Compound binding to CRBN protein and degradation agent of protein

Abstract

The present invention belongs to the technical field of medicinal chemistry, specifically relates to a compound capable of binding to a CRBN protein and a composition thereof, and also relates to a protein degradation agent based on a CRBN protein and the use thereof. Specifically disclosed is a compound capable of binding to a CRBN protein, wherein the compound is composed of two sub-structure units A and B, the two sub-structures A and B are connected by means of a chemical single bond between Y of the sub-structure A and one of C2 (carbon at position 2), C4 (carbon at position 4), C5 (carbon at position 5), C6 (carbon at position 6) and C7 (carbon at position 7) of the sub-structure B, and the compound is as shown in formula I. The compound can be used as a structural unit of an E3 ubiquitin ligase ligand in PROTAC technology, thereby providing more therapeutic means for cancers or diseases such as prostate cancer, breast cancer, non-small cell lung cancer, Alzheimer's disease, neuroblastoma, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, malignant rhabdomyosarcoma, and oral squamous cell carcinoma.

Description

A compound binding to CRBN protein and a degrader of the protein Technical Field

[0001] The present invention belongs to the technical field of medicinal 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 its application. Background Art

[0002] CRBN (Cereblon) is a substrate receptor protein of the CRL4 (CRBN) isoform of the E3 ubiquitin ligase complex. Together with the DDB1 (Damage-specific DNA Binding protein 1), the zinc-finger domain protein RBX1, and the Cullin4 (Cul4) scaffold protein, it forms the DDB1–Cul4–Rbx1–CRBN E3 ubiquitin ligase complex, which determines the substrate specificity of the CRL4 E3 ubiquitin ligase. It is widely expressed in the cytoplasm, nucleus, and peripheral membranes of the prostate, liver, pancreas, placenta, kidney, lung, peripheral blood leukocytes, and brain. E3 ubiquitin ligases specifically recognize substrate proteins and induce polyubiquitination, leading to their degradation via the ubiquitin-proteasome pathway. This impacts various physiological processes, including cellular energy metabolism, membrane potential regulation, and transcription factor degradation.

[0003] In 2010, Ito et al. first demonstrated that thalidomide's direct target is CRBN, a substrate receptor protein for an E3 ubiquitin ligase. When thalidomide and other immunomodulators bind to CRBN, they activate the activity of the E3 ubiquitin ligase, prompting it to recruit the substrate proteins IKZF1 / IKZF3 (Ikaros / Aiolos are zinc finger transcription factors that play an important role in blood cell differentiation). The E3 ubiquitin ligase, the substrate proteins IKZF1 / IKZF3, and the immunomodulator then form a stable ternary complex, transferring ubiquitin to the substrate proteins IKZF1 / IKZF3, leading to their degradation by the 26S proteasome. IKZF1 and IKZF3 are essential transcriptional regulatory factors 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 exerting 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 T cell immune response and inhibiting the function of B cells, achieving tumor killing and inhibiting tumor proliferation. Simultaneously, it reduces the expression of tumor necrosis factor (TNF) and promotes the secretion of the 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 targeting chimeras (PROTACs) designed using the chemical structure of thalidomide, lenalidomide, and pomalidomide, a class of immunomodulators, have emerged.

[0004] PROTAC, Proteolysis Targeting Chimera, protein degradation targeting chimera, is a bifunctional molecule that consists of an E3 ligand structural unit that can bind to a specific E3 ubiquitin ligase, a target protein ligand structural unit that can bind to the target protein, and a linker connecting the 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 PROTACs. 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 rhabdomyomas, oral squamous cell carcinoma and other cancers or diseases.

[0006] Summary of the Invention

[0007] The compounds exhibited varying degrees of inhibitory activity against the binding of CRBN to the immunomodulator thalidomide, suggesting that these CRBN-binding compounds could potentially serve as alternative structures to thalidomide, binding to CRBN. Therefore, the compounds of the present invention can be used as structural units for E3 ubiquitin ligase ligands in PROTAC technology. PROTACs designed based on these compounds can use inhibitors of specific target proteins to be degraded or other small molecule compounds as target protein ligands, achieving degradation of target proteins that are dependent on CRBN-type E3 ubiquitin ligases, providing more therapeutic options for the aforementioned diseases.

[0008] In a first aspect, the present invention provides a compound that can bind to the CRBN protein, wherein the compound is composed of two substructure units, A and B, wherein the two substructures A and B are connected by a chemical single bond through Y of the A substructure and 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 shown in Formula I;

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

[0010] In formula I, when Y is one of CH, C-alkyl, CF or CD (carbon deuterium), the substructure A is the glutarimide (G) skeleton A 1 , at this time A 1 R in 5 is one of H, alkyl, F or D (deuterium);

[0011] 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 in 6 is one of H, alkyl or halo;

[0012] 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 (alkyl), Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), Bn (benzyl) or aryl (aryl).

[0013] In formula I, the substructure B comprises the following B 1 、B2a～d 、B 3a～b 、B 4a～c or B 5 Five types:

[0014] W of the B substructure in Formula I 1 It can only be one of N, CH or CR (R is a substituent).

[0015] W of the B substructure in Formula I 2 It can only be one of N, CH or CR (R is a substituent).

[0016] W of the B substructure in Formula I 3 It can only be one of N, CH or CR (R is a substituent).

[0017] W of the B substructure in Formula I 4 It can only be one of N, CH or CR (R is a substituent).

[0018] 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 a benzimidazole skeleton B 1 , at this time A substructure and B 1 The substructure consists of A's Y and B 1 One of the C2 (carbon 2 position), 4 (4th position), 5 (5th position), 6 (6th position) or 7 (7th position) positions is connected by a CC single bond or a CN single bond.

[0019] 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 B substructure 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) positions is connected by a CC single bond or a CN single bond.

[0020] 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 2bOne of the C2 (carbon 2 position), 4 (4th position), 6 (6th position) or 7 (7th position) positions is connected by a CC single bond or a CN single bond.

[0021] 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 (4th position), 5 (5th position) or 7 (7th position) positions is connected by a CC single bond or a CN single bond.

[0022] 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 B substructure 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 (4th position), 5 (5th position) or 6 (6th position) positions is connected by a CC single bond or a CN single bond.

[0023] 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.

[0024] 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 pyrrolo[3,2-d]pyrimidine B 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 via a CC single bond or a CN single bond.

[0025] W of the B substructure in Formula I 3 and W4 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.

[0026] 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) positions is connected by a CC single bond or a CN single bond.

[0027] 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.

[0028] 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 B substructure 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) positions is connected by a C-C single bond or a C-N single bond;

[0029] The compound structure is as follows:

[0030] Among them, R in the compound structure 1 Select one of the following structures

[0031] In the compound structure, R 2 、R 3 、R 7 、R 8 、R 9 , and R 10 One of the following structures

[0032] Wherein, 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 .

[0033] In a second aspect, the present invention further provides a pharmaceutically acceptable salt of the compound (Formula I) described in the first aspect.

[0034] Furthermore, the pharmaceutically acceptable salt refers to a salt prepared from the parent compound by addition of a non-toxic acid or base.

[0035] 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.

[0036] The structural formula of the protein degradation agent of the present invention is shown in Formula II:

[0037] 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.

[0038] The specific connection mode is as follows: Indicates the B substructure and L 1 The attachment site is selected from one of the following:

[0039] The Linker substructure L 1 , L 3 and L 5 One or more structures can be selected;

[0040] Among them, R a One or more selected from H, alkyl, SO2-alkyl or SO2-aryl;

[0041] The Linker substructure L 2 , and L 4 Selected from

[0042] One of the following;

[0043] Wherein, the target protein ligand is a ligand of the target protein that causes related diseases.

[0044] 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.

[0045] Furthermore, the target protein ligand, i.e., the POI ligand in Formula II, can be selected from one or more of the following structures:

[0046] Furthermore, in some embodiments of the present invention, the specific structure of the protein degradation agent is as follows:

[0047] 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.

[0048] Furthermore, the pharmaceutical composition may also comprise an enantiomer, diastereomer, stereoisomer or pharmaceutically acceptable salt of the compound of formula (I) and a pharmaceutically acceptable diluent or carrier.

[0049] In a fifth aspect, the present invention provides a pharmaceutical composition for targeted protein degradation, 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.

[0050] Furthermore, the pharmaceutical composition for targeted protein degradation may also contain its enantiomer, diastereomer, stereoisomer or pharmaceutically acceptable salt and a pharmaceutically acceptable diluent or carrier.

[0051] 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 degrader (II) or a pharmaceutically acceptable salt, hydrate, solvate, prodrug, stereoisomer or tautomer thereof.

[0052] Furthermore, the transcriptional regulatory factor is a regulatory factor necessary for the proliferation and development of B cells and T cells.

[0053] Furthermore, the regulation may be positive regulation and / or negative regulation.

[0054] Furthermore, the transcription factors include but are not limited to IRF4 and Myc.

[0055] In a 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 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.

[0056] Furthermore, the pathological conditions or symptoms include, but are not limited to, bone marrow failure, anemia, immune paralysis and infection, fractures and bone pain, high calcium levels and renal failure. BRIEF DESCRIPTION OF THE DRAWINGS DETAILED DESCRIPTION

[0057] The following is a further description of specific embodiments of the present invention. It should be noted that the description of these embodiments is intended to facilitate understanding of the present invention and does not constitute a limitation of the present invention. In addition, the technical features involved in the embodiments described below may be combined with each other as long as they do not conflict with each other.

[0058] The terms "C2 (carbon 2 position), 4 (4th position), 5 (5th position), 6 (6th position) and 7 (7th position)" described herein refer to the position number of a specific element, substituent or functional group on the core skeleton of the compound, that is, they are 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 position), the carbon position where the five-membered ring R3 substituent is located is called the C3 position (carbon 3 position), and the six-membered ring W1, W2, W3, and W4 positions are respectively referred to as 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.

[0059] As used herein, the terms "CD" and "D" refer to the hydrogen isotope deuterium, D.

[0060] The term "stereoisomer" as used herein refers to compounds that have identical chemical constitution but differ with regard to the arrangement of atoms or groups in space, and includes "diastereomers" and "enantiomers".

[0061] As used herein, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral characteristics, and reactivity. Mixtures of diastereomers can be separated by high-resolution analytical procedures such as electrophoresis and crystallization in the presence of a resolving agent or chromatographic method, such as using a chiral HPLC column.

[0062] 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 can occur in chemical reactions or processes without stereoselectivity or stereospecificity.

[0063] As used herein, the terms "pharmaceutically acceptable salts" and "salts of compounds" are interchangeable and refer to derivatives of the disclosed compounds wherein the parent compound is formed by the preparation of non-toxic acid or base addition salts; examples of pharmaceutically acceptable salts include, but are not limited to, non-toxic acid addition 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, as appropriate.

[0064] Table 1 Structures of exemplary compounds that bind to CRBN protein

[0065] Table 2 Exemplary compound structures of PROTAC protein degraders

[0066] The experimental methods in the following examples, unless otherwise specified, are conventional methods. The experimental materials used in the following examples, unless otherwise specified, are all commercially available. In the following examples, compounds A1 and E1 are commercially available compounds.

[0067] Example 1 Synthesis of Compound A4

[0068] Route A:

[0069] To an oven-dried, argon-purged flask, 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.), and Pd(dppf)Cl2 (10 mol%). After purging the atmosphere with argon, a mixture of dry 1,4-dioxane and a previously deoxygenated, saturated aqueous sodium bicarbonate solution (3:1, v:v, 0.1 M) was added. The atmosphere was purged with argon, and the reaction mixture was heated in an 85°C oil bath overnight. TLC confirmed the absence of bromoindole starting material. After cooling the reaction system to room temperature, it was diluted with water and EtOAc. The resulting aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, the solvent was removed under reduced pressure, and purification by silica gel flash column chromatography afforded intermediate A3.

[0070] To an oven-dried, argon-replaced flask, intermediate A3, MeOH-THF (0.2M, 1:1, v / v), and 10% Pd / C (20 wt%) were added. Hydrogen was withdrawn during vigorous stirring, and the reaction solution was stirred vigorously under a hydrogen balloon for 8 h. TLC analysis revealed no residual starting material, and LC-MS analysis revealed no unreacted intermediate. The reaction solution was filtered through a silica gel cake and dried under reduced pressure to afford crude product A4. The target final product, A4, was purified by preparative HPLC (MeCN / H2O) to obtain a pure product. Intermediate A4 was used directly in the next reaction without purification.

[0071] Example 2 Synthesis of Compound 5-bromo-3-fluoro-1-methyl-1H-indole

[0072] To an oven-dried flask that had been purged with argon three times, DCE (4 mL), distilled water (2 mL), Selectfluor (708 mg, 2.00 mmol, 2.0 equiv.), and LiCO (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 then added to the mixture at 0°C. The reaction mixture was stirred under argon at the same temperature for 24 h. TLC confirmed the absence of residual starting material. The mixture was diluted with water and DCM, and the resulting aqueous phase was extracted with DCM (3 × 10 mL). The combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to yield 123 mg of the intermediate 5-bromo-3-fluoro-1-methyl-1H-indole in a 54% yield.

[0073] 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.

[0074] Example 3 Compound 5-bromo-1-methyl-3-(trifluoromethyl)-1H-indole

[0075] Route B:

[0076] To an oven-dried, argon-purged flask, the starting material, 4-bromo-2-iodoaniline (500 mg, 1.68 mmol, 1.0 equiv.), and dry DCM (10 mL) were added. The reaction system was placed in an ice-water bath at 0°C. Pyridine (159 mg, 2.01 mmol, 1.2 equiv.) and p-toluenesulfonyl chloride (384 mg, 2.01 mmol, 1.2 equiv.) were then added sequentially. The reaction system was stirred at room temperature overnight. TLC analysis indicated no residual starting material. The reaction was quenched with water, and the aqueous phase was extracted with DCM (3 × 10 mL). The combined organic phases were washed with saturated sodium chloride solution (1 × 20 mL) and dried over anhydrous sodium sulfate. The product was filtered, the solvent was removed under reduced pressure, and the product was purified by flash column chromatography on silica gel to yield 725 mg of Intermediate B1 in 95% yield. MS (ESI) m / z 451.9 was obtained.

[0077] To an oven-dried, argon-purged 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.), and PdCl₂(PPh₃)₂ (22 mg, 0.03 mmol, 0.02 equiv.) were added. The mixture was purged with argon and then charged with dry THF and pre-degassed distilled water. The reaction system was heated to reflux in an oil bath with stirring for 20 h. TLC analysis confirmed the absence of residual starting material. The reaction system was cooled to room temperature, diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phases were 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.

[0078] To a microwave reaction tube, intermediate B2 (80 mg, 0.19 mmol, 1.0 equiv.), t-BuOH (2 mL), and cerium ammonium nitrate (314 mg, 0.57 mmol, 3.0 equiv.) were added. After securing the rubber stopper, the reaction system was incubated at 100°C under microwave irradiation (60 W) for 5 min. The microwave irradiation was turned off, and the reaction system was cooled to room temperature. TLC confirmed no residual starting material. The reaction system was diluted with water and EtOAc. 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. The product was filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to afford 85 mg of intermediate B3 in a 65% yield. MS (ESI) m / z 418.0.

[0079] To a solution of Intermediate B3 (200 mg, 0.48 mmol, 1.0 equiv.) in anhydrous DMF (2 mL) were added lithium hydroxide monohydrate (80 mg, 1.92 mmol, 4.0 equiv.) and thioglycolic acid (53 mg, 0.57 mmol, 1.2 equiv.). The reaction mixture was stirred under argon for another 4 h. TLC analysis indicated no residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc (3 x 4 mL). The combined organic phases were washed with saturated sodium chloride solution (1 x 5 mL) and dried over anhydrous sodium sulfate. The product was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to afford 107 mg of the desired intermediate, 5-bromo-3-(trifluoromethyl)-1H-indole, in an 85% yield.

[0080] 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.

[0081] To a solution of the intermediate 5-bromo-3-(trifluoromethyl)-1H-indole (80 mg, 0.30 mmol, 1.0 equiv.) in anhydrous DMF (2 mL) were added anhydrous potassium carbonate (84 mg, 0.60 mmol, 2.0 equiv.) and iodomethane (64 mg, 0.45 mmol, 1.5 equiv.). The reaction mixture was stirred under an argon atmosphere for 5 h. TLC confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc (3 x 4 mL). The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to yield 72 mg of the target intermediate 5-bromo-1-methyl-3-(trifluoromethyl)-1H-indole in 85% yield.

[0082] 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.

[0083] Example 4 Synthesis of Compounds C7-12

[0084] Route C:

[0085] To a 0.5 M solution of starting material C1-6 (1.0 equiv.) in anhydrous DMSO, CF3SO2Na (2.0 equiv.), K2S2O8 (1.5 equiv.), and glucose (0.6 equiv.) were added. The reaction mixture was stirred under argon for an additional 8 h. TLC confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc (3 x 4 mL). The combined organic phases were washed with saturated sodium chloride solution (3 x 4 mL) and dried over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, and purification by silica gel flash column chromatography afforded the target intermediates C7-12.

[0086] Example 5 Synthesis of Compounds methyl 2-bromo-1H-indole-5-carboxylate and methyl 2-bromo-1-methyl-1H-indole-5-carboxylate

[0087] Route D:

[0088] To a solution of methyl3-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. The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. TLC confirmed the absence of residual starting material. The reaction mixture was diluted with water and DCM, and 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. The mixture was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to yield 653 mg of intermediate D1 in a 75% yield.

[0089] 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. The reaction mixture was stirred at reflux for 2 h. After cooling to room temperature, TLC confirmed the absence of residual starting material. The reaction mixture was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc (3 × 15 mL). The combined organic phases were washed with saturated sodium chloride solution (1 × 25 mL) and dried over anhydrous sodium sulfate. The residue was filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to afford 518 mg of intermediate D2 in a 94% yield.

[0090] To an oven-dried, three-purge argon round-bottom flask were added 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%), and K2CO3 (371 mg, 2.69 mmol, 2.0 equiv.). The mixture was purge-purged with argon three times, and then poured into dry 1.4-dioxane (6 mL). The reaction system was heated to 100°C in an oil bath and stirred for 12 h. TLC analysis indicated no residual starting material. The reaction system was cooled to room temperature, diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic phases were 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%.

[0091] 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.

[0092] To a solution of methyl 2-bromo-1H-indole-5-carboxylate (120 mg, 0.47 mmol, 1.0 equiv.) in dry DMF (5 mL) was added NaH (28 mg, 60 wt%, 0.71 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature for 30 min. Methyl iodide (80 mg, 0.57 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred under argon for another 4 h. TLC analysis revealed no residual starting material. The reaction system was diluted with water and EtOAc, 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. The product was filtered, the solvent was removed under reduced pressure, and then purified by flash column chromatography on silica gel to afford 111 mg of the desired intermediate, methyl 2-bromo-1-methyl-1H-indole-5-carboxylate, in an 88% yield.

[0093] 1 H 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.

[0094] Example 6 Synthesis of Compounds E7 and E8

[0095] Route E:

[0096] To an oven-dried, argon-purged flask, add Intermediate E1 (1.0 equiv.) and dry DCM (0.2 M). Pyridine (2.0 equiv.) and p-toluenesulfonyl chloride (1.2 equiv.) were added to the solution with stirring at 0°C. The reaction system was stirred overnight at room temperature. TLC confirmed the absence of residual starting material. The solution was diluted with water and DCM, and the aqueous phase was extracted with DCM. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, and purification by silica gel flash column chromatography yielded Intermediate E2.

[0097] In an oven-dried, argon-purged flask, a halogenated indole or halogenated azaindole (1.0 equiv.) and dry DMF (0.2 M) were added. NaH (1.5 equiv.) was added to the solution with stirring at 0°C. The reaction mixture was stirred at room temperature for 30 minutes. A solution of Intermediate E2 (1.2 equiv.) in dry DMF was added, and the reaction system was stirred at room temperature for 15 hours. TLC analysis indicated no residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to yield Intermediate E3.

[0098] Intermediates E3 and A1 were synthesized according to steps 1 and 2 of Route A to obtain intermediates E4 and E5. Intermediate E5 (1.0 equiv.) was dissolved in dry DCM (0.2 M). A solution of HCl in dioxane (4 M, 8.0 equiv.) was added to the solution with stirring at 0°C. The reaction was stirred at room temperature for 2 h. TLC confirmed the absence of residual starting material, and the solvent was removed under reduced pressure to yield intermediate E6.

[0099] To a 0.3 M solution of intermediate E6 (1.0 equiv.) in DCE was added AcOH (1.15 equiv.), NaOAc (1.15 equiv.), and NaBH(OAc)3 (2.5 equiv.) with stirring at 0°C. Aqueous formaldehyde (37%, 2.0 equiv.) or benzaldehyde (2.0 equiv.) was then added. The reaction mixture was stirred at room temperature for 8-18 hours. After LC-MS monitoring, the pH was adjusted to 6-7 by adding saturated aqueous sodium bicarbonate. The mixture was extracted with a 3:1 DCM-MeOH mixture. The combined organic phases were dried over anhydrous sodium sulfate, filtered, the solvent removed under reduced pressure, and purified by preparative HPLC to yield the desired product E7 or E8.

[0100] Example 7 Synthesis of Compounds F5 and F6

[0101] Route F:

[0102] Halogenated indole or halogenated azaindole (1.0 equiv.) and A1 (1.2 equiv.) were synthesized according to the first step of Route A to obtain intermediate F1. To a round-bottom flask that had been oven-dried 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 the argon three times, dry dioxane (0.2 M) was added. The reaction system was stirred at 100°C under argon for 12-20 hours. TLC analysis indicated no residual starting material. After cooling the reaction system to room temperature, the mixture was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, the intermediate F2 was purified by silica gel flash column chromatography.

[0103] Referring to the fourth and fifth steps of Route E, F3 was synthesized from intermediate F2, and F4 was obtained from F3. Referring to the sixth and seventh steps of Route E, the target compounds F5 and F6 were synthesized.

[0104] Example 8 Synthesis of Compounds G5, G6, G7, and G8

[0105] Route G:

[0106] To a 0.2 M solution of a halogenated indole or halogenated azaindole (1.0 equiv.) in dry DMF (0.2 M) was added NaH (1.5 equiv.). The reaction mixture was stirred at room temperature for 30 minutes, followed by the slow dropwise addition of methyl 2-bromoacetate (1.3 equiv.), and the reaction system was stirred at room temperature for 15 hours. TLC confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to yield Intermediate G1.

[0107] Intermediate G1 (1.0 equiv.) and A1 (1.2 equiv.) were synthesized according to the first step of Route A to obtain Intermediate G2. Intermediate G2 (1.0 equiv.) was dissolved in dry DCM (0.2 M). DIBAL-H (1.0 M in hexanes, 1.2 equiv.) was added dropwise at -78°C. The reaction mixture was stirred at the same temperature for 2 h. TLC analysis indicated no residual starting material. The reaction was quenched by methanol, and water and saturated sodium potassium tartrate solution were added. Stirring was continued at room temperature for 30 min. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was removed by filtration under reduced pressure, and the product was purified by flash column chromatography on silica gel to obtain Intermediate G3.

[0108] To a 0.3 M solution of intermediate G3 (1.0 equiv.) in DCE was added AcOH (1.15 equiv.) and NaBH(OAc)3 (2.5 equiv.) with stirring at 0°C. A secondary amine (2.0 equiv.) was then added, and the reaction mixture was stirred at room temperature for 8-18 hours. LC-MS analysis indicated no residual starting material. The pH was adjusted to 6-7 by adding saturated aqueous sodium bicarbonate. The mixture was extracted with a DCM-MeOH (3:1) mixed solvent. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent removed under reduced pressure. The product G4 was then purified by silica gel flash column chromatography.

[0109] Referring to the third, fourth, fifth and sixth steps of Route F, G5, G6, G7 and G8 were synthesized from intermediate G4.

[0110] Example 9 Synthesis of Compound H4

[0111] Route H:

[0112] 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.) with stirring at 0°C. The reaction mixture was stirred at room temperature for 15 min, followed by the slow dropwise addition of (2-(chloromethoxy)ethyl)trimethylsilane (120 mg, 0.72 mmol, 1.1 equiv.), and the reaction system was stirred at room temperature for 1 h. TLC analysis confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to afford 154 mg of intermediate H1 in a 65% yield.

[0113] To a 0.2 M solution of intermediate H1 (120 mg, 0.33 mmol, 1.0 equiv.) in dry DMF was added NaH (16 mg, 0.40 mmol, 1.2 equiv.) with stirring at 0°C. The reaction mixture was stirred at room temperature for 15 min, followed by the addition of 4-(bromomethyl)benzaldehyde (80 mg, 0.40 mmol, 1.2 equiv.), and the reaction system was stirred at room temperature for 2 h. TLC analysis confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to afford 106 mg of intermediate H2 in a 66% yield.

[0114] Referring to step 7 of Route E, intermediate H2 reacts with secondary amine HNRR through reductive amination to synthesize intermediate H3.

[0115] To a solution of intermediate H3 (1.0 equiv.) in dry DCM (0.1 M) at 0°C was added dropwise TFA (1 / 2 volume of DCM) with stirring. The reaction was stirred at room temperature for 1 hour. LC-MS analysis confirmed the absence of residual starting material. The solvent was removed under reduced pressure and the product was purified by preparative HPLC to yield the desired product H4.

[0116] Example 10 Synthesis of Compounds J1-5

[0117] Route J:

[0118] To a stirred solution of a secondary amine (1.0 equiv.) in dry THF (0.2 M) was added potassium bromomethyl trifluoroborate (1.0 equiv.). The reaction mixture was stirred at 80°C for 2-4 hours, followed by removal of the solvent under reduced pressure. The residue was dissolved in acetone (0.02 M), followed by addition of potassium carbonate (1.0 equiv.), and the reaction system was stirred at room temperature for 30 minutes. The resulting filtrate was filtered, the solvent removed under reduced pressure, and then dissolved in a minimal amount of hot acetone-ether (2:1) mixture. Pentane was then added dropwise, and the resulting precipitate was collected by filtration and dried under vacuum to yield the desired products J1-5.

[0119] Example 11 Synthesis of Compound K8

[0120] Route K:

[0121] To a 0.2 M solution of a halogenated indole or halogenated azaindole (1.0 equiv.) in dry THF was added NaH (1.2 equiv.) with stirring at 0°C. The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of benzenesulfonyl chloride (1.2 equiv.), and the reaction system was stirred at room temperature for 2 hours. TLC confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The reaction mixture was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to yield Intermediate K1.

[0122] To a solution of intermediate K1 (1.0 equiv.) in dry THF (0.2 M) was added dropwise LDA (1.1 equiv.), followed by a 1 M solution of TMEDA (1.1 equiv.) in dry THF, with stirring at -78°C. The reaction mixture was stirred at the same temperature for 1 hour. A 1 M solution of I2 (1.1 equiv.) in dry THF was added dropwise at the same temperature. The reaction system was allowed to warm to room temperature and stirred overnight. TLC analysis indicated no residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed sequentially with saturated sodium thiosulfate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The product was filtered, the solvent removed under reduced pressure, and then purified by flash column chromatography on silica gel to yield intermediate K2.

[0123] Intermediate K2 (1.0 equiv.) was dissolved in anhydrous ethanol (0.2 M), and a 3N aqueous NaOH solution (3 / 4 of the volume of EtOH) was added. The reaction mixture was refluxed under an argon atmosphere for 5 h. TLC confirmed the absence of residual starting material. The reaction system was cooled to room temperature, diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to obtain Intermediate K3.

[0124] To a solution of intermediate K3 (1.0 equiv.) in dry DMF (0.2 M) was added NaH (1.2 equiv.) with stirring at 0°C. The reaction mixture was stirred at room temperature for 15 minutes, followed by the addition of dimethyl sulfate (1.2 equiv.), and the reaction system was stirred at room temperature for 2 hours. TLC confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to yield intermediate K4.

[0125] To a 0.2 M solution of a halogenated N-methylindole or halogenated aza-N-methylindole (1.0 equiv.) in DMSO was added NIS (1.05 equiv.). The reaction mixture was stirred at room temperature for 30 minutes, followed by the addition of benzenesulfonyl chloride (1.2 equiv.), and the reaction system was stirred at room temperature for 2 hours. TLC confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed sequentially with saturated sodium thiosulfate solution and saturated sodium chloride solution, and dried over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, and purification by silica gel flash column chromatography yielded Intermediate K5.

[0126] To an oven-dried, three-purge argon-filled round-bottom flask, intermediates 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), and XPhos (0.20 equiv) were added. The mixture was then purge-filled with argon three times, and then charged with dry THF and pre-degassed distilled water (THF:H2O, 10:1, v:v, 0.2 M). The reaction system was heated to 80°C in an oil bath and stirred under argon for 20 h. TLC confirmed the absence of residual starting material. The reaction system was cooled to room temperature, diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to yield intermediate K6.

[0127] According to the first step of Route A, intermediate K6 and A1 are synthesized by Suzuki reaction to obtain intermediate K7; according to the second step of Route A, intermediate K7 is synthesized by catalytic hydrogenation reaction to obtain the target final product K8.

[0128] Example 12 Synthesis of Compound L3

[0129] Route L:

[0130] 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.

[0131] Example 13 Synthesis of Compound M3

[0132] Route M:

[0133] In an oven-dried flask purged with argon, 1-methyl-4-methylenepiperidine (1.1 equiv.) and dry THF (0.4 M) were added. 9-BBN (0.5 M in THF, 1.15 equiv.) was added dropwise to the solution with stirring at 0°C. The reaction system was heated under reflux for 1 h. In another oven-dried flask purged with argon, Pd(dppf)Cl₂·CH₂Cl₂ (0.1 equiv.), K₂CO₃ (2.0 equiv.), and intermediate K4 or K5 (1.0 equiv.) were added. After purging with argon, dry DMF and pre-degassed distilled water (DMF:H₂O, 16:1, v:v, 0.4 M) were added. The THF reaction solution containing the 9-BBN adduct was then introduced into the reaction system via a double-ended needle. The reaction system was heated to 70°C in an oil bath and stirred under argon for 4 h. TLC confirmed no residual starting material. The reaction system was cooled to room temperature and diluted with water. The pH was adjusted to approximately 11 with 2N NaOH aqueous solution. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The reaction mixture was filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to obtain intermediate M1.

[0134] According to the first step of Route A, intermediate M1 and A1 are synthesized by Suzuki reaction to obtain intermediate M2; according to the second step of Route A, intermediate M2 is synthesized by catalytic hydrogenation reaction to obtain the target final product M3.

[0135] Example 14 Synthesis of Compound P10

[0136] Route P:

[0137] Following Route K, Step 2, intermediate P5 was synthesized from starting materials P1, P2, P3, or P4. To a solution of intermediate P5 (1.0 equiv.) in dry THF (0.2 M) was added dropwise TBAF (1.0 M in THF, 1.1 equiv.). The reaction mixture was stirred at 70°C for 2 h. TLC confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, and purification by silica gel flash column chromatography afforded intermediate P6.

[0138] Referring to the fourth step of Route K, intermediate P7 was synthesized from intermediate P6. Following the first step of Route A, intermediate P7 and A1 were synthesized via a 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 under reflux for 2 h under an argon atmosphere. After cooling to room temperature, TLC showed that no starting material remained. AcOH was added to quench the reaction, and the aqueous phase was extracted with EtOAc after dilution with water. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. After filtration and removal of the solvent under reduced pressure, intermediate P9 was purified by flash column chromatography on silica gel.

[0139] According to the second step of Route A, the intermediate P9 is synthesized by catalytic hydrogenation to obtain the target final product P10.

[0140] Example 15 Synthesis of Compound 1-33

[0141] Following 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.

[0142] Following the synthetic route of Route A, compound 2 was synthesized starting from 5-bromo-1-methyl-1H-indole. 1H NMR (400MHz, DMSO-d6) δ10.795 (s, 1H), 7.366 (d, 1H), 7.305 (d, J = 3.0 Hz,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.

[0143] Following the synthetic route of Route A, compound 3 was synthesized starting from 5-bromo-1-ethyl-1H-indole. 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.

[0144] Following the synthetic route of Route A, compound 3 was synthesized starting from 5-bromo-3-fluoro-1-methyl-1H-indole. 1 H 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 / z 261.1.

[0145] Following the synthetic route of Route A, compound 5 was synthesized starting from 5-bromo-3-methyl-1H-indole. 1 H NMR (400MHz, DMSO-d6) δ10.753(s,1H),10.658(d,J=2.2Hz,1H),7.242(d,J=2.0H z,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.

[0146] Following the synthetic route of Route A, compound 6 was synthesized starting from 5-bromo-1,3-dimethyl-1H-indole. 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.

[0147] Following the synthetic route of Route A, compound 7 was synthesized from 5-bromo-1H-indole-3-carbonitrile as the starting material. 1H 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.

[0148] Following the synthetic route of Route A, compound 8 was synthesized from 5-bromo-1-methyl-1H-indole-3-carbonitrile. 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.

[0149] Following the synthetic route of Route A, compound 9 was synthesized starting from methyl5-bromo-1H-indole-3-carboxylate. 1 H NMR (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.

[0150] Following the synthetic route of Route A, compound 10 was synthesized starting from methyl5-bromo-1-methyl-1H-indole-3-carboxylate. 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.

[0151] Following the synthetic route of Route A, compound 11 was synthesized starting from 5-bromo-3-isopropyl-1H-indole. 1 H 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),3.52 7–3.398(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 / z 271.1.

[0152] Following the synthetic route of Route A, compound 12 was synthesized starting from 5-bromo-3-isopropyl-1-methyl-1H-indole. 1H 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), 1.991–1.917(m,1H),1.435(d,J=6.3Hz,3H),1.385(d,J=6.4Hz,3H).MS(ESI)m / z 285.2.

[0153] Following the synthetic route of Route A, compound 13 was synthesized from 5-bromo-N,N-dimethyl-1H-indole-3-carboxamide. 1 H 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.

[0154] Following the synthetic route of Route A, compound 14 was synthesized starting from 5-bromo-N,N,1-trimethyl-1H-indole-3-carboxamide. 1H 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.

[0155] Following the synthetic route of Route A, compound 15 was synthesized from 1-(5-bromo-1H-indol-3-yl)-N,N-dimethylmethanamine. 1 H 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.

[0156] Following the synthetic route of Route A, compound 16 was synthesized from 1-(5-bromo-1-methyl-1H-indol-3-yl)-N,N-dimethylmethanamine. 1H 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.

[0157] Following the synthetic route of Route A, compound 17 was synthesized from 1-(5-bromo-1-methyl-1H-indol-3-yl)-N,N-dimethylmethanamine. 1 H 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.

[0158] Following the synthetic route of Route A, compound 18 was synthesized starting from 5-bromo-1-methyl-3-(trifluoromethyl)-1H-indole. 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.

[0159] Following the synthetic route of Route A, compound 19 was synthesized starting from 5-bromo-2-methyl-1H-indole. 1 H 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),5.88 1(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.

[0160] Following the synthetic route of Route A, compound 20 was synthesized starting from 5-bromo-1,2-dimethyl-1H-indole. 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.

[0161] Following the synthetic route of Route A, compound 21 was synthesized from 5-bromo-N,N-dimethyl-1H-indole-2-carboxamide. 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.

[0162] Following the synthetic route of Route A, compound 22 was synthesized starting from 5-bromo-N,N,1-trimethyl-1H-indole-2-carboxamide. 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),7.263–7.19 2(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.

[0163] Following the synthetic route of Route A, compound 23 was synthesized starting from ethyl5-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.

[0164] Following the synthetic route of Route A, compound 24 was synthesized starting from ethyl5-bromo-1-methyl-1H-indole-2-carboxylate. 1 H NMR (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.

[0165] Following the synthetic route of Route A, compound 25 was synthesized from 5-bromo-1H-indole-2-carbonitrile. 1H NMR (400MHz, DMSO-d6) δ11.524(s,1H),10.784(s,1H),7.727(t,J=2.0 Hz,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=6.1,5.3H z,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.

[0166] Following the synthetic route of Route A, compound 26 was synthesized starting from 5-bromo-1-methyl-1H-indole-2-carbonitrile. 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.

[0167] Following the synthetic route of Route A, compound 27 was synthesized starting from 5-bromo-2-(trifluoromethyl)-1H-indole. 1 H 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.

[0168] Following 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 = 2.0 Hz,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.

[0169] Following the synthetic route of Route A, compound 29 was synthesized starting from intermediate C7 in Route C. 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.

[0170] Following the synthetic route of Route A, compound 30 was synthesized starting from intermediate C8 in Route C. 1H 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.

[0171] Following the synthetic route of Route A, compound 31 was synthesized starting from intermediate C9 in Route C. 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.

[0172] Following the synthetic route of Route A, compound 32 was synthesized starting from intermediate C10 in Route C. 1 H 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 / z 369.1.

[0173] To a solution of 5-bromo-1H-indole (100 mg, 0.51 mmol, 1.0 equiv.) in dry DMF (2 mL) 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 under argon for an additional 8 h. TLC analysis revealed no residual starting material. The reaction mixture was diluted with water and EtOAc, 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. The product was filtered, the solvent removed under reduced pressure, and then purified by flash column chromatography on silica gel to afford 117 mg of the desired intermediate, 5-bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-indole, in a 77% yield. 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.

[0174] Following the synthetic route of Route A, compound 33 was synthesized starting from the intermediate 5-bromo-1-(2-(2-methoxyethoxy)ethyl)-1H-indole. 1 H NMR(400MHz,DMSO-d6)δ10.784(s,1H),7.565(q,J =1.7,1.2Hz,1H),7.505(d,J=8.3Hz,1H),7.248(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.

[0175] Example 16 Synthesis of Compounds 82-97

[0176] Following the synthetic route of Route A, compound 82 was synthesized starting from 6-bromo-1H-indole. 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.

[0177] Following the synthetic route of Route A, compound 83 was synthesized starting from 6-bromo-1-methyl-1H-indole. 1 H 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, 2.3Hz,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 / z 243.1.

[0178] Following the synthetic route of Route A, compound 84 was synthesized starting from 6-bromo-1-ethyl-1H-indole. 1H NMR (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.

[0179] Following the synthetic route of Route A, compound 85 was synthesized starting from 6-bromo-1,3-dimethyl-1H-indole. 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 / z 257.1.

[0180] Following the synthetic route of Route A, compound 86 was synthesized starting from intermediate C8 in Route C. 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.

[0181] Following the synthetic route of Route A, compound 87 was synthesized starting from intermediate C8 in Route C. 1H 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,1H),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.

[0182] Following the synthetic route of Route A, compound 88 was synthesized starting from the intermediate C8 in Route C. 1 H NMR(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=2 0.9,8.3,5.6Hz,2H),1.44(d,J=6.3Hz,3H),1.39(d,J=6.3Hz,3H).MS(ESI)m / z 285.2.

[0183] Following the synthetic route of Route A, compound 89 was synthesized starting from intermediate C8 in Route C. 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.

[0184] Following the synthetic route of Route A, compound 90 was synthesized starting from intermediate C8 in Route C. 1H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.90–7.85(m,1H),7.70(d,J=2.2Hz,1H),7.55(s,1H ),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.

[0185] Following the synthetic route of Route A, compound 91 was synthesized starting from intermediate C8 in Route C. 1 H 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.

[0186] Following the synthetic route of Route A, compound 92 was synthesized starting from intermediate C8 in Route C. 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.

[0187] Following the synthetic route of Route A, compound 93 was synthesized starting from intermediate C8 in Route C. 1H 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.

[0188] Following the synthetic route of Route A, compound 94 was synthesized starting from intermediate C8 in Route C. 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.

[0189] Following the synthetic route of Route A, compound 95 was synthesized starting from intermediate C8 in Route C. 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.

[0190] Following the synthetic route of Route A, compound 96 was synthesized starting from intermediate C11 in Route C. 1H NMR (400MHz, DMSO-d6) δ10.81 (s, 1H), 7.59–7.52 (m, 1H), 7.36 (d, J = 2.5Hz, 1H), 7.15–7.08 (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.

[0191] Following the synthetic route of Route A, compound 97 was synthesized starting from intermediate C12 in Route C. 1 H 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 / z 369.1.

[0192] Example 17 Synthesis of Compounds 116 and 117

[0193] Following 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.

[0194] Following the synthetic route of Route A, compound 117 was synthesized starting from 4-bromo-1-methyl-1H-indole. 1H NMR (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.

[0195] Example 18 Synthesis of Compounds 122, 123, and 124

[0196] Following 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.

[0197] Following the synthetic route of Route A, compound 123 was synthesized starting from methyl 2-bromo-1-methyl-1H-indole-5-carboxylate in Route D. 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.

[0198] Following the synthetic route of Route A, compound 124 was synthesized using methyl 2-bromo-1-methyl-1H-indole-6-carboxylate synthesized by the synthetic method of Route D as the starting material. 1 H 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.

[0199] Example 19 Synthesis of Compounds 131-140

[0200] Following the synthetic route of Route A, compound 131 was synthesized starting from 2-iodo-1-methyl-1H-pyrrolo[3,2-b]pyridine. 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.

[0201] Following the synthetic route of Route A, compound 132 was synthesized starting from 5-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridine. 1H 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.

[0202] Following 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.

[0203] Following 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),4.0 0–3.93(m,1H),3.77(s,3H),2.58–2.43(m,2H),2.11–1.92(m,2H).MS(ESI)m / z 244.1.

[0204] Following the synthetic route of Route A, compound 135 was synthesized starting from 2-iodo-1-methyl-1H-pyrrolo[3,2-c]pyridine. 1H 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 / z 244.1.

[0205] Following 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.

[0206] Following 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.

[0207] Following the synthetic route of Route A, compound 138 was synthesized starting from 2-iodo-1-methyl-1H-pyrrolo[2,3-c]pyridine. 1H 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.

[0208] Following the synthetic route of Route A, compound 139 was synthesized starting from 5-chloro-1-methyl-1H-pyrrolo[2,3-c]pyridine. 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.

[0209] Following 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), 5.83(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 / z 244.1.

[0210] Example 20 Synthesis of Compounds 142, 144, 147, 149, and 150

[0211] Following the synthetic route of Route A, compound 142 was synthesized starting from 2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine.1 H 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.

[0212] Following 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.

[0213] Following the synthetic route of Route A, compound 146 was synthesized starting from 3-chloro-5-methyl-5H-pyrrolo[3,2-c]pyridazine. 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.

[0214] Following 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.

[0215] Following the synthetic route of Route A, compound 149 was synthesized starting from 4-bromo-7-methyl-7H-pyrrolo[2,3-c]pyridazine. 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.

[0216] Following 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.

[0217] Example 21 Synthesis of Compounds 151-153, 34-37, 119-120, 160, 162, 165, 168, 170, and 172

[0218] Following the synthetic route of Route A, compound 151 was synthesized starting from 6-iodo-5-methyl-5H-pyrrolo[2,3-b]pyrazine. 1H NMR (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=0.6H z,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.

[0219] Following 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.

[0220] Following 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.

[0221] Following the synthetic route of Route E, compound 34 was synthesized. 1H 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.

[0222] 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.

[0223] Following the synthetic route of Route E, compound 36 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),7.2 73–7.190(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,2 H),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),2.2 17(s,3H),1.991(ddt,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.

[0224] 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.

[0225] 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.

[0226] 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 / z 354.2.

[0227] Following the synthetic route of Route E, compound 160 was synthesized. 1 H 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.

[0228] 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.

[0229] Following the synthetic route of Route E, compound 165 was synthesized. 1 H 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.

[0230] Following the synthetic route of Route E, compound 168 was synthesized. 1H 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.

[0231] Following the synthetic route of Route E, compound 170 was synthesized. 1 H 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.

[0232] Following the synthetic route of Route E, compound 172 was synthesized. 1H 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.

[0233] Example 22 Synthesis of Compounds 38, 39, 102, 103, and 118

[0234] Following the synthetic route of Route F, compound 38 was synthesized. 1 H 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.

[0235] Following the synthetic route of Route F, compound 39 was synthesized. 1H NMR(400MHz,DMSO-d6)δ 10.784(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.

[0236] Following the synthetic route of Route F, compound 102 was synthesized. 1 H 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.

[0237] Following the synthetic route of Route F, compound 103 was synthesized. 1H 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.

[0238] Following the synthetic route of Route F, compound 118 was synthesized. 1 H 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.

[0239] Example 23 Synthesis of Compounds 40-47, 98-101

[0240] Following the synthetic route of Route G, compound 40 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),7.237(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.

[0241] Following the synthetic route of Route G, compound 41 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 .335–7.250(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.

[0242] Following the synthetic route of Route G, compound 42 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),7.237(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.

[0243] Following the synthetic route of Route G, compound 43 was synthesized. 1 H 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– 3.858(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 / z 471.3.

[0244] Following the synthetic route of Route G, compound 44 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),7.237(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.

[0245] Following the synthetic route of Route G, compound 45 was synthesized. 1 H NMR (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.

[0246] Following the synthetic route of Route G, compound 46 was synthesized. 1H NMR (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. 7Hz,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 / z 410.3.

[0247] Following the synthetic route of Route G, compound 47 was synthesized. 1 H NMR (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=5.0,2.2H z,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.

[0248] Following the synthetic route of Route G, compound 98 was synthesized. 1H 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),6.44(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.

[0249] Following the synthetic route of Route G, compound 99 was synthesized. 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.74–7.68(m,1H),7.53–7.46(m,1H),7.34–7.22(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.

[0250] 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.

[0251] Following the synthetic route of Route G, compound 101 was synthesized. 1 H NMR(400MHz,DMSO-d6)δ 10.81(s,1H),7.71(d,J=2.2Hz,1H),7.53–7.46(m,1H),7.36–7.27(m,3H),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,1H ),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 / z 471.3.

[0252] Example 24 Synthesis of Compounds 48-51

[0253] Following the synthetic route of Route H, compound 48 was synthesized. 1 H NMR(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,3H ),6.54(dd,J=5.0,2.2Hz,1H),5.42(dt,J=2.1,1.0Hz,2H),4.02–3.88(m,6H),3.87 –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.

[0254] To an oven-dried, argon-purged flask, intermediate H1 (80 mg, 0.22 mmol, 1.0 equiv.) was added 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.). After purging the argon atmosphere, dry dioxane (2 mL) was added, and the reaction system was stirred at 100°C under argon for 15 h. TLC analysis confirmed the absence of residual starting material. After cooling the reaction system to room temperature, it was diluted with water and EtOAc. The aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The product was filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to yield 54 mg of intermediate I1 in a 52% yield. 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.

[0255] Following the synthetic route of Route H, compound 50 was synthesized. 1H NMR(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+ ).

[0256] Following the synthetic route of Route H, compound 51 was synthesized. 1 H NMR (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,6H),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.

[0257] Example 25 Synthesis of Compounds 52-57, 69-72, 104, 106, 110, 112, 121, 155-157, 161, 163, 166, 169, 171, 173, 174

[0258] Following the synthetic route of Route K, compound 52 was synthesized. 1 H NMR (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(dd ,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.

[0259] Following the synthetic route of Route K, compound 54 was synthesized. 1 H NMR (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.

[0260] Following the synthetic route of Route K, compound 55 was synthesized. 1H NMR (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(d d,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=5.4,2.5H z,2H),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(d dt,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 / z 395.2.

[0261] Following the synthetic route of Route K, compound 56 was synthesized. 1 H NMR (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=7.9,2.1 Hz,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.

[0262] Following the synthetic route of Route K, compound 57 was synthesized. 1H NMR (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.

[0263] Following the synthetic route of Route K, compound 69 was synthesized. 1 H NMR(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.

[0264] Following the synthetic route of Route K, compound 70 was synthesized. 1H NMR (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.

[0265] Following the synthetic route of Route K, compound 71 was synthesized. 1 H NMR(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(d d,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.

[0266] Following the synthetic route of Route K, compound 72 was synthesized. 1H NMR (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.

[0267] 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.

[0268] Following the synthetic route of Route K, compound 106 was synthesized. 1 H 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.

[0269] 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.

[0270] 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.

[0271] 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 / z 355.2.

[0272] Following the synthetic route of Route K, compound 155 was synthesized. 1H 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.

[0273] 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.

[0274] 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.

[0275] Following the synthetic route of Route K, compound 161 was synthesized. 1H 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 / z 356.2.

[0276] 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.

[0277] Following the synthetic route of Route K, compound 166 was synthesized. 1 H 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.

[0278] 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.

[0279] 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.

[0280] Following the synthetic route of Route K, compound 173 was synthesized. 1 H 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.

[0281] 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.

[0282] Example 26 Synthesis of Compounds 125-128, 154, 158, 159, 164, 167, 175, and 176

[0283] Following the synthetic route of Route L, compound 125 was synthesized. 1H 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.

[0284] Following the synthetic route of Route L, compound 126 was synthesized. 1 H 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.

[0285] 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=7.8,1.4 Hz,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,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.

[0286] Following the synthetic route of Route L, compound 128 was synthesized. 1H 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.

[0287] 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.

[0288] 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=5.3,0.7Hz,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.

[0289] Following the synthetic route of Route L, compound 159 was synthesized. 1H 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.

[0290] 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.

[0291] 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.

[0292] Following the synthetic route of Route L, compound 175 was synthesized. 1H 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.

[0293] Following the synthetic route of Route L, compound 176 was synthesized. 1 H 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 / z 357.2.

[0294] Example 27 Synthesis of Compounds 53, 67, 129, and 130

[0295] 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.

[0296] Following the synthetic route of Route M, compound 67 was synthesized.1 H 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– 2.54(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=2 3.5,8.3,5.7Hz,2H),1.83(dt,J=11.6,5.9Hz,1H),1.70(ddt,J=27.2,8.5,5.7Hz,4H).MS(ESI)m / z 354.2.

[0297] To an argon-filled reaction tube, N1 (102 mg or 108 mg, 0.47 mmol, 1.0 equiv.), chiral prolinamide cat-1 (31 mg, 0.09 mmol, 0.3 equiv.), and 4-iodo-1-methyl-1H-indole (170 mg, 0.71 mmol, 1.5 equiv.) were added. The atmosphere was replaced with argon, and deoxygenated ultrapure water (2.5 mL) was added. CuI (9 mg, 0.05 mmol, 0.1 equiv.) and KCO (130 mg, 0.94 mmol, 2.0 equiv.) were also added. The atmosphere was replaced with argon, and the reaction system was stirred at 100°C for 24 h. TLC analysis indicated no residual starting material. The reaction system was cooled to room temperature, and the aqueous phase was extracted with EtOAc (3 × 5 mL). The combined organic phases were 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%.

[0298] To a sealed reactor, add the intermediate N2 (1.0 equiv.), anhydrous methanol (0.2 M), and hydrazine hydrate (20.0 equiv.). After replacing the argon atmosphere three times, the sealed reactor was sealed and heated in an oil bath at 100°C with stirring for 3 h. After cooling the reactor to room temperature, the stopcock was opened, and TLC monitoring confirmed the absence of residual starting material. After dilution with water, the aqueous phase was extracted with DCM-MeOH (4:1), and the combined organic phases were dried over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, and purification by preparative HPLC yielded the desired product, compound 129 or 130.

[0299] Compound 129: 1 H NMR (400MHz, DMSO-d6) δ11.35(s,1H),8.35(d,J=7.5Hz,1H),7.61(dd,J=6.8,1.3Hz,1H),7.48–7.37(m,2 H),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.

[0300] Compound 130: 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),8.43(q,J=1.5Hz,1H),7.65(dd,J=7.1,1.5Hz,1H),7.48–7.37(m,2 H),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.

[0301] Example 28 Synthesis of Compounds 141, 143, 145, and 148

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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.

[0306] Example 29 Synthesis of Compounds JQ1acid and JQ1-L1

[0307] To a solution of JQ1 (1.00 g, 2.19 mmol, 1.0 equiv.) in dry DCM (1,2-dichloroethane) (20 mL) was slowly added TFA (trifluoroacetic acid) (8 mL) at 0°C, and the reaction system was stirred at room temperature for 6 h. TLC showed that no starting material remained. The reaction solution was concentrated under reduced pressure to obtain a residue, which was dissolved in EtOAc, washed with saturated brine, 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 805 mg of compound JQ1acid with a yield of 92%. MS (ESI) m / z 399.1 ([M+H] + ).

[0308] 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.), and DIPEA (diisopropylethylamine) (78 μL, 0.45 mmol, 3.0 equiv.) were dissolved in anhydrous DMF (2 mL). The reaction system was stirred at room temperature overnight under argon. TLC confirmed the absence of residual starting material. The reaction was quenched with water, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with saturated brine and dried over anhydrous sodium sulfate. The product was filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to obtain 72 mg of compound JQ1-L1-Boc in an 84% yield. MS (ESI) m / z 472.0 ([M+H-Boc] + ).

[0309] JQ1-L1-Boc (150 mg, 0.26 mmol, 1.0 equiv.) was dissolved in dry DCM (dichloromethane) (3 mL). TFA (trifluoroacetic acid) (1 mL) was slowly added to the solution at 0°C. The reaction system was allowed to warm to room temperature under an argon atmosphere and stirred for 4 h. TLC confirmed the absence of residual starting material. The solvent was removed under reduced pressure and the product was dissolved in methanol. The pH was adjusted to 8 with saturated sodium bicarbonate solution, followed by extraction with a DCM-MeOH (5:1, v / v) solvent mixture. The combined organic phases were dried over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, and subsequent drying at 45°C and 0.6 mbar for 30 min afforded the crude product, JQ1-L1, which was used directly in the next step.

[0310] Example 30 Synthesis of Intermediates Q4, Q5, Q6, and Q7

[0311] Route Q:

[0312] To a solution of raw material Q1 (1.0 equiv.) in dry DMF (0.2 M) was added NaH (1.1 equiv.) with stirring at 0°C. The reaction mixture was stirred at room temperature for 15 minutes, followed by the slow dropwise addition of benzyl 2-bromoacetate (1.1 equiv.), and the reaction system was stirred at room temperature for 1 hour. TLC confirmed the absence of residual starting material. The reaction system was diluted with water and EtOAc, and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The residue was filtered, the solvent removed under reduced pressure, and then purified by silica gel flash column chromatography to yield intermediate Q2.

[0313] Referring to the first step of Route A, intermediate Q2 is reacted with A1 through Suzuki reaction to obtain intermediate Q3; referring to the second step of Route A, intermediate Q3 is subjected to catalytic hydrogenation reaction to obtain intermediate Q4 or Q5 or Q6 or Q7.

[0314] 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.

[0315] Q5: 1 H NMR (400MHz, DMSO-d6) δ12.73(brs,1H),10.81(s,1H),7.87(d,J=2.1Hz,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 / z 355.1.

[0316] Q6: 1H NMR (400MHz, DMSO-d6) δ12.74(brs,1H),10.81(s,1H),7.77(d,J=2.4Hz,1H),7.53–7.46(m,1H),7.31–7.25(m,1H),7.19(d d,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.

[0317] Q7: 1 H NMR (400MHz, DMSO-d6) δ12.74(brs,1H),10.78(s,1H),7.50(dd,J=5.2,2.5Hz,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.

[0318] Example 31 Synthesis of Intermediates R1, R2, and R3

[0319] Route R:

[0320] Intermediate G4 (90 mg, 0.14 mmol, 1.0 equiv.) was dissolved in dry DCM (dichloromethane) (3 mL). A solution of dioxane hydrochloride (1 mL) was slowly added to the solution at 0°C. The reaction system was allowed to warm to room temperature under an argon atmosphere and stirred for 2 h. TLC confirmed the absence of residual starting material. The solvent was removed under reduced pressure and the product was dissolved in methanol. The pH was adjusted to 8 with saturated sodium bicarbonate solution, followed by extraction with a DCM-MeOH (5:1, v / v) mixture. The combined organic phases were dried over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, and subsequent drying at 45°C and 0.6 mbar for 30 min afforded 75 mg of crude product R1, which was used directly in the next step.

[0321] The crude intermediate R1 (75 mg, ~0.14 mmol, 1.0 equiv.) was dissolved in acetone (4 mL). 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. The atmosphere was replaced with argon three times, and the reaction mixture was heated under reflux for 4 h. LC-MS analysis revealed no residual starting material. The reaction mixture was cooled to room temperature, filtered, concentrated under reduced pressure, and diluted with water. The mixture was extracted with a DCM-MeOH (5:1, v / v) mixture, and the combined organic phases were dried over anhydrous sodium sulfate. The mixture was filtered, the solvent was removed under reduced pressure, and then purified by silica gel flash column chromatography to afford 78 mg of intermediate R2 in an 83% yield. MS (ESI) m / z 646.3 ([M+Ht-Bu] + ).

[0322] 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] + ).

[0323] Referring to the fifth step of Route E, intermediate R3 (43 mg) was deprotected from the Boc protecting group to obtain 32 mg of the crude hydrochloride salt 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 lyophilization, dichloromethane was added and the product was ultrasonically shaken for 30 seconds. After filtration, the solvent was removed under reduced pressure to obtain the crude product R4, which was used directly 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.

[0324] Example 32 Synthesis of Compounds S6 and S7

[0325] Route S:

[0326] Intermediate J6 was synthesized by Route J. Intermediate J6 (1.1 equiv.) was reacted with 2- / 3-iodo-5-bromo-N-methylindole (1.0 equiv.) via Suzuki reaction according to Route K, step 6, to produce intermediate S1. Intermediate S1 was reacted with A1 via Suzuki reaction according to Route A, step 1, to produce intermediate S2. Intermediate S2 was subjected to Boc removal according to Route R, step 1, to produce intermediate S3. Intermediate S3 (1.0 equiv.) was reacted with tert-butyl(3-bromopropyl)carbamate (1.1 equiv.) according to Route R, step 2, to produce intermediate S4. Intermediate S4 was then subjected to catalytic hydrogenation according to Route A, step 2, to produce intermediate S5. Referring to step 5 of Route E, the Boc protecting group of intermediate S5 was removed to obtain a crude hydrochloride product of intermediate S6 or a crude hydrochloride product of S7. 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 lyophilization, dichloromethane was added, and the product was ultrasonically shaken for 30 seconds, filtered, and the solvent was removed by vacuum rotation to obtain the crude product of S6 or S7, which was used directly in the next step without purification.

[0327] S6: 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),7.53(t,J=1.8Hz,1H),7.29(d,J=7.9Hz,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.

[0328] 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 ),2.09–1.95(m,2H),1.90(t,J=6.5Hz,2H),1.66(tt,J=5.7,4.5Hz,2H).MS(ESI)m / z 410.3.

[0329] Example 33 Synthesis of Compounds T6 and T7

[0330] Route T:

[0331] Referring to the first step of Route A, intermediate K4 reacts with A1 via Suzuki reaction to obtain intermediate T1. Referring to the synthesis of Route J to obtain J7, intermediate T1 and intermediate J7 are synthesized via 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 subjected to 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 used directly in the next step without purification.

[0332] T6: 1H 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 =8.1,2.2Hz,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,2H),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.

[0333] T7: 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,1 H),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.

[0334] Example 34 Synthesis of protein degradation agent dBI-51-1

[0335] 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.), and DIPEA (diisopropylethylamine) (39 μL, 0.24 mmol, 3.0 equiv.) were dissolved in anhydrous DMF (1 mL). The reaction system was stirred at room temperature overnight under argon. TLC confirmed the absence of residual starting material. The reaction was quenched with water, and the aqueous phase was extracted with a DCM-MeOH (4:1, v / v) mixture. The combined organic phases were dried over anhydrous sodium sulfate. Filtration, removal of the solvent under reduced pressure, and purification by preparative HPLC afforded 39 mg of the desired final product, dBI-51-1, in a 65% yield.

[0336] 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.

[0337] Example 35 Synthesis of Protein Degrader dBI-51-2

[0338] Referring to the synthesis method of the final product dBI-51-1, 40 mg of the target final product dBI-51-2 was obtained by condensation of intermediate JQ1-L1 (30 mg, 0.07 mmol, 1.0 equiv.) and intermediate Q5 (25 mg, 0.07 mmol, 1.05 equiv.) with a yield of 70%.

[0339] 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.

[0340] Example 36 Synthesis of Protein Degrader dBI-61-1

[0341] 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%.

[0342] 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.

[0343] Example 37 Synthesis of Protein Degrader dBI-41-1

[0344] 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%.

[0345] 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.

[0346] Example 38 Synthesis of Protein Degrader dBI-51-3

[0347] Referring to the synthesis method of the final product dBI-51-1, the intermediate JQ1acid (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%.

[0348] 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 / z 806.3.

[0349] Example 39 Synthesis of Protein Degrader dBI-52-1

[0350] Referring to the synthesis method of the final product dBI-51-1, 33 mg of the target final product dBI-52-1 was obtained by condensation of intermediate JQ1acid (21 mg, 0.05 mmol, 1.0 equiv.) and intermediate S6 (23 mg, 0.06 mmol, 1.05 equiv.) with a yield of 78%.

[0351] 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 (dd,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 / z 792.3.

[0352] Example 40 Synthesis of Protein Degrader dBI-53-1

[0353] Referring to the synthesis method of the final product dBI-51-1, 30 mg of the target final product dBI-53-1 was obtained by condensation of intermediate JQ1acid (21 mg, 0.05 mmol, 1.0 equiv.) and intermediate S7 (23 mg, 0.06 mmol, 1.05 equiv.) with a yield of 71%.

[0354] 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.

[0355] Example 41 Synthesis of Protein Degrader dBI-25-1

[0356] Referring to the synthesis method of the final product dBI-51-1, 35 mg of the target final product dBI-25-1 was obtained by condensation of intermediate JQ1acid (25 mg, 0.06 mmol, 1.0 equiv.) and intermediate T6 (26 mg, 0.06 mmol, 1.05 equiv.) with a yield of 72%.

[0357] 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.

[0358] Example 42 Synthesis of Protein Degrader dBI-25-1

[0359] Referring to the synthesis method of the final product dBI-51-1, 30 mg of the target final product dBI-25-1 was obtained by condensation of intermediate JQ1acid (25 mg, 0.06 mmol, 1.0 equiv.) and intermediate T7 (26 mg, 0.06 mmol, 1.05 equiv.) with a yield of 62%.

[0360] 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,3 H),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 / z 780.3.

[0361] Example 43 Verification of the Binding Activity of Compound 1-176 to E3 Ubiquitin Ligase CRBN

[0362] The binding activity of the compounds disclosed in the present application to the E3 ubiquitin ligase CRBN is determined by the competitive binding of the compounds disclosed in the present application to the CRBN protein with thalidomide labeled with XL665, thereby preventing the occurrence of fluorescence resonance energy transfer (FRET), thereby determining the binding force of the compounds to the CRBN protein.

[0363] CRBN binding activity test kit (CEREBLON BINDING KITS (PE, 64BD CRBN PEG).

[0364] The detection is based on homogeneous time-resolved fluorescence (HTRF) technology. When the donor (Donor) and acceptor (Acceptor) are close to each other, the donor can transfer energy to the acceptor, causing it to be excited and emit light at 665nm.

[0365] This kit uses a europium-labeled GST (GST Eu Cryptate Antibody) as the donor and XL665-labeled thalidomide (Thalidomide-Red) as the receptor. The donor binds to the GST-tagged CRBN protein, and the compounds disclosed herein compete with thalidomide for binding to the CRBN protein. The binding activity of the compound is determined by the fluorescence emitted by the receptor at 665 nm. Stronger binding compounds produce weaker signals.

[0366] Dilute the donor and receptor 50-fold using the PROTAC binding buffer 1 provided in the kit. Dilute the CRBN protein 45-fold. Dilute the 8 mM solution of the compound disclosed in this patent 10-fold using the 1X diluent provided in the kit. Then, perform a 5-fold gradient dilution of the diluent seven times.

[0367] 5 μl of compound, 5 μl of diluted CRBN protein, and 10 μl of equal volumes of donor-receptor mixture were sequentially added to the wells of a white 384-well plate (PE, Part number: 6008280) and incubated at room temperature for 3 hours.

[0368] The ratio of the acceptor and donor emission signals was calculated for each individual well.

[0369] Ratio=665nm signal value / 620nm signal value*10 4

[0370] Calculate the coefficient of variation (CV) = standard deviation (SD) / ratio mean * 100

[0371] IC was calculated based on compound concentration, Ratio, and coefficient of variation using GraphPad Prism. 50 value.

[0372] Table 3 summarizes the evaluation of the inhibitory effect 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 >20 μM).

[0373] Table 3 Binding activity of Compounds 1-176 towards E3 ubiquitin ligase CRBN

[0374] Example 43 Evaluation of the Effect of Protein Degrader Compounds on Reducing Bromodomain Protein (BRD) Expression

[0375] 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%, the cells were seeded into 6-well plates using medium containing the compound at a cell density of 1x10 6 / ml, with final compound concentrations of 0.1, 1, 10, and 20 μM. After 24 hours of treatment, cells were harvested and washed twice with PBS. RIPA lysis buffer containing protease and phosphatase inhibitors was added to the cells. Total protein extracts were obtained after lysis and centrifugation, and the protein concentration in the extracts was determined by the BCA assay.

[0376] Protein electrophoresis was performed using SDS-PAGE, and then the protein was transferred to a PVDF membrane by constant current electrophoresis at 200mA for 150min. The PVDF membrane was placed in 5% skim milk and blocked at room temperature for 1h. BRD4 (#13440, CST) (1:1000) and C-MYC (ab32072, 1:1000) were added and incubated at 4°C overnight. The membrane was washed with TBST 3 times for 10min each time. The secondary antibody (1:5000, absin) was incubated at room temperature for 60min. The membrane was washed with TBST 3 times for 10min each time. ECL luminescent solution 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 is: 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.

[0377] 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 >10 μM). Where D max It 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(Dmax 85~50%)、C(DC 50 <50%)

[0378] Table 4 Evaluation of the effect of protein degraders on reducing BRD protein expression

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 substructure B 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 substructure B 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 substructure B 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 substructure B 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 substructure B 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 substructure B 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 substructure B 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 substructure B 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 substructure B 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 One or more selected from H, alkyl, SO2-alkyl or SO2-aryl; The Linker substructure L 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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