESI)m / z 326.2.

[0391]

[0392] Following the synthetic route of Route F, compound 39 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.784 (s, 1H), 7.628 (dd, J = 2.5, 1.7Hz, 1H), 7.579–7. 512(m,1H),7.335–7.210(m,6H),7.200(dd,J=8.2,2.1Hz,1H),6.683–6.619(m ,1H),4.293–4.214(m,1H),3.935–3.858(m,1H),3.498(d,J=1.0Hz,2H),2.728 (dd,J=6.6,4.0Hz,2H),2.532–2.444(m,4H),2.084–1.855(m,6H).MS(ESI)m / z 402.2.

[0393]

[0394] According to the synthetic route of Route F, compound 102 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.72 (d, J = 2.2Hz, 1H), 7.52 (dd, J = 7.9 ,1.1Hz,1H),7.37(d,J=5.3Hz,1H),7.23–7.15(m,1H),6.50–6.44(m,1H),4.3 4–4.26(m,1H),3.84–3.76(m,1H),2.70–2.54(m,4H),2.58–2.45(m,1H),2.49 –2.42(m,1H),2.25(s,3H),2.08–1.89(m,4H),1.88–1.77(m,2H).MS(ESI)m / z 326.2.

[0395]

[0396] Following the synthetic route of Route F, compound 103 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.72(d,J=2.1Hz,1H),7.52(dd,J=7.9,1.1Hz,1H),7.37(d,J=5.2Hz,1H),7 .34–7.29(m,1H),7.31(t,J=0.9Hz,1H),7.32–7.21(m,3H),7.25–7.16(m,1H),6.47(dt,J=5.3,0.9Hz,1H),4.31( pd,J=3.3,0.7Hz,1H),3.84–3.76(m,1H),3.49(t,J=1.0Hz,2H),2.69(ddd,J=12.5,6.8,4.2Hz,2H),2.58(ddd,J= 12.3,6.6,4.1Hz,2H),2.52–2.39(m,2H),2.09–1.92(m,4H),1.87(dddd,J=12.5,6.8,4.2,3.3Hz,2H).MS(ESI)m / z 402.3.

[0397]

[0398] According to the synthetic route of Route F, compound 118 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.78 (s, 1H), 7.59–7.50 (m, 1H), 7.35 (d, J = 5.3Hz, 1H), 7.27–7.18(m,2H),6.80(d,J=5.2Hz,1H),4.34–4.26(m,1H),3.98(td,J=5.8,0. 7Hz,1H),2.70–2.53(m,4H),2.57–2.47(m,1H),2.48(dd,J=6.3,3.2Hz,1H),2.2 5(s,3H),2.11–2.00(m,1H),2.03–1.89(m,3H),1.88–1.77(m,2H)..MS(ESI)m / z 326.2.

[0399] Example 23 Synthesis of Compounds 40-47, 98-101

[0400]

[0401] According to the synthetic route of Route G, compound 40 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.563(dd,J=2.4,1.6Hz,1H),7.505(d,J=8.3Hz,1H),7.237(dd,J=8 .5,2.4Hz,1H),7.171(dd,J=5.1,0.7Hz,1H),6.522(dd,J=5.0,2.2Hz,1H),3.951(t,J=3.8Hz,2H),3.918–3. 866(m,1H),2.772(t,J=3.9Hz,2H),2.620(s,1H),2.549(dd,J=6.2,3.5Hz,2H),2.524–2.453(m,4H),2.427 (dd,J=6.1,3.3Hz,2H),2.227(s,3H),1.991(ddt,J=23.5,8.3,5.7Hz,2H),1.711–1.548(m,8H).MS(ESI)m / z 423.3.

[0402]

[0403] Following the synthetic route of Route G, compound 41 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.563(dd,J=2.4,1.6Hz,1H),7.505(d,J=8.3Hz,1H),7.33 5–7.250(m,4H),7.289–7.199(m,2H),7.171(dd,J=5.1,0.7Hz,1H),6.522(dd,J=5.0,2.2Hz,1H), 3.951(t,J=3.8Hz,2H),3.927–3.858(m,1H),3.523(s,2H),2.772(t,J=3.9Hz,2H),2.689–2.531( m,6H),2.531–2.444(m,4H),1.991(ddt,J=23.5,8.3,5.7Hz,2H),1.712–1.548(m,8H).MS(ESI)m / z 499.3.

[0404]

[0405] Following the synthetic route of Route G, compound 42 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.563(dd,J=2.4,1.6Hz,1H),7.505(d,J=8.3Hz,1H),7.237(dd,J=8.5 ,2.3Hz,1H),7.171(dd,J=5.0,0.7Hz,1H),6.522(dd,J=5.0,2.2Hz,1H),3.951(t,J=3.8Hz,2H),3.927–3.858( m,1H),2.749(d,J=10.9Hz,2H),2.607(dd,J=5.5,2.6Hz,2H),2.558(s,2H),2.534–2.444(m,4H),2.254(s,3H ),1.991(ddt,J=23.5,8.3,5.7Hz,2H),1.744(dd,J=5.5,2.6Hz,2H),1.656(dd,J=5.5,2.6Hz,2H).MS(ESI)m / z 395.2.

[0406]

[0407] Following the synthetic route of Route G, compound 43 was synthesized. 1H NMR(400MHz, DMSO-d6)δ10.784(s,1H),7.564(dd,J=2.4,1.6Hz,1H),7.505(d,J=8.3Hz,1H),7.335–7.244(m,4H), 7.285–7.199(m,2H),7.171(dd,J=5.1,0.7Hz,1H),6.522(dd,J=5.0,2.2Hz,1H),3.951(t,J=3.8Hz,2H),3.927–3.8 58(m,1H),3.595(s,2H),2.779(s,2H),2.772(t,J=3.9Hz,2H),2.607(dd,J=5.5,2.6Hz,2H),2.534–2.444(m,4H), 1.991(ddt,J=23.5,8.3,5.7Hz,2H), 1.736(dd,J=5.4,2.7Hz,2H), 1.664(dd,J=5.5,2.6Hz,2H).MS(ESI)m / z471.3.

[0408]

[0409] Following the synthetic route of Route G, compound 44 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.784(s,1H),7.563(dd,J=2.4,1.6Hz,1H),7.505(d,J=8.3Hz,1H),7.237(dd,J=8. 4,2.3Hz,1H),7.171(dd,J=5.1,0.7Hz,1H),6.522(dd,J=5.0,2.2Hz,1H),3.951–3.858(m,3H),2.808–2.745( m,4H),2.561(dd,J=5.5,2.6Hz,2H),2.484(dd,J=8.3,5.5Hz,2H),2.436(dd,J=5.5,2.6Hz,2H),2.205(s,3H) ,1.991(ddt,J=23.5,8.3,5.7Hz,2H),1.755(dd,J=5.3,2.6Hz,2H),1.645(dd,J=5.3,2.6Hz,2H).MS(ESI)m / z 395.2.

[0410]

[0411] According to the synthetic route of Route G, compound 45 was synthesized. 1HNMR(400MHz, DMSO-d6)δ10.78(s,1H),7.56(dd,J=2.4,1.6Hz,1H),7.50(d,J=8.3Hz,1H),7.33–7.24 (m,4H),7.28–7.20(m,2H),7.17(dd,J=5.1,0.7Hz,1H),6.52(dd,J=5.0,2.2Hz,1H),3.95–3.86(m,3H ),2.81–2.75(m,4H),2.72(dd,J=5.4,2.5Hz,2H),2.64–2.55(m,3H),2.48(dd,J=8.3,5.5Hz,2H),1.9 9(ddt,J=23.5,8.3,5.7Hz,2H),1.74(dd,J=5.4,2.5Hz,2H),1.69(dd,J=5.3,2.6Hz,2H).MS(ESI)m / z 471.3.

[0412]

[0413] Following the synthetic route of Route G, compound 46 was synthesized. 1 HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.56(dd,J=2.4,1.6Hz,1H),7.50(d,J=8.3Hz,1H),7.24 (dd,J=8.5,2.3Hz,1H),7.17(dd,J=5.1,0.7Hz,1H),6.52(dd,J=5.0,2.2Hz,1H),3.95(t,J=3.7H z,2H),3.93–3.86(m,1H),3.00(p,J=4.0Hz,1H),2.82–2.67(m,7H),2.60(d,J=4.0Hz,2H),2.57– 2.44(m,5H),2.42(dd,J=6.3,3.2Hz,2H),1.99(ddt,J=23.5,8.3,5.7Hz,2H).MS(ESI)m / z410.3.

[0414]

[0415] According to the synthetic route of Route G, compound 47 was synthesized. 1HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.56(dd,J=2.4,1.7Hz,1H),7.50(d,J=8.4Hz,1H ),7.34–7.24(m,4H),7.28–7.20(m,2H),7.17(dd,J=5.0,0.7Hz,1H),6.52(dd,J=5.0,2.2 Hz,1H),3.95(t,J=3.7Hz,2H),3.93–3.86(m,1H),3.00(p,J=4.0Hz,1H),2.82–2.71(m,4H ),2.75–2.67(m,1H),2.63–2.44(m,10H),1.99(ddt,J=23.5,8.3,5.7Hz,2H).MS(ESI)m / z 486.3.

[0416]

[0417] Following the synthetic route of Route G, compound 98 was synthesized. 1 HNMR (400MHz, DMSO-d6) δ10.81(s,1H),7.74–7.68(m,1H),7.53–7.46(m,1H),7.24(d,J=5.0Hz,1H),7.19(dd,J=7.8,2.3Hz,1H),6.44(dd,J=5.0 ,1.0Hz,1H),4.04(td,J=4.0,0.8Hz,2H),3.84–3.76(m,1H),2.71–2.58 (m,2H),2.56–2.36(m,10H),2.30(s,3H),2.09–1.92(m,2H).MS(ESI)m / z 355.2.

[0418]

[0419] Following the synthetic route of Route G, compound 99 was synthesized. 1HNMR(400MHz, DMSO-d6)δ10.81(s,1H),7.74–7.68(m,1H),7.53–7.46(m,1H),7.34–7.22(m,6H),7.19(dd,J=7.9,2.3Hz,1H),6.44(dd,J=4.9 ,1.0Hz,1H),4.04(td,J=3.9,0.8Hz,2H),3.84–3.76(m,1H),3.62(dt,J=2.1,0.9Hz,2H),2.71–2.39(m,12H),2.09–1.92(m,2H).MS(ESI)m / z 431.3.

[0420]

[0421] Following the synthetic route of Route G, compound 100 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.74–7.68(m,1H),7.53–7.46(m,1H),7.24(d,J=5. 0Hz,1H),7.19(dd,J=7.8,2.3Hz,1H),6.47–6.41(m,1H),4.02(t,J=2.6Hz,2H),3.84–3.7 6(m,1H),2.84(s,2H),2.69(d,J=5.3Hz,1H),2.69(s,2H),2.59–2.38(m,6H),2.22(s,3H) ,2.09–1.92(m,2H),1.72(dd,J=5.4,2.7Hz,2H),1.63(dd,J=5.3,2.6Hz,2H).MS(ESI)m / z 395.3.

[0422]

[0423] Following the synthetic route of Route G, compound 101 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.71(d,J=2.2Hz,1H),7.53–7.46(m,1H),7.36–7.27(m,3 H),7.31–7.21(m,3H),7.19(dd,J=7.8,2.3Hz,1H),6.44(dd,J=4.9,1.0Hz,1H),4.02(t,J=2.6Hz ,2H),3.84–3.76(m,1H),3.52(d,J=1.9Hz,1H),2.84(s,2H),2.72–2.64(m,5H),2.68–2.62(m,1 H),2.59–2.39(m,4H),2.09–1.92(m,2H),1.68(ddd,J=13.2,5.4,2.6Hz,4H).MS(ESI)m / z471.3.

[0424] Example 24 Synthesis of Compounds 48-51

[0425]

[0426] According to the synthetic route of Route H, compound 48 was synthesized. 1 HNMR(400MHz,DMSO-d6)δ10.81(s,1H),9.84–9.72(m,1H),8.06–8.00(m,1H),7.58( d,J=8.6Hz,1H),7.43(dt,J=7.7,1.1Hz,2H),7.36(d,J=5.0Hz,1H),7.26–7.18(m,3 H),6.54(dd,J=5.0,2.2Hz,1H),5.42(dt,J=2.1,1.0Hz,2H),4.02–3.88(m,6H),3.8 7–3.79(m,1H),3.22–3.14(m,4H),2.54–2.39(m,2H),2.09–1.92(m,2H).MS(ESI)m / z 418.2.

[0427]

[0428] In an oven-dried, argon-displaced flask, intermediate H1 (80 mg, 0.22 mmol, 1.0 equiv.), 4-bromobenzaldehyde (50 mg, 0.27 mmol, 1.2 equiv.), Pd2(dba)3 (20 mg, 0.02 mmol, 10 mol%), XPhos (21 mg, 0.04 mmol, 20 mol%), and NaOt-Bu (26 mg, 0.27 mmol, 1.2 equiv.) were added. After replacing the argon, dry dioxane (2 mL) was added, and the reaction system was stirred for 15 h under argon atmosphere at 100 ° C. TLC detected that there was no residual raw material. After the reaction system was cooled to room temperature, water and EtOAc were added to dilute it, and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and vacuum decompression, the solvent was removed and purified by silica gel flash column chromatography to obtain 54 mg of intermediate I1 with a yield of 52%. Referring to the third and fourth steps of Route H, I2 and compound 49 were synthesized from intermediate I1. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),7.72(d,J=5.0Hz,1H),7.65–7.56(m,2H),7.48–7.40(m,2H),7.32–7.21(m,3H),6.96–6.90(m,1H),3. 94–3.86(m,1H),3.61(ddd,J=7.3,5.9,3.1Hz,4H),3.53(q,J=1.1Hz,2H),2.52–2.42(m,7H),1.99(ddt,J=23.5,8.3,5.7Hz,2H).MS(ESI)m / z 404.2.

[0429]

[0430] According to the synthetic route of Route H, compound 50 was synthesized. 1HNMR(400MHz,DMSO-d6)δ10.81(s,1H),8.75(dq,J=10.4,5.2Hz,1H),8.06–8.00(m,1H),7.82(dp,J=5.5,4.2Hz,1H),7.58 (d,J=8.6Hz,1H),7.43(dt,J=7.9,1.1Hz,2H),7.36(d,J=5.0Hz,1H),7.26–7.18(m,3H),6.54(dd,J=5.0,2.2Hz,1H),5.42 (dt,J=2.1,1.0Hz,2H),4.21(dt,J=5.5,1.1Hz,2H),3.99–3.79(m,8H),3.50(dt,J=13.6,4.9Hz,2H),3.42–3.35(m,1H),3 .38–3.31(m,1H),3.14(dtd,J=12.3,5.2,4.2Hz,2H),2.54–2.45(m,1H),2.48–2.39(m,1H),2.09–1.92(m,2H).MS(ESI)m / z 237.1([M+2H] 2+ ).

[0431]

[0432] Following the synthetic route of Route H, compound 51 was synthesized. 1 HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.65(d,J=7.9Hz,1H),7.60–7.53(m,2H),7.27–7.12(m,6 H),6.98(d,J=2.1Hz,1H),6.90(dd,J=7.9,2.2Hz,1H),6.67–6.61(m,1H),5.45(dt,J=3.0,0.9Hz, 2H),3.94–3.86(m,1H),3.59(q,J=1.1Hz,2H),3.25(dt,J=6.2,3.1Hz,4H),2.62(ddd,J=17.4,5. 7, 2.9Hz, 4H), 2.48 (dd, J=8.3, 5.5Hz, 2H), 1.99 (ddt, J=23.5, 8.3, 5.7Hz, 2H). MS (ESI) m / z 552.2.

[0433] Example 25 Synthesis of Compounds 52-57, 69-72, 104, 106, 110, 112, 121, 155-157, 161, 163, 166, 169, 171, 173, 174

[0434]

[0435] Following the synthetic route of Route K, compound 52 was synthesized. 1 HNMR (400MHz, DMSO-d6) δ10.78(s,1H),7.53(t,J=2.1Hz,1H),7.39(dd,J=7.9,1.0Hz,1H),7.19(dd,J=8.0,2.1Hz,1H),6.52(d,J=2.2Hz,1H),3.90(d d,J=6.1,5.3Hz,1H),3.60(d,J=12.5Hz,1H),3.54(d,J=12.5Hz,1H),2.61– 2.40(m,10H),2.24(s,3H),1.99(ddt,J=23.5,8.3,5.7Hz,2H).MS(ESI)m / z 355.2.

[0436]

[0437] Following the synthetic route of Route K, compound 54 was synthesized. 1 HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.53(t,J=2.1Hz,1H),7.39(dd,J=7.9,1 .0Hz,1H),7.19(dd,J=7.8,2.1Hz,1H),6.52(d,J=2.2Hz,1H),3.90(dd,J=6.1,5 .2Hz,1H),3.74(s,3H),2.74–2.68(m,2H),2.61–2.54(m,3H),2.57–2.39(m,6H) ,2.23(s,3H),1.99(ddt,J=23.5,8.3,5.7Hz,2H),1.71–1.56(m,9H).MS(ESI)m / z 423.3.

[0438]

[0439] Following the synthetic route of Route K, compound 55 was synthesized. 1HNMR (400MHz, DMSO-d6) δ10.78(s,1H),7.53(t,J=2.1Hz,1H),7.39(dd,J=7.9,1.0Hz,1H),7.19(dd ,J=7.8,2.1Hz,1H),6.52(d,J=2.2Hz,1H),3.94–3.86(m,1H),3.74(s,3H),2.65(dd,J=5.4,2.5Hz,2 H),2.56(dd,J=5.3,2.6Hz,2H),2.56(s,2H),2.48(dd,J=8.3,5.5Hz,2H),2.25(s,3H),1.99(ddt,J =23.5,8.3,5.7Hz,2H),1.77(dd,J=5.3,2.6Hz,2H),1.67(dd,J=5.4,2.5Hz,2H).MS(ESI)m / z395.2.

[0440]

[0441] Following the synthetic route of Route K, compound 56 was synthesized. 1 HNMR (400MHz, DMSO-d6) δ10.78(s,1H),7.53(t,J=2.1Hz,1H),7.39(dd,J=7.9,1.0Hz,1H),7.19(dd,J=7.9,2. 1Hz,1H),6.52(d,J=2.2Hz,1H),3.94–3.86(m,1H),3.74(s,3H),3.66(d,J=12.3Hz,1H),3.60(s,1H),2.81(s,2 H),2.67(s,2H),2.56(dd,J=5.5,2.6Hz,2H),2.48(dd,J=8.3,5.5Hz,2H),2.44(dd,J=5.5,2.6Hz,2H),2.21(s ,3H),1.99(ddt,J=23.5,8.3,5.7Hz,2H),1.76(dd,J=5.5,2.6Hz,2H),1.65(dd,J=5.5,2.6Hz,2H).MS(ESI)m / z 395.2.

[0442]

[0443] Following the synthetic route of Route K, compound 57 was synthesized. 1HNMR (400MHz, DMSO-d6) δ10.78(s,1H),7.53(t,J=2.1Hz,1H),7.39(dd,J=8.0,1.0Hz,1H),7.19(dd,J= 8.0,2.1Hz,1H),6.52(d,J=2.2Hz,1H),3.90(dd,J=6.1,5.2Hz,1H),3.70(d,J=27.2Hz,4H),3.62(s,1H) ,3.05(p,J=3.9Hz,1H),2.78(d,J=3.9Hz,2H),2.71(dd,J=6.3,3.1Hz,2H),2.64(d,J=4.0Hz,2H),2.56 –2.44(m,3H),2.42(dd,J=6.3,3.2Hz,2H),2.24(s,3H),1.99(ddt,J=23.5,8.3,5.7Hz,2H).MS(ESI)m / z 410.3.

[0444]

[0445] Following the synthetic route of Route K, compound 69 was synthesized. 1 HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.54–7.49(m,1H),7.42(d,J=7.9Hz,1H) ,7.25(s,1H),7.19(dd,J=8.0,2.1Hz,1H),3.99–3.92(m,1H),3.74(s,2H),2.72– 2.66(m,2H),2.62–2.39(m,9H),2.23(s,3H),1.99(ddt,J=23.5,8.3,5.7Hz,2H), 1.68(ddd,J=6.2,3.3,0.8Hz,4H),1.59(ddd,J=6.1,3.3,1.3Hz,4H).MS(ESI)m / z 423.3.

[0446]

[0447] Following the synthetic route of Route K, compound 70 was synthesized. 1HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.54–7.49(m,1H),7.42(d,J=7.9Hz,1H),7.25(s,1H) ,7.19(dd,J=8.0,2.1Hz,1H),3.99–3.92(m,1H),3.74(s,2H),2.74(s,2H),2.73(dd,J=5.3,2 .6Hz,2H),2.61(dd,J=5.4,2.5Hz,2H),2.48(dd,J=8.3,5.5Hz,2H),2.25(s,3H),1.99(ddt,J =23.5,8.3,5.7Hz,2H),1.76(dd,J=5.3,2.6Hz,2H),1.67(dd,J=5.3,2.6Hz,2H).MS(ESI)m / z 395.2.

[0448]

[0449] Following the synthetic route of Route K, compound 71 was synthesized. 1 HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.54–7.49(m,1H),7.42(d,J=7.9Hz,1H),7.27–7.16 (m,2H),3.96(dd,J=6.1,5.2Hz,1H),3.83(d,J=2.9Hz,5H),2.82(s,2H),2.69(s,2H),2.56( dd,J=5.5,2.6Hz,2H),2.48(dd,J=8.3,5.5Hz,2H),2.44(dd,J=5.5,2.6Hz,2H),1.99(ddt,J =23.5,8.3,5.7Hz,2H),1.76(dd,J=5.5,2.6Hz,2H),1.65(dd,J=5.5,2.6Hz,2H).MS(ESI)m / z 395.2.

[0450]

[0451] Following the synthetic route of Route K, compound 72 was synthesized. 1HNMR(400MHz,DMSO-d6)δ10.78(s,1H),7.54–7.49(m,1H),7.42(d,J=7.9Hz,1H),7.24( s,1H),7.19(dd,J=8.0,2.1Hz,1H),3.99–3.92(m,1H),3.83(s,3H),3.77(s,2H),3.00(q ,J=3.9Hz,1H),2.82(d,J=3.8Hz,2H),2.71(dd,J=5.9,3.5Hz,4H),2.57–2.44(m,4H),2 .42(dd,J=6.3,3.2Hz,2H),2.24(s,3H),1.99(ddt,J=23.5,8.3,5.7Hz,2H).MS(ESI)m / z 410.3.

[0452]

[0453] Following the synthetic route of Route K, compound 104 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.63(d,J=2.5Hz,1H),7.49–7.42(m,1H),7.17(dd,J=7.7,2.2Hz,1H),6.67(q,J=1.0Hz,1H),3 .84–3.76(m,1H),3.73(s,3H),3.72–3.61(m,2H),2.66–2.56(m,8H),2.54–2.39(m,2H),2.32(s,3H),2.09–1.92(m,2H).MS(ESI)m / z 355.2.

[0454]

[0455] Following the synthetic route of Route K, compound 106 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.63(d,J=2.5Hz,1H),7.45(dd,J=7.6,2.0Hz,1 H),7.17(dd,J=7.7,2.2Hz,1H),6.67(q,J=1.0Hz,1H),3.84–3.76(m,1H),3.74–3.64( m,5H),3.35(dd,J=12.3,3.9Hz,2H),3.19(p,J=3.9Hz,1H),2.80(dd,J=12.3,3.9Hz,2 H),2.73–2.61(m,2H),2.59–2.40(m,8H),2.32(s,3H),2.09–1.92(m,2H).MS(ESI)m / z 410.3.

[0456]

[0457] Following the synthetic route of Route K, compound 110 was synthesized. 1 H NMR(400MHz, DMSO-d6)δ10.81(s,1H),7.68(d,J=2.6Hz,1H),7.65–7.58(m,1H),7.19–7.12(m,1H),7.04(s,1H),3 .84–3.77(m,4H),3.68(s,2H),2.79–2.58(m,8H),2.54–2.39(m,2H),2.33(s,3H),2.09–1.92(m,2H).MS(ESI)m / z 355.2.

[0458]

[0459] Following the synthetic route of Route K, compound 112 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.68 (d, J = 2.4Hz, 1H), 7.65–7.58 (m, 1H), 7.19–7.12(m,1H),7.03(s,1H),3.83(s,3H),3.82–3.76(m,1H),3.70(s,2H),3.3 6(dd,J=12.4,3.9Hz,2H),3.17(p,J=3.9Hz,1H),2.86(dd,J=12.4,3.9Hz,2H),2 .74–2.63(m,2H),2.59–2.39(m,8H),2.32(s,3H),2.09–1.92(m,2H).MS(ESI)m / z 410.3.

[0460]

[0461] Following the synthetic route of Route K, compound 121 was synthesized. 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.43–7.35(m,1H),7.24–7.15(m,2H),6.84(s,1H),3.76–3.63(m,6H ),2.66–2.54(m,8H),2.49(ddd,J=7.5,6.1,3.2Hz,2H),2.32(s,3H),2.11–1.92(m,2H).MS(ESI)m / z355.2.

[0462]

[0463] Following the synthetic route of Route K, compound 155 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.01(s,1H),7.53(d,J=7.7Hz,1H),7.35(dd,J=7.7,0.7Hz,1H),6.60(s,1H),3.94(td,J=5.7,0.7 Hz,1H),3.80(s,3H),3.73–3.60(m,2H),2.66–2.48(m,10H),2.32(s,3H),2.19–2.06(m,1H),2.09–1.97(m,1H).MS(ESI)m / z 356.2.

[0464]

[0465] Following the synthetic route of Route K, compound 156 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.41(d,J=2.3Hz,1H),7.71–7.66(m,1H),6.60(d,J=0.7Hz,1H),3.93(td,J=6.1,0.8 Hz,1H),3.81(s,3H),3.73–3.59(m,2H),2.66–2.54(m,9H),2.53–2.41(m,2H),2.32(s,3H),2.15–2.01(m,2H).MS(ESI)m / z 356.2.

[0466]

[0467] Following the synthetic route of Route K, compound 157 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.87(s,1H),8.52(d,J=4.4Hz,1H),7.25–7.19(m,1H),6.59(s,1H),4.05–3.98(m,1H),3.82(s,3H),3. 73(d,J=12.5Hz,1H),3.67(d,J=12.7Hz,1H),2.66–2.51(m,8H),2.55–2.43(m,2H),2.32(s,3H),2.11–1.92(m,2H).MS(ESI)m / z 356.2.

[0468]

[0469] Following the synthetic route of Route K, compound 161 was synthesized. 1 H NMR(400MHz,DMSO-d6)δ10.96(s,1H),8.36(d,J=4.4Hz,1H),7.29–7.23(m,1H),6.89(s,1H),3.78(t,J =5.8Hz,1H),3.74–3.62(m,5H),2.66–2.49(m,10H),2.32(s,3H),2.17–2.01(m,2H).MS(ESI)m / z356.2.

[0470]

[0471] Following the synthetic route of Route K, compound 163 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),8.70(d,J=1.7Hz,1H),7.42(s,1H),6.07(d,J=1.7Hz,1H),3.94–3.87( m,1H),3.74–3.60(m,5H),2.66–2.53(m,9H),2.57–2.48(m,2H),2.32(s,3H),2.17–2.01(m,2H).MS(ESI)m / z 356.2.

[0472]

[0473] Following the synthetic route of Route K, compound 166 was synthesized. 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),8.36(s,1H),7.43(d,J=2.5Hz,1H),6.11(dd,J=2.2,0.7Hz,1H),3.94(td,J =5.7,0.7Hz,1H),3.75(s,3H),3.73–3.60(m,2H),2.66–2.48(m,11H),2.32(s,3H),2.19–1.98(m,2H).MS(ESI)m / z 356.2.

[0474]

[0475] Following the synthetic route of Route K, compound 169 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.13(s,1H),8.62(s,1H),6.59(s,1H),4.16(t,J=5.7Hz,1H),3.79( s,3H),3.67(d,J=2.6Hz,2H),2.67–2.51(m,10H),2.32(s,3H),2.24–2.01(m,2H).MS(ESI)m / z 357.2.

[0476]

[0477] Following the synthetic route of Route K, compound 171 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),9.08(d,J=1.8Hz,1H),6.05(d,J=1.5Hz,1H),4.13(t,J=5.7Hz,1 H),3.74(s,3H),3.67(d,J=0.9Hz,1H),2.67–2.51(m,9H),2.32(s,3H),2.24–2.01(m,2H).MS(ESI)m / z 357.2.

[0478]

[0479] Following the synthetic route of Route K, compound 173 was synthesized. 1H NMR (400MHz, DMSO-d6) δ11.08(s,1H),7.63(s,1H),6.57(s,1H),4.03(t,J=6.1Hz,1H),3.80( s,3H),3.68(d,J=1.8Hz,2H),2.66–2.49(m,11H),2.32(s,3H),2.22–2.05(m,2H).MS(ESI)m / z 357.2.

[0480]

[0481] Following the synthetic route of Route K, compound 174 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.06(s,1H),7.27(s,1H),4.06(td,J=6.2,0.7Hz,1H),3.87(s,3H) ,3.69(d,J=0.7Hz,2H),2.79–2.58(m,9H),2.58–2.48(m,2H),2.33(s,3H),2.24–2.05(m,2H).MS(ESI)m / z 357.2.

[0482] Example 26 Synthesis of Compounds 125-128, 154, 158, 159, 164, 167, 175, 176

[0483]

[0484] Following the synthetic route of Route L, compound 125 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.43(t,J=2.2Hz,1H),7.29(d,J=7.8Hz,1H),7.20(dd,J=8.0,1.9Hz,1H),6.93(d,J=2.3Hz,1H),4.10– 4.03(m,1H),3.83(s,3H),3.66(d,J=3.1Hz,2H),2.87–2.63(m,8H),2.50(dd,J=6.7,5.9Hz,2H),2.33(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 355.2.

[0485]

[0486] Following the synthetic route of Route L, compound 126 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.33–7.25(m,2H),7.16–7.09(m,1H),6.73–6.68(m,1H),4.10–4.03(m,1H),3.82( s,3H),3.62(d,J=3.1Hz,2H),2.87–2.63(m,8H),2.50(dd,J=6.7,5.9Hz,2H),2.33(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 355.2.

[0487]

[0488] Following the synthetic route of Route L, compound 127 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.39(dd,J=6.5,1.4Hz,1H),7.21(dd,J=7.7,6.6Hz,1H),7.14(dd,J=7.8,1.4Hz,1H),6.81(d,J=0.8Hz,1H),4.10 (td,J=5.3,0.7Hz,1H),3.87(d,J=0.7Hz,2H),3.82(s,3H),2.78–2.58(m,8 H),2.50(dd,J=6.7,5.9Hz,2H),2.33(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 355.2.

[0489]

[0490] Following the synthetic route of Route L, compound 128 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.46–7.39(m,1H),7.30(dd,J=7.5,7.0Hz,1H),7.16(dd,J=7.4,1.2Hz,1H),6.93(d,J=2.3Hz,1H),4 .10(td,J=5.3,0.7Hz,1H),3.88–3.77(m,5H),2.76–2.62(m,8H),2.50(dd,J=6.7,5.9Hz,2H),2.33(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 355.2.

[0491]

[0492] Following the synthetic route of Route L, compound 154 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.67–7.61(m,1H),7.38(d,J=7.8Hz,1H),6.93(s,1H),4.05(td,J=5.3,0.7H z,1H),3.81(s,3H),3.65(s,1H),2.70–2.55(m,7H),2.59–2.44(m,2H),2.32(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 356.2.

[0493]

[0494] Following the synthetic route of Route L, compound 158 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.24(d,J=4.2Hz,1H),7.31(dd,J=4.2,0.7Hz,1H),7.04(s,1H),4.10(td,J=5.3,0.7H z,1H),3.99(s,2H),3.81(s,3H),2.67–2.51(m,9H),2.50(dd,J=6.8,6.0Hz,2H),2.32(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 356.2.

[0495]

[0496] Following the synthetic route of Route L, compound 159 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.68(d,J=1.9Hz,1H),7.37(d,J=1.0Hz,1H),5.84(d,J=1.6Hz,1H),4.10–4.03(m,1 H),3.81(s,3H),3.66(s,2H),2.70–2.54(m,8H),2.50(dd,J=6.8,6.0Hz,2H),2.32(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 356.2.

[0497]

[0498] Following the synthetic route of Route L, compound 164 was synthesized.1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.43(s,1H),7.40(d,J=2.2Hz,1H),5.85(d,J=2.3Hz,1H),4.10–4.03(m,1H),3 .81(s,3H),3.66(s,2H),2.70–2.54(m,9H),2.50(dd,J=6.8,6.0Hz,2H),2.32(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 356.2.

[0499]

[0500] Following the synthetic route of Route L, compound 167 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),7.85(dd,J=7.7,2.0Hz,1H),7.40–7.34(m,1H),5.83(d,J=2.1Hz,1H),4.05(td,J=5.3,0.7Hz, 1H),3.81(s,3H),3.62(d,J=2.2Hz,2H),2.70–2.54(m,8H),2.50(dd,J=6.8,6.0Hz,2H),2.32(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 356.2.

[0501]

[0502]

[0503] Following the synthetic route of Route L, compound 175 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.28(s,1H),6.85(d,J=0.6Hz,1H),4.14–4.07(m,1H),3.9 2–3.86(m,5H),2.66–2.55(m,8H),2.58–2.44(m,2H),2.32(s,3H),2.07–1.90(m,2H).MS(ESI)m / z 357.2.

[0504]

[0505] Following the synthetic route of Route L, compound 176 was synthesized. 1H NMR (400MHz, DMSO-d6) δ11.03(s,1H),8.37(s,1H),7.17(d,J=0.6Hz,1H),4.14–4.07(m,1H),3.89(d,J =8.0Hz,5H),2.66–2.55(m,8H),2.58–2.44(m,2H),2.32(s,3H),2.07–1.90(m,2H).MS(ESI)m / z357.2.

[0506] Example 27 Synthesis of Compounds 53, 67, 129, and 130

[0507]

[0508] Following the synthetic route of Route M, compound 53 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),7.48(t,J=2.0Hz,1H),7.39(dd,J=8.0,0.9Hz,1H),7.19(dd,J=7 .9,2.0Hz,1H),6.35(d,J=2.2Hz,1H),3.90(dd,J=6.1,5.3Hz,1H),2.81–2.72(m,2H),2.73(d,J=5.7Hz, 1H),2.68–2.60(m,1H),2.48(dd,J=8.3,5.5Hz,2H),2.41(dd,J=8.4,5.7Hz,2H),2.22(s,3H),1.99(ddt ,J=23.5,8.4,5.7Hz,2H),1.83(dt,J=10.7,5.4Hz,1H),1.71(ddt,J=22.5,8.6,5.6Hz,4H).MS(ESI)m / z 354.2.

[0509]

[0510] Following the synthetic route of Route M, compound 67 was synthesized. 1H NMR(400MHz, DMSO-d6)δ10.78(s,1H),7.62–7.57(m,1H),7.42(d,J=7.9Hz,1H),7.23–7.16(m,1H), 6.95(s,1H),3.99–3.92(m,1H),2.79(dd,J=13.9,6.2Hz,1H),2.74(dd,J=8.4,5.7Hz,2H),2.62–2.5 4(m,1H),2.48(dd,J=8.3,5.5Hz,2H),2.30(dd,J=8.5,5.7Hz,2H),2.22(s,3H),1.99(ddt,J=23.5,8 .3,5.7Hz,2H),1.83(dt,J=11.6,5.9Hz,1H),1.70(ddt,J=27.2,8.5,5.7Hz,4H).MS(ESI)m / z354.2.

[0511]

[0512] N1 (102mg or 108mg, 0.47mmol, 1.0equiv.), chiral proline amide cat-1 (31mg, 0.09mmol, 0.3equiv.), 4-iodo-1-methyl-1H-indole (170mg, 0.71mmol, 1.5equiv.) were added to the reaction tube filled with argon, the gas was replaced with argon, deoxygenated ultrapure water (2.5mL) was added, CuI (9mg, 0.05mmol, 0.1equiv.), K2CO3 (130mg, 0.94mmol, 2.0equiv.) were added, the gas was replaced with argon, and the reaction system was stirred at 100°C for 24h under argon atmosphere. TLC detected that there was no residual raw material, and the reaction system was cooled to room temperature, and the aqueous phase was extracted with EtOAc (3×5mL), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, purification by chromatography was performed to obtain 61 mg of product N2 (R=H) or 72 mg of product N2 (R=Me), with a yield of 54% or 60%.

[0513] Add intermediate N2 (1.0 equiv.) to the sealed tube reactor, add anhydrous methanol (0.2 M), hydrazine hydrate (20.0 equiv.), replace argon three times, seal the sealed tube reactor, and heat and stir in an oil bath at 100°C for 3 hours. After the reactor is cooled to room temperature, open the sealed tube stopcock, and TLC monitoring shows that there is no residual raw material. After dilution with water, extract the aqueous phase with DCM-MeOH (4:1), and combine the organic phases and dry them over anhydrous sodium sulfate. After suction filtration and decompression, the solvent is removed and purified by preparative HPLC to obtain the target product compound 129 or 130.

[0514] Compound 129: 1 H NMR (400MHz, DMSO-d6) δ11.35 (s, 1H), 8.35 (d, J = 7.5Hz, 1H),

[0515] 7.61(dd,J=6.8,1.3Hz,1H),7.48–7.37(m,2H),7.12(d,J=5.2Hz,1H),6.55 (d,J=5.2Hz,1H),5.83(d,J=7.2Hz,1H),3.77(d,J=0.7Hz,3H).MS(ESI)m / z 242.1.

[0516] Compound 130: 1 H NMR (400MHz, DMSO-d6) δ11.14 (s, 1H), 8.43 (q, J = 1.5Hz, 1H),

[0517] 7.65(dd,J=7.1,1.5Hz,1H),7.48–7.37(m,2H),7.12(d,J=5.2Hz,1H),6.55 (d,J=5.2Hz,1H),3.77(d,J=0.7Hz,3H),1.89(d,J=1.5Hz,3H).MS(ESI)m / z 256.1.

[0518] Example 28 Synthesis of Compounds 141, 143, 145, and 148

[0519]

[0520] Following the synthetic route of Route P, compound 141 was synthesized. 1 H NMR(400MHz,DMSO-d6)δ10.98(s,1H),8.35(s,1H),6.90(s,1H),4.05(td,J=5.3,0.7Hz,1 H),3.90(s,3H),3.81(s,3H),2.50(dd,J=6.8,6.0Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z 275.1.

[0521]

[0522] Following the synthetic route of Route P, compound 143 was synthesized. 1H NMR (400MHz, DMSO-d6) δ10.98(s,1H),8.79(d,J=1.8Hz,1H),5.83(d,J=1.8Hz,1H),4.05(td,J =5.3,0.7Hz,1H),3.90(s,3H),3.86(s,3H),2.52–2.46(m,1H),2.07–1.90(m,2H).MS(ESI)m / z 275.1.

[0523]

[0524] Following the synthetic route of Route P, compound 145 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),6.95(s,1H),6.14(d,J=1.0Hz,1H),4.05(td,J=5.3,0.7 Hz,1H),3.93(s,3H),3.80(s,3H),2.50(dd,J=6.8,6.0Hz,2H),2.07–1.90(m,2H).MS(ESI)m / z 275.1.

[0525]

[0526]

[0527] Following the synthetic route of Route P, compound 148 was synthesized. 1 H NMR(400MHz, DMSO-d6)δ10.98(s,1H),7.08(d,J=2.2Hz,1H),5.84–5.79(m,1H),4.05(td,J= 5.3,0.7Hz,1H),3.93(s,3H),3.90(s,3H),2.52–2.46(m,1H),2.07–1.90(m,2H).MS(ESI)m / z 275.1.

[0528] Example 29 Synthesis of Compounds JQ1 acid and JQ1-L1

[0529]

[0530] TFA (trifluoroacetic acid) (8 mL) was slowly added dropwise to a solution of JQ1 (1.00 g, 2.19 mmol, 1.0 equiv.) in dry DCM (1,2-dichloroethane) (20 mL) at 0°C, and the reaction system was stirred at room temperature for 6 h. TLC detected that no starting material remained, and the reaction solution was concentrated under reduced pressure to obtain a residue, which was dissolved in EtOAc and washed with saturated brine and dried over anhydrous sodium sulfate. After filtration and decompression of the solvent, it was purified by silica gel flash column chromatography to obtain 805 mg of compound JQ1 acid with a yield of 92%. MS (ESI) m / z 399.1 ([M+H] + ).

[0531]

[0532]

[0533] Compound JQ1 acid (60 mg, 0.15 mmol, 1.0 equiv.), tert-butyl (4-aminobutyl) carbamate (30 mg, 0.16 mmol, 1.05 equiv.), HATU (85 mg, 0.22 mmol, 1.5 equiv.), DIPEA (diisopropylethylamine) (78 μL, 0.45 mmol, 3.0 equiv.) were dissolved in anhydrous DMF (2 mL), and the reaction system was stirred at room temperature overnight under argon protection. TLC detected that there was no residual raw material, and water was added to quench the reaction. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the compound JQ1-L1-Boc was purified by silica gel flash column chromatography to obtain 72 mg of compound JQ1-L1-Boc with a yield of 84%. MS (ESI) m / z 472.0 ([M+H-Boc] + ).

[0534] JQ1-L1-Boc (150 mg, 0.26 mmol, 1.0 equiv.) was dissolved in dry DCM (dichloromethane) (3 mL), and TFA (trifluoroacetic acid) (1 mL) was slowly added to the solution at 0 ° C. The reaction system was automatically heated to room temperature under argon atmosphere and continued to stir for 4 h. TLC detected that there was no residual raw material, the solvent was removed under reduced pressure and then dissolved in methanol, saturated sodium bicarbonate solution was added to adjust the pH to 8, and then extracted with DCM-MeOH (5:1, v / v) mixed solvent, and the organic phases were combined and dried over anhydrous sodium sulfate. After filtering and removing the solvent under reduced pressure, continue to reduce pressure and dry at 45 ° C and 0.6 mbar for 30 min to obtain the crude product JQ1-L1, which was directly used in the next step.

[0535] Example 30 Synthesis of Intermediates Q4, Q5, Q6, and Q7

[0536] Route Q:

[0537]

[0538] NaH (1.1 equiv.) was added to a solution of raw material Q1 (1.0 equiv.) in dry DMF (0.2 M) under stirring at 0°C, and the reaction mixture was stirred at room temperature for 15 min, and then benzyl 2-bromoacetate (1.1 equiv.) was slowly added dropwise thereto, and the reaction system was stirred at room temperature for 1 h. TLC detected that there was no residual raw material, water and EtOAc were added to the reaction system for dilution, the aqueous phase was extracted with EtOAc, the organic phases were combined, washed with saturated sodium chloride solution, and dried over anhydrous sodium sulfate. After suction filtration and decompression of the solvent, the intermediate Q2 was purified by silica gel flash column chromatography.

[0539] Referring to the first step of RouteA, intermediate Q2 and A1 are reacted by Suzuki reaction to obtain intermediate Q3; referring to the second step of RouteA, intermediate Q3 is subjected to catalytic hydrogenation reaction to obtain intermediate Q4 or Q5 or Q6 or Q7.

[0540] Q4: 1 H NMR (400MHz, DMSO-d6) δ12.74(brs,1H),10.81(s,1H),7.91–7.86(m,1H),7.48(d,J=8.3Hz,1H),7.31–7.26(m,1H),7.22(dd,J= 8.1,2.0Hz,1H),6.55(dd,J=5.5,2.2Hz,1H),4.99(s,2H),3.87–3.79(m,1H),2.54–2.39(m,2H),2.09–1.92(m,2H).MS(ESI)m / z 287.1.

[0541] Q5: 1 H NMR (400MHz, DMSO-d6) δ12.73 (brs, 1H), 10.81 (s, 1H), 7.87 (d, J = 2.1Hz,

[0542] 1H),7.54(d,J=0.7Hz,1H),7.44–7.37(m,1H),7.26–7.19(m,1H),4.98(s,2H),3.91–3. 83(m,1H),2.54–2.45(m,1H),2.48–2.39(m,1H),2.09–1.92(m,2H).MS(ESI)m / z355.1.

[0543] Q6:1 H NMR (400MHz, DMSO-d6) δ12.74 (brs, 1H), 10.81 (s, 1H), 7.77 (d, J = 2.4Hz,

[0544] 1H),7.53–7.46(m,1H),7.31–7.25(m,1H),7.19(dd,J=7.9,2.3Hz,1H),6.53–6.47(m, 1H),4.98(s,2H),3.84–3.76(m,1H),2.54–2.39(m,2H),2.09–1.92(m,2H).MS(ESI)m / z 287.1.

[0545] Q7: 1 H NMR (400MHz, DMSO-d6) δ12.74(brs,1H),10.78(s,1H),7.50(dd,J=5.2,2.5

[0546] Hz,1H),7.25–7.15(m,3H),6.80(d,J=5.2Hz,1H),4.98(s,2H),3.98(t,J=5.8Hz,1H),2.57–2.42(m,2H),2.11–1.92(m,2H).MS(ESI)m / z 287.1.

[0547] Example 31 Synthesis of intermediates R1, R2, and R3

[0548] Route R:

[0549]

[0550] Intermediate G4 (90 mg, 0.14 mmol, 1.0 equiv.) was dissolved in dry DCM (dichloromethane) (3 mL), and dioxane hydrochloride solution (1 mL) was slowly added to the solution at 0 ° C. The reaction system was automatically heated to room temperature under argon atmosphere and continued to stir for 2 h. TLC detected that there was no residual raw material, the solvent was removed under reduced pressure and then dissolved in methanol, saturated sodium bicarbonate solution was added to adjust the pH to 8, and then extracted with DCM-MeOH (5:1, v / v) mixed solvent, and the organic phases were combined and dried over anhydrous sodium sulfate. After filtering and removing the solvent under reduced pressure, continue to decompress and dry at 45 ° C and 0.6 mbar for 30 min to obtain 75 mg of crude product R1, which was directly used in the next step.

[0551] The crude intermediate R1 (75 mg, ~0.14 mmol, 1.0 equiv.) was dissolved in acetone (4 mL), and potassium carbonate (37 mg, 0.28 mmol, 2.0 equiv.), sodium iodide (4 mg, 0.03 mmol, 0.2 equiv.), and tert-butyl (2-bromoethyl) carbamate (33 mg, 0.15 mmol, 1.1 equiv.) were added to the solution. After the gas was replaced with argon three times, the reaction mixture was heated under reflux for 4 h. LC-MS monitoring showed that there was no residual raw material. After the reaction was cooled to room temperature, it was filtered, concentrated under reduced pressure, diluted with water, extracted with a mixed solvent of DCM-MeOH (5:1, v / v), and the organic phases were combined and dried over anhydrous sodium sulfate. After filtering and removing the solvent under reduced pressure, it was purified by silica gel flash column chromatography to obtain 78 mg of intermediate R2 with a yield of 83%. MS (ESI) m / z 646.3 ([M+Ht-Bu] + ).

[0552] Referring to the second step of Route A, intermediate R2 (70 mg) was catalytically hydrogenated to give 43 mg of intermediate R3 with a yield of 82%. MS (ESI) m / z 468.3 ([M+Ht-Bu] + ).

[0553] Referring to the fifth step of Route E, intermediate R3 (43 mg) was freed from the Boc protecting group to obtain 32 mg of crude hydrochloride of intermediate R4. The crude product was dissolved in a minimum amount of water, and the pH was adjusted to 7-8 with saturated sodium bicarbonate solution. After freeze-drying, dichloromethane was added, and the product was ultrasonically shaken for 30 s and filtered. The solvent was removed under reduced pressure to obtain crude R4, which was directly used in the next step without purification. 1 H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.89 (t, J = 2.0Hz, 1H), 7.50–7.44 (m, 1H), 7. 27–7.19(m,2H),6.50(dd,J=5.0,2.2Hz,1H),3.99(t,J=2.6Hz,2H),3.87–3.79(m,1 H),3.00(t,J=6.8Hz,1H),2.84(s,2H),2.73–2.59(m,7H),2.59–2.39(m,8H),2.09 –1.92(m,2H),1.70(dd,J=5.4,2.7Hz,2H),1.65(dd,J=5.4,2.7Hz,2H).MS(ESI)m / z 424.3.

[0554] Example 32 Synthesis of Compounds S6 and S7

[0555] Route S:

[0556]

[0557] Intermediate J6 was synthesized by Route J. Intermediate J6 (1.1 equiv.) and 2- / 3-iodo-5-bromo-N-methylindole (1.0 equiv.) were synthesized by Suzuki reaction according to the sixth step of Route K to obtain intermediate S1. Intermediate S1 and A1 were synthesized by Suzuki reaction according to the first step of Route A to obtain intermediate S2. Intermediate S2 was subjected to Boc removal according to the first step of Route R to obtain intermediate S3. Intermediate S3 (1.0 equiv.) and tert-butyl (3-bromopropyl) carbamate (1.1 equiv.) were synthesized according to the second step of Route R to obtain intermediate S4. Referring to the second step of Route A, intermediate S4 was subjected to catalytic hydrogenation to obtain intermediate S5. Referring to the fifth step of Route E, the Boc protecting group of intermediate S5 is removed to obtain a crude hydrochloride product of intermediate S6 or a crude hydrochloride product of S7. The crude product is dissolved in a minimum amount of water, and the pH is adjusted to 7-8 with a saturated sodium bicarbonate solution. After freeze-drying, dichloromethane is added, and the product is ultrasonically shaken for 30 seconds and then filtered. The solvent is removed under reduced pressure to obtain a crude product of S6 or S7, which is directly used in the next step without purification.

[0558] S6: 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.53(t,J=1.8Hz,1H),7.29(d,J=7.9

[0559] Hz,1H),7.18(dd,J=8.0,2.2Hz,1H),6.61(d,J=2.2Hz,1H),3.87–3.79(m,1H ),3.74(d,J=12.3Hz,1H),3.73(s,3H),3.67(d,J=12.3Hz,1H),2.93(s,2H),2 .85(d,J=2.2Hz,4H),2.78(s,2H),2.81–2.71(m,1H),2.54–2.39(m,4H),2.09 –1.95(m,2H),1.90(t,J=6.5Hz,2H),1.66(tt,J=5.7,4.5Hz,2H).MS(ESI)m / z 410.3.

[0560] S7: 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.58(d,J=2.1Hz,1H),7.34(d,J=7.9Hz,1H),7. 20(ddd,J=7.9,2.2,0.7Hz,1H),7.04(s,1H),3.91–3.83(m,1H),3.80(s,3H),3.76(s, 2H),2.97(s,2H),2.88(s,2H),2.85(s,2H),2.81–2.71(m,4H),2.54–2.39(m,4H),2.0 9–1.95(m,2H),1.90(t,J=6.5Hz,2H),1.66(tt,J=5.7,4.5Hz,2H).MS(ESI)m / z410.3.

[0561] Example 33 Synthesis of Compounds T6 and T7

[0562] Route T:

[0563]

[0564] Referring to the first step of Route A, intermediate K4 and A1 are reacted by Suzuki reaction to obtain intermediate T1. Referring to Route J to synthesize J7, intermediate T1 and intermediate J7 are synthesized by Suzuki reaction according to the sixth step of Route K to obtain intermediate T2. Referring to the second step of Route R, intermediate T2 is deprotected by Boc to obtain intermediate T3. Referring to the fourth step of Route S, intermediate T3 is reacted with tert-butyl(3-bromopropyl)carbamate to obtain intermediate T4. Referring to the second step of Route A, intermediate T4 is reacted by catalytic hydrogenation to obtain intermediate T5. According to the sixth step of Route S, intermediate T5 is deprotected by Boc to obtain crude intermediate T6 or T7, which is directly used in the next step without purification.

[0565] T6: 1 H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 7.43 (t, J = 2.2Hz, 1H), 7.29 (d, J = 7.8

[0566] Hz,1H),7.20(dd,J=8.1,2.2Hz,1H),6.93(d,J=2.2Hz,1H),4.10–4.03(m,1H ),3.83(s,3H),3.66(d,J=3.1Hz,2H),2.76(dddd,J=12.3,6.6,5.6,2.0Hz,2 H),2.67–2.54(m,4H),2.57–2.44(m,6H),2.44(td,J=5.8,1.0Hz,2H),2.07– 1.91(m,2H),1.90(t,J=6.5Hz,2H),1.65(pd,J=5.7,1.5Hz,2H).MS(ESI)m / z 398.3.

[0567] T7: 1 H NMR (400MHz, DMSO-d6) δ10.98 (s, 1H), 7.39 (dd, J = 6.5, 1.4Hz, 1H), 7.21 (dd,

[0568] J=7.7,6.6Hz,1H),7.14(dd,J=7.8,1.4Hz,1H),6.81(d,J=0.8Hz,1H),4. 10(td,J=5.3,0.7Hz,1H),3.87(d,J=0.7Hz,2H),3.82(s,3H),2.83–2.72( m,2H),2.75–2.62(m,3H),2.68–2.57(m,1H),2.55–2.39(m,8H),2.07–1. 91(m,2H),1.90(t,J=6.5Hz,2H),1.65(pd,J=5.7,1.5Hz,2H).MS(ESI)m / z 398.3.

[0569] Example 34 Synthesis of protein degradation agent dBI-51-1

[0570]

[0571] Compound JQ1-L1 (36 mg, 0.08 mmol, 1.0 equiv.), intermediate Q4 (23 mg, 0.08 mmol, 1.05 equiv.), HATU (43 mg, 0.11 mmol, 1.5 equiv.), DIPEA (diisopropylethylamine) (39 μL, 0.24 mmol, 3.0 equiv.) were dissolved in anhydrous DMF (1 mL), and the reaction system was stirred at room temperature overnight under argon protection. TLC detected that there was no residual raw material, and water was added to quench the reaction. The aqueous phase was extracted with a mixed solvent of DCM-MeOH (4:1, v / v), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration and decompression, the solvent was removed by purification by preparative HPLC to obtain 39 mg of the target final product dBI-51-1 with a yield of 65%.

[0572] 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.89(q,J=1.3,0.8Hz,1H),7.76(t,J=4.3Hz,1H),7.71–7.62(m,3H),7.55–7. 48(m,2H),7.48(d,J=8.6Hz,1H),7.27–7.19(m,2H),6.56(dd,J=5.5,2.2Hz,1H),5.78(t,J=9.3Hz,1H),4.80(s,2H), 3.87–3.79(m,1H),3.20–3.11(m,3H),3.12(td,J=7.1,3.2Hz,1H),3.07(d,J=5.9Hz,1H),3.08–2.98(m,1H),2.63(s ,3H),2.54–2.45(m,1H),2.48–2.39(m,1H),2.31(d,J=1.5Hz,6H),2.09–1.92(m,2H),1.50–1.38(m,4H).MS(ESI)m / z 739.3.

[0573] Example 35 Synthesis of protein degradation agent dBI-51-2

[0574]

[0575] Referring to the synthesis method of the final product dBI-51-1, intermediate JQ1-L1 (30 mg, 0.07 mmol, 1.0 equiv.) was condensed with intermediate Q5 (25 mg, 0.07 mmol, 1.05 equiv.) to obtain 40 mg of the target final product dBI-51-2 with a yield of 70%.

[0576] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.87(d,J=2.1Hz,1H),7.76(t,J=4.3Hz,1H),7.71–7.62(m,3H),7.55–7 .48(m,2H),7.42(d,J=8.3Hz,1H),7.27(s,1H),7.26–7.19(m,1H),5.78(t,J=9.3Hz,1H),4.85(d,J=0.9Hz,2H) ,3.91–3.83(m,1H),3.20–3.14(m,1H),3.18–3.08(m,3H),3.12–3.04(m,1H),3.08–2.98(m,1H),2.63(s,3H), 2.54–2.45(m,1H),2.48–2.39(m,1H),2.31(d,J=1.5Hz,6H),2.09–1.92(m,2H),1.50–1.38(m,4H).MS(ESI)m / z 807.3.

[0577] Example 36 Synthesis of protein degradation agent dBI-61-1

[0578]

[0579] Referring to the synthesis method of the final product dBI-51-1, 36 mg of the target final product dBI-61-1 was obtained by condensation of intermediate JQ1-L1 (30 mg, 0.07 mmol, 1.0 equiv.) and intermediate Q6 (20 mg, 0.07 mmol, 1.05 equiv.) with a yield of 69%.

[0580] 1 H NMR(400MHz,DMSO-d6)δ10.81(s,1H),7.80–7.73(m,2H),7.71–7.62(m,3H),7.55–7.46(m,3H), 7.27–7.22(m,1H),7.19(dd,J=7.9,2.3Hz,1H),6.54–6.48(m,1H),5.78(t,J=9.3Hz,1H),4.83( s,2H),3.84–3.76(m,1H),3.20–3.08(m,4H),3.07(d,J=5.9Hz,1H),3.08–2.98(m,1H),2.63(s, 3H),2.54–2.39(m,2H),2.31(d,J=1.5Hz,6H),2.09–1.94(m,2H),1.50–1.38(m,4H).MS(ESI)m / z 739.3.

[0581] Example 37 Synthesis of protein degradation agent dBI-41-1

[0582]

[0583] Referring to the synthesis method of the final product dBI-51-1, 34 mg of the target final product dBI-41-1 was obtained by condensation of intermediate JQ1-L1 (30 mg, 0.07 mmol, 1.0 equiv.) and intermediate Q7 (20 mg, 0.07 mmol, 1.05 equiv.) with a yield of 65%.

[0584] 1 H NMR(400MHz,DMSO-d6)δ10.78(s,1H),7.76(d,J=8.6Hz,0H),7.76(s,1H),7.71–7.63(m,3H ),7.55–7.47(m,3H),7.28(s,1H),7.25–7.16(m,2H),7.17(d,J=5.0Hz,1H),6.82(d,J=5.2 Hz,1H),5.78(t,J=9.3Hz,1H),4.83(s,2H),3.98(t,J=5.8Hz,1H),3.20–2.98(m,6H),2.63 (s,3H),2.55–2.43(m,2H),2.45(s,3H),2.11–1.92(m,2H),1.50–1.38(m,4H).MS(ESI)m / z 739.3.

[0585] Example 38 Synthesis of protein degradation agent dBI-51-3

[0586]

[0587] Referring to the synthesis method of the final product dBI-51-1, the intermediate JQ1 acid (23 mg, 0.06 mmol, 1.0 equiv.) was condensed with the intermediate R4 (25 mg, 0.06 mmol, 1.05 equiv.) to obtain 29 mg of the target final product dBI-51-3 with a yield of 64%.

[0588] 1H NMR(400MHz, DMSO-d6)δ10.81(s,1H),7.89(t,J=2.0Hz,1H),7.69–7.60(m,3H),7.55–7.48(m,2H),7.52–7.44(m,1H),7.27–7.19(m ,2H),6.50(dd,J=5.0,2.2Hz,1H),5.78(t,J=9.3Hz,1H),3.99(t,J=2.6Hz,2H),3.87–3.79(m,1H),3.29(tt,J=5.4,4.4Hz,2H),3.15 –2.98(m,2H),2.84(s,2H),2.69(t,J=2.6Hz,2H),2.69(s,2H),2.63(s,3H),2.55(s,1H),2.56–2.46(m,6H),2.50–2.44(m,1H),2.48 –2.39(m,1H),2.31(d,J=1.5Hz,6H),2.07–1.93(m,2H),1.70(dd,J=5.2,2.9Hz,2H),1.65(dd,J=5.2,2.9Hz,2H).MS(ESI)m / z806.3.

[0589] Example 39 Synthesis of protein degradation agent dBI-52-1

[0590]

[0591] Referring to the synthesis method of the final product dBI-51-1, the intermediate JQ1 acid (21 mg, 0.05 mmol, 1.0 equiv.) was condensed with the intermediate S6 (23 mg, 0.06 mmol, 1.05 equiv.) to obtain 33 mg of the target final product dBI-52-1 with a yield of 78%.

[0592] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.80(t,J=4.9Hz,1H),7.69–7.62(m,2H),7.56–7.48(m,3H),7.29(d,J=7.9Hz,1H),7.18(d d,J=8.0,2.2Hz,1H),6.61(d,J=2.2Hz,1H),5.78(t,J=9.3Hz,1H),3.87–3.79(m,1H),3.74(d,J=12.3Hz,1H),3.73(s,3H),3.67( d,J=12.3Hz,1H),3.12(td,J=6.1,5.1Hz,2H),3.07(d,J=5.9Hz,1H),3.08–2.98(m,1H),2.93(s,2H),2.85(d,J=2.2Hz,4H),2.78 (s,2H),2.63(s,3H),2.54–2.39(m,4H),2.31(d,J=1.5Hz,6H),2.09–1.93(m,2H),1.66(tt,J=6.0,4.7Hz,2H).MS(ESI)m / z792.3.

[0593] Example 40 Synthesis of protein degradation agent dBI-53-1

[0594]

[0595] Referring to the synthesis method of the final product dBI-51-1, the intermediate JQ1 acid (21 mg, 0.05 mmol, 1.0 equiv.) was condensed with the intermediate S7 (23 mg, 0.06 mmol, 1.05 equiv.) to obtain 30 mg of the target final product dBI-53-1 with a yield of 71%.

[0596] 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.80(t,J=4.9Hz,1H),7.69–7.62(m,2H),7.58(d,J=2.2Hz,1H),7.55 –7.48(m,2H),7.34(d,J=7.9Hz,1H),7.20(ddd,J=7.9,2.2,0.7Hz,1H),7.04(s,1H),5.78(t,J=9.3Hz,1H), 3.91–3.83(m,1H),3.80(s,3H),3.76(s,2H),3.16–3.00(m,4H),2.97(s,2H),2.86(d,J=11.4Hz,4H),2.78( s,2H),2.53–2.40(m,4H),2.31(d,J=1.5Hz,6H),2.07–1.93(m,2H),1.66(tt,J=6.0,4.7Hz,2H).MS(ESI)m / z 792.3.

[0597] Example 41 Synthesis of protein degradation agent dBI-25-1

[0598]

[0599] Referring to the synthesis method of the final product dBI-51-1, the intermediate JQ1 acid (25 mg, 0.06 mmol, 1.0 equiv.) was condensed with the intermediate T6 (26 mg, 0.06 mmol, 1.05 equiv.) to obtain 35 mg of the target final product dBI-25-1 with a yield of 72%.

[0600] 1H NMR(400MHz, DMSO-d6)δ10.98(s,1H),7.80(t,J=4.9Hz,1H),7.69–7.62(m,2H),7.55–7.48(m,2H),7.43(t,J=2.2Hz,1 H),7.29(d,J=7.8Hz,1H),7.20(dd,J=8.1,2.2Hz,1H),6.93(d,J=2.2Hz,1H),5.78(t,J=9.3Hz,1H),4.10–4.03(m,1H) ,3.83(s,3H),3.66(d,J=3.1Hz,2H),3.16–3.10(m,1H),3.13–3.04(m,2H),3.08–2.98(m,1H),2.67–2.55(m,7H),2.59 –2.45(m,6H),2.42(td,J=5.9,1.3Hz,2H),2.31(d,J=1.5Hz,6H),2.07–1.90(m,2H),1.65(p,J=6.0Hz,2H).MS(ESI)m / z 780.3.

[0601] Example 42 Synthesis of protein degradation agent dBI-25-1

[0602]

[0603] Referring to the synthesis method of the final product dBI-51-1, the intermediate JQ1 acid (25 mg, 0.06 mmol, 1.0 equiv.) was condensed with the intermediate T7 (26 mg, 0.06 mmol, 1.05 equiv.) to obtain 30 mg of the target final product dBI-25-1 with a yield of 62%.

[0604] 1H NMR(400MHz, DMSO-d6)δ10.98(s,1H),7.80(t,J=4.9Hz,1H),7.69–7.62(m,2H),7.55–7.48(m,2H),7.39(dd,J=6.5,1.4Hz,1H),7 .21(dd,J=7.7,6.6Hz,1H),7.14(dd,J=7.8,1.4Hz,1H),6.81(d,J=0.8Hz,1H),5.78(t,J=9.3Hz,1H),4.10(td,J=5.3,0.7Hz,1H) ,3.87(d,J=0.7Hz,2H),3.82(s,3H),3.16–3.10(m,1H),3.13–3.04(m,2H),3.08–2.98(m,1H),2.72–2.57(m,4H),2.63(s,3H),2. 55–2.44(m,6H),2.42(td,J=5.9,1.3Hz,2H),2.31(d,J=1.5Hz,6H),2.07–1.90(m,2H),1.65(p,J=6.0Hz,2H).MS(ESI)m / z780.3.

[0605] Example 43 Verification of the Binding Activity of Compound 1-176 to E3 Ubiquitin Ligase CRBN

[0606] The binding activity of the compounds disclosed in the present application and the E3 ubiquitin ligase CRBN is determined by the competitive binding of the compounds disclosed in the present application with thalidomide labeled with XL665 to the CRBN protein, thereby preventing the occurrence of fluorescence resonance energy transfer (FRET), thereby judging the binding force of the compounds to the CRBN protein.

[0607] CRBN binding activity test kit (CEREBLON BINDING KITS (PE, 64BD CRBN PEG).

[0608] The detection is based on homogeneous time-resolved fluorescence (HTRF) technology. When the donor and acceptor are close to each other, the donor can transfer energy to the acceptor, causing it to be excited and emit light at 665nm.

[0609] The donor used in this kit is a europium-labeled GST antibody (GST Eu CryptateAntibody) and the receptor is thalidomide (Thalidomide-Redreagent) labeled with XL665. The donor binds to the CRBN protein containing the GST tag, and the compound disclosed in this application competes with thalidomide to bind to the CRBN protein, and the compound binding activity is judged based on the fluorescence value emitted by the receptor at 665nm. The stronger the compound binding force, the weaker the signal.

[0610] The donor and receptor were diluted 50 times respectively using the buffer in the kit (PROTAC binding buffer 1). The CRBN protein was diluted 45 times. The 8 mM compound solution disclosed in this patent was diluted 10 times using the diluent (1X diluent) in the kit, and then the diluent was diluted 5 times in a gradient manner, and diluted 7 times in sequence.

[0611] 5 μl of compound, 5 μl of diluted CRBN protein and 10 μl of donor-receptor mixture were added to the wells of a white 384-well plate (PE, Part number: 6008280) in sequence and incubated at room temperature for 3 hours.

[0612] The ratio of the acceptor and donor emission signals was calculated for each individual well.

[0613] Ratio=665nm signal value / 620nm signal value*10 4

[0614] Calculate the coefficient of variation (CV) = standard deviation (SD) / Ratio mean * 100

[0615] IC was calculated based on compound concentration, Ratio and coefficient of variation using GraphPad Prism. 50 value.

[0616] Table 3 summarizes the evaluation of the inhibitory effects of compounds 1 to 176 on thalidomide binding to CRBN protein. 50 Level graded as A(IC 50 <1μΜ), B(IC 50 1~20μΜ)、C(IC 50 >20μΜ).

[0617] Table 3 Binding activity of Compound 1-176 to E3 ubiquitin ligase CRBN

[0618]

[0619]

[0620]

[0621] Example 43 Evaluation of the effect of protein degrader compounds on reducing the expression of bromodomain proteins (BRD)

[0622] Human chronic myelomonocytic leukemia MV-4-11 cells were cultured in IMDM medium containing 10% fetal bovine serum (Gibco, USA) at 37°C, 5% CO2, and 95% humidity in an incubator. When the growth density reached 80%, a medium containing the compound was selected and the cells were seeded into 6-well plates at a cell density of 1x10 6 / ml, so that the final concentration of the compound is 0.1, 1, 10 and 20 μM. After 24 hours of treatment, the cells were collected and washed twice with PBS, and RIPA lysis buffer containing protease inhibitors and phosphatase inhibitors was added to the cells. After lysis and centrifugation, the total protein extract was obtained, and the protein concentration in the extract was detected by the BCA method.

[0623] Protein electrophoresis was performed using SDS-PAGE, and then the protein was transferred to a PVDF membrane by constant current electrophoresis at 200 mA for 150 min. The PVDF membrane was placed in 5% skim milk and blocked at room temperature for 1 h. BRD4 (#13440, CST) (1:1000) and C-MYC (ab32072, 1:1000) were added and incubated overnight at 4°C. The membrane was washed 3 times with TBST for 10 min each time. The secondary antibody (1:5000, absin) was incubated at room temperature for 60 min. The membrane was washed 3 times with TBST for 10 min each time. ECL luminescent liquid was added and exposed. Each sample was simultaneously detected using GAPDH protein as an internal reference. The protein map was analyzed by grayscale value analysis using the analysis software ImageJ. The formula used was: grayscale correction value = (grayscale value of target protein / corresponding grayscale value of internal reference>10 3 , calculate the grayscale correction value of each sample. Then compare it with the grayscale correction value of the control group to calculate the degradation rate. Then use Prism to perform nonlinear curve fitting with logarithmic concentration-inhibition rate to obtain the DC of the compound. 50 and D max value.

[0624] Table 4 summarizes the evaluation of the protein degradation agents PRTB-01 to 16 on the reduction of BRD protein expression. 50 represents the concentration of protein degrader when the protein degrader induces BRD protein degradation to 50%, and the level is graded as A (DC 50 <1μΜ), B(DC 50 1~10μΜ)、C(DC 50 >10μΜ). Where D maxIt represents the ratio of the maximum extent of BRD protein degradation induced by protein degraders to the total amount of BRD protein, and the level is graded as A (D max >85%)、B(D max 85~50%)、C(DC 50 <50%)

[0625] Table 4 Evaluation of the effect of protein degraders on reducing BRD protein expression

[0626]

[0627]

[0628]

Claims

1. A compound that can bind to a CRBN protein, the compound consisting of two substructure units A and B, wherein the two substructures A and B are connected by a chemical single bond from Y of the A substructure to one of C2 (carbon 2), 4 (4th), 5 (5th), 6 (6th) and 7 (7th) of the B substructure, and the compound is as shown in Formula I; In formula I, the A substructure comprises the following A 1 , A 2 , A 3 Three types: In Formula I, when Y is one of CH, C-alkyl, CF or CD (carbon deuterium), the substructure A is a glutarimide (G) skeleton A 1 , at this time A 1 R 5 is one of H, alkyl, F or D (deuterium); In formula I, when Y is N, the substructure A can be a dihydrouracil (DHU) skeleton A 2 or uracil (U) backbone A 3 , at this time A 3 R 6 is one of H, alkyl (alkyl) or halo (halogen); The A substructure in formula I, wherein A 1 , A 2 and A 3 R in three types 4 is one of H, alkyl, Boc, Cbz, Bn, or aryl; In Formula I, the substructure B comprises the following B 1 , B 2a～d , B 3a～b , B 4a～c or B 5 Five types: W of the B substructure in Formula I 1 Can only be one of N, CH or CR (R is a substituent); W of the B substructure in Formula I 2 Can only be one of N, CH or CR (R is a substituent); W of the B substructure in Formula I 3 Can only be one of N, CH or CR (R is a substituent); W of the B substructure in Formula I 4 Can only be one of N, CH or CR (R is a substituent); W of the B substructure in Formula I 1 , W 2 , W 3 and W 4 When both are not N, the substructure B is the benzimidazole skeleton B 1 , at this time, the A substructure and B 1 The substructure consists of A's Y and B 1 One of the C2 (carbon 2 position), 4 (carbon 4 position), 5 (carbon 5 position), 6 (carbon 6 position) or 7 (carbon 7 position) of the molecule is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 1 is N, and W 2 , W 3 and W 4 When both are not N, the substructure B is B of pyrrolo[3,2-b]pyridine 2a Type, A substructure and B 2a The substructure consists of A's Y and B 2a One of the C2 (carbon 2 position), 5 (carbon 5 position), 6 (carbon 6 position) or 7 (carbon 7 position) of the molecule is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 2 is N, and W 1 , W 3 and W 4 When both are not N, the substructure B is B of pyrrolo[3,2-c]pyridine 2b Type, A substructure and B 2b The substructure consists of A's Y and B 2b One of the C2 (carbon 2 position), 4 (carbon 4 position), 6 (carbon 6 position) or 7 (carbon 7 position) positions is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 3 is N, and W 1 , W 2 and W 4 When both are not N, the substructure B is B of pyrrolo[2,3-c]pyridine 2c Type, A substructure and B 2c The substructure consists of A's Y and B 2c One of the C2 (carbon 2 position), 4 (carbon 4 position), 5 (carbon 5 position) or 7 (carbon 7 position) of the molecule is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 4 is N, and W 1 , W 2 and W 3 When both are not N, the substructure B is B of pyrrolo[2,3-b]pyridine 2d Type, A substructure and B 2d The substructure consists of A's Y and B 2d One of the C2 (carbon 2 position), 4 (carbon 4 position), 5 (carbon 5 position) or 6 (carbon 6 position) is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 2 and W 4 is N, and W 1 and W 3 When both are not N, the substructure B is B of pyrrolo[2,3-d]pyrimidine 3a Type, A substructure and B 3a The substructure consists of A's Y and B 3a One of the C2 (carbon 2 position), 4 (carbon 4 position) or 6 (carbon 6 position) positions is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 1 and W 3 is N, and W 2 and W 4 When both are not N, the substructure B is B of pyrrolo[3,2-d]pyrimidine 3b Type, A substructure and B 3b The substructure consists of A's Y and B 3b One of the C2, 5 or 7 positions is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 3 and W 4 is N, and W 1 and W 2 When both are not N, the substructure B is the B of pyrrolo[2,3-c]pyridazine 4a Type, A substructure and B 4a The substructure consists of A's Y and B 4a One of the C2 (carbon 2 position), 4 (4th position) or 5 (5th position) positions is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 2 and W 3 is N, and W 1 and W 4 When both are not N, the substructure B is the B of pyrrolo[2,3-d]pyridazine 4b Type, A substructure and B 4b The substructure consists of A's Y and B 4b One of the C2 (carbon 2 position), 4 (4th position) or 7 (7th position) of the molecule is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 1 and W 2 is N, and W 3 and W 4 When both are not N, the substructure B is the B of pyrrolo[3,2-c]pyridazine 4c Type, A substructure and B 4c The substructure consists of A's Y and B 4c One of the C2 (carbon 2 position), 6 (sixth position) or 7 (seventh position) positions is connected by a CC single bond or a CN single bond; W of the B substructure in Formula I 1 and W 4 is N, and W 2 and W 3 When both are not N, the substructure B is the B of pyrrolo[2,3-b]pyrazine 5 Type, A substructure and B 5 The substructure consists of A's Y and B 5 One of the C2 (carbon 2 position), 5 (5th position) or 6 (6th position) of the molecule is connected by a CC single bond or a CN single bond; The compound structure is as follows: in, In the structure of the compound, R 1 Select one of the following structures In the structure of the compound, R 2 , R 3 , R 7 , R 8 , R 9 , and R 10 One of the following structures Among them, A in the compound structure 1 / 2 / 3 A 1 or A 2 or A 3 , A 1 / 3 Representative A 1 or A 3 , A 2 / 3 Representative A 2 or A 3 .

2. A pharmaceutically acceptable salt of the compound (Formula I) according to claim 1, characterized in that: The pharmaceutically acceptable salt refers to a salt prepared from the parent compound by addition of non-toxic acids or bases.

3. A protein degrader, wherein the structure of the protein degrader is: target protein ligand (POI ligand) + linker (Linker) + CRBN protein ligand; wherein the CRBN protein ligand is the compound according to claim 1; the structural formula of the protein degrader is shown in Formula II:

4. A protein degradation agent according to claim 1, characterized in that: The linker is shown in Formula II, wherein L of the linker substructure 1 It can be connected to one of the positions N1 (nitrogen position 1), C2 (carbon position 2), C3 (carbon position 3), 4 (4th position), 5 (5th position), 6 (6th position) or 7 (7th position) on the B substructure of the structure represented by Formula I through one of the chemical single bonds of CC chemical single bond, CN chemical single bond, NC chemical single bond or OC chemical single bond, and the connection mode is as follows, wherein Indicates the B substructure and L 1 The attachment site is selected from one of the following: The Linker substructure L 1 , L 3 and L 5 One or more structures can be selected; Among them, R a is selected from one or more of H, alkyl, SO2-alkyl or SO2-aryl; the substructure L of the Linker 2 , and L 4 Selected from One of them.

5. The protein degradation agent according to claim 4, characterized in that The target protein ligand is a ligand of the target protein that causes the relevant disease; the target protein ligand, i.e., the POI ligand in formula II, can be selected from one or more of the following structures:

6. The protein degradation agent according to claim 4, characterized in that The protein degrading agent can be selected from the following:

7. A pharmaceutical composition comprising the compound of formula I or a pharmaceutically acceptable salt thereof according to the first aspect and a pharmaceutically acceptable diluent or carrier.

8. A pharmaceutical composition for targeted protein degradation, comprising the protein degrading agent (Formula II) according to claim 3 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

9. A regulator for regulating a transcriptional regulatory factor, the regulator comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof or a protein degrading agent (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

10. A method for treating or preventing pathological conditions or symptoms of diseases caused by limiting or inhibiting the expression of IRF4 and Myc, comprising administering to a patient in need of treatment an effective amount of at least one compound of Formula I or Formula II or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

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