Benzo five-membered aromatic heterocyclic compound and pharmaceutical use thereof

Abstract

Disclosed in the present invention are a benzo five-membered aromatic heterocyclic compound and a pharmaceutical use thereof. The present invention provides a benzo five-membered aromatic heterocyclic compound as shown in formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated product or solvate thereof. The compound or the pharmaceutically acceptable salt, ester, stereoisomer, deuterated product or solvate thereof in the present invention can inhibit the activity of a USP7 enzyme, and can be used for preparing a drug for treating USP7-mediated diseases.

Description

Benzopentatomic aromatic heterocyclic compounds and medical uses thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, and particularly relates to benzopentatomic aromatic heterocyclic compounds and medical uses thereof. BACKGROUND

[0002] Ubiquitination is an important post-translational modification of proteins, and deubiquitination is its reverse process. Ubiquitination / deubiquitination is an important pathway for the body to dynamically regulate the stability, function, nuclear and extranuclear shuttle, and signal transduction of proteins. Deubiquitinating enzymes are key enzymes that catalyze protein deubiquitination, among which USP7 (ubiquitin-specific protease 7) is the most widely studied. USP7 is involved in many important biological events in the human body through deubiquitination, and is closely related to tumor development, nervous system disorders, inflammation, and viral infection. USP7 can stabilize MDM2 protein through deubiquitination, thereby reducing the level of p53 (Cell 1998, 95, 5). Inhibition of USP7 in tumor cells can promote MDM2 protein degradation and increase p53 levels, thereby inhibiting tumor cell proliferation (Mol Cell 2004, 6, 879; Nature 2004, 428, 6982). USP7 can also stabilize Foxp3 protein in Treg cells, promoting the differentiation and immunosuppressive function of Treg cells. Inhibition of USP7 in Treg cells can reduce the level of Foxp3 protein, down-regulate the level and activity of Treg cells, and thus improve the immunosuppressive microenvironment of tumors (Immunity 2013, 39(2), 259; EBioMedicine 2016, 13, 99). USP7 also interacts with NF-κB, stabilizing and promoting the transcription process mediated by NF-κB. Inhibition of USP7 can increase the ubiquitination and degradation of NF-κB, block the release of related pro-inflammatory factors downstream of Toll-like receptors, and promote the development of inflammatory diseases (Cell Death and Disease 2014, 5, e1229). USP7 can also assist in the replication of viruses such as herpes virus, Ebola virus, Kaposi's sarcoma herpes virus, human cytomegalovirus, adenovirus, and HIV. USP7 has a strong affinity for the nuclear antigen 1 protein of Epstein-Barr virus and plays an auxiliary role in the carcinogenicity of Epstein-Barr virus (Biochemical Society Transactions 2004, 32(5):731-732). In Kaposi's sarcoma herpes virus (KSHV), nuclear antigen 1 (LANA) is involved in latent viral replication and maintenance of the viral genome. Studies have shown that USP7 interacts with LANA, thereby enhancing latent viral DNA replication of KSHV (JoV 2012, 86(12):6745-57). USP7 can also control the generation of HIV-1 by stabilizing Tat protein (Biochem J. 2017, 474(10):1653-1668). USP7 inhibitors can synergize with proteasome inhibitors to reduce the replication capacity of HIV virus and resist retroviral activity (Frontiers in Microbiology 2022, 13, 13:839624.).Therefore, USP7 is considered a potential therapeutic target for the above-mentioned diseases. However, there are only a few reported structural types of potent USP7 inhibitors, and no USP7 inhibitors have yet entered clinical trials. The development of highly active USP7 inhibitors with novel structural types has potential clinical translational value. Summary of the Invention

[0003] Purpose of the invention: To address the problems existing in the prior art, the present invention provides a class of benzo-pentacyclic aromatic heterocyclic compounds. These compounds or pharmaceutically acceptable salts, esters, stereoisomers, deuterated compounds or solvates thereof can be used as USP7 inhibitors. They have strong inhibitory activity against the USP7 enzyme and can be used to prepare drugs for preventing and treating USP7-mediated diseases.

[0004] Technical solution: In order to achieve the above-mentioned purpose, the present invention provides a benzene unsaturated five-membered heterocyclic compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof:

[0005] Wherein: L is selected from -(CR 5 R 6 ) n1 -、-O-、-S-、-NR 7 -、-(CO)-,-(CO)NR 7 -、-(CO)O-、-S(O) n2 -or-S(O) n2 NR 7 -;

[0006] R 1 is a 5-12 membered heteroaryl, a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, or the 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl is optionally replaced by R 8 or the 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl may be optionally fused with a 5-10 membered aromatic group or a 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, and the 5-10 membered aromatic group or a 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl fused with a 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl may be optionally replaced by R 9 replace;

[0007] R 8 and R 9 Each independently selected from (=O), halogen, NO2, -CN, OR 10 NR 10 R 11 、-(CO)NR 10R 11 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl, or said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl can optionally be substituted with (=0), halogen, -CN, -OR 12 , -NR 12 R 13 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl;

[0008] R 3 and R 4 are each independently selected from H, halogen, -CN, -N3, -CO NR 14 R 15 , -(CO)OR 14 , OR 14 , NR 14 R 15 , -NO2, SR 14 -, -S(O) n3 R 14 , -S(O) n3 NR 14 R 15 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-12 membered heteroaryl, or said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-12 membered heteroaryl can optionally be substituted with halogen, -CN, -(CO)OR 16 , -(CO)NR 16 R 17 -, -NO2, OR 16 , -NR 16 R 17 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl substituted;

[0009] R 5 and R 6 are each independently selected from H, halogen, OH, or C 1-6 alkyl; R 2 is selected from C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, or said C 1-6 alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl are optionally substituted with (=0), halogen, -CN, -N02, -OR 18 , -(CO)NR 18 R 19 , -(CO)OR 18 , -NR 18 R 19 , -SR 18 -, -S(O) n4 R 18 , -S(O) n4 NR 18 R 19 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl substituted;

[0010] R 7 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 are each independently selected from H, C 1-6 alkyl or C 3-8 cycloalkyl; n1 is 0, 1, 2, 3 or 4;

[0011] n2, n3, n4 are optionally 1 or 2;

[0012] X 1 , X 2 and X 3 wherein any one is selected from O, S, N or NH, and the other two are independently selected from O, S, N, NH or CH;

[0013] The above-mentioned heterocycloalkyl or heteroaryl means that 1 to 4 heteroatoms selected independently from oxygen, nitrogen or sulfur are present in the ring atoms thereof.

[0014] In some embodiments, preferably selected from any one of the following structural fragments:

[0015] Further, L is preferably selected from O, NH, -(CO)- or C 1-6 alkyl.

[0016] R 1 preferably selected from any one of the following structural fragments:

[0017] Further, the R 2 preferably selected from any one of the following structural fragments:

[0018] Further, R 3 preferably selected from H, R 4 preferably selected from H, halogen, -CN, -C≡CH, -CF3.

[0019] The benzopentaheteroaromatic compound of Formula I of the present application is any one of the following compounds in Table 1 or a pharmaceutically acceptable salt, ester, stereoisomer, deuteride or solvate thereof:

[0020] Table 1, some compounds of the present application

[0021] The compounds of the present application can also be used as pharmaceutical salts. The salts can be acid salts of at least one of the following acids: galactaric acid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalene- disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic acid, n-dodecanesulfonic acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrobromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharin acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, 4-benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid.

[0022] Further, the salts are salts of the compounds of the present application with metal (including sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, etc.) or ammonium ions.

[0023] The compounds of the present application can also be used as solvates.

[0024] The present application includes various deuterated forms of the compounds of the present application, i.e., each hydrogen atom bound to a carbon atom can be independently replaced with a deuterium atom.

[0025] The present application includes various prodrug forms of the compounds of the present application.

[0026] In certain embodiments, the compounds of the present application can be used in combination with one or more other types of drugs that prevent or treat the diseases described above, including but not limited to the following combinations:

[0027] The other types of prevention or treatment drugs that can be used in combination with the compounds of the present application can be one or more anticancer drugs, including alkylating agents (such as cisplatin, cyclophosphamide, ifosfamide, melphalan, chlorambucil, bendamustine, estramustine, triaziquone, imidazole carboxamide, bisulfan, dibromomannitol, cyclohexyl nitrosurea, carmustine, pyrimidine nitrosourea, methylcyclohexyl nitrosurea, methylhydrazine, and the like), antimetabolites (such as fluorouracil, cytarabine, furofuracil, bifuracil, mercaptopurine, sulfomercaptopurine sodium, azathioprine, thioguanine, methotrexate, aminopterin, and the like), antitumor antibiotics (such as mitomycin C, bleomycin, dactinomycin, mithramycin, daunorubicin, doxorubicin, chromomycin A3, enomycin, neocarzinostatin, anticancerin, duocarmycin, and the like), natural anticancer drugs (such as vincristine, colchicine, camptothecin, topotecan, ellipticine, indirubin, and the like), hormone drugs (such as prednisone, hydrocortisone, hydrocortisone, dexamethasone, diethylstilbestrol, bromoacetyl hexaethylstilbestrol, propionic testosterone, methyltestosterone, phenylpropionic nandrolone, naphthoxin, tamoxifen, and the like), immunotherapeutic agents (such as PD-1 inhibitors nivolumab and pembrolizumab, and the like; PD-L1 inhibitors atezolizumab, durvalumab, and avelumab, and the like; CTLA-4 inhibitors Ipilimumab, and the like; other immune checkpoint inhibitors; cellular therapeutic agents; and the like), antibody drug conjugates (such as Kadcyla, and the like), kinase inhibitors (such as SHP-2 inhibitors, B-RAF inhibitors, MEK inhibitors, and BTK inhibitors, and the like), IDO inhibitors (such as Epacadostat, and the like), and the like.

[0028] The present application provides the use of any one of the compounds of Formula I and Table 1, or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated form, or solvate thereof, in the manufacture of a USP7 inhibitor, and in the manufacture of a medicament for the prevention or treatment of a USP7-mediated disease. The USP7-mediated disease includes, but is not limited to, a tumor, an infectious disease, and an inflammatory disease.

[0029] The present application provides a pharmaceutical composition for preventing or treating a USP7-mediated disease, which contains a therapeutically effective amount of any one of the compounds of Formula I and Table 1 or a pharmaceutically acceptable salt, ester, stereoisomer, deuteride or solvate thereof as an active ingredient and a pharmaceutically acceptable carrier. The carrier includes, but is not limited to, excipients, binders, disintegrants, lubricants, flavoring agents, odorants, colorants or sweeteners, etc. The pharmaceutical composition includes, but is not limited to, capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch, etc. in the form of a conventional preparation in pharmacy.

[0030] Advantages: Compared with the prior art, the present application has the following advantages:

[0031] The benzopentagonal aromatic heterocyclic compound or its pharmaceutically acceptable salt, ester, stereoisomer, deuteride or solvate provided by the present application represents a new structural type of USP7 inhibitor, which has excellent inhibitory activity on USP7 enzyme and can be used for preparing a medicine for preventing or treating a USP7-mediated disease.

[0032] The benzopentagonal aromatic heterocyclic compound or its pharmaceutically acceptable salt, ester, stereoisomer, deuteride or solvate provided by the present application has simple structure, ingenious design, cheap and easily available raw materials, safe and environmentally friendly synthesis process and easy scale production. DETAILED DESCRIPTION

[0033] The content of the present application is specifically described below by way of examples. In the present application, the examples described below are for better illustrating the present application and are not intended to limit the scope of the present application. Various changes and modifications can be made to the present application without departing from the spirit and scope of the present application.

[0034] Example 1

[0035] 3-((7-(7-chloro-4-(piperidin-4-yloxy)benzofuran-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-1)

[0036] Compound A2 (11.5 g, 59 mmol) was added to 150 mL of methanol, sodium borohydride (4.46 g, 118 mmol) was added portionwise under ice bath, then the reaction was slowly warmed to room temperature for half an hour. TLC monitoring showed that the reaction was completed, saturated ammonium chloride solution was added to quench the reaction, most of the solvent was removed under reduced pressure, the residue was added to 100 mL of water to make a slurry, suction filtration, the filter cake was washed with a small amount of water, and dried to obtain compound A3 as a yellow solid (10.4 g, crude yield 89.6%), which was directly used in the next step without purification.

[0037] Compound A3 (10.4 g, 52.86 mmol) was added to 150 mL of anhydrous dichloromethane, and thionyl chloride (11.5 mL, 158.58 mmol) was slowly added dropwise under ice bath, and the reaction was carried out at room temperature overnight. TLC monitoring showed that the reaction was completed, saturated sodium bicarbonate solution was slowly added under ice bath to quench the reaction, extracted with dichloromethane (80 mL x 2), the combined organic phase was washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain compound A4 as a white solid (8.21 g, yield 72.2%).

[0038] Compound A4 (8.21 g, 37.64 mmol) and 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (A5) (5.5 g, 39.52 mmol) were dissolved in 120 mL of acetonitrile, potassium carbonate (10.39 g, 75.28 mmol) was added, and the reaction was carried out at reflux for 8 hours. TLC monitoring showed that the reaction was completed, the reaction liquid was cooled to room temperature, 150 mL of water was added, extracted with dichloromethane (80 mL x 3), the combined organic phase was washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound A6 as a pink solid (11.34 g, yield 93.9%).

[0039] Compound A4 (8.21 g, 37.64 mmol) and 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (A5) (5.5 g, 39.52 mmol) were dissolved in 120 mL of acetonitrile, potassium carbonate (10.39 g, 75.28 mmol) was added, and the reaction was carried out at reflux for 8 hours. TLC monitoring showed that the reaction was completed, the reaction liquid was cooled to room temperature, 150 mL of water was added, extracted with dichloromethane (80 mL x 3), the combined organic phase was washed with saturated sodium chloride aqueous solution (100 mL), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound A6 as a pink solid (11.34 g, yield 93.9%).

[0040] Compound A6 (11.34 g, 35.35 mmol), bis(pinacolato)diboron (A7) (8.98 g, 35.35 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, dichloromethane complex (1.72 g, 2.12 mmol) and potassium acetate (10.41 g, 106.05 mmol) were added into 110 mL of anhydrous dimethyl sulfoxide, replaced with argon for three times, and warmed to 120 °C for 10 hours. TLC monitoring showed that the reaction was completed. The reaction solution was cooled to room temperature, diluted with 100 mL of ethyl acetate, and filtered with celite. 300 mL of water was added to the filtrate, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with water (200 mL x 2) and saturated aqueous sodium chloride solution (200 mL x 2), respectively. After the solvent was removed under reduced pressure, 150 mL of n-hexane was added to the residue to form a slurry, which was filtered. The filter cake was washed with a small amount of n-hexane and dried to obtain compound A8 as a dark brown solid (11.45 g). The crude product was used directly in the next reaction without purification.

[0041] 2-Chloro-5-methoxyphenol (B1) (4.9 g, 30.9 mmol) was dissolved in 120 mL of 1,1,1,3,3,3-hexafluoro-2-propanol, and N-bromosuccinimide (5.5 g, 30.9 mmol) was added portionwise. The reaction was carried out at room temperature for 2 hours. TLC monitoring showed that the reaction was completed. The solvent was removed under reduced pressure, 50 mL of water was added to the residue, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60:1→20:1) to obtain compound B2 as a light yellow oil (6.24 g, yield 85%). 1 H NMR (400 MHz, Chloroform-d) δ 7.49 (s, 1H), 6.64 (s, 1H), 5.61 (s, 1H), 3.88 (s, 3H).

[0042] Compound B2 (6.24 g, 28.75 mmol) was dissolved in 58 mL of N,N- dimethylformamide, sodium hydride (1.38 g, 34.5 mmol) was added portionwise at room temperature, stirred for 15 minutes, then bromoacetaldehyde diethyl acetal (B3) (4.76 mL, 31.62 mmol) was added, and the reaction was heated to 120 °C for 6 hours. The reaction was monitored by TLC, and when the reaction was completed, the reaction solution was cooled to room temperature, 150 mL of water was added, and the mixture was extracted with ethyl acetate (60 mL x 3), and the combined organic phases were washed with 1 N aqueous sodium hydroxide solution (30 mL x 2), water (100 mL x 2), and saturated aqueous sodium chloride solution (100 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound B4 (crude), which was dissolved in 90 mL of toluene, 6 g of polyphosphoric acid was added, and the reaction was heated to 120 °C for 2 hours. The reaction was monitored by TLC, and when the reaction was completed, the reaction solution was cooled to room temperature, the pH was adjusted to 7 by adding saturated aqueous sodium bicarbonate solution, the mixture was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 200: 1) to obtain compound B5 as a white solid (1.53 g, 21.5% yield over two steps). 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 2.2 Hz, 1H), 7.41 (s, 1H), 6.95 (d, J = 2.1 Hz, 1H), 5.80 (s, 1H).

[0043] Compound B5 (1.53 g, 5.85 mmol) was added to a three-necked flask dried under vacuum, replaced with argon three times, 24 mL of anhydrous dichloromethane was added, and the mixture was cooled to -40 °C. Boron tribromide (2.0 M in DCM, 3.51 mL, 7.02 mmol) was slowly added dropwise, and the mixture was stirred at -40 °C for 1 h, then the temperature was increased to room temperature and the reaction was allowed to proceed for 5 hours. The reaction was monitored by TLC, and when the reaction was completed, the reaction solution was cooled to 0 °C, quenched by slowly adding 10 mL of methanol, then 20 mL of saturated aqueous sodium bicarbonate solution was added, the mixture was extracted with dichloromethane (15 mL x 2), and the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound B6 as a white solid (1.39 g, 96% yield). 1 H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J = 2.2 Hz, 1H), 7.41 (s, 1H), 6.95 (d, J = 2.1 Hz, 1H), 5.80 (s, 1H).

[0044] Compound B6 (74.2 mg, 0.3 mmol), N-Boc-4-hydroxypiperidine (B7) (72.5 mg, 0.36 mmol) and triphenylphosphine (102.3 mg, 0.39 mmol) were added into a dry Schlenk tube, purged with argon for three times, 2 mL of anhydrous tetrahydrofuran was added, diisopropyl azodicarboxylate (0.077 mL, 0.39 mmol) was added dropwise slowly under ice-bath, and the reaction was carried out overnight at room temperature. TLC monitoring showed that the reaction was completed, the solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain compound B8 as a colorless oil (113 mg, yield 87.6%). 1 H NMR (300 MHz, Chloroform-d) δ 7.67 (d, J = 2.3 Hz, 1H), 7.51 (s, 1H), 6.85 (d, J = 2.2 Hz, 1H), 4.57 - 4.47 (m, 1H), 3.96 - 3.84 (m, 2H), 3.28 - 3.18 (m, 2H), 2.02 - 1.93 (m, 2H), 1.92 - 1.82 (m, 2H), 1.50 (s, 9H).

[0045] Compound B8 (109 mg, 0.253 mmol), compound A8 (313 mg, 0.759 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (9.3 mg, 0.013 mmol) and potassium carbonate (69.8 mg, 0.506 mmol) were added into 3 mL of a mixed solvent of 1,4-dioxane and 0.5 mL of water, purged with argon for three times, heated at 90°C for 4 hours. TLC monitoring showed that the reaction was completed, the reaction liquid was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1.5: 1) to obtain compound B9 as a light yellow oil (130 mg, crude yield 80.7%), which was directly used in the next step reaction.

[0046] Compound B9 (130 mg, 0.204 mol) was dissolved in 1.5 mL of dichloromethane, trifluoroacetic acid (0.235 mL, 3.065 mmol) was added dropwise slowly under ice-bath, and the reaction was carried out at room temperature for 4 hours. TLC monitoring showed that the reaction was completed, 5 mL of dichloromethane was added for dilution, then neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (5 mL x 2), the solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain compound I-1 as a white solid (51 mg, yield 46%). 1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 4.79 (s, 2H), 4.19 - 4.10 (m, 1H), 2.58 (s, 2H), 2.56 - 2.52 (m, 2H), 2.27 - 2.16 (m, 2H), 1.88 (s, 1H), 1.57 - 1.47 (m, 2H), 1.20 - 1.12 (m, 5H), 0.99 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.49, 155.90, 151.76, 147.93, 147.82, 147.63, 144.09, 140.75, 133.96, 126.04, 125.59, 125.34, 122.85, 121.02, 110.71, 106.71, 79.63, 43.19, 36.95, 36.04, 33.35, 32.38, 25.96, 15.78. HRMS (ESI) calcd. for C 28 H 27 ClN3O4S [M+H] + 536.1405, found 536.1410.

[0047] Example 2

[0048] 3-((7-(7-chloro-4-(piperidin-3-yloxy)benzofuran-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-2)

[0049] Compound I-2 was prepared (white solid, yield 68.7%) by reacting compound B6 with N-Boc-3-hydroxypiperidine according to the procedure of Reference Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 7.51 (s, 1H), 7.51 (s, 1H), 7.42 (d, J = 4.8 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 4.79 (s, 2H), 3.95 - 3.87 (m, 1H), 2.72 - 2.66 (m, 1H), 2.58 (s, 2H), 2.56 - 2.53 (m, 1H), 2.28 - 2.19 (m, 2H), 1.66 - 1.57 (m, 1H), 1.35 - 1.27 (m, 1H), 1.24 - 1.17 (m, 1H), 1.15 (s, 3H), 1.11 - 1.07 (m, 1H), 0.99 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.50, 155.95, 151.73, 148.00, 147.87, 147.78, 144.14, 140.58, 133.82, 125.88, 125.66, 125.33, 123.01, 120.97, 110.83, 106.63, 78.93, 50.45, 45.36, 36.97, 36.06, 33.37, 30.61, 25.97, 24.12, 15.80. HRMS (ESI) calcd. for C 28 H 27 ClN3O4S [M+H] + 536.1405, found 536.1406.

[0050] Example 3

[0051] 6,6-dimethyl-3-((7-(7-methyl-4-(pyrrolidin-3-yloxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-3)

[0052] Compound I-3 was prepared (white solid, yield 59.4%) by reacting compound B6 with N-Boc-3-hydroxypyrrolidine according to the method of Reference Example 1. 1H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 1.7 Hz, 2H), 7.43 - 7.39 (m, 2H), 4.79 (s, 3H), 2.88 - 2.75 (m, 2H), 2.73 - 2.63 (m, 1H), 2.58 (s, 2H), 2.47 - 2.38 (m, 1H), 1.59 (m, 2H), 1.16 (s, 3H), 0.99 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.52, 173.50, 156.01, 151.84, 148.13, 147.93, 147.36, 144.22, 140.37, 133.72, 125.75, 125.38, 125.35, 122.34, 120.92, 110.86, 106.75, 83.07, 52.12, 44.62, 36.98, 36.07, 33.38, 32.35, 25.96, 15.80. HRMS (ESI) calcd. for C 27 H 25 ClN3O4S [M+H] + 522.1249, found 522.1253.

[0053] Example 4

[0054] 3-((7-(7-chloro-4-((3-fluoroazetidin-3-yl)methoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-4)

[0055] Compound I-4 was prepared (white solid, yield 62.0%) by the method of Reference Example 1 using compound B6 and 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester. 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.53 (d, J = 1.7 Hz, 2H), 7.43 - 7.39 (m, 2H), 4.79 (s, 3H), 2.88 - 2.75 (m, 2H), 2.73 - 2.63 (m, 1H), 2.58 (s, 2H), 2.47 - 2.38 (m, 1H), 1.59 (m, 2H), 1.16 (s, 3H), 0.99 (s, 3H).13 C NMR (101 MHz, DMSO-d6) δ 173.50, 155.92, 151.95, 148.93, 147.89, 147.76, 144.11, 140.06, 133.98, 125.55, 125.33, 124.56, 121.41, 120.97, 110.72, 106.62, 94.07 (d, J = 215.1 Hz), 74.70 (d, J = 22.4 Hz), 53.92 (d, J = 21.4 Hz), 36.98, 36.06, 33.40, 25.97, 15.81. HRMS (ESI) calcd. for C 27 H 24 ClFN3O4S [M+H] + 540.1155, found 540.1157.

[0056] Example 5

[0057] 3-((7-(7-chloro-4-(piperidin-4-ylmethoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-5)

[0058] Compound I-5 was prepared by the method of Reference Example 1 using compound B6 and N-Boc-4-piperidinemethanol (white solid, yield 65.7%). 1 H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.51 (s, 1H), 7.48 (s, 1H), 7.37 - 7.33 (m, 2H), 4.77 (s, 2H), 3.83 (d, J = 6.3 Hz, 2H), 2.73 - 2.64 (m, 2H), 2.58 (s, 2H), 2.20 - 2.10 (m, 2H), 1.46 - 1.33 (m, 1H), 1.18 - 1.10 (m, 5H), 1.02 (s, 3H), 0.81 - 0.65 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 173.47, 155.85, 151.99, 149.27, 147.94, 147.52, 144.17, 140.56, 134.16, 125.49, 125.24, 124.63, 121.43, 120.89, 110.19, 106.85, 78.58, 45.73, 37.00, 36.77, 36.04, 33.40, 29.35, 25.95, 15.84. HRMS (ESI) calcd. for C 29 H 29 ClN3O4S [M+H] + 550.1562, found 550.1564.

[0059] Example 6

[0060] 3-((7-(7-chloro-4-(piperidin-3-ylmethoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-6)

[0061] Compound I-6 was prepared (white solid, yield 57.6%) by reacting compound B6 with N-Boc-3-piperidinemethanol according to the procedure of Reference Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.72 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 7.52 (s, 1H), 7.51 (s, 1H), 7.42 (d, J = 2.3 Hz, 1H), 7.38 (d, J = 4.7 Hz, 1H), 4.79 (s, 2H), 4.07 - 3.96 (m, 2H), 3.11 - 3.04 (m, 1H), 2.97 - 2.90 (m, 1H), 2.59 (s, 2H), 2.48 - 2.42 (m, 1H), 2.37 - 2.29 (m, 1H), 1.98 - 1.88 (m, 1H), 1.60 - 1.37 (m, 3H), 1.17 (s, 3H), 1.03 (s, 3H), 0.98 - 0.88 (m, 1H). 13C NMR (101 MHz, DMSO-d6) δ 173.53, 155.93, 152.03, 148.74, 148.07, 147.61, 144.31, 140.34, 134.01, 125.52, 125.21, 124.21, 121.04, 120.83, 110.35, 106.93, 74.85, 45.37, 43.68, 37.07, 36.09, 34.03, 33.43, 25.95, 24.72, 21.51, 15.85. HRMS (ESI) calcd. for C 29 H 29 ClN3O4S [M+H] + 550.1562, found 550.1566.

[0062] Example 7

[0063] 3-((7-(7-chloro-4-(2-(piperidin-4-yl)ethoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-7)

[0064] Compound I-7 was prepared (white solid, yield 57.6%) by reacting compound B6 with N-Boc-4-piperidinethanol according to the procedure of Reference Example 1. 1 H NMR (300 MHz, Chloroform-d) δ 8.72 (d, J = 4.8 Hz, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.58 (s, 1H), 7.35 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 7.00 (d, J = 2.3 Hz, 1H), 4.85 (s, 2H), 3.96 (t, J = 6.2 Hz, 2H), 2.95 - 2.85 (m, 2H), 2.38 (s, 2H), 2.34 - 2.23 (m, 2H), 1.41 - 1.36 (m, 2H), 1.31 - 1.22 (m, 7H), 1.13 (s, 3H), 0.93 - 0.86 (m, 2H). 13C NMR(101MHz,DMSO-d6)δ173.46,155.91,152.00,149.14,147.91,147.51,144.19,140.60,134.14,125.53,125.22 ,124.66,121.42,120.92,110.19,106.86,71.10,46.10,37.01,36.03,33.41,25.94,15.88.HRMS(ESI)calcd.for C 30 H 31 ClN3O4S[M+H] + 564.1718, found 564.1721.

[0065] Example 8

[0066] 3-((7-(4-((1r,3r)-3-aminocyclobutyloxy)-7-chlorobenzofuran-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-8)

[0067] Referring to the method of Example 1, compound B6 was reacted with tert-butyl (cis-3-hydroxycyclobutyl)carbamate to prepare compound I-8 (white solid, yield 60.1%). 1 H NMR (400MHz, DMSO-d6) δ8.70(d,J=4.8Hz,1H),8.20(d,J=2.3Hz,1H),7.51(s,1H),7.47(s,1H),7.36(d,J=4.8Hz,1H),7.24(d,J=2.3Hz ,1H),4.98–4.92(m,1H),4.78(s,2H),3.25–3.17(m,1H),2.58(s,2H),2.00–1.94(m,2H),1.87–1.78(m,2H),1.16(s,3H),1.01(s,3H). 13 C NMR(101MHz,DMSO-d6)δ173.50,155.87,151.94,147.98,147.84,147.53,144.09,140.81,133.90,125.76,125.24 ,124.21,120.89,120.68,109.71,106.98,74.64,43.88,36.97,36.06,33.39,25.96,15.83.HRMS(ESI)calcd.for C 27 H 25ClN3O4S[M+H] + 522.1249, found 522.1255.

[0068] Example 9

[0069] 3-((7-(4-(((1s,3s)-3-aminocyclobutyl)methoxy)-7-chlorobenzofuran-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-9)

[0070] Referring to the method of Example 1, compound B6 was reacted with cis-tert-butyl 3-hydroxymethylcyclobutylcarbamate to prepare compound I-9 (white solid, yield 58.8%). 1 H NMR (300MHz, Chloroform-d) δ8.72(d,J=4.8Hz,1H),7.73(d,J=2.2Hz,1H),7.58(s,1H),7.36(s,1H),7.30(d,J=4.8Hz,1H),7.00(d,J=2.3Hz,1H),4.85( s,2H),3.86(d,J=5.2Hz,2H),3.18–3.05(m,1H),2.39(s,2H),2.13–2.03(m, 2H),2.03–1.92(m,1H),1.24(s,3H),1.20–1.10(m,5H).HRMS(ESI)calcd.for C 27 H 25 ClN3O4S[M+H] + 522.1249, found 522.1255.

[0071] Example 10

[0072] 3-((7-(4-(2-aminoethoxy)-7-chlorobenzofuran-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-10)

[0073] Referring to the method of Example 1, compound B6 was reacted with N-Boc ethanolamine to prepare compound I-10 (white solid, yield 72.9%). 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 7.39 (d, J = 2.4 Hz, 1H), 4.78 (s, 2H), 3.99 (t, J = 5.7 Hz, 2H), 2.58 (s, 2H), 2.54 (d, J = 5.6 Hz, 2H), 1.16 (s, 3H), 1.01 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.50, 155.94, 151.98, 149.24, 148.04, 147.49, 144.16, 140.56, 133.92, 125.62, 125.30, 124.27, 121.36, 120.83, 110.13, 106.92, 106.71, 76.20, 41.75, 36.98, 36.06, 33.40, 25.96, 15.82. HRMS (ESI) calcd. for C 25 H 23 ClN3O4S [M+H] + 496.1092, found 496.1101.

[0074] Example 11

[0075] 3-((7-(4-(3-aminopropoxy)-7-chlorobenzofuran-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-11)

[0076] Compound I-11 was prepared by the method of Reference Example 1 using compound B6 and tert-butyl N-(3-hydroxypropyl)carbamate (white solid, yield 69.1%). 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 4.8 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 7.51 (s, 1H), 7.49 (s, 1H), 7.41 (s, 1H), 7.39 (d, J = 2.4 Hz, 1H), 4.78 (s, 2H), 3.99 (t, J = 5.7 Hz, 2H), 2.58 (s, 2H), 2.54 (d, J = 5.6 Hz, 2H), 1.16 (s, 3H), 1.01 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 173.46, 155.91, 152.00, 149.14, 147.91, 147.51, 144.19, 140.60, 134.14, 125.53, 125.22, 124.66, 121.42, 120.92, 110.19, 106.86, 71.10, 46.10, 37.01, 36.03, 33.41, 25.94, 15.88. HRMS (ESI) calcd. for C 27 H 26 ClN3O4S [M+H] + 509.1296, found 509.1288.

[0077] Example 12

[0078] 3-((7-(7-chloro-4-(2-(methylamino)ethoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-12)

[0079] Compound I-12 was prepared according to the procedure of Reference Example 1 by reacting compound B6 with N-Boc-N-methylaminoethanol (white solid, yield 61.4%). 1 H NMR (300 MHz, DMSO-d6) δ 8.71 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 7.53 (s, 1H), 7.50 (s, 1H), 7.43 - 7.38 (m, 2H), 4.79 (s, 2H), 4.08 (t, J = 5.5 Hz, 2H), 2.59 (s, 2H), 2.49 - 2.46 (m, 2H), 1.99 (s, 3H), 1.17 (s, 3H), 1.02 (s, 3H). HRMS (ESI) calcd. for C 27 H 25 ClN2O4S [M+H] + 509.1296, found 509.1287.

[0080] Example 13

[0081] 3-((7-(4-(azepan-4-yloxy)-7-chlorobenzofuran-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-13)

[0082] Compound I-13 (white solid, yield 54.7%) was prepared by reacting compound B6 with 4-hydroxyazepan-1-carboxylic acid tert-butyl ester according to the procedure of Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J = 4.8 Hz, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.52 (s, 1H), 7.50 (s, 1H), 7.38 (d, J = 4.8 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 4.79 (s, 2H), 4.35 - 4.28 (m, 1H), 2.58 (s, 2H), 2.49 - 2.46 (m, 1H), 2.43 - 2.36 (m, 1H), 2.29 - 2.18 (m, 2H), 1.67 - 1.58 (m, 2H), 1.57 - 1.50 (m, 1H), 1.50 - 1.41 (m, 1H), 1.33 - 1.26 (m, 1H), 1.16 (s, 3H), 1.10 - 1.02 (m, 1H), 0.99 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 172.36, 154.88, 150.72, 146.92, 146.85, 146.64, 143.05, 139.73, 132.94, 124.95, 124.53, 124.25, 121.76, 119.91, 109.46, 105.55, 82.02, 47.34, 41.91, 35.91, 34.88, 32.35, 31.19, 24.91, 23.34, 14.74. HRMS (ESI) calcd. for C 29 H 29 ClN3O4S [M+H] + 550.1562, found 550.1569.

[0083] Example 14

[0084] 2-((7-(7-chloro-4-(piperidin-4-yloxy)benzofuran-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)isoindoline-1,3-dione (I-22)

[0085] Compound I-22 (white solid, yield 32.5%) was prepared by replacing intermediate A5 with phthalimide according to the procedure of Example 1. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.94 - 7.85 (m, 4H), 7.63 (s, 1H), 7.54 (s, 1H), 7.40 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 5.11 (s, 2H), 4.53 - 4.45 (m, 1H), 2.79 - 2.69 (m, 2H), 2.65 - 2.55 (m, 2H), 1.82 - 1.73 (m, 2H), 1.51 - 1.42 (m, 2H). HRMS (ESI) calcd. for C 29 H 27 ClN3O4S[M+H] + 544.1092, found 544.1100.

[0086] Example 15

[0087] 1-((7-(7-chloro-4-(piperidin-4-yloxy)benzofuran-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)piperidine-2,6-dione (I-23)

[0088] Compound I-23 was prepared according to the procedure of Reference Example 1 by replacing intermediate A5 with glutarimide to give a white solid (33.5% yield). 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.94 - 7.85 (m, 4H), 7.63 (s, 1H), 7.54 (s, 1H), 7.40 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 2.3 Hz, 1H), 5.11 (s, 2H), 4.53 - 4.45 (m, 1H), 2.79 - 2.69 (m, 2H), 2.65 - 2.55 (m, 2H), 1.82 - 1.73 (m, 2H), 1.51 - 1.42 (m, 2H). HRMS (ESI) calcd. for C 26 H 25 ClN3O4S[M+H] + 510.1249, found 510.1251.

[0089] Example 16

[0090] 3-((7-(7-chloro-4-(piperidin-4-yloxy)benzofuran-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-1-methylimidazolidine-2,4-dione (I-24)

[0091] Compound I-24 was prepared according to the procedure of Example 1, replacing intermediate A5 with 1-methylimidazoline-2,4-dione (cas (616-04-6)) (white solid, yield 31.2%). 1 H NMR (400 MHz, DMSO-d6) d 8.72 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 2.3 Hz, 1H), 7.55 (s, 2H), 7.40 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 2.4 Hz, 1H), 4.86 (s, 2H), 4.54 - 4.47 (m, 1H), 4.03 (s, 2H), 2.85 (s, 3H), 2.81 - 2.73 (m, 2H), 2.68 - 2.60 (m, 2H), 1.85 - 1.77 (m, 2H), 1.54 - 1.45 (m, 2H). HRMS (ESI) calcd. for C 25 H 24 ClN4O4S [M+H] + 511.1201, found 511.1202.

[0092] Example 17

[0093] 3-((7-(7-chloro-4-(piperidin-4-yloxy)benzofuran-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-25)

[0094] Dissolve 2-fluoro-5-methoxyphenol (C1) (1.66 g, 11.68 mmol) in 46 mL of 1,1,1,3,3,3-hexafluoro-2-propanol, add N-bromosuccinimide (2.079 g, 11.68 mmol) portionwise, and react at room temperature for 2 hours. Monitor the reaction completion by TLC, evaporate the solvent under reduced pressure, add 20 mL of water to the residue, extract with dichloromethane (20 mL x 2), combine the organic phases, wash with saturated aqueous sodium chloride solution (10 mL x 2), and evaporate the solvent under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain compound C2 as a light yellow oil (2.348 g, yield 90.9%). 1H NMR (300 MHz, Chloroform-d) δ 7.28 (s, 1H), 6.65 - 6.61 (m, 1H), 5.44 - 5.40 (m, 1H), 3.86 (s, 3H).

[0095] Compound C2 (2.348 g, 10.62 mmol) was dissolved in 22 mL of N,N- dimethylformamide, sodium hydride (0.51 g, 12.75 mmol) was added portionwise at room temperature, after stirring for 15 minutes, bromoacetaldehyde diethyl acetal (B3) (1.76 mL, 11.69 mmol) was added, and the reaction was allowed to proceed at 120 °C for 6 hours. The reaction was monitored by TLC, and after completion, the reaction was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL x 3), the combined organic phases were washed with 1 N aqueous sodium hydroxide solution (10 mL x 2) and saturated aqueous sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound C3 (crude), which was dissolved in 30 mL of toluene, 2 g of polyphosphoric acid was added, and the reaction was allowed to proceed at reflux for 2 hours. The reaction was monitored by TLC, and after completion, the reaction was cooled to room temperature, the pH was adjusted to 7-8 by the addition of saturated aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL x 3), the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 200: 1) to obtain compound C4 as a white solid (0.59 g, 22.7% yield over two steps). 1 H NMR (400 MHz, Chloroform-d) δ 7.65 (d, J = 2.2 Hz, 1H), 7.25 (d, J = 9.5 Hz, 1H), 6.97 - 6.95 (m, 1H), 4.03 (s, 3H).

[0096] Compound C4 (0.508 g, 2.073 mmol) was added to a three-necked flask that was dried under argon, the flask was replaced with argon three times, 8.5 mL of anhydrous dichloromethane was added, and the mixture was cooled to -40 °C, and boron tribromide (2.0 M in DCM, 1.25 mL, 2.488 mmol) was added dropwise slowly, the mixture was stirred at -40 °C for 1 h after the dropwise addition was completed, and then the reaction was allowed to proceed at room temperature for 4 hours. After the reaction was completed as monitored by TLC, the reaction was cooled to 0 °C, and the reaction was quenched by the slow addition of 4 mL of methanol, and then 10 mL of saturated aqueous sodium bicarbonate solution was added, the mixture was extracted with dichloromethane (10 mL x 2), the combined organic phases were washed with saturated aqueous sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound C5 as a white solid (0.468 g, 97.7% yield). 1H NMR (300 MHz, Chloroform-d) δ 7.62 (d, J = 2.1 Hz, 1H), 7.18 (d, J = 9.4 Hz, 1H), 6.96 - 6.93 (m, 1H), 5.66 (s, 1H).

[0097] Compound C5 (80 mg, 0.346 mmol), N-Boc-4-hydroxypiperidine (B7) (83.6 mg, 0.415 mmol) and triphenylphosphine (118.08 mg, 0.45 mmol) were added into a dry Schlenk tube, purged with argon for three times, 2 mL of anhydrous tetrahydrofuran was added, diisopropyl azodicarboxylate (0.089 mL, 0.45 mmol) was added dropwise slowly under ice-bath, the reaction was carried out at room temperature overnight after dropping. TLC monitoring reaction was completed, the solvent was removed by reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain compound C6 as a light yellow oil (92 mg, yield 64.1%). 1 H NMR (300 MHz, Chloroform-d) δ 7.62 (d, J = 2.1 Hz, 1H), 7.18 (d, J = 9.4 Hz, 1H), 6.96 - 6.93 (m, 1H), 4.52 - 4.43 (m, 1H), 3.97 - 3.87 (m, 2H), 3.26 - 3.16 (m, 2H), 2.47 (s, 3H), 2.00 - 1.91 (m, 2H), 1.91 - 1.81 (m, 2H), 1.50 (s, 9H).

[0098] Compound C6 (92 mg, 0.222 mmol), compound A8 (274.7 mg, 0.666 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (9.1 mg, 0.011 mmol) and potassium carbonate (69.8 mg, 0.444 mmol) were added into 3 mL of a mixed solvent of 1,4-dioxane and 0.5 mL of water, purged with argon for three times, heated at 90 °C for 4 hours. TLC monitoring reaction was completed, the reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed by reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1.5: 1) to obtain compound C7 as a light yellow oil (96 mg, crude product yield 69.8%), which was directly used in the next step reaction.

[0099] Compound C7 (96 mg, 0.155 mmol) was dissolved in 1.2 mL of dichloromethane, trifluoroacetic acid (0.178 mL, 2.234 mmol) was added dropwise slowly under ice bath, after the dropwise addition was completed, the reaction was allowed to react at room temperature for 4 hours. TLC monitoring showed that the reaction was completed, 5 mL of dichloromethane was added to dilute it, then saturated aqueous sodium bicarbonate solution was added to neutralize it, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (5 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain white solid of compound I-25 (50.2 mg, yield 62.3%). 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 7.51 (s, 1H), 7.39 (d, J = 4.8 Hz, 1H), 7.36 (d, J = 10.9 Hz, 1H), 7.24 (t, J = 2.6 Hz, 1H), 4.78 (s, 2H), 4.02 - 3.93 (m, 1H), 2.58 (s, 2H), 2.19 - 2.11 (m, 2H), 1.50 - 1.43 (m, 2H), 1.15 (s, 3H), 1.13 - 1.06 (m, 2H), 0.97 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 172.41, 154.86, 146.89 (d, J = 13.8 Hz), 143.57 (d, J = 2.7 Hz), 143.03, 142.72 (d, J = 244.1 Hz), 141.71 (d, J = 12.8 Hz), 139.84, 132.85, 124.26, 124.04 (d, J = 5.8 Hz), 123.79 (d, J = 3.3 Hz), 119.95, 110.94 (d, J = 18.4 Hz), 105.36, 79.24, 42.51, 35.88, 34.96, 32.29, 31.74, 24.90, 14.70. HRMS (ESI) calcd. for C 28 H 27 FN3O4S [M+H] + 520.1701, found 520.1699.

[0100] Example 18

[0101] 3-((7-(7-Fluoro-4-(pyrrolidin-3-yloxy)benzofuran-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-26)

[0102] Compound I-26 (white solid, yield 64.2%) was prepared by the reaction of compound C5 with N-Boc-3-hydroxypyrrolidine according to the method of Reference Example 17. 1 H NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 4.8 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.55 (s, 1H), 7.47 (m, 1H), 7.46 - 7.41 (m, 2H), 4.80 (s, 2H), 4.70 - 4.65 (m, 1H), 3.15 - 3.05 (m, 2H), 3.01 - 2.94 (m, 1H), 2.63 - 2.54 (m, 3H), 1.72 - 1.54 (m, 2H), 1.17 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 27 H 25 FN3O4S [M+H] + 506.1544, found 506.1551.

[0103] Example 19

[0104] 3-((7-(7-Fluoro-4-((3-fluoroazetidin-3-yl)methoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-27)

[0105] Compound I-27 (white solid, yield 58.3%) was prepared by the reaction of compound C5 with 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester according to the method of Reference Example 17. 1 H NMR (400 MHz, DMSO-d6) δ 8.70 (d, J = 4.8 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.52 (s, 1H), 7.40 (d, J = 10.9 Hz, 1H), 7.38 (d, J = 4.8 Hz, 1H), 7.35 (t, J = 2.6 Hz, 1H), 4.79 (s, 2H), 4.30 (s, 1H), 4.24 (s, 1H), 3.28 - 3.19 (m, 2H), 3.09 - 3.01 (m, 2H), 2.58 (s, 2H), 1.24 (s, 1H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 27 H 23 F2N3O4S [M+H] +524.1450, found 524.1450.

[0106] Example 20

[0107] 3-((7-(7-Fluoro-4-(piperidin-4-ylmethoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-28)

[0108] Compound I-28 was prepared according to the procedure described in Example 17 by reacting compound C5 with N-Boc-4-piperidinemethanol (white solid, yield 66.7%). 1 H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.8 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 7.34 (d, J = 5.7 Hz, 1H), 7.30 (t, J = 2.6 Hz, 1H), 4.77 (s, 2H), 3.72 (d, J = 6.3 Hz, 2H), 2.72 - 2.65 (m, 2H), 2.58 (s, 2H), 2.19 - 2.11 (m, 2H), 1.44 - 1.35 (m, 1H), 1.18 - 1.09 (m, 5H), 1.02 (s, 3H), 0.77 - 0.65 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 173.46, 155.88, 147.89 (d, J = 12.5 Hz), 146.16 (d, J = 2.7 Hz), 143.62 (d, J = 243.6 Hz), 143.01 (d, J = 12.8 Hz), 140.59, 134.09, 125.22, 123.83 (d, J = 5.9 Hz), 123.51 (d, J = 3.1 Hz), 111.95 (d, J = 18.6 Hz), 106.41, 78.67, 45.24, 36.99, 36.31, 36.03, 33.40, 28.68, 25.94, 15.82. HRMS (ESI) calcd. for C 29 H 29 FN3O4S [M+H] + 534.1857, found 534.1859.

[0109] Example 21

[0110] 6,6-dimethyl-3-((7-(7-methyl-4-(piperidin-4-yloxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-37)

[0111] Dissolve 2-methyl-5-methoxyphenol (D1) (0.983 g, 7.115 mmol) in 28 mL of 1,1,1,3,3,3-hexafluoro-2-propanol, add N-bromosuccinimide (1.266 g, 7.115 mmol) portionwise, and react at room temperature for 2 hours. Monitor the reaction completion by TLC, evaporate the solvent under reduced pressure, add 20 mL of water to the residue, extract with dichloromethane (20 mL x 2), wash the combined organic phase with saturated aqueous sodium chloride solution (10 mL x 2), and evaporate the solvent under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to obtain compound D2 as a light yellow oil (1.32 g, yield 85.5%). 1 H NMR (400 MHz, Chloroform-d) δ 7.28 (s, 1H), 6.45 (s, 1H), 4.87 (s, 1H), 3.86 (s, 3H), 2.18 (s, 3H).

[0112] Dissolve compound D2 (1.21 g, 5.574 mmol) in 12 mL of N,N-dimethylformamide, add sodium hydride (0.268 g, 6.689 mmol) portionwise at room temperature, stir for 15 minutes, then add bromoacetaldehyde diethyl acetal (B3) (0.923 mL, 6.132 mmol), and react at 120 °C for 6 hours. Monitor the reaction completion by TLC, cool the reaction solution to room temperature, add 50 mL of water, extract with ethyl acetate (20 mL x 3), wash the combined organic phase with 1 N aqueous sodium hydroxide solution (10 mL x 2) and saturated aqueous sodium chloride solution (30 mL x 2), dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain compound D3 (crude). Dissolve it in 15 mL of toluene, add 1.1 g of polyphosphoric acid, and reflux for 2 hours. Monitor the reaction completion by TLC, cool the reaction solution to room temperature, adjust the pH to 7-8 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (20 mL x 2), wash the combined organic phase with saturated aqueous sodium chloride solution (20 mL x 2), evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 200: 1) to obtain compound D4 as a white solid (0.77 g, two-step yield 57.2%). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 2.3 Hz, 1H), 7.33 (s, 1H), 7.21 (d, J = 2.3 Hz, 1H), 4.00 (s, 3H), 2.40 (s, 3H).

[0113] Compound D4 (0.694 g, 2.879 mmol) was added to a dry three-necked flask, replaced with argon for three times, 11.5 mL of anhydrous dichloromethane was added, cooled to -40 °C, and boron tribromide (1.0 M in DCM, 4.3 mL, 4.3 mmol) was added dropwise slowly. After the dropwise addition was completed, the reaction was stirred at -40 °C for 1 h, and then was allowed to warm to room temperature for 4 h. After the reaction was completed as monitored by TLC, the reaction was quenched by slowly adding 4 mL of methanol at 0 °C, followed by the addition of 10 mL of saturated aqueous sodium bicarbonate solution. The mixture was extracted with dichloromethane (10 mL x 2), and the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100: 1) to give compound D5 as a white solid (0.4 g, yield 61.3%). 1 H NMR (300 MHz, Chloroform-d) δ 7.58 (d, J = 2.2 Hz, 1H), 7.17 (s, 1H), 6.90 (d, J = 2.2 Hz, 1H), 5.66 (s, 1H), 2.45 (s, 3H).

[0114] Compound D5 (80 mg, 0.332 mmol), N-Boc-4-hydroxypiperidine (B7) (80.1 mg, 0.398 mmol), and triphenylphosphine (113.1 mg, 0.432 mmol) were added to a dry Schlenk tube, replaced with argon for three times, 2 mL of anhydrous tetrahydrofuran was added, and diisopropyl azodicarboxylate (0.085 mL, 0.432 mmol) was added dropwise slowly in an ice bath. After the dropwise addition was completed, the reaction was allowed to react at room temperature overnight. After the reaction was completed as monitored by TLC, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15: 1) to give compound D6 as a light yellow oil (119 mg, yield 87.4%). 1 H NMR (400 MHz, Chloroform-d) δ 7.60 (d, J = 2.2 Hz, 1H), 7.29 (s, 1H), 6.79 (d, J = 2.0 Hz, 1H), 4.52 - 4.43 (m, 1H), 3.97 - 3.87 (m, 2H), 3.26 - 3.16 (m, 2H), 2.47 (s, 3H), 2.00 - 1.91 (m, 2H), 1.91 - 1.81 (m, 2H), 1.50 (s, 9H).

[0115] Compound D6 (115 mg, 0.222 mmol), compound A8 (346.7 mg, 0.841 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (10.3 mg, 0.014 mmol) and potassium carbonate (77.4 mg, 0.561 mmol) were added into 3 mL of 1.4-dioxane and 0.5 mL of water, replaced by argon for 3 times, heated at 90 °C for 4 hours. TLC monitoring reaction was completed, the reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1.5: 1) to obtain compound D7 as a light yellow oil (75 mg, crude yield 43.5%), which was directly used in the next step reaction.

[0116] Compound D7 (75 mg, 0.122 mmol) was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (0.14 mL, 1.83 mmol) was slowly added dropwise under ice bath, and the reaction was carried out at room temperature for 4 hours. TLC monitoring reaction was completed, 5 mL of dichloromethane was added to dilute, then saturated aqueous sodium bicarbonate solution was added to neutralize, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (5 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain compound I-37 as a white solid (35.7 mg, yield 56.9%). 1 H NMR (300 MHz, DMSO-d6) δ 8.67 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.49 (s, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.18 (s, 1H), 7.10 (d, J = 2.3 Hz, 1H), 4.78 (s, 2H), 4.03 - 3.94 (m, 1H), 2.57 (s, 2H), 2.55 - 2.51 (m, 2H), 2.47 (s, 3H), 2.21 - 2.10 (m, 2H), 1.52 - 1.42 (m, 2H), 1.14 (s, 3H), 1.13 - 1.05 (m, 2H), 0.97 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 172.38, 154.79, 154.20, 146.72, 145.46, 142.88, 141.15, 133.05, 125.40, 124.23, 123.74, 119.91, 116.01, 104.74, 78.56, 42.46, 35.90, 34.90, 32.29, 31.72, 24.91, 14.68, 13.72. HRMS (ESI) calcd. for C 29 H 30 N3O4S [M+H] + 516.1952, found 516.1964.

[0117] Example 22

[0118] 6,6-dimethyl-3-((7-(7-methyl-4-(piperidin-3-yloxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-38)

[0119] Compound I-38 was prepared (white solid, yield 60.8%) by reacting compound D5 with N-Boc-3-hydroxypiperidine according to the method of Reference Example 21. 1 H NMR (400 MHz, DMSO-d6) δ 8.73 (d, J = 4.8 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.54 (s, 1H), 7.46 (t, J = 2.6 Hz, 1H), 7.45 - 7.41 (m, 2H), 4.79 (s, 2H), 4.69 - 4.64 (m, 1H), 3.14 - 3.04 (m, 2H), 3.00 - 2.93 (m, 1H), 2.62 - 2.53 (m, 3H), 1.71 - 1.53 (m, 2H), 1.16 (s, 3H), 1.00 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 172.38, 154.79, 154.20, 146.72, 145.46, 142.88, 141.15, 133.05, 125.40, 124.23, 123.74, 119.91, 116.01, 104.74, 78.56, 42.46, 35.90, 34.90, 32.29, 31.72, 24.91, 14.68, 13.72. HRMS (ESI) calcd. for C 29 H30 Example 23N3O4S[M+H] + 516.1952, found 516.1958.

[0120] Example 23

[0121] 6,6-dimethyl-3-((7-(7-methyl-4-(pyrrolidin-3-yloxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-39)

[0122] Compound I-39 was prepared (white solid, yield 53.5%) by reacting compound D5 with N-Boc-3-hydroxypyrrolidine according to the method of Reference Example 21. 1 H NMR (300 MHz, DMSO-d6) d 8.68 (d, J = 4.8 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 7.50 (s, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.21 (d, J = 2.3 Hz, 2H), 4.78 (s, 2H), 4.66 - 4.59 (m, 1H), 2.64 - 2.59 (m, 2H), 2.57 (s, 2H), 2.49 - 2.44 (m, 4H), 2.39 - 2.28 (m, 1H), 1.51 - 1.43 (m, 2H), 1.15 (s, 3H), 0.97 (s, 3H).

[0123] 13 C NMR (101 MHz, DMSO-d6) d 173.49, 159.66, 156.05, 151.90, 148.79, 148.16, 144.30, 139.88, 133.43, 130.89, 128.24, 128.16, 125.42, 122.29, 120.72, 80.97, 43.62, 36.93, 36.06, 33.35, 33.06, 25.97, 15.78. HRMS (ESI) calcd. for C 28 H 28 N3O4S[M+H] + 502.1795, found 502.1802.

[0124] Example 24

[0125] 3-((7-(4-((3-fluoroazetidin-3-yl)methoxy)-7-methylbenzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-40)

[0126] Compound I-40 (white solid, yield 57.6%) was prepared by the method described in Reference Example 21, using the reaction of compound D5 with 3-fluoro-3- (hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, DMSO-d6) d 8.67 (d, J = 4.8 Hz, 1H), 8.13 (d, J = 2.3 Hz, 1H), 7.50 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.24 - 7.20 (m, 2H), 4.78 (s, 2H), 4.29 (s, 1H), 4.23 (s, 1H), 3.28 - 3.22 (m, 2H), 3.12 - 3.04 (m, 2H), 2.57 (s, 2H), 2.49 (s, 3H), 1.24 (s, 1H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 28 H 26 FN3O4S [M+H] + 520.1701, found 520.1705.

[0127] Example 25

[0128] 6,6-dimethyl-3-((7-(7-methyl-4-(piperidin-4-ylmethoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-41)

[0129] Compound I-41 (white solid, yield 62.8%) was prepared by the method described in Reference Example 21, using the reaction of compound D5 with N-Boc-4-piperidinemethanol. 1H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 4.8 Hz, 1H), 8.08 (d, J = 2.2 Hz, 1H), 7.49 (s, 1H), 7.31 (d, J = 4.8 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.15 (s, 1H), 4.76 (s, 2H), 3.72 (d, J = 6.3 Hz, 2H), 2.71 - 2.65 (m, 2H), 2.57 (s, 2H), 2.47 (s, 3H), 2.18 - 2.10 (m, 2H), 1.43 - 1.34 (m, 1H), 1.18 - 1.12 (m, 5H), 1.01 (s, 3H), 0.78 - 0.67 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 172.36, 154.75, 154.41, 147.06, 146.75, 145.28, 142.99, 140.90, 133.24, 125.30, 124.13, 122.51, 119.78, 118.64, 115.68, 104.75, 77.43, 44.57, 35.95, 35.54, 34.90, 32.35, 28.20, 24.90, 14.75, 13.69. HRMS (ESI) calcd. for C 30 H 32 N3O4S [M+H] + 530.2108, found 530.2115.

[0130] Example 26

[0131] 6,6-dimethyl-3-((7-(4-(piperidin-4-yloxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-50)

[0132] Into a three-necked flask, 6,7-dihydro-4(5H)-benzofuranone (E1) (4.792 g, 35.2 mmol) and copper bromide (17.282 g, 77.4 mmol) were added, replaced with argon for three times, 55 mL of chloroform and 55 mL of ethyl acetate were added, and the reaction was heated to 80 °C for 8 hours. TLC monitoring showed that the reaction was completed. The reaction liquid was cooled to room temperature, and the filter cake was washed with 20 mL of ethyl acetate. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20: 1) to obtain compound E2 as a light yellow oil (4.2 g, yield 55.5%). 1H NMR (400 MHz, Chloroform-d) δ 7.40 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 1.9 Hz, 1H), 4.59 (t, J = 3.8 Hz, 1H), 3.20 - 3.10 (m, 1H), 2.95 - 2.86 (m, 1H), 2.61 - 2.50 (m, 2H).

[0133] Compound E2 (4.15 g, 19.3 mmol) and copper bromide (12.93 g, 57.89 mmol) were added into a three-necked flask, replaced with argon for three times, 30 mL chloroform and 30 mL ethyl acetate were added, and the reaction was carried out at 80 °C for 6 hours. TLC monitoring showed that the reaction was completed. The reaction solution was cooled to room temperature, and the filter cake was extracted with 20 mL of ethyl acetate. The filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain pink solid of compound E3 (2.51 g, yield 44.1%). 1 H NMR (400 MHz, Chloroform-d) δ 7.41 (d, J = 2.1 Hz, 1H), 6.79 (d, J = 2.1 Hz, 1H), 3.15 (t, J = 5.7 Hz, 2H), 3.04 (t, J = 5.7 Hz, 2H).

[0134] Compound E3 (1 g, 3.402 mmol) was dissolved in 24 mL of acetonitrile, and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.813 mL, 5.443 mmol) was slowly added dropwise in an ice bath, and then slowly warmed to room temperature for 2 hours. TLC monitoring showed that the reaction was completed. 20 mL of saturated aqueous ammonium chloride solution was added, extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (15 mL x 2). The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 60: 1) to obtain light purple solid of compound E4 (0.67 g, yield 92.5%). 1 H NMR (400 MHz, Chloroform-d) δ 7.57 (d, J = 2.2 Hz, 1H), 7.36 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 8.8, 1.0 Hz, 1H), 6.91 (dd, J = 2.2, 1.0 Hz, 1H), 5.83 (s, 1H).

[0135] Compound E4 (80 mg, 0.376 mmol), N-Boc-4-hydroxypiperidine (B7) (90.7 mg, 0.451 mmol) and triphenylphosphine (128 mg, 0.488 mmol) were added into a dry Schlenk tube, purged with argon for three times, 2 mL of anhydrous tetrahydrofuran was added, diisopropyl azodicarboxylate (0.096 mL, 0.488 mmol) was added dropwise slowly under ice-bath, and the reaction was carried out overnight at room temperature. TLC monitoring showed that the reaction was completed, the solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 15:1) to obtain compound E5 as a colorless oil (106 mg, yield 71.2%). 1 H NMR (400 MHz, Chloroform-d) δ 7.59 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.18 (dd, J = 8.7, 1.0 Hz, 1H), 6.81 (dd, J = 2.3, 1.0 Hz, 1H), 4.62 - 4.51 (m, 1H), 3.96 - 3.85 (m, 2H), 3.30 - 3.19 (m, 2H), 2.03 - 1.82 (m, 4H), 1.50 (s, 9H).

[0136] Compound E5 (100 mg, 0.252 mmol), compound A8 (312.1 mg, 0.757 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.3 mg, 0.013 mmol) and potassium carbonate (69.6 mg, 0.505 mmol) were added into 3 mL of a mixed solvent of 1.4-dioxane and 0.5 mL of water, purged with argon for three times, and the reaction was carried out at 90 °C for 4 hours. TLC monitoring showed that the reaction was completed, the reaction liquid was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1.5:1) to obtain compound E6 as a light yellow oil (82 mg, crude yield 54%), which was directly used in the next step reaction.

[0137] Compound E6 (82 mg, 0.136 mmol) was dissolved in 1 mL of dichloromethane, trifluoroacetic acid (0.157 mL, 2.044 mmol) was added dropwise slowly under ice-bath, and the reaction was carried out at room temperature for 4 hours. TLC monitoring showed that the reaction was completed, 5 mL of dichloromethane was added for dilution, then neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (5 mL x 2), the solvent was removed by reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound I-50 as a white solid (46 mg, yield 67.3%).1 H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J = 4.8 Hz, 1H), 8.09 (d, J = 2.3 Hz, 1H), 7.53 - 7.48 (m, 2H), 7.38 (d, J = 2.7 Hz, 1H), 7.36 (s, 1H), 7.13 (dd, J = 2.3, 0.9 Hz, 1H), 4.78 (s, 2H), 4.16 - 4.07 (m, 1H), 2.57 (s, 2H), 2.56 - 2.51 (m, 2H), 2.24 - 2.13 (m, 2H), 1.56 - 1.46 (m, 2H), 1.21 - 1.11 (m, 5H), 0.97 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.48, 156.68, 155.90, 148.51, 147.81, 146.76, 143.97, 142.05, 134.14, 126.18, 125.37, 124.72, 121.28, 121.08, 107.48, 105.61, 79.47, 43.49, 36.95, 36.03, 33.33, 32.78, 25.96, 15.74. HRMS (ESI) calcd. for C 28 H 28 N3O4S [M+H] + 502.1795, found 502.1801.

[0138] Example 27

[0139] 6,6-dimethyl-3-((7-(4-(piperidin-3-yloxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-51)

[0140] Compound I-51 (white solid, yield 69.3%) was prepared by reacting compound E4 with N-Boc-3-hydroxypiperidine according to the method of Reference Example 26. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.55 - 7.49 (m, 2H), 7.43 - 7.36 (m, 2H), 7.15 (d, J = 1.8 Hz, 1H), 4.78 (s, 2H), 3.95 - 3.86 (m, 1H), 2.74 - 2.66 (m, 1H), 2.58 (s, 2H), 2.57 - 2.52 (m, 1H), 2.28 - 2.18 (m, 2H), 1.70 - 1.59 (m, 1H), 1.39 - 1.28 (m, 1H), 1.26 - 1.18 (m, 1H), 1.16 (s, 3H), 1.13 - 1.05 (m, 1H), 0.99 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.49, 156.66, 155.95, 148.67, 147.88, 146.81, 144.03, 141.87, 133.99, 126.24, 125.36, 124.53, 121.37, 121.02, 107.58, 105.53, 78.76, 50.80, 45.55, 36.96, 36.04, 33.35, 30.89, 25.97, 24.47, 15.76. HRMS (ESI) calcd. for C 28 H 28 N3O4S [M+H] + 502.1795, found 502.1802.

[0141] Example 28

[0142] 3-((7-(4-((3-Fluoroazetidin-3-yl)methoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-52)

[0143] Compound I-52 was prepared (white solid, yield 64.9%) by the method described in Reference Example 26, using compound E4 and 3-fluoro-3-(hydroxymethyl)azetidine-1- carboxylate tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (d, J = 4.8 Hz, 1H), 8.12 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.4, 1.0 Hz, 1H), 7.50 (s, 1H), 7.40 (d, J = 8.5 Hz, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.27 (dd, J = 2.3, 1.0 Hz, 1H), 4.77 (s, 2H), 4.39 (s, 1H), 4.33 (s, 1H), 3.29 - 3.22 (m, 2H), 3.14 - 3.06 (m, 2H), 2.57 (s, 2H), 1.15 (s, 3H), 1.00 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.49, 156.89, 155.92, 149.76, 147.80, 146.75, 144.02, 141.32, 134.13, 126.16, 125.34, 123.24, 121.00, 119.83, 107.58, 105.49, 94.13 (d, J = 214.8 Hz), 74.49 (d, J = 22.8 Hz), 53.98 (d, J = 21.5 Hz), 36.97, 36.05, 33.38, 25.96, 15.78. HRMS (ESI) calcd. for C 27 H 25 FN3O4S [M+H] + 506.1544, found 506.1549.

[0144] Example 29

[0145] 6,6-dimethyl-3-((7-(4-(pyrrolidin-3-yloxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-53)

[0146] Compound I-53 was prepared (white solid, yield 68%) by reacting compound E4 with N-Boc-3-hydroxypyrrolidine according to the method of Reference Example 26. 1H NMR (300 MHz, DMSO-d6) δ 8.69 (d, J = 4.8 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.56 - 7.44 (m, 2H), 7.39 (d, J = 5.8 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 7.24 (dd, J = 2.3, 0.9 Hz, 1H), 4.78 (s, 2H), 4.77 - 4.73 (m, 1H), 2.68 - 2.63 (m, 2H), 2.58 (s, 2H), 2.56 - 2.52 (m, 1H), 2.42 - 2.33 (m, 1H), 1.57 - 1.48 (m, 2H), 1.16 (s, 3H), 0.98 (s, 3H).

[0147] Example 30

[0148] 6,6-dimethyl-3-((7-(4-(piperidin-4-ylmethoxy)benzofuran-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (I-54)

[0149] Compound I-54 (white solid, yield 73.2%) was prepared by the method of Reference Example 26, using compound E4 and N-Boc-4-piperidinemethanol. HRMS (ESI) calcd. for C 29 H 29 N3O4S [M+H] + 516.1952, found 516.1953.

[0150] Example 31

[0151] 3-((7-(4-chloro-7-(piperidin-4-yloxy)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-71)

[0152] Compound F2 was prepared by the method of Reference Example 1, using compound F1 (2.118 g, 13.88 mmol) and 2-bromo-5-methoxybenzene-1,2-diamine (2.016 g, 7.05 mmol). TLC monitoring showed the reaction was completed after 1 hour. The reaction mixture was diluted with 40 mL of ethyl acetate, washed with 40 mL of 1 N aqueous sodium hydroxide solution and 40 mL of saturated aqueous sodium chloride solution, respectively, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to give compound F2 as a brown oil (3.12 g, crude yield 97%), which was used in the next step without purification.

[0153] Compound F2 (2.73 g, 11.54 mmol) was dissolved in 35 mL of acetone, and benzoyl isothiocyanate (F3) (2.28 g, 13.85 mmol) was added at room temperature, and the reaction was carried out at reflux for 1 hour, and a large amount of insoluble matter was gradually generated in the system. The reaction was monitored by TLC, and after the reaction was completed, the system was cooled to room temperature, filtered, and the filter cake was washed with 10 mL of acetone, and then the filter cake was transferred to a mixed solvent of 20 mL of ethanol and 20 mL of water, and sodium hydroxide (1.385 g, 34.62 mmol) was added, and the temperature was raised to 80°C and the reaction was carried out for 4 hours. The reaction was monitored by TLC, and after the reaction was completed, the system was cooled to room temperature, 30 mL of water was added, and extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound F4 as an off-white solid (2.77 g, yield 81.2%).

[0154] Compound F4 (2.74 g, 9.27 mmol) was dissolved in 40 mL of chloroform, and liquid bromine (0.52 mL, 10.2 mmol) was slowly added dropwise at ice bath, and the temperature was raised to 60°C and the reaction was carried out for 8 hours. The reaction was monitored by TLC, and after the reaction was completed, the system was cooled to room temperature, 30 mL of saturated aqueous sodium thiosulfate solution was added to quench the residual liquid bromine, extracted with dichloromethane (30 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL x 3), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound F5 as an off-white solid (2.72 g, crude yield, quantitative), which was used directly in the next step without purification.

[0155] Compound F5 (2.72 g, 9.266 mmol) was added to 30 mL of tetrahydrofuran, and isopentyl nitrite (2.74 mL, 20.384 mmol) was added dropwise at room temperature, and the reaction was carried out at reflux for 2 hours. The reaction was monitored by TLC, and after the reaction was completed, the solvent was directly removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound F6 as a light yellow solid (1.82 g, yield 70.5%). 1 H NMR (400 MHz, Chloroform-d) δ 9.06 (s, 1H), 7.76 (s, 1H), 4.05 (s, 3H).

[0156] Compound F6 (1.814 g, 6.51 mmol) was added to a dry three-necked flask, replaced by argon for three times, 25 mL of anhydrous dichloromethane was added, and boron tribromide (2.0 M in DCM, 3.9 mL, 7.81 mmol) was slowly added dropwise under ice bath, and the reaction was carried out overnight at room temperature after dropping. TLC monitoring showed that the reaction was complete. The system was cooled to 0°C, 10 mL of methanol was slowly added to quench the residual boron tribromide, then 20 mL of saturated aqueous sodium bicarbonate solution was added and stirred for 10 minutes, extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound F7 as a light yellow solid (1.45 g, crude yield 84.2%), which was used directly in the next step without purification. 1 H NMR (300 MHz, Chloroform-d) δ 9.07 (s, 1H), 7.68 (s, 1H).

[0157] Compound F7 (79.4 mg, 0.3 mmol), N-Boc-4-hydroxypiperidine (B7) (72.5 mg, 0.36 mmol), and triphenylphosphine (102.3 mg, 0.39 mmol) were added to a dry Schlenk tube, replaced by argon for three times, 2 mL of anhydrous tetrahydrofuran was added, and diisopropyl azodicarboxylate (0.077 mL, 0.39 mmol) was slowly added dropwise under ice bath, and the reaction was carried out overnight at room temperature after dropping. TLC monitoring showed that the reaction was complete, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain compound F8 as a light yellow oil (130 mg, yield 97%). 1 H NMR (400 MHz, Chloroform-d) δ 9.03 (s, 1H), 7.77 (s, 1H), 4.67-4.59 (m, 1H), 3.98-3.87 (m, 2H), 3.25-3.17 (m, 2H), 2.01-1.93 (m, 2H), 1.93-1.83 (m, 2H), 1.50 (s, 9H).

[0158] Compound F8 (125 mg, 0.279 mmol), compound A8 (345.3 mg, 0.837 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (11.4 mg, 0.013 mmol) and potassium carbonate (77 mg, 0.558 mmol) were added into 3 mL of 1.4-dioxane and 0.5 mL of water, replaced with argon for 3 times, heated at 90 °C for 4 hours. TLC monitoring reaction was completed, the reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound F9 as a light yellow oil (160 mg, crude yield 87.7%), which was directly used in the next step reaction.

[0159] Compound F9 (160 mg, 0.245 mmol) was dissolved in 2 mL of dichloromethane, and trifluoroacetic acid (0.281 mL, 3.674 mmol) was slowly added dropwise under ice bath, and the reaction was carried out at room temperature for 4 hours. TLC monitoring reaction was completed, 5 mL of dichloromethane was added to dilute, then saturated aqueous sodium bicarbonate solution was added to neutralize, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (5 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain compound I-71 as a white solid (75.1 mg, yield 55.4%). 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.87 - 3.79 (m, 1H), 2.61 - 2.58 (m, 1H), 2.58 (s, 2H), 2.57 - 2.54 (m, 1H), 2.14 - 2.06 (m, 2H), 1.43 - 1.35 (m, 2H), 1.15 (s, 3H), 1.14 - 1.09 (m, 2H), 0.98 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 173.52, 159.80, 156.09, 151.96, 149.03, 148.24, 144.39, 139.72, 133.35, 130.44, 128.29, 127.77, 125.44, 122.26, 120.73, 85.11, 53.30, 45.36, 36.94, 36.09, 33.39, 33.37, 25.96, 15.77. HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 553.1129, found 553.1137.

[0160] Example 32

[0161] 3-((7-(4-chloro-7-(piperidin-3-yloxy)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-72)

[0162] Compound I-72 was prepared (white solid, yield 60.9%) by reacting compound F7 with N-Boc-3-hydroxypiperidine according to the method of Reference Example 31. 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.55 (s, 1H), 7.50 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.69 - 3.62 (m, 1H), 2.60 - 2.54 (m, 3H), 2.49 - 2.44 (m, 1H), 2.24 - 2.14 (m, 2H), 1.54 - 1.47 (m, 1H), 1.39 - 1.32 (m, 1H), 1.22 - 1.12 (m, 4H), 1.04 - 0.96 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 173.52, 159.80, 156.09, 151.96, 149.03, 148.24, 144.39, 139.72, 133.35, 130.44, 128.29, 127.77, 125.44, 122.26, 120.73, 85.11, 53.30, 45.36, 36.94, 36.09, 33.39, 33.37, 25.96, 15.77. HRMS (ESI) calcd. for C 27H 26 CIN4O3S2 [M+H] + 553.1129, found 553.1142.

[0163] Example 33

[0164] 3-((7-(4-chloro-7-((3-fluoroazetidin-3-yl)methoxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-74)

[0165] Compound I-73 (white solid, yield 57.3%) was prepared by the method of Reference Example 31, using compound F7 and N-Boc-3-hydroxypyrrolidine. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.78 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.45 - 4.40 (m, 1H), 2.58 (s, 2H), 2.57 - 2.52 (m, 2H), 2.49 - 2.37 (m, 2H), 1.50 - 1.35 (m, 2H), 1.15 (s, 3H), 0.98 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.52, 159.80, 156.09, 151.96, 149.03, 148.24, 144.39, 139.72, 133.35, 130.44, 128.29, 127.77, 125.44, 122.26, 120.73, 85.11, 53.30, 45.36, 36.94, 36.09, 33.39, 33.37, 25.96, 15.77. HRMS (ESI) calcd. for C 27 H 26 CIN4O3S2 [M+H] + 539.0973, found 539.0984.

[0166] Example 34

[0167] 3-((7-(4-chloro-7-((3-fluoroazetidin-3-yl)methoxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-74)

[0168] Compound I-74 (white solid, yield 58.6%) was prepared by the reaction of compound F7 with 3-fluoro-3-(hydroxymethyl)azetidine-1-carboxylic acid tert-butyl ester according to the method described in Reference Example 31. 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.81 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.04 (s, 1H), 3.98 (s, 1H), 3.31 - 3.26 (m, 2H), 3.07 - 3.00 (m, 2H), 2.58 (s, 2H), 1.15 (s, 3H), 1.00 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.51, 159.93, 156.11, 152.13, 149.91, 148.21, 144.41, 139.04, 133.38, 129.83, 128.27, 127.41, 125.38, 122.76, 120.72, 93.79 (d, J = 215.3 Hz), 74.72 (d, J = 22.5 Hz), 53.91 (d, J = 21.1 Hz), 36.96, 36.09, 33.39, 25.96, 15.80. HRMS (ESI) calcd. for C 26 H 23 ClFN4O3S2[M+H] + 557.0879, found 557.0884.

[0169] Example 35

[0170] 3-((7-(4-Chloro-7-(piperidin-4-ylmethoxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-75)

[0171] Compound I-75 (white solid, yield 63.3%) was prepared by the reaction of compound F7 with N-Boc-4-piperidinemethanol according to the method described in Reference Example 31. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.55 (s, 1H), 7.46 (d, J = 4.8 Hz, 1H), 4.79 (s, 2H), 3.52 (d, J = 6.1 Hz, 2H), 2.75 - 2.68 (m, 2H), 2.58 (s, 2H), 2.24 - 2.14 (m, 2H), 1.44 - 1.34 (m, 1H), 1.26 - 1.17 (m, 2H), 1.16 (s, 3H), 1.01 (s, 3H), 0.81 - 0.69 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 178.24, 164.46, 160.78, 156.90, 155.03, 152.93, 149.20, 144.27, 138.36, 134.41, 132.95, 132.28, 130.06, 127.04, 125.40, 83.47, 50.47, 41.74, 41.49, 40.82, 38.15, 34.07, 30.71, 20.58. HRMS (ESI) calcd. for C 28 H 28 ClN4O3S2[M+H] + 567.1286, found 567.1294.

[0172] Example 36

[0173] 3-((7-(7-(2-Aminoethoxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-76)

[0174] Compound I-76 was prepared (white solid, yield 69.2%) by reacting compound F7 with N-Boc ethanolamine according to the method of Reference Example 31. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.55 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.68 (t, J = 5.7 Hz, 2H), 2.58 (s, 2H), 2.49 - 2.48 (m, 2H), 1.16 (s, 3H), 1.01 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 172.42, 158.66, 155.05, 151.03, 149.29, 147.17, 143.34, 138.48, 132.34, 128.52, 127.17, 126.03, 124.30, 121.08, 119.53, 75.35, 40.75, 35.91, 34.98, 32.36, 24.90, 14.75. HRMS (ESI) calcd. for C 24 H 22 ClN4O3S2[M+H] + 513.0816, found 513.0833.

[0175] Example 37

[0176] 3-((7-(4-Chloro-7-(piperidin-3-ylmethoxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-77)

[0177] Compound I-77 was prepared according to the procedure described in Reference Example 31 by reacting compound F7 with N-Boc-3-piperidinemethanol (white solid, yield 66.5%). 1 H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.55 (s, 1H), 7.46 (d, J = 4.8 Hz, 1H), 4.79 (s, 2H), 3.59 - 3.53 (m, 2H), 2.74 - 2.64 (m, 1H), 2.63 - 2.55 (m, 3H), 2.27 - 2.15 (m, 1H), 1.99 - 1.89 (m, 1H), 1.54 - 1.41 (m, 1H), 1.35 - 1.26 (m, 2H), 1.18 - 1.09 (m, 4H), 1.00 (s, 3H), 0.87 - 0.74 (m, 1H). 13C NMR(101MHz,DMSO-d6)δ172.41,158.64,158.60,154.97,151.08,149.15,147.11,143.36,138.40,132.47,128.36,127.15,126.26, 124.25,121.18,119.51,75.59,47.74,45.20,35.92,35.80,34.98,34.96,32.33,26.02,24.88,24.04,14.74.HRMS(ESI)calcd.for C 28 H 28 ClN4O3S2[M+H] + 567.1286, found 567.1292.

[0178] Example 38

[0179] 3-((7-(7-((1r,3r)-3-aminocyclobutyloxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-78)

[0180] Referring to the method of Example 31, compound F7 was reacted with tert-butyl (cis-3-hydroxycyclobutyl)carbamate to prepare compound I-78 (white solid, yield 59.1%). 1 H NMR(400MHz, DMSO-d6)δ9.61(s,1H),8.76(d,J=4.8Hz,1H),7.75(s,1H),7.55(s,1H),7.46(d,J=4.8Hz,1H),4.81(s,2H),4.59–4 .53(m,1H),3.26–3.20(m,1H),2.59(s,2H),1.99–1.89(m,2H),1.74–1.64(m,2H),1.17(s,3H),1.02(s,3H).HRMS(ESI)calcd.for C 26 H 23 ClN4O3S2[M+H] + 539.0973,found 539.0980.

[0181] Example 39

[0182] 3-((7-(7-(((1s,3s)-3-aminocyclobutyl)methoxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-79)

[0183] Referring to the method of Example 31, compound F7 was reacted with cis-tert-butyl 3-hydroxymethylcyclobutylcarbamate to prepare compound I-79 (white solid, yield 63.6%). 1 H NMR (300MHz, DMSO-d6) δ9.62(s,1H),8.76(d,J=4.8Hz,1H),7.77(s,1H),7.56(s,1H),7.48(d,J=4.8Hz,1H),4.81(s,2H) ,3.65(d,J=5.6Hz,2H),3.00–2.89(m,1H),2.59(s,2H),1.96–1.73(m,4H),1.16(s,3H),1.10–1.04(m,1H),1.01(s,3H). HRMS(ESI)calcd.for C 26 H 24 ClN4O3S2[M+H] + 553.1129, found 553.1127.

[0184] Example 40

[0185] 3-((7-(4-chloro-7-(((S)-piperidin-3-yl)oxy)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-80)

[0186] Referring to the method of Example 31, compound F7 was reacted with (R)-N-Boc-3-hydroxypiperidine to prepare compound I-80 (white solid, yield 61.3%). 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.50 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.69 - 3.62 (m, 1H), 2.60 - 2.55 (m, 3H), 2.49 - 2.44 (m, 1H), 2.25 - 2.14 (m, 2H), 1.55 - 1.46 (m, 1H), 1.40 - 1.31 (m, 1H), 1.20 - 1.11 (m, 4H), 1.04 - 0.95 (m, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 172.39, 158.58, 155.06, 150.85, 147.84, 147.13, 143.28, 138.66, 132.25, 129.89, 127.20, 126.91, 124.32, 121.29, 119.59, 78.88, 49.90, 44.34, 35.89, 34.93, 32.35, 30.01, 24.92, 23.41, 14.74. HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 553.1129, found 553.1140.

[0187] Example 41

[0188] 3-((7-(4-Chloro-7-(((R)-piperidin-3-yl)oxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-81)

[0189] Compound I-81 was prepared (white solid, yield 56.8%) by the method described in Reference Example 31, using compound F7 and (S)-N-Boc-3-hydroxypiperidine. 1H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.55 (s, 1H), 7.50 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.70 - 3.63 (m, 1H), 2.58 (s, 3H), 2.21 (tdd, J = 11.7, 8.9, 3.6 Hz, 2H), 1.55 - 1.46 (m, 1H), 1.36 (dt, J = 14.0, 4.7 Hz, 1H), 1.16 (s, 4H), 1.00 (s, 4H). 13 C NMR (101 MHz, DMSO-d6) δ 173.49, 159.71, 156.11, 151.91, 148.87, 148.22, 144.35, 139.70, 133.30, 130.99, 128.29, 127.98, 125.40, 122.39, 120.68, 79.86, 50.83, 45.32, 36.95, 36.06, 36.04, 33.39, 30.99, 25.97, 24.32, 15.81. HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 553.1129, found 553.1139.

[0190] Example 42

[0191] 3-((7-(4-chloro-7-(((S)-pyrrolidin-3-yl)oxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-82)

[0192] Compound I-82 was prepared (white solid, yield 55.7%) by reacting compound F7 with (R)-N-Boc-3-hydroxypyrrolidine according to the method of Reference Example 31. 1H NMR (300 MHz, Chloroform-d) δ 9.14 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.33 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.47 - 4.41 (m, 1H), 2.93 - 2.86 (m, 1H), 2.79 - 2.64 (m, 2H), 2.56 - 2.48 (m, 1H), 2.37 (s, 2H), 1.68 - 1.62 (m, 1H), 1.59 - 1.50 (m, 1H), 1.22 (s, 3H), 1.10 (s, 3H).

[0193] HRMS (ESI) calcd for C 27 H 26 ClN4O3S2[M+H] + 539.0973, found 539.0969.

[0194] Example 43

[0195] 3-((7-(4-chloro-7-(((R)-pyrrolidin-3-yl)oxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-83)

[0196] Compound I-83 was prepared (white solid, yield 58%) by reacting compound F7 with (S)-N-Boc-3-hydroxypyrrolidine according to the procedure of Reference Example 31. 1 H NMR (300 MHz, Chloroform-d) δ 9.14 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.64 (s, 1H), 7.60 (s, 1H), 7.33 (d, J = 4.8 Hz, 1H), 4.84 (s, 2H), 4.47 - 4.41 (m, 1H), 2.93 - 2.86 (m, 1H), 2.79 - 2.64 (m, 2H), 2.56 - 2.48 (m, 1H), 2.37 (s, 2H), 1.68 - 1.62 (m, 1H), 1.59 - 1.50 (m, 1H), 1.22 (s, 3H), 1.10 (s, 3H).HRMS (ESI) calcd for C 27 H 26 ClN4O3S2[M+H] + 539.0973, found 539.0970.

[0197] Example 44

[0198] 3-((7-(7-(azepan-4-yloxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-84)

[0199] Compound I-84 was prepared (white solid, yield 55.4%) by the method described in Reference Example 31, using the reaction of compound F7 with 4-hydroxyazepan-1-carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.56 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.07 - 4.02 (m, 1H), 2.58 (s, 2H), 2.48 - 2.44 (m, 2H), 2.40 - 2.33 (m, 1H), 2.22 - 2.14 (m, 1H), 1.57 - 1.30 (m, 6H), 1.16 (s, 3H), 1.00 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 172.40, 158.60, 155.00, 150.83, 147.91, 147.13, 143.29, 138.78, 132.38, 129.74, 127.20, 127.00, 124.34, 121.08, 119.62, 82.72, 47.20, 44.55, 41.71, 35.87, 34.97, 32.29, 31.37, 24.88, 23.01, 14.72. HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 567.1286, found 567.1284.

[0200] Example 45

[0201] 3-((7-(7-(3-aminopropoxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-85)

[0202] Compound I-85 (white solid, yield 65.7%) was prepared by the method described in Reference Example 31, using compound F7 and tert-butyl N-(3-hydroxypropyl)carbamate. 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.75 (s, 1H), 7.55 (s, 1H), 7.47 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.81 (t, J = 6.2 Hz, 2H), 2.58 (s, 2H), 2.30 (t, J = 6.7 Hz, 2H), 1.42 (p, J = 6.5 Hz, 2H), 1.17 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 527.0973, found 527.0969.

[0203] Example 46

[0204] 3-((7-(7-(azepan-3-yloxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-86)

[0205] Compound I-86 (white solid, yield 51.3%) was prepared by the method described in Reference Example 31, using compound F7 and tert-butyl 3-hydroxyazepane-1-carboxylate. 1 H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 3.94 - 3.85 (m, 1H), 2.69 - 2.62 (m, 1H), 2.61 - 2.54 (m, 3H), 2.46 - 2.37 (m, 2H), 1.45 - 1.36 (m, 2H), 1.35 - 1.20 (m, 3H), 1.16 (s, 3H), 1.00 (s, 3H), 0.98 - 0.90 (m, 1H). HRMS (ESI) calcd. for C 28 H 28 ClN4O3S2[M+H] + 567.1286, found 567.1285.

[0206] Example 47

[0207] 3-((7-(7-((1,4-oxazepan-6-yl)oxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-87)

[0208] Compound I-87 (white solid, yield 60.5%) was prepared by the method described in Reference Example 31, using compound F7 and 6-hydroxy-1,4-oxazepane-4-carboxylic acid tert-butyl ester. 1 H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 3.87 - 3.79 (m, 1H), 3.58 - 3.45 (m, 2H), 3.32 - 3.20 (m, 2H), 2.66 - 2.53 (m, 6H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 27 H 26 ClN4O4S2[M+H] + 569.1079, found 569.1077.

[0209] Example 48

[0210] 3-((7-(4-chloro-7-((tetrahydro-2H-pyran-4-yl)oxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-88)

[0211] Compound I-88 (white solid, yield 39.1%) was prepared by the method described in Reference Example 31, using compound F7 and tetrahydropyran-4-ol. 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.51 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.09 - 3.99 (m, 1H), 3.45 - 3.38 (m, 2H), 3.12 - 3.01 (m, 2H), 2.59 (s, 2H), 1.53 - 1.42 (m, 2H), 1.31 - 1.21 (m, 2H), 1.16 (s, 3H), 0.98 (s, 3H). HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 554.0970, found 554.0968.

[0212] Example 49

[0213] 3-((7-(4-chloro-7-((1-methylpiperidin-4-yl)oxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-89)

[0214] Compound I-89 was prepared according to the procedure described in Reference Example 31 by reacting compound F7 with N-methyl-4-hydroxypiperidine (light yellow solid, yield 31.8%). 1 H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 7.80 (s, 1H), 7.56 (s, 1H), 7.51 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.09 - 3.99 (m, 1H), 3.45 - 3.38 (m, 2H), 3.12 - 3.01 (m, 2H), 2.59 (s, 2H), 1.53 - 1.42 (m, 2H), 1.31 - 1.21 (m, 2H), 1.16 (s, 3H), 0.98 (s, 3H). HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 567.1286, found 567.1280.

[0215] Example 50

[0216] 3-((7-(4-chloro-7-(octahydrocyclopenta[c]pyrrol-5-yl)oxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-90)

[0217] Compound I-90 was prepared (white solid, 54.2% yield) by the method described in Reference Example 31 using compound F7 and tert-butyl 5-hydroxyhexahydrocyclopenta[c]pyrrole-2(lH)-carboxylate. 1 H NMR (300 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.49 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.44 - 4.40 (m, 1H), 2.59 (s, 2H), 2.46 - 2.39 (m, 2H), 2.30 - 2.23 (m, 2H), 2.17 - 2.08 (m, 2H), 1.70 - 1.60 (m, 2H), 1.16 (s, 3H), 1.12 - 1.03 (m, 2H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 579.1286, found 579.1284.

[0218] Example 51

[0219] 6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hex-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)-7- ((3-fluorazetidin-3-yl)methoxy)benzo[d]thiazole-4-carbonitrile (I-91)

[0220] tert-Butyl 3-(((4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3- yl)methyl)thieno[3,2-b]pyridin-7-yl)benzo[d]thiazol-7-yl)oxy)methyl]-3-fluoroazetidine- 1-carboxylate (G1, refer to synthesis of Example 31) (630 mg, 0.944 mmol) was dissolved in 4.5 mL of N-methylpyrrolidine, zinc cyanide (1.109 g, 9.44 mmol) and bis(tri-tert-butylphosphine)palladium (96.9 mg, 0.189 mmol) were added, and the reaction was replaced with argon three times, and the temperature was raised to 100 °C for 9 hours. TLC monitoring showed that the reaction was complete, the reaction was cooled to room temperature, and the reaction was filtered with celite, the filter cake was washed with a small amount of ethyl acetate, the filtrate was added to 20 mL of water, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound G2 as a light yellow oil (370 mg, yield 59.6%). 1 H NMR (400 MHz, Chloroform-d) δ 9.30 (s, 1H), 8.82 (d, J = 4.8 Hz, 1H), 7.98 (s, 1H), 7.65 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 4.87 (s, 2H), 4.01 (s, 1H), 3.97 - 3.88 (m, 3H), 3.82 - 3.73 (m, 2H), 2.42 (s, 2H), 1.44 (s, 9H), 1.26 (s, 3H), 1.14 (s, 3H).

[0221] Compound G2 (60 mg, 0.093 mmol) was dissolved in 1 mL of dichloromethane, and trifluoroacetic acid (106 μL, 1.395 mmol) was slowly added dropwise under ice bath, and the reaction was allowed to react at room temperature for 4 hours. TLC monitoring showed that the reaction was complete, the reaction was diluted with 5 mL of dichloromethane, then neutralized with saturated aqueous sodium bicarbonate solution, and extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine (5 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound I-91 as a white solid (41 mg, yield 80.9%). 1H NMR (400 MHz, Chloroform-d) δ 9.17 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.61 (s, 1H), 7.42 (s, 1H), 7.10 (d, J = 4.7 Hz, 1H), 4.85 - 4.78 (m, 2H), 4.43 - 4.35 (m, 1H), 3.59 (s, 2H), 3.56 - 3.51 (m, 2H), 2.86 - 2.76 (m, 2H), 2.36 (s, 2H), 2.19 (d, J = 7.1 Hz, 1H), 1.22 (s, 3H), 1.10 (s, 3H). HRMS (ESI) calcd. for C 27 H 23 FN5O3S2[M+H] + 548.1221, found 548.1221.

[0222] Example 52

[0223] 7-(azepan-4-yloxy)-6-(2-(((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3- yl)methyl)thieno[3,2-b]pyridin-7-yl)benzo[d]thiazole-4-carbonitrile (I-92)

[0224] Referring to the method of Example 51, the compound G1 is replaced with tert-butyl 4-((4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3- yl)methyl)thieno[3,2-b]pyridin-7-yl)benzo[d]thiazol-7-yl)oxy)azepane-1-carboxylate (reference to the synthesis method of Example 31 and I84) to prepare the compound I-92 (white solid, yield 76.5%). 1 H NMR (400 MHz, DMSO-d6) δ 9.79 (s, 1H), 9.02 (s, 2H), 8.79 (d, J = 4.8 Hz, 1H), 8.27 (s, 1H), 7.57 (s, 1H), 7.50 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.40 - 4.35 (m, 1H), 2.96 - 2.67 (m, 5H), 2.59 (s, 2H), 1.93 - 1.83 (m, 1H), 1.79 - 1.67 (m, 1H), 1.66 - 1.44 (m, 4H), 1.37 - 1.31 (m, 1H), 1.01 (s, 4H). 13C NMR (101 MHz, DMSO-d6) δ 173.51, 162.11, 156.21, 156.10, 153.50, 148.36, 144.56, 139.10, 134.53, 133.42, 129.33, 127.35, 125.40, 120.79, 116.72, 101.86, 81.61, 45.32, 39.10, 37.00, 36.11, 33.42, 32.10, 30.44, 25.95, 18.82, 15.85. HRMS (ESI) calcd. for C 29 H 28 N5O3S2[M+H] + 558.1628, found 558.1626.

[0225] Example 53

[0226] 3-((7-(4-chloro-7-(piperazin-1-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-93)

[0227] Dissolve 2-methyl-4-nitro-5-chloroaniline (H1) (9.33 g, 50 mmol) in 175 mL acetic acid, add 14 mL hydrobromic acid, add sodium nitrite (3.45 g, 50 mmol) in batches at room temperature, and heat to 85 °C for 3 hours. Monitor the reaction completion by TLC, cool the reaction to room temperature, add 200 mL ice water, and a large amount of solid is precipitated. Filter, wash the filter cake with water 3 times, and freeze-dry to obtain orange solid of compound H2 (11.7 g, crude yield 93.3%), which is used directly in the next step without further purification.

[0228] Dissolve compound H2 (9.7 g, 38.68 mmol) in 90 mL anhydrous ethanol, add stannous chloride dihydrate (34.9 g, 154.74 mmol), replace with argon for 3 times, heat to 70 °C for 2 hours. Monitor the reaction completion by TLC, place the reaction bottle in an ice bath, and slowly add 4 mol / L sodium hydroxide aqueous solution to adjust the pH to about 8. A large amount of solid is precipitated. Filter, wash the filter cake with ethyl acetate several times, add 150 mL water to the filtrate, extract with ethyl acetate (100 mL x 3), wash the combined organic phase with saturated sodium chloride aqueous solution (100 mL x 2), and evaporate the solvent under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 50:1) to obtain white solid of compound H3 (5.82 g, yield 68.2%). 1H NMR (300 MHz, CDCI3) δ 7.39 (s, 1 H), 6.65 (s, 1 H), 3.98 (s, 2 H), 2.28 (s, 3 H).

[0229] Compound H3 (5.8 g, 26.3 mmol) was dissolved in 80 mL of acetone, and benzoylisothiocyanate (F3) (5.15 g, 31.57 mmol) was added at room temperature. The reaction was heated to reflux for 1 h, and a large amount of insoluble substance was gradually generated in the system. The reaction was monitored by TLC, and after the reaction was completed, the system was cooled to room temperature, filtered, and the filter cake was washed with 40 mL of n-hexane. Then the filter cake was transferred to a mixture of 50 mL of ethanol and 50 mL of water, and sodium hydroxide (3.156 g, 78.9 mmol) was added. The reaction was heated to 80 °C for 4 h. The reaction was monitored by TLC, and after the reaction was completed, the system was cooled to room temperature, 50 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 4). The combined organic phase was washed with saturated aqueous sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation to obtain compound H4 as an off-white solid (7.1 g, yield 96.6%). 1 H NMR (400 MHz, Chloroform-d) δ 7.73 - 7.67 (m, 2 H), 7.37 (s, 1 H), 6.10 (s, 2 H), 2.41 (s, 3 H).

[0230] Compound H4 (7.1 g, 25.4 mmol) was added to 100 mL of chloroform, and bromine (2.6 mL, 50.8 mmol) was added dropwise under ice bath. After stirring for 10 min after the dropwise addition was completed, the reaction was heated to 60 °C for 8 h, and the system gradually changed from clear to turbid. The reaction was monitored by TLC, and after the reaction was completed, the system was cooled to room temperature, and saturated sodium sulfite aqueous solution was added to quench the residual bromine until the red-brown color completely disappeared. The mixture was filtered, the filter cake was washed with water, and the filter cake was dried to obtain compound H5 as a white solid (7 g, crude yield about 100%), which was directly used in the next step without purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 2 H), 7.55 (s, 1 H), 2.40 (s, 3 H).

[0231] Compound H5 (7.0 g, 25.22 mmol) was added to 85 mL of tetrahydrofuran, and isoamyl nitrite (5.91 g, 6.78 mL) was added dropwise under ice bath. After the dropwise addition was completed, the reaction was heated to reflux for 2 h. The reaction was monitored by TLC, and after the reaction was completed, the system was cooled to room temperature, 100 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated brine (50 mL x 2), and the solvent was removed by reduced pressure evaporation. The residue was slurried with a mixture of petroleum ether: ethyl acetate = 100 mL: 20 mL to obtain compound H6 as a yellow solid (4.1 g, yield 61.9%).1 H NMR (400 MHz, Chloroform-d) δ 9.03 (s, 1H), 7.76 (s, 1H), 2.64 (s, 3H).

[0232] Compound H6 (2 g, 7.62 mmol) was added to a mixed solvent of 50 mL of pyridine and 50 mL of water, and potassium permanganate (9.63 g, 60.9 mmol) was added portionwise with stirring at room temperature, and then the reaction was heated to reflux for 6 hours. The reaction was monitored by TLC, and after the reaction was completed, the reaction solution was cooled to room temperature, suction filtered through celite, and the filter cake was washed with ethyl acetate. Most of the filtrate was removed under reduced pressure, and 100 mL of ethyl acetate was added to the residue to dilute it, and then it was back-extracted with 4 mol / L aqueous sodium hydroxide solution (50 mL x 2). The combined aqueous phase was then adjusted to a pH of about 2 with 6 mol / L hydrochloric acid, and a large amount of solid was precipitated. The solid was suction filtered, and the filter cake was washed with water and dried to obtain compound H7 as a light yellow solid (2.15 g, crude yield 96.5%), which was used directly in the next reaction without purification. 1 H NMR (400 MHz, DMSO-d6) δ 14.47 (s, 1H), 9.55 (s, 1H), 8.11 (s, 1H).

[0233] Compound H7 (146 mg, 0.5 mmol), N-Boc piperazine (H8) (111.8 mg, 0.6 mmol), EDCI (143.8 mg, 0.75 mmol), HOBt (101.3 mg, 0.75 mmol), and triethylamine (174 μL, 1.25 mmol) were sequentially added to 2 mL of N,N-dimethylformamide, and the reaction was heated to 70°C for 5 hours. The reaction was monitored by TLC, and after the reaction was completed, the system was cooled to room temperature, 10 mL of water was added, and extraction was performed with ethyl acetate (10 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound H9 as a light yellow oil (120 mg, yield 52.2%). 1 H NMR (400 MHz, Chloroform-d) δ 9.11 (s, 1H), 7.82 (s, 1H), 3.96-3.89 (m, 1H), 3.85-3.78 (m, 1H), 3.71-3.64 (m, 1H), 3.60-3.51 (m, 2H), 3.34-3.26 (m, 2H), 3.25-3.16 (m, 1H), 1.49 (s, 9H).

[0234] Compound H9 (105 mg, 0.228 mmol), compound A8 (281.8 mg, 0.684 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (8.3 mg, 0.011 mmol) and potassium carbonate (62.9 mg, 0.456 mmol) were added into 3 mL of 1.4-dioxane and 0.5 mL of water, replaced with argon for 3 times, heated at 90 °C for 4 h. TLC monitoring reaction was completed, the reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride (10 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound H10 as a light yellow oil (58 mg, crude yield 38.2%), which was directly used in the next step reaction.

[0235] Compound H10 (58 mg, 0.087 mmol) was dissolved in 1 mL of dichloromethane, trifluoroacetic acid (100 μL, 1.306 mmol) was slowly added dropwise under ice bath, and the reaction was carried out at room temperature for 4 h. TLC monitoring reaction was completed, 5 mL of dichloromethane was added to dilute, then saturated aqueous sodium bicarbonate was added to neutralize, and then dichloromethane was extracted (5 mL x 2), the combined organic phase was washed with saturated brine (5 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound I-93 as a white solid (26 mg, yield 52.8%). 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.31-3.29 (m, 1H), 2.94-2.85 (m, 1H), 2.68-2.54 (m, 5H), 2.26-2.16 (m, 2H), 1.59-1.50 (m, 1H), 1.16 (s, 3H), 1.01 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.20, 160.61, 156.39, 150.68, 148.27, 144.81, 140.33, 135.39, 133.35, 132.31, 129.36, 128.21, 126.81, 125.67, 119.61, 47.95, 45.90, 45.43, 42.93, 36.98, 36.08, 33.43, 33.37, 25.96, 15.87. HRMS (ESI) calcd. for C 27 H 26CIN4O3S2 [M+H] + 566.1082, found 566.1077.

[0236] Example 54

[0237] 3-((7-(4-chloro-7-(1,4-diazepan-1- carbonyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2,4-dione (I-94)

[0238] The compound I-94 was prepared according to the procedure described in Reference Example 53, by replacing compound H8 with N-Boc homopiperazine to give compound I-94 (white solid, yield 55.4%). 1 H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 7.92 (s, 1H), 7.53 (s, 1H), 7.46 - 7.30 (m, 1H), 4.81 (s, 2H), 3.59 - 3.22 (m, 3H), 2.91 - 2.58 (m, 3H), 2.54 (s, 2H), 2.48 - 2.39 (m, 1H), 2.28 - 1.96 (m, 1H), 1.71 - 1.43 (m, 1H), 1.36 - 1.24 (m, 1H), 1.19 (s, 3H), 1.05 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.26, 166.63, 160.06, 156.61, 150.70, 148.13, 144.66, 140.36, 135.17, 133.32, 132.14, 130.38, 128.12, 126.89, 125.62, 119.72, 51.79, 49.46, 48.76, 48.02, 47.72, 46.68, 44.26, 37.06, 35.68, 33.70, 30.49, 28.87, 26.04, 15.89. HRMS (ESI) calcd. for C 27 H 26 CIN4O3S2 [M+H] + 580.1238, found 580.1234.

[0239] Example 55

[0240] 3-((7-(4-chloro-7-(2,8-diazaspiro[4.5]dec-8-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-97)

[0241] Compound I-97 (white solid, yield 57.3%) was prepared according to the procedure of Reference Example 53, replacing compound H8 with tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate. 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.78 - 8.71 (m, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.59 (s, 1H), 7.32 - 7.26 (m, 1H), 4.82 (s, 2H), 3.58 - 3.48 (m, 1H), 3.08 - 2.88 (m, 2H), 2.84 - 2.65 (m, 3H), 2.63 - 2.52 (m, 4H), 2.38 - 2.12 (m, 1H), 1.48 - 1.32 (m, 2H), 1.29 - 1.22 (m, 1H), 1.22 - 1.12 (m, 4H), 1.06 - 0.94 (m, 5H). HRMS (ESI) calcd. for C 31 H 31 ClN5O3S2[M+H] + 620.1551, found 620.1549.

[0242] Example 56

[0243] 3-((7-(7-(4-aminopiperidine-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-101)

[0244] Compound I-101 (white solid, yield 63.1%) was prepared according to the procedure of Reference Example 53, replacing compound H8 with 4-tert-butoxycarbonylamino piperidine. 1H NMR (300 MHz, DMSO-d6) δ 9.68 (d, J = 4.1 Hz, 1H), 8.73 (dd, J = 10.5, 4.8 Hz, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.59 (d, J = 5.5 Hz, 1H), 7.27 (dd, J = 17.8, 4.8 Hz, 1H), 4.82 (s, 2H), 4.10 - 3.96 (m, 1H), 3.29 - 3.14 (m, 2H), 3.13 - 2.97 (m, 1H), 2.95 - 2.80 (m, 1H), 2.76 - 2.54 (m, 4H), 1.64 - 1.49 (m, 2H), 1.17 (s, 3H), 1.02 (d, J = 7.6 Hz, 3H). HRMS (ESI) calcd. for C 28 H 27 ClN5O3S2[M+H] + 580.1238, found 580.1240.

[0245] Example 57

[0246] 3-((7-(4-Chloro-7-(piperazin-1-ylmethyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-102)

[0247] Compound H6 (2.437 g, 9.28 mmol), N-bromosuccinimide (1.735 g, 9.75 mmol), benzoyl peroxide (0.225 g, 0.928 mmol) were added into 45 mL of carbon tetrachloride successively, heated to reflux for 6 hours. After TLC monitoring reaction was substantially complete, the reaction was cooled to room temperature, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to obtain compound H11 as a light yellow solid (2.74 g, yield 86.5%). 1 H NMR (400 MHz, Chloroform-d) δ 9.12 (s, 1H), 7.82 (s, 1H), 4.83 (s, 2H).

[0248] Compound H11 (136.6 mg, 0.4 mmol), compound H8 (74.5 mg, 0.4 mmol) and triethylamine (111 μL, 0.8 mmol) were added into 2 mL of acetonitrile successively, stirred at room temperature overnight. After TLC monitoring reaction was complete, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain compound H12 as a white solid (163 mg, yield 91.8%).1 H NMR (300 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.77 (s, 1H), 3.90 (s, 2H), 3.55 - 3.47 (m, 4H), 2.57 - 2.46 (m, 4H), 1.48 (s, 9H).

[0249] Compound H12 (160 mg, 0.358 mmol), compound A8 (295.3 mg, 0.716 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (13.1 mg, 0.018 mmol) and potassium carbonate (98.8 mg, 0.716 mmol) were added into 3 mL of 1.4-dioxane and 0.5 mL of water, replaced by argon for 3 times, heated at 90 °C for 4 hours. TLC monitored the reaction was completed, the reaction solution was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:2) to obtain compound H13 as a light yellow oil (185 mg, crude yield 79.2%), which was directly used in the next step reaction.

[0250] Compound H13 (185 mg, 0.284 mmol) was dissolved in 2 mL of dichloromethane, and trifluoroacetic acid (326 μL, 4.25 mmol) was slowly added dropwise under ice bath, and the reaction was carried out at room temperature for 4 hours. TLC monitored the reaction was completed, diluted with 5 mL of dichloromethane, then neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine (5 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound I-102 as a white solid (107 mg, yield 68.3%). 1 H NMR (300 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.75 (d, J = 4.7 Hz, 1H), 7.62 (s, 1H), 7.58 (s, 1H), 7.33 (d, J = 4.7 Hz, 1H), 4.78 (s, 2H), 3.43 (s, 2H), 2.67 - 2.59 (m, 4H), 2.57 (s, 2H), 2.18 - 2.08 (m, 4H), 1.15 (s, 3H), 1.00 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 173.47, 161.69, 155.89, 150.74, 148.23, 144.74, 141.78, 135.10, 134.42, 133.98, 130.82, 126.88, 126.04, 125.50, 120.37, 58.63, 54.09, 45.62, 37.03, 36.05, 33.40, 25.96, 15.83. HRMS (ESI) calcd. for C 27 H 27 ClN5O3S2[M+H] + 552.1289, found 552.1287.

[0251] Example 58

[0252] 3-((7-(7-((1,4-Diazepan-1-yl)methyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-103)

[0253] Refer to the method of Example 57, replace compound H8 with N-Boc homopiperazine to prepare compound I-103 (white solid, yield 67.1%). 1 H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.86 (s, 1H), 8.76 (d, J = 4.7 Hz, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.34 (d, J = 4.7 Hz, 1H), 4.78 (s, 2H), 3.64 (d, J = 4.3 Hz, 2H), 3.09 - 2.98 (m, 4H), 2.71 - 2.65 (m, 2H), 2.59 (s, 2H), 2.49 - 2.44 (m, 2H), 1.82 - 1.73 (m, 2H), 1.16 (s, 3H), 1.02 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.47, 161.69, 155.89, 150.74, 148.23, 144.74, 141.78, 135.10, 134.42, 133.98, 130.82, 126.88, 126.04, 125.50, 120.37, 58.63, 54.09, 45.62, 37.03, 36.05, 33.40, 25.96, 15.83. HRMS (ESI) calcd. for C28 H 29 ClN5O3S2[M+H] + 566.1446, found 566.1445.

[0254] Example 59

[0255] 3-((7-(4-chloro-7-((3-oxopiperazin-1-yl)methyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-104)

[0256] Compound I-104 was prepared according to the procedure of Example 57, replacing compound H8 with 2-oxopiperazine (light yellow solid, yield 45.8%). 1 H NMR (400 MHz, DMSO-d6) δ 9.55 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.78 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.36 (d, J = 4.7 Hz, 1H), 4.79 (s, 2H), 3.62 (d, J = 14.6 Hz, 1H), 3.51 (d, J = 14.4 Hz, 1H), 3.14 - 3.06 (m, 2H), 2.82 (s, 2H), 2.58 (s, 2H), 2.45 - 2.41 (m, 2H), 1.16 (s, 3H), 1.02 (s, 3H). HRMS (ESI) calcd. for C 27 H 25 ClN5O3S2[M+H] + 566.1082, found 566.1082.

[0257] Example 60

[0258] 3-((7-(4-chloro-7-((2-oxopiperazin-1-yl)methyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-105)

[0259] Compound I-105 was prepared according to the procedure of Example 57, replacing compound H8 with 3-oxo-1-piperazinecarboxylic acid tert-butyl ester (white solid, yield 59.3%). 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.76 (d, J = 4.7 Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 7.43 (d, J = 4.7 Hz, 1H), 4.80 (s, 2H), 4.64 (d, J = 15.2 Hz, 1H), 4.54 (d, J = 15.2 Hz, 1H), 3.16 (d, J = 7.9 Hz, 2H), 2.73 - 2.67 (m, 2H), 2.66 - 2.61 (m, 2H), 2.59 (s, 2H), 1.16 (s, 3H), 1.03 (s, 3H). HRMS (ESI) calcd. for C 27 H 25 ClN5O3S2[M+H] + 566.1082, found 566.1080.

[0260] Example 61

[0261] 3-((7-(4-chloro-7-(3-hydroxyazetidin-1-yl)methyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-106)

[0262] Compound I-106 was prepared according to the procedure described in Reference Example 57, by replacing compound H8 with 3-hydroxyazetidine hydrochloride to give a white solid (yield 41.7%). 1 H NMR (400 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 7.63 (s, 1H), 7.45 (s, 1H), 7.13 (d, J = 4.7 Hz, 1H), 4.84 (d, J = 6.4 Hz, 2H), 4.41 (p, J = 6.0 Hz, 1H), 3.62 (d, J = 1.3 Hz, 2H), 3.56 (td, J = 6.3, 2.0 Hz, 2H), 2.88 - 2.79 (m, 2H), 2.38 (s, 2H), 2.22 (d, J = 7.1 Hz, 1H), 1.24 (s, 3H), 1.13 (s, 3H).

[0263] Example 62

[0264] 3-((7-(7-chloro-4-(piperidin-4-yloxy)benzo[c][1,2,5]thiadiazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-115)

[0265] Dissolve 2-nitro-3-fluoro-4-bromoaniline (II) (4.724 g, 20.1 mmol) in 50 mL of anhydrous methanol, add sodium methoxide solid (1.303 g, 24.12 mmol), and warm to 70 °C for 4 hours. Monitor the reaction by TLC. When the reaction is complete, cool the reaction to room temperature, evaporate most of the solvent under reduced pressure, dilute the residue with 50 mL of water, extract with dichloromethane (40 mL x 3), wash the combined organic phases with saturated aqueous sodium chloride (30 mL x 2), and evaporate the solvent under reduced pressure. Purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound I2 as a yellow solid (3.784 g, yield 76.2%). 1 H NMR (400 MHz, Chloroform-d) δ 7.01 (s, 1H), 3.84 (s, 3H), 3.71 (s, 4H).

[0266] Dissolve compound I2 (1.146 g, 4.639 mmol) in 20 mL of acetonitrile, add N- chlorosuccinimide (0.65 g, 4.871 mmol), and warm to 80 °C for 6 hours. Monitor the reaction by TLC. When the reaction is complete, cool the reaction to room temperature, evaporate most of the solvent under reduced pressure, dilute the residue with 30 mL of water, extract with ethyl acetate (15 mL x 3), wash the combined organic phases with saturated aqueous sodium chloride (15 mL x 2), dry over anhydrous sodium sulfate, and evaporate the solvent under reduced pressure to obtain compound I3 as a dark red oil (1.3 g, yield quantitative). Use directly in the next step without further purification.

[0267] Dissolve compound I3 (1.30 g, 4.62 mmol) in a mixture of 23 mL of ethanol and 7 mL of water, and add zinc powder (1.51 g, 23.09 mmol) and ammonium chloride (1.235 g, 23.09 mmol) portionwise. Warm to 70 °C for 6 hours. Monitor the reaction by TLC. When the reaction is complete, cool the reaction to room temperature, evaporate most of the solvent under reduced pressure, dilute the residue with 30 mL of water, extract with ethyl acetate (20 mL x 3), wash the combined organic phases with saturated aqueous sodium chloride (15 mL x 2), evaporate the solvent under reduced pressure, and purify the residue by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain compound I4 as a red-brown oil (1.037 g, yield 89.4%). 1 H NMR (400 MHz, Chloroform-d) δ 7.01 (s, 1H), 3.84 (s, 3H), 3.71 (s, 4H).

[0268] Compound I4 (0.79 g, 3.141 mmol) was dissolved in 60 mL of chloroform, triethylamine (1.75 mL, 12.564 mmol) was added, and the ice bath was then slowly added with dropwise addition of thionyl chloride (0.46 mL, 6.282 mmol), and the temperature was raised to 60°C for 4 hours of reaction. The reaction was monitored by TLC, and after completion of the reaction, the reaction liquid was cooled to room temperature, 20 mL of saturated aqueous sodium bicarbonate solution was added to quench, extracted with dichloromethane (20 mL x 2), the combined organic phase was washed with saturated aqueous sodium chloride solution (15 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 100:1) to obtain compound I5 as a yellow solid (0.772 g, yield 87.9%). 1 H NMR (400 MHz, Chloroform-d) δ 7.81 (s, 1H), 4.41 (s, 3H).

[0269] Compound I5 (0.714 g, 2.554 mmol) was dissolved in 10 mL of toluene, anhydrous aluminum chloride (0.579 g, 4.342 mmol) was added, and the temperature was raised to 110°C for 6 hours of reaction. The reaction was monitored by TLC, and after completion of the reaction, the reaction liquid was cooled to room temperature, 10 mL of 1N hydrochloric acid was added to stir for 5 minutes, extracted with ethyl acetate (10 mL x 2), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), dried with anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain compound I6 as a yellow solid (0.65 g, crude yield 95.9%), which was directly used in the next step reaction without purification. 1 H NMR (400 MHz, Chloroform-d) δ 7.77 (s, 1H), 6.82 (s, 1H).

[0270] Compound I6 (79.7 mg, 0.3 mmol), N-Boc-4-hydroxypiperidine (B7) (72.5 mg, 0.36 mmol), and triphenylphosphine (102.3 mg, 0.39 mmol) were added to a dry Schlenk tube, argon was replaced three times, 2 mL of anhydrous tetrahydrofuran was added, and diisopropyl azodicarboxylate (0.077 mL, 0.39 mmol) was slowly added dropwise under ice bath, and the reaction was carried out overnight at room temperature. The reaction was monitored by TLC, and after completion of the reaction, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound I7 as a yellow oil (119 mg, yield 88.4%). 1 H NMR (400 MHz, Chloroform-d) δ 7.81 (s, 1H), 5.51-5.44 (m, 1H), 3.87-3.77 (m, 2H), 3.47-3.37 (m, 2H), 1.99-1.88 (m, 4H), 1.50 (s, 9H).

[0271] Compound I7 (116 mg, 0.258 mmol), compound A8 (319.7 mg, 0.775 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (10.6 mg, 0.013 mmol) and potassium carbonate (71.3 mg, 0.516 mmol) were added into 3 mL of 1.4-dioxane and 0.5 mL of water, replaced with argon for 3 times, heated at 90 °C for 4 hours. TLC monitoring reaction was completed, the reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1.5: 1) to obtain compound I8 as a yellow oil (130 mg, crude yield 76.9%), which was directly used in the next step reaction.

[0272] Compound I8 (130 mg, 0.199 mmol) was dissolved in 1.5 mL of dichloromethane, and trifluoroacetic acid (0.228 mL, 2.98 mmol) was slowly added dropwise under ice bath, and the reaction was carried out at room temperature for 4 hours. TLC monitoring reaction was completed, 5 mL of dichloromethane was added to dilute, then saturated aqueous sodium bicarbonate solution was added to neutralize, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (5 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound I-115 as a yellow solid (63.3 mg, yield 57.5%). 1 H NMR (400 MHz, Chloroform-d) δ 8.77 (d, J = 4.8 Hz, 1H), 7.71 (s, 1H), 7.61 (s, 1H), 7.37 (d, J = 4.8 Hz, 1H), 5.16 - 5.09 (m, 1H), 4.86 (s, 2H), 2.77 - 2.69 (m, 2H), 2.55 - 2.46 (m, 2H), 2.39 (s, 2H), 1.84 - 1.77 (m, 2H), 1.48 - 1.40 (m, 2H), 1.24 (s, 3H), 1.12 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.49, 156.04, 153.43, 149.76, 148.01, 145.22, 144.31, 139.52, 133.47, 130.32, 128.20, 125.33, 120.84, 118.89, 79.26, 42.80, 36.97, 36.06, 33.36, 31.93, 25.96, 15.82. HRMS (ESI) calcd. for C 26H 25 CIN5O3S2[M+H] + 554.1082, found 554.1092.

[0273] Example 63

[0274] 3-((7-(7-chloro-4-(piperidin-3-yloxy)benzo[c][l,2,5]thiadiazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-116)

[0275] Compound I-116 (yellow solid, yield 60.2%) was prepared according to the method described in Reference Example 62, using compound I6 and N-Boc-3-hydroxypiperidine. 1 H NMR (300 MHz, DMSO-d6) d 8.78 (d, J = 4.8 Hz, 1H), 7.99 (s, 1H), 7.58 (s, 1H), 7.54 (d, J = 4.8 Hz, 1H), 4.88 - 4.78 (m, 3H), 3.14 - 3.07 (m, 1H), 2.79 - 2.68 (m, 2H), 2.64 - 2.56 (m, 3H), 1.77 - 1.67 (m, 1H), 1.47 - 1.37 (m, 1H), 1.29 - 1.21 (m, 2H), 1.16 (s, 3H), 1.01 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) d 172.44, 172.40, 155.08, 152.34, 148.67, 147.07, 144.06, 143.31, 137.94, 132.24, 129.15, 127.14, 124.29, 119.83, 118.46, 75.82, 46.75, 42.62, 35.94, 34.97, 32.40, 32.37, 27.71, 24.90, 19.43, 14.77. HRMS (ESI) calcd. for C 26 H 25 CIN5O3S2[M+H] + 554.1082, found 554.1087.

[0276] Example 64

[0277] 3-((7-(7-chloro-4-(pyrrolidin-3-yloxy)benzo[c][l,2,5]thiadiazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (1-117)

[0278] Compound 1-117 was prepared according to the procedure described in Example 62 by reacting compound 16 with N-Boc-3-hydroxypyrrolidine (yellow solid, 54.9% yield). 1 H NMR (300 MHz, Chloroform-d) δ 8.78 (d, J = 4.8 Hz, 1H), 7.71 (s, 1H), 7.62 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 5.66 (s, 1H), 4.86 (s, 2H), 3.12 - 3.04 (m, 1H), 2.89 - 2.81 (m, 1H), 2.80 - 2.61 (m, 2H), 2.39 (s, 2H), 1.86 - 1.76 (m, 2H), 1.24 (s, 3H), 1.12 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.51, 156.07, 153.47, 149.51, 148.09, 145.24, 144.33, 139.32, 133.36, 130.29, 127.77, 125.37, 120.78, 118.81, 84.66, 53.21, 45.19, 36.96, 36.08, 33.37, 25.95, 15.82. HRMS (ESI) calcd. for C 25 H 23 ClN5O3S2[M+H] + 540.0925, found 540.0936.

[0279] Example 65

[0280] 3-((7-(7-chloro-4-(pyrrolidin-3-yloxy)benzo[c][l,2,5]thiadiazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (1-117)

[0281] Into a dried three-necked flask, 20 mL of anhydrous tetrahydrofuran was added, replaced by argon for three times, then DIPA (1.7 mL, 12 mmol) was added, followed by slow addition of n-BuLi (5 mL, 12 mmol) at -78 °C, after stirring for 0.5 h, a solution of 1-chloro-2-fluoro-4-methoxybenzene (J1) (1.3 mL, 10 mmol) in 20 mL of anhydrous tetrahydrofuran was slowly added, after stirring for 20 min, anhydrous N,N-dimethylformamide (2 mL, 26 mmol) was slowly added, and the reaction was carried out at -78 °C for 2 h. The reaction was monitored by TLC, and after the reaction was completed, 30 mL of saturated aqueous ammonium chloride solution was added at -78 °C to quench, and extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate for 2 h, filtered, and the filtrate was evaporated under reduced pressure to obtain compound J2 as a yellow powdery solid (2.4 g, yield 100%). 1 H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 7.57-7.51 (m, 1H), 6.78-6.73 (m, 1H), 3.94 (s, 3H).

[0282] Compound J2 (1 g, 5.3 mmol), 4-nitrobenzenesulfonic acid hydrate (108 mg, 0.53 mmol) and dibromohydantoin (910 mg, 3.2 mmol) were dissolved in 26.5 mL of 1,1,1,3,3,3-hexafluoro-2-propanol, and the reaction was carried out at 60 °C for 16 h. The reaction was monitored by TLC, and after the reaction was completed, 30 mL of saturated aqueous sodium thiosulfate solution was added to quench, and extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL x 2), and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30:1) to obtain compound J3 as a light yellow crystal (710 mg, yield 50.1%). 1 H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.87-7.82 (m, 1H), 3.96 (s, 3H).

[0283] Compound J3 (617 mg, 2.3 mmol) was dissolved in 12 mL of pyridine, and 1.2 mL of hydrazine hydrate was added, and the reaction was carried out at 100 °C for 6 h. The reaction was monitored by TLC, and after the reaction was completed, the reaction liquid was cooled to room temperature, and 30 mL of water was added, and extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with 1N hydrochloric acid (40 mL x 3) and saturated aqueous sodium chloride solution (40 mL) in turn, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound J4 as a beige powdery solid (368 mg, yield 61.2%). 1H NMR (400 MHz, CDC13) δ 10.28 (s, 1H), 8.26 (s, 1H), 7.51 (s, 1H), 4.24 (s, 3H).

[0284] Compound J4 (500 mg, 1.9 mmol) was added to a dry two-necked flask, replaced by argon for three times, 7 mL aqueous hydrobromic acid was added, heated to reflux at 100 °C for 10 hours. TLC monitored the reaction was completed, the reaction was cooled to room temperature, 30 mL water was added, extracted with ethyl acetate (20 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride (30 mL x 2), the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3: 1) to obtain compound J5 of light purple powder solid (410 mg, yield 87.2%). 1 H NMR (300 MHz, DMSO) δ 13.62 (s, 1H), 11.02 (s, 1H), 8.32 (s, 1H), 7.49 (s, 1H).

[0285] Compound J5 (130 mg, 0.52 mmol), N-Boc-4-hydroxypiperidine (B7) (126 mg, 0.63 mmol) and triphenylphosphine (178 mg, 0.68 mmol) were added to a dry Schlenk tube, replaced by argon for three times, 3.5 mL of anhydrous tetrahydrofuran was added, diisopropyl azodicarboxylate (0.13 mL, 0.68 mmol) was slowly added dropwise in an ice bath, and the reaction was carried out overnight at room temperature after dropping. TLC monitored the reaction was completed, the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5: 1) to obtain compound J6 of light yellow oil (205 mg, yield 93.5%). 1 H NMR (300 MHz, CDC13) δ 8.10 (s, 1H), 7.52 (s, 1H), 4.80-4.65 (m, 1H), 3.97-3.75 (m, 2H), 3.39-3.21 (m, 2H), 1.75-1.52 (m, 4H), 1.48 (s, 9H).

[0286] Compound J6 (135 mg, 0.31 mmol), compound A8 (388 mg, 0.94 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (12 mg, 0.016 mmol) and potassium carbonate (87 mg, 0.63 mmol) were added into 2.5 mL of 1.4-dioxane and 0.4 mL of water, replaced with argon for 3 times, heated at 100 °C for 4 hours. TLC monitoring reaction was completed, the reaction was cooled to room temperature, 10 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound J7 as a light yellow oil (63 mg, crude yield 21.5%), which was directly used in the next step reaction.

[0287] Compound J7 (63 mg, 0.1 mmol) was dissolved in 1.5 mL of dichloromethane, and hydrogen chloride solution in 1.4-dioxane (0.4 mL, 1.5 mmol) was slowly added dropwise in ice bath, and the reaction was carried out at room temperature for 4 hours. TLC monitoring reaction was completed, 3 mL of dichloromethane was added to dilute, then saturated sodium bicarbonate aqueous solution was added to neutralize, extracted with dichloromethane (5 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane: methanol = 15: 1) to obtain compound I-134 as a white solid (20 mg, yield 37.3%). 1 H NMR (300 MHz, DMSO-d6) d 8.71 (d, J = 4.8 Hz, 1H), 8.51 (s, 1H), 7.52 (d, J = 3.0 Hz, 2H), 7.41 (d, J = 4.9 Hz, 1H), 4.79 (s, 2H), 4.72 - 4.63 (m, 1H), 2.77 - 2.68 (m, 2H), 2.65 - 2.56 (m, 4H), 1.87 - 1.74 (m, 2H), 1.54 - 1.40 (m, 2H), 1.15 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 27 H 27 ClN5O3S[M+H] + 536.1518, found 536.1515.

[0288] Example 66

[0289] 3-((7-(4-(azepan-4-yloxy)-7-chloro-1H-indazol-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-135)

[0290] Compound I-135 (white solid, yield 47.3%) was prepared by the method described in Reference Example 65, using compound J5 and tert-butyl 4-hydroxyazepane-1-carboxylate. 1 H NMR (300 MHz, DMSO-d6) d 8.71 (d, J = 4.8 Hz, 1H), 8.49 (s, 1H), 7.52 (d, J = 7.1 Hz, 2H), 7.40 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.72 - 4.63 (m, 1H), 2.86 (d, J = 10.7 Hz, 2H), 2.74 (d, J = 4.1 Hz, 2H), 2.60 (s, 2H), 2.04 - 1.89 (m, 1H), 1.86 - 1.69 (m, 2H), 1.64 - 1.52 (m, 1H), 1.43 - 1.29 (m, 2H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 28 H 29 ClN5O3S[M+H] + 550.1675, found 550.1571.

[0291] Example 67

[0292] 3-((7-(7-chloro-4-(pyrrolidin-3-yloxy)-1H-indazol-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-136)

[0293] Compound I-136 (white solid, yield 15.9%) was prepared by the method described in Reference Example 65, using compound J5 and 1-Boc-3-hydroxypyrrolidine. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 4.8 Hz, 1H), 8.56 (s, 1H), 7.51 (d, J = 3.5 Hz, 2H), 7.42 (d, J = 4.8 Hz, 1H), 5.11 - 5.02 (m, 1H), 4.79 (s, 2H), 3.09 - 2.88 (m, 2H), 2.87 - 2.75 (m, 1H), 2.63 - 2.53 (m, 3H), 1.82 - 1.54 (m, 2H), 1.15 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 26 H 25 ClN5O3S[M+H] + 522.1361, found 552.1365.

[0294] Example 68

[0295] 3-((7-(7-chloro-4-(pyrrolidin-3-yloxy)-lH-indazol-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-153)

[0296] Compound 2-bromo-4-chloro-6-fluorophenol (Kl) (1 g, 4.4 mmol) was dissolved in 15 mL of anhydrous N,N-dimethylformamide, sodium hydride (213 mg, 5.3 mmol) was added portionwise at 0 °C, after stirring at room temperature for 30 min, iodomethane (331 μL, 5.3 mmol) was added dropwise slowly, and the reaction was warmed to 40 °C for 3 h. The reaction was monitored by TLC, and 40 mL of water was added to quench the reaction, and the organic phase was extracted with ethyl acetate (15 mL x 3), and the combined organic phase was washed with 1 N NaOH (20 mL x 3) and saturated aqueous sodium chloride (30 mL x 2), and the organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 6: 1) to give compound K2 as a light yellow oil (889 mg, yield 83.6%). 1 H NMR (300 MHz, DMSO-d6) δ 8.70 (d, J = 4.8 Hz, 1H), 8.56 (s, 1H), 7.51 (d, J = 3.5 Hz, 2H), 7.42 (d, J = 4.8 Hz, 1H), 5.11 - 5.02 (m, 1H), 4.79 (s, 2H), 3.09 - 2.88 (m, 2H), 2.87 - 2.75 (m, 1H), 2.63 - 2.53 (m, 3H), 1.82 - 1.54 (m, 2H), 1.15 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C

[0297] Compound K2 (544 mg, 2.3 mmol) was added to a double-necked flask which was dried and replaced with argon for 3 times, then 4.5 mL of anhydrous tetrahydrofuran was added, and LDA (1.3 mL, 2.5 mmol) was slowly added dropwise at -78 ℃, and stirred for 20 min, then anhydrous N, N-dimethylformamide (0.36 mL, 4.6 mmol) was slowly added, and reacted at -78 ℃ for 2 h. The reaction was monitored by TLC, and 30 mL of saturated aqueous ammonium chloride solution was added at -78 ℃ to quench, and extracted with ethyl acetate (15 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL x 2), and the organic solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 70:1) to obtain compound K3 as a light yellow powdery solid (389 mg, yield 63.2%). 1 H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.50 (s, 1H), 3.99 (s, 3H).

[0298] Compound K3 (380 mg, 1.4 mmol) was dissolved in 7.5 mL of pyridine, and 0.76 mL of hydrazine hydrate was added, and heated to 100 ℃ for 8 h. The reaction was monitored by TLC, and the reaction liquid was cooled to room temperature, and 30 mL of water was added, and extracted with ethyl acetate (20 mL x 3), and the combined organic phase was washed with 1N hydrochloric acid (40 mL x 3) and saturated aqueous sodium chloride solution (40 mL), and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound K4 as a light yellow powdery solid (286 mg, yield 77.0%). 1 H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.30 (s, 1H), 4.04 (s, 3H).

[0299] Compound K4 (3.3 g, 12.6 mmol) was added to a double-necked flask which was dried and replaced with argon for 3 times, then 26 mL of aqueous hydrobromic acid was added, and heated to reflux at 100 ℃ for 10 h. The reaction was monitored by TLC, and the reaction liquid was cooled to room temperature, and 100 mL of water was added, and extracted with ethyl acetate (30 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (50 mL x 2), and the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1) to obtain compound K5 as a light purple powdery solid (2.56 g, yield 82.5%). 1 H NMR (300 MHz, DMSO) δ 13.39 (s, 1H), 10.35 (s, 1H), 8.06 (m, 1H), 7.26 (s, 1H).

[0300] Compound K5 (200 mg, 0.81 mmol), N-Boc-4-hydroxypiperidine (B7) (195 mg, 0.97 mmol) and triphenylphosphine (275 mg, 1.05 mmol) were added into a dry Schlenk tube, purged with argon for three times, 5 mL of anhydrous tetrahydrofuran was added, diisopropyl azodicarboxylate (0.2 mL, 1.05 mmol) was added dropwise slowly under ice bath, and the reaction was carried out overnight after dropping. The reaction was monitored by TLC, and the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound K6 as a light yellow oil (420 mg, yield 97.5%). 1 H NMR (400 MHz, CDCl3) δ 10.66 (s, 1H), 8.09 (s, 1H), 7.30 (s, 1H), 4.56-4.44 (m, 1H), 4.07-3.97 (m, 2H), 3.06-2.98 (m, 2H), 2.05-1.97 (m, 2H), 1.87-1.78 (m, 2H), 1.48 (s, 9H).

[0301] Compound K6 (330 mg, 0.77 mmol), compound A8 (474 mg, 1.15 mmol), dichlorobis-(4-dimethylaminophenyl)palladium(II) (27 mg, 0.0385 mmol) and potassium phosphate (245 mg, 1.15 mmol) were added into 4.5 mL of a mixed solvent of dioxane and water (0.75 mL), purged with argon for three times, and heated at 100°C for 4 hours. The reaction was monitored by TLC, and the reaction solution was cooled to room temperature. 15 mL of water was added, extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2). The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound K7 as a light yellow oil (85 mg, crude yield 17.4%), which was directly used in the next step reaction.

[0302] Compound K7 (85 mg, 0.13 mmol) was dissolved in 1.5 mL of dichloromethane, and hydrogen chloride in dioxane (0.5 mL, 2 mmol) was added dropwise slowly under ice bath. After dropping, the reaction was carried out at room temperature for 4 hours. The reaction was monitored by TLC, and the reaction solution was diluted with 3 mL of dichloromethane, then neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (5 mL x 3), and the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2). The solvent was removed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound I-153 as a white solid (30 mg, yield 43.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J = 4.8 Hz, 1H), 8.66 - 8.50 (m, 1H), 8.34 (s, 1H), 7.55 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 7.26 (s, 1H), 4.81 (s, 2H), 4.49 - 4.19 (m, 1H), 2.77 - 2.64 (m, 4H), 2.59 (s, 2H), 1.83 - 1.68 (m, 2H), 1.56 - 1.35 (m, 2H), 1.16 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 27 H 27 ClN5O3S[M+H] + 536.1518, found 586.1519.

[0303] Example 69

[0304] 3-((7-(7-(azepan-4-yloxy)-4-chloro-lH-indazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-155)

[0305] Compound I-155 (white solid, yield 27.3%) was prepared according to the method of Reference Example 68, using compound K5 and tert-butyl 4-hydroxyazepane-l-carboxylate. 1 H NMR (300 MHz, DMSO-d6) δ 9.10 - 8.91 (m, 1H), 8.89 - 8.78 (m, 1H), 8.74 (d, J = 4.8 Hz, 1H), 8.29 (s, 1H), 7.55 (s, 1H), 7.46 (d, J = 4.9 Hz, 1H), 7.26 (s, 1H), 4.80 (s, 2H), 4.29 - 4.12 (m, 1H), 2.91 - 2.61 (m, 4H), 2.59 (s, 2H), 1.98 - 1.85 (m, 1H), 1.85 - 1.69 (m, 1H), 1.66 - 1.55 (m, 1H), 1.56 - 1.42 (m, 1H), 1.41 - 1.28 (m, 1H), 1.22 - 1.10 (m, 4H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 28 H 29 ClN5O3S[M+H] + 550.1674, found 550.1677.

[0306] Example 70

[0307] 3-((7-(7-chloro-4-(piperidin-4-yloxy)-lH-indol-5-yl)thieno[3,2-b]pyridin-2-yl)methyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-176)

[0308] Compound 2-bromo-4-chloro-5-nitrosophenol (L1) (500 mg, 1.98 mmol), N-Boc-4- hydroxypiperidine (B7) (488 mg, 2.38 mmol) and triphenylphosphine (674 mg, 2.57 mmol) were added into a dry two-necked flask, purged with argon for three times, 12 mL of anhydrous tetrahydrofuran was added, diisopropyl azodicarboxylate (2.57 mL, 0.5 mmol) was added dropwise slowly under ice-bath, the reaction was carried out at room temperature overnight after dropping. TLC monitoring reaction was completed, the solvent was removed by reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10: 1) to obtain compound L2 as a light yellow powdery solid (939 mg, yield 100%). 1 H NMR (400 MHz, CDC13) δ 7.76 (s, 1H), 7.43 (s, 1H), 4.67-4.57 (m, 1H), 3.62-3.53 (m, 4H), 1.97-1.82 (m, 4H), 1.47 (s, 9H).

[0309] Compound L2 (600 mg, 1.38 mmol) was added into a dry two-necked flask, purged with argon for three times, 1M vinylmagnesium bromide (0.4 mL, 0.4 mmol) was added dropwise slowly at -50°C, the reaction was carried out at -50°C for 1 hour after dropping. TLC monitoring reaction was completed, 30 mL of saturated aqueous ammonium chloride solution was added to quench, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated sodium chloride (10 mL x 2), the solvent was removed by reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain compound L3 as a light yellow oil (187 mg, yield 31.5%). 1 H NMR (300 MHz, CDC13) δ 8.49 (s, 1H), 7.34 (s, 1H), 7.24-7.19 (m, 1H), 6.61-6.57 (m, 1H), 4.60-4.48 (m, 1H), 3.99-3.83 (m, 2H), 3.24-3.11 (m, 2H), 2.01-1.81 (m, 4H), 1.48 (s, 9H).

[0310] Compound L3 (185 mg, 0.43 mmol), compound A8 (355 mg, 0.86 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (16 mg, 0.023 mmol) and potassium carbonate (119 mg, 0.86 mmol) were added into 4 mL of 1.4-dioxane and 0.7 mL of water, replaced with argon for 3 times, heated at 100 °C for 4 hours. TLC monitoring reaction was completed, the reaction was cooled to room temperature, 15 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (10 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound L4 as a light yellow oil (260 mg, crude yield 95.2%), which was directly used in the next step reaction.

[0311] Compound L4 (260 mg, 0.41 mmol) was dissolved in 3 mL of dichloromethane, and hydrogen chloride solution in 1.4-dioxane (1.5 mL, 6.15 mmol) was slowly added dropwise in ice bath, and the reaction was carried out at room temperature for 4 hours after dropping. TLC monitoring reaction was completed, 5 mL of dichloromethane was added to dilute, then saturated sodium bicarbonate aqueous solution was added to neutralize, extracted with dichloromethane (8 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (15 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound I-176 as a white solid (114 mg, yield 52.0%). 1 H NMR (300 MHz, DMSO-d6) d 11.90 (s, 1H), 8.69 (d, J = 4.8 Hz, 1H), 8.34 - 8.08 (m, 1H), 7.55 (t, J = 2.8 Hz, 1H), 7.51 (s, 1H), 7.40 (d, J = 4.8 Hz, 1H), 7.23 (s, 1H), 6.73 (dd, J = 3.2, 1.7 Hz, 1H), 4.79 (s, 2H), 4.42 - 4.29 (m, 1H), 2.73 - 2.54 (m, 6H), 1.81 - 1.64 (m, 2H), 1.52 - 1.35 (m, 2H), 1.15 (s, 3H), 0.99 (s, 3H). HRMS (ESI) calcd. for C 28 H 28 ClN4O3S[M+H] + 535.1565, found 535.1567.

[0312] Example 71

[0313] 3-((7-(7-(azetidin-3-ylmethoxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetic acid salt (I-402)

[0314] Compound I-402 (white solid, yield 56.4%) was prepared by the method of Reference Example 31, using the reaction of compound F7 with 3-hydroxymethylazetidine-1-carboxylic acid tert-butyl ester. 1 H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.93 - 8.52 (m, 3H), 7.82 (s, 1H), 7.57 (s, 1H), 7.52 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 3.90 (d, J = 6.3 Hz, 2H), 3.75 - 3.63 (m, 2H), 3.46 - 3.39 (m, 2H), 2.89 - 2.76 (m, 1H), 2.60 (s, 2H), 1.17 (s, 3H), 1.03 (s, 3H). HRMS (ESI) calcd. for C 26 H 24 ClN4O3S2[M+H] + 539.0973, found 539.0973.

[0315] Example 72

[0316] 3-(7-(7-((2-azaspiro[3.3]heptan-6-yl)oxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetic acid salt (I-403)

[0317] Compound I-403 (white solid, yield 48.7%) was prepared by the method of Reference Example 31, using the reaction of compound F7 with 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester. 1H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.88 - 8.61 (m, 3H), 7.77 (s, 1H), 7.56 (s, 1H), 7.45 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.28 (p, J = 6.8 Hz, 1H), 3.70 (s, 2H), 3.66 (s, 2H), 2.60 (s, 2H), 2.27 - 2.17 (m, 2H), 2.02 - 1.92 (m, 2H), 1.17 (s, 3H), 1.02 (s, 3H). HRMS (ESI) calcd. for C 28 H 26 ClN4O3S2[M+H] + 565.1129, found 565.1131.

[0318] Example 73

[0319] 3-((7-(4-chloro-7-(pyrrolidin-3-ylmethoxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetic acid salt (I-404)

[0320] Compound I-404 was prepared (white solid, yield 50.2%) by the method described in Reference Example 31, using compound F7 and 3-hydroxymethylpyrrolidine-1- carboxylic acid tert-butyl ester. 1 H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.88 - 8.61 (m, 3H), 7.77 (s, 1H), 7.56 (s, 1H), 7.45 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.28 (p, J = 6.8 Hz, 1H), 3.70 (s, 2H), 3.66 (s, 2H), 2.60 (s, 2H), 2.27 - 2.17 (m, 2H), 2.02 - 1.92 (m, 2H), 1.17 (s, 3H), 1.02 (s, 3H). HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 553.1129, found 553.1130.

[0321] Example 74

[0322] 3-(7-(7-((2-azaspiro[4.5]dec-8-yl)oxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-405)

[0323] Compound I-405 was prepared (white solid, yield 41.5%) by the method described in Reference Example 31, using compound F7 and tert-butyl 8-hydroxy-2-azaspiro[4.5]decan-2-carboxylate. 1 H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.77 (d, J = 1.7 Hz, 1H), 7.55 (s, 1H), 7.48 (d, J = 4.7 Hz, 1H), 4.80 (s, 2H), 3.91 (s, 1H), 3.17 - 3.09 (m, 1H), 2.82 (d, J = 24.0 Hz, 1H), 2.69 - 2.62 (m, 1H), 2.58 (s, 2H), 2.28 (d, J = 28.8 Hz, 1H), 1.39 - 1.20 (m, 5H), 1.19 - 1.07 (m, 6H), 0.99 (s, 3H), 0.94 - 0.84 (m, 2H). HRMS (ESI) calcd. for C 31 H 32 ClN4O3S2 [M+H] + 607.1599, found 607.1599.

[0324] Example 75

[0325] 3-(7-(7-((3-azaspiro[5.5]undec-9-yl)oxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-406)

[0326] Compound I-406 was prepared (white solid, yield 39.8%) by the method described in Reference Example 31, using compound F7 and tert-butyl 9-hydroxy-3-azaspiro[5.5]undecane-3-carboxylate. HRMS (ESI) calcd. for C 32 H 34 ClN4O3S2 [M+H] + 621.1755, found 621.1755.

[0327] Example 76

[0328] 3-(7-(7-((2-azaspiro[5.5]undecan-9-yl)oxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-407)

[0329] Compound I-407 (white solid, yield 47.1%) was prepared by the method described in Reference Example 31, using compound F7 and 9-hydroxy-2-azaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester. 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 4.79 (s, 2H), 4.01 - 3.91 (m, 1H), 3.30 - 3.14 (m, 2H), 2.57 (s, 2H), 2.56 - 2.51 (m, 2H), 2.26 (s, 1H), 1.34 - 1.13 (m, 11H), 1.01 - 0.93 (m, 5H), 0.91 - 0.75 (m, 2H). HRMS (ESI) calcd. for C 32 H 34 ClN4O3S2[M+H] + 621.1755, found 621.1762.

[0330] Example 77

[0331] 3-(7-(7-((2-azaspiro[3.5]nonan-7-yl)oxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetic acid salt (I-408)

[0332] Compound I-408 (white solid, yield 34.3%) was prepared by the method described in Reference Example 31, using compound F7 and 7-hydroxy-2-azaspiro[3.5]nonane-2-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 8.51 (s, 2H), 7.76 (s, 1H), 7.55 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.82 - 3.78 (m, 1H), 3.47 (m, 4H), 2.59 (s, 2H), 1.45 (m, 2H), 1.36 - 1.19 (m, 6H), 1.19 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 30 H 30 ClN4O3S2[M+H] + 593.1442, found 593.1432.

[0333] Example 78

[0334] 3-((7-(4-chloro-7-(cycloheptyloxy)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-409)

[0335] Following the procedure of Reference Example 31, compound F7 was reacted with cycloheptanol to give compound I-409 (white solid, yield 56.3%). 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.74 (s, 1H), 7.55 (s, 1H), 7.46 (d, J = 4.8 Hz, 1H), 4.82 - 4.78 (m, 2H), 3.98 (m, 1H), 2.57 (s, 2H), 1.50 - 1.32 (m, 4H), 1.29 - 1.18 (m, 6H), 1.15 (s, 3H), 0.99 (s, 3H), 0.95 - 0.81 (m, 2H). HRMS (ESI) calcd. for C 29 H 29 ClN3O3S2[M+H] + 566.1333, found 566.1324.

[0336] Example 79

[0337] 4-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)benzo[d]thiazol-7-yl)oxy)piperidine-1-carboxamide (I-410)

[0338] I-71 (276 mg, 0.5 mmol), trimethylsilyl isocyanate (69 mg, 0.6 mmol) and triethylamine (208 μL, 1.5 mmol) were added to tetrahydrofuran (2 mL) and stirred at room temperature for about 2 hours. After TLC monitoring reaction was completed, 1 M hydrochloric acid (0.2 mL) was added to quench and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 25:1) to give I-410 as a white solid (241 mg, yield 81%). 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.77 (s, 1H), 7.54 (s, 1H), 7.50 (d, J = 4.8 Hz, 1H), 5.82 (s, 2H), 4.80 (s, 2H), 4.21 - 3.89 (m, 1H), 3.17 - 3.02 (m, 2H), 2.86 - 2.74 (m, 2H), 2.57 (s, 2H), 1.51 - 1.37 (m, 2H), 1.21 - 1.11 (m, 5H), 0.99 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.48, 159.66, 158.07, 156.05, 152.04, 148.74, 148.22, 144.36, 139.78, 133.41, 130.69, 128.31, 128.21, 125.43, 122.50, 120.77, 79.71, 46.01, 36.93, 36.06, 33.38, 31.36, 25.97, 15.77. HRMS (ESI) calcd. for C 28 H 27 ClN5O4S2[M+H] + 596.1187, found 596.1179.

[0339] Example 80

[0340] 3-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)benzo[d]thiazol-7-yl)oxy)piperidine-1 -carboxamide (I-411)

[0341] Compound I-411 (yellow solid, yield 59.8%) was prepared according to the method of Example 79 by reacting I-72 with trimethylsilyl isocyanate. 1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.48 (d, J = 4.9 Hz, 1H), 5.80 (s, 2H), 4.80 (s, 2H), 3.81 - 3.65 (m, 1H), 3.57 - 3.46 (m, 1H), 3.27 - 3.19 (m, 1H), 2.86 - 2.73 (m, 2H), 2.57 (s, 2H), 1.42 - 1.30 (m, 2H), 1.24 - 1.13 (m, 5H), 0.98 (s, 3H). HRMS (ESI) calcd. for C 28 H 27 ClN5O4S2[M+H] + 596.1187, found 596.1179.

[0342] Example 81

[0343] 4-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)benzo[d]thiazol-7-yl)oxo)azepane-1-carboxamide (I-412)

[0344] Compound I-412 was prepared (white solid, yield 79%) by the method described in Reference Example 79 using I-84 and trimethylsilyl isocyanate. 1 H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 7.47 (d, J = 4.8 Hz, 1H), 5.63 (s, 2H), 4.80 (s, 2H), 4.11 - 3.81 (m, 1H), 3.19 - 3.03 (m, 1H), 2.97 - 2.84 (m, 2H), 2.86 - 2.74 (m, 1H), 2.57 (s, 2H), 1.61 - 1.31 (m, 6H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 29 H 30 ClN5O4S2[M+H] + 610.1344, found 610.1333.

[0345] Example 82

[0346] 4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)-N-(piperidin-4-yl)benzo[d]thiazole-7-carboxamide (I-413)

[0347] Compound I-413 was prepared according to the procedure of Reference Example 53, replacing compound H8 with 4-tert-butoxycarbonylamino piperidine, as a white solid in 51.6% yield. 1 H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 8.71 (d, J = 4.8 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.88 (s, 1H), 7.54 (s, 1H), 7.37 (d, J = 4.8 Hz, 1H), 4.78 (s, 2H), 3.62 - 3.49 (m, 1H), 2.77 - 2.68 (m, 2H), 2.58 (s, 2H), 2.40 - 2.29 (m, 2H), 1.38 - 1.28 (m, 2H), 1.17 (s, 3H), 1.03 (s, 3H), 0.99 - 0.86 (m, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 173.47, 164.99, 160.98, 155.96, 150.38, 148.06, 144.51, 141.30, 135.83, 133.59, 133.51, 130.56, 128.49, 127.60, 125.22, 120.23, 46.96, 44.61, 37.01, 36.05, 33.42, 31.76, 25.96, 15.90. HRMS (ESI) calcd. for C 28 H 27 ClN5O3S2[M+H] + 580.1238, found 580.1238.

[0348] Example 83

[0349] 4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)-N-(piperidin-4-yl)benzo[d]thiazole-7-carboxamide (I-413)

[0350] Compound I-414 was prepared according to the procedure of Reference Example 53, replacing compound H8 with 3-amino pyrrolidine-1-carboxylic acid tert-butyl ester, as a white solid in 40.9% yield.1 H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.31 (d, J = 7.3 Hz, 1H), 7.89 (s, 1H), 7.55 (s, 1H), 7.38 (d, J = 4.8 Hz, 1H), 4.79 (s, 2H), 4.10 - 3.98 (m, 1H), 2.74 - 2.66 (m, 1H), 2.63 - 2.55 (m, 3H), 2.24 - 2.15 (m, 1H), 1.72 - 1.60 (m, 1H), 1.17 (s, 4H), 1.04 (s, 3H). HRMS (ESI) calcd. for C 27 H 25 ClN5O3S2[M+H] + 566.1082, found 566.1082.

[0351] Example 84

[0352] N-(azetidin-3-yl)-4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3- yl)methyl)thieno[3,2-b]pyridin-7-yl)benzo[d]thiazole-7-carboxamide trifluoroacetic acid salt (I-415)

[0353] Refer to the method of Example 53, replace compound H8 with 3-aminoazetidine-1-carboxylic acid tert-butyl ester to prepare compound I-415 (white solid, yield 58.2%). 1 H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 8.31 (d, J = 7.3 Hz, 1H), 7.89 (s, 1H), 7.55 (s, 1H), 7.38 (d, J = 4.8 Hz, 1H), 4.79 (s, 2H), 4.10 - 3.98 (m, 1H), 2.74 - 2.66 (m, 1H), 2.63 - 2.55 (m, 3H), 2.24 - 2.15 (m, 1H), 1.72 - 1.60 (m, 1H), 1.17 (s, 4H), 1.04 (s, 3H). HRMS (ESI) calcd. for C 26 H 23 ClN5O3S2[M+H] + 552.0925, found 552.0924.

[0354] Example 85

[0355] 3-(7-(7-(3-(aminomethyl)azetidine-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-416)

[0356] Compound I-416 was prepared according to the procedure described in Reference Example 53, replacing compound H8 with 3-Boc-aminomethylazetidine, as a white solid (yield 49.4%). 1 H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.75 (d, J = 4.5 Hz, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.31 (d, J = 4.4 Hz, 1H), 4.82 (s, 2H), 3.84 - 3.73 (m, 1H), 3.55 - 3.43 (m, 2H), 3.16 - 3.05 (m, 1H), 2.59 (s, 2H), 2.28 (s, 3H), 1.14 (s, 3H), 0.96 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.53, 166.84, 161.62, 152.80, 150.85, 147.48, 145.86, 143.84, 135.72, 134.52, 133.05, 129.30, 127.52, 127.34, 123.41, 120.34, 54.47, 52.31, 41.82, 37.02, 36.18, 33.48, 27.31, 25.97, 15.90. HRMS (ESI) calcd. for C 27 H 25 ClN5O3S2[M+H] + 566.1082, found 566.1081.

[0357] Example 86

[0358] 3-(7-(7-(4-(aminomethyl)piperidine-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-417)

[0359] Compound I-417 was prepared according to the procedure described in Reference Example 53, replacing compound H8 with 4-Boc-aminomethylpiperidine, as a white solid (yield 49.4%). 1H NMR (300 MHz, DMSO-d6) δ 9.66 (s, 0.5H), 9.66 (s, 0.5H), 8.73 (d, J = 4.9 Hz, 0.5H), 8.71 (d, J = 4.8 Hz, 0.5H), 8.03 (s, 1H), 7.97 (s, 1H), 7.58 (s, 0.5H), 7.57 (s, 0.5H), 7.31 (d, J = 4.8 Hz, 0.5H), 7.22 (d, J = 4.8 Hz, 0.5H), 4.81 (s, 2H), 4.40 - 4.22 (m, 1H), 3.09 - 2.96 (m, 1H), 2.83 - 2.71 (m, 1H), 2.66 - 2.54 (m, 3H), 2.42 - 2.29 (m, 2H), 1.95 - 1.89 (m, 1H), 1.73 - 1.57 (m, 1H), 1.57 - 1.35 (m, 1H), 1.18 - 1.11 (m, 4H), 1.04 (s, 2H), 1.00 (s, 2H), 0.97 - 0.86 (m, 1H). HRMS (ESI) calcd. for C 29 H 29 ClN5O3S2[M+H] + 594.1395, found 594.1396.

[0360] Example 87

[0361] 3-((7-(4-chloro-7-(4-((dimethylamino)methyl)piperidine-l-carbonyl)benzo[d]thiazol-6- yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-419)

[0362] Following the procedure of Reference Example 53, replacing compound H8 with tert-butyl methyl(piperidin-4-ylcarbamate) to afford compound I-418 (pale yellow solid, yield 44.6%). HRMS (ESI) calcd. for C 30 H 31 ClN5O3S2[M+H] + 608.1551, found 608.1542.

[0363] Example 88

[0364] 3-((7-(4-chloro-7-(4-((dimethylamino)methyl)piperidine-l-carbonyl)benzo[d]thiazol-6- yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-419)

[0365] Referring to the method of Example 53, the compound H8 was replaced with N,N-dimethyl-1-(piperidin-4-yl)methanamine to produce compound I-419 (brown yellow solid, yield 62.3%). HRMS (ESI) calcd for C 31 H 33 ClN5O3S2[M+H] + 622.1708, found 622.1697.

[0366] Example 89

[0367] 3-(7-(4-chloro-7-(2,9-diazaspiro[5.5]undecane-9-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-420)

[0368] Referring to the method of Example 53, the compound H8 was replaced with 2,9-diazaspiro[5.5]undecane-2-carboxylic acid tert-butyl ester to produce compound I-420 (white solid, yield 65.1%). 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.77 - 8.71 (m, 1H), 8.02 (s, 0.5H), 8.00 (s, 0.5H), 7.59 (s, 1H), 7.58 (s, 0.5H), 7.30 (d, J = 4.8 Hz, 0.5H), 7.28 (d, J = 4.8 Hz, 0.5H), 4.82 (s, 2H), 3.69 - 3.53 (m, 1H), 3.21 - 3.11 (m, 1H), 3.00 - 2.87 (m, 1H), 2.79 - 2.66 (m, 1H), 2.61 - 2.57 (m, 2H), 2.56 - 2.51 (m, 2H), 2.49 - 2.43 (m, 1H), 2.43 - 2.32 (m, 1H), 2.08 (s, 1H), 1.47 - 1.14 (m, 8H), 1.04 (s, 1.5H), 1.03 (s, 1.5H), 0.99 - 0.74 (m, 3H). HRMS (ESI) calcd for C 32 H 33 ClN5O3S2[M+H] + 634.1708, found 634.1709.

[0369] Example 90

[0370] 3-(7-(4-chloro-7-(1-oxa-4,9-diazaspiro[5.5]undecane-9-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-421)

[0371] Compound I-421 (white solid, yield 39.5%) was prepared according to the procedure of Reference Example 53, replacing compound H8 with tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate. 1 H NMR (300 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.78 - 8.69 (m, 1H), 8.03 (s, 0.5H), 7.98 (s, 0.5H), 7.59 (s, 0.5H), 7.58 (s, 0.5H), 7.31 (d, J = 4.8 Hz, 0.5H), 7.23 (d, J = 4.8 Hz, 0.5H), 4.82 (s, 2H), 4.01 - 3.90 (m, 1H), 3.43 - 3.37 (m, 2H), 3.07 - 2.91 (m, 2H), 2.89 - 2.71 (m, 1H), 2.64 - 2.53 (m, 4H), 2.49 - 2.40 (m, 2H), 2.11 (s, 1H), 1.88 - 1.79 (m, 1H), 1.38 - 1.27 (m, 1H), 1.20 - 1.14 (m, 4H), 1.05 (s, 1.5H), 1.01 (s, 1.5H). HRMS (ESI) calcd. for C 31 H 31 ClN5O4S2[M+H] + 636.1501, found 636.1500.

[0372] Example 91

[0373] 3-((7-(4-chloro-7-(1,8-diazaspiro[4.5]decane-8-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-422)

[0374] Compound I-422 (white solid, yield 59%) was prepared according to the procedure of Reference Example 53, replacing compound H8 with tert-butyl 1,8-diazaspiro[4.5]decane-1-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 0.5H), 9.66 (s, 0.5H), 8.75 (d, J = 4.8 Hz, 0.5H), 8.71 (d, J = 4.8 Hz, 0.5H), 7.98 (s, 0.5H), 7.97 (s, 0.5H), 7.57 (s, 1H), 7.25 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 3.78 (s, 1H), 3.12 (m, 4H), 2.74 (s, 1H), 2.59 (s, 1H), 2.57 (s, 1H), 1.92 - 1.60 (m, 5H), 1.45 (m, 3H), 1.15 (s, 3H), 1.04 (s, 1.5H), 1.01 (s, 1.5H). HRMS (ESI) calcd. for C 31 H 31 ClN5O3S2[M+H] + 620.1551, found 620.1552.

[0375] Example 92

[0376] 3-((7-(4-chloro-7-(2,7-diazaspiro[3.5]nonane-2-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-423)

[0377] Following the procedure of Reference Example 53, replacing compound H8 with tert-butyl 2,7-diazaspiro[3.5]nonane-7-carboxylate, compound I-423 was prepared (white solid, yield 48.2%). 1 H NMR (400 MHz, DMSO-d6) δ 9.71 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.99 (s, 1H), 7.60 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.59 (s, 2H), 3.24 (s, 2H), 2.89 - 2.71 (m, 4H), 2.60 (s, 2H), 1.59 - 1.34 (m, 4H), 1.16 (s, 3H), 0.98 (s, 3H). HRMS (ESI) calcd. for C 30 H 29 ClN5O3S2[M+H] + 606.1395, found 606.1395.

[0378] Example 93

[0379] 3-((7-(4-chloro-7-(2,8-diazaspiro[4.5]decane-2-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-424)

[0380] Compound I-424 (white solid, yield 51.9%) was prepared according to the method of Reference Example 53, replacing compound H8 with tert-butyl 2,8-diazaspiro[4.5]decane-8- carboxylate. 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 0.5H), 9.69 (s, 0.5H), 8.72 (d, J = 4.8 Hz, 1H), 8.03 (s, 0.5H), 8.00 (s, 0.5H), 7.59 (s, 0.5H), 7.57 (s, 0.5H), 7.29 (d, J = 4.8 Hz, 0.5H), 7.26 (d, J = 4.8 Hz, 0.5H), 4.85 - 4.80 (m, 2H), 3.56 - 3.39 (m, 2H), 3.25 (m, 1H), 3.15 (m, 1H), 2.98 - 2.85 (m, 2H), 2.76 (m, 2H), 2.62 (s, 1H), 2.60 (s, 1H), 1.74 - 1.64 (m, 1H), 1.63 - 1.54 (m, 2H), 1.49 - 1.40 (m, 2H), 1.28 (s, 1H), 1.18 (s, 1.5H), 1.16 (s, 1.5H), 1.07 (s, 1.5H), 0.99 (s, 1.5H). HRMS (ESI) calcd. for C 31 H 31 ClN5O3S2[M+H] + 620.1551, found 620.1554.

[0381] Example 94

[0382] 3-(7-(4-chloro-7-(2,6-diazaspiro[3.4]octane-2-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-425)

[0383] Compound I-425 (white solid, yield 56%) was prepared according to the method of Reference Example 53, replacing compound H8 with tert-butyl 2,6-diazaspiro[3.4]octane-6- carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.92 - 3.81 (m, 1H), 3.76 - 3.71 (m, 1H), 3.46 - 3.39 (m, 1H), 3.11 - 2.86 (m, 5H), 2.56 (s, 2H), 1.88 - 1.74 (m, 1H), 1.67 - 1.50 (m, 1H), 1.15 (s, 3H), 0.99 (s, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.53, 166.73, 161.26, 156.29, 150.65, 148.42, 144.68, 140.92, 135.67, 133.64, 133.05, 129.23, 127.48, 127.23, 125.59, 119.85, 59.59, 57.97, 52.25, 43.75, 37.02, 36.14, 34.98, 33.44, 25.96, 15.88.

[0384] HRMS (ESI) calcd for C 29 H 27 ClN5O3S2[M+H] + 592.1238, found 592.1240.

[0385] Example 95

[0386] 3-(7-(4-chloro-7-(2,6-diazaspiro[3.4]octane-6-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione trifluoroacetic acid salt (I-426)

[0387] The compound I-426 (white solid, yield 57%) was prepared according to the method of Reference Example 53, replacing compound H8 with tert-butyl 2,6-diazaspiro[3.4]octane-2-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 0.5H), 9.66 (s, 0.5H), 8.70 (d, J = 4.8 Hz, 1H), 8.00 (s, 0.5H), 7.99 (s, 0.5H), 7.57 (s, 0.5H), 7.56 (s, 0.5H), 7.26 (d, J = 4.7 Hz, 0.5H), 7.24 (d, J = 4.8 Hz, 0.5H), 4.81 (s, 2H), 4.00 - 3.88 (m, 0.5H), 3.83 - 3.76 (m, 1H), 3.72 - 3.60 (m, 2H), 3.47 - 3.32 (m, 2.5H), 3.15 - 3.03 (m, 1H), 2.93 - 2.86 (m, 0.5H), 2.71 - 2.62 (m, 0.5H), 2.58 (s, 2H), 2.17 - 2.06 (m, 0.5H), 1.98 - 1.90 (m, 0.5H), 1.89 - 1.77 (m, 0.5H), 1.71 - 1.59 (m, 0.5H), 1.17 (s, 1.5H), 1.15 (s, 1.5H), 1.04 (s, 1.5H), 0.98 (s, 1.5H). HRMS (ESI) calcd. for C 29 H 27 ClN5O3S2[M+H] + 592.1238, found 592.1240.

[0388] Example 96

[0389] 3-((7-(4-chloro-7-(2,6-diazaspiro[3.3]heptane-2-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-99)

[0390] Following the procedure of Reference Example 53, replacing compound H8 with tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate, compound I-99 was prepared (white solid, yield 42%). 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.94 (s, 1H), 7.58 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.00 (s, 2H), 3.96 - 3.88 (m, 2H), 3.80 - 3.68 (m, 4H), 2.59 (s, 2H), 1.17 (s, 3H), 1.03 (s, 3H). HRMS (ESI) calcd. for C 28 H 25 ClN5O3S2[M+H] + 578.1082, found 578.1084.

[0391] Example 97

[0392] 3-((7-(4-chloro-7-(3,9-diazaspiro[5.5]undecane-3-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-96)

[0393] Following the procedure of Reference Example 53, replacing compound H8 with tert-butyl 3,9-diazaspiro[5.5]undecane-3-carboxylate, compound I-96 was prepared (white solid, yield 53%). 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.94 (s, 1H), 7.58 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.00 (s, 2H), 3.96 - 3.88 (m, 2H), 3.80 - 3.68 (m, 4H), 2.59 (s, 2H), 1.17 (s, 3H), 1.03 (s, 3H). HRMS (ESI) calcd. for C 13C NMR(101MHz,DMSO-d6)δ173.54,173.45,165.01,160.65,156.43,150.69,148.34,145.01,140.32,135.24,133.53,132.17,1 29.53,128.16,126.78,125.61,119.66,42.42,37.26,36.97,36.14,33.43,33.39,29.26,25.91,15.98.HRMS(ESI)calcd.for C 32 H 33 ClN5O3S2[M+H] + 634.1708, found 634.1710.

[0394] Example 98

[0395] 3-(7-(7-(3-aminoazetidine-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-427)

[0396] Referring to the method of Example 53, compound H8 was replaced with 3-tert-butoxycarbonylaminoazetidine to prepare compound I-427 (white solid, yield 48.2%). 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),8.75(d,J=4.8Hz,1H),7.95(s,1H),7.59(s,1H),7.30(d,J=4.8Hz,1H),4.82(s,2H),4.0 0–3.93(m,1H),3.60–3.53(m,1H),3.47–3.39(m,2H),3.12–3.04(m,1H),2.59(s,2H),2.05(s,2H),1.15(s,3H),0.98(s,3H). 13 C NMR(101MHz,DMSO-d6)δ173.52,166.68,161.25,156.34,150.55,148.43,144.46,140.98,135.81,133.47,132.98,12 8.97,127.72,127.38,125.74,119.87,61.16,58.81,43.03,36.95,36.13,33.40,25.99,15.80.HRMS(ESI)calcd.for C 26 H23 CIN5O3S2 [M+H] + 552.0925, found 552.0927.

[0397] Example 99

[0398] 3-(7-(7-(3-aminopyrrolidine-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-428)

[0399] Compound I-428 was prepared according to the procedure of Example 53, replacing compound H8 with 3-(Boc-amino)pyrrolidine, as a white solid (18.5% yield). 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.01 (s, 1H), 7.58 (s, 1H), 7.42 - 7.22 (m, 1H), 4.82 (s, 2H), 3.66 - 3.43 (m, 2H), 3.22 - 2.88 (m, 2H), 2.87 - 2.62 (m, 1H), 2.59 (s, 2H), 1.97 - 1.65 (m, 1H), 1.63 - 1.38 (m, 1H), 1.22 - 1.11 (m, 3H), 1.06 - 0.95 (m, 3H). HRMS (ESI) calcd. for C 27 H 25 CIN5O3S2 [M+H] + 566.1082, found 566.1083.

[0400] Example 100

[0401] 3-(7-(7-(4-aminazepan-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-429)

[0402] Compound I-429 was prepared according to the procedure of Example 53, replacing compound H8 with 4-tert-butoxycarbonyl-1H-azepine, as a white solid (55.4% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.70 - 9.67 (m, 1H), 8.77 - 8.71 (m, 1H), 8.03 - 8.01 (m, 1H), 7.59 (s, 1H), 7.35 - 7.29 (m, 1H), 4.83 (s, 2H), 3.63 - 3.48 (m, 1H), 3.22 - 3.11 (m, 1H), 3.09 - 2.84 (m, 2H), 2.67 - 2.56 (m, 3H), 1.97 - 1.49 (m, 3H), 1.47 - 1.32 (m, 1H), 1.20 - 1.13 (m, 4H), 1.02 - 0.91 (m, 4H). HRMS (ESI) calcd. for C 29 H 29 ClN5O3S2[M+H] + 594.1395, found 594.1395.

[0403] Example 101

[0404] 3-((7-(4-chloro-7-(4-hydroxypiperidine-l-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-430)

[0405] Following the procedure of Reference Example 53, replacing compound H8 with 4- hydroxypiperidine, compound I-430 was prepared (yellow solid, yield 52.5%). 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 0.5H), 9.67 (s, 0.5H), 8.75 (d, J = 4.8 Hz, 0.5H), 8.72 (d, J = 4.8 Hz, 0.5H), 8.01 (s, 0.5H), 7.99 (s, 0.5H), 7.59 (s, 0.5H), 7.58 (s, 0.5H), 7.28 (d, J = 4.8 Hz, 0.5H), 7.25 (d, J = 4.8 Hz, 0.5H), 4.83 (s, 2H), 4.74 (d, J = 3.8 Hz, 0.5H), 4.63 (d, J = 3.6 Hz, 0.5H), 3.84 - 3.66 (m, 1H), 3.55 - 3.44 (m, 1H), 3.22 - 3.13 (m, 1H), 3.04 - 2.85 (m, 2H), 2.60 (s, 2H), 1.62 - 1.43 (m, 1H), 1.36 - 1.28 (m, 1H), 1.17 (s, 3H), 1.02 (s, 1.5H), 1.01 (s, 1.5H), 0.98 - 0.83 (m, 2H). HRMS (ESI) calcd. for C 28 H 26 ClN4O4S2[M+H] + 581.1079, found 581.1080.

[0406] Example 102

[0407] 3-((7-(4-chloro-7-(4-hydroxyazepan-1- carbonyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2,4-dione (I-431)

[0408] Compound I-431 (yellow solid, yield 38.1%) was prepared according to the method of Reference Example 53, replacing compound H8 with 4-azepan-1-ol hydrochloride. 1 H NMR (300 MHz, DMSO-d6) δ 9.69 - 9.66 (m, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.03 - 7.98 (m, 1H), 7.58 (s, 1H), 7.32 (d, J = 4.9 Hz, 1H), 4.82 (s, 2H), 4.54 - 4.33 (m, 1H), 3.72 - 3.42 (m, 1H), 3.33 - 2.80 (m, 1H), 2.59 (s, 2H), 1.80 - 1.19 (m, 5H), 1.18 - 1.12 (m, 4H), 1.00 (s, 3H). HRMS (ESI) calcd. for C29 H 28 ClN4O4S2[M+H] + 595.1235, found 595.1235.

[0409] Example 103

[0410] 3-((7-(4-chloro-7-(4-(hydroxymethyl)piperidine-1-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-432)

[0411] Refer to the method of Example 53, replace compound H8 with 4-hydroxymethylpiperidine to prepare compound I-432 (light yellow solid, yield 28.7%). 1 H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 0.5H), 9.66 (s, 0.5H), 8.73 (d, J = 4.8 Hz, 0.5H), 8.71 (d, J = 4.8 Hz, 0.5H), 8.01 (s, 0.5H), 7.95 (s, 0.5H), 7.58 (s, 0.5H), 7.56 (s, 0.5H), 7.31 (d, J = 4.8 Hz, 0.5H), 7.22 (d, J = 4.8 Hz, 0.5H), 4.81 (s, 2H), 4.46 (t, J = 5.3 Hz, 0.5H), 4.32 (t, J = 5.2 Hz, 0.5H), 4.30 - 4.24 (m, 1H), 3.30 - 2.96 (m, 3H), 2.87 - 2.63 (m, 1H), 2.59 (s, 1H), 2.58 (s, 1H), 2.47 - 2.32 (m, 1H), 1.71 - 1.24 (m, 3H), 1.16 (s, 3H), 1.08 - 0.82 (m, 4H). HRMS (ESI) calcd. for C 29 H 28 ClN4O4S2[M+H] + 595.1235, found 595.1224.

[0412] Example 104

[0413] 3-((7-(4-chloro-7-(3-(hydroxymethyl)azetidine-1-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-433)

[0414] Compound I-433 (light yellow solid, yield 43.7%) was prepared according to the procedure of Example 53, replacing compound H8 with 3-azetidinemethanol hydrochloride. 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 7.31 (d, J = 4.7 Hz, 1H), 4.82 (s, 2H), 4.69 (t, J = 5.2 Hz, 1H), 3.85 - 3.76 (m, 1H), 3.60 - 3.52 (m, 1H), 3.50 - 3.43 (m, 1H), 3.24 - 3.01 (m, 3H), 2.58 (s, 2H), 2.45 - 2.36 (m, 1H), 1.15 (s, 3H), 0.97 (s, 3H). HRMS (ESI) calcd. for C 27 H 24 ClN4O4S2[M+H] + 567.0922, found 567.0912.

[0415] Example 105

[0416] 3-((7-(4-Chloro-7-(1,4-oxazepan-4-ylcarbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-434)

[0417] Compound I-434 (light yellow solid, yield %) was prepared according to the procedure of Example 53, replacing compound H8 with 1,4-oxazepane hydrochloride. 1 H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 0.5H), 9.67 (s, 0.5H), 8.74 (d, J = 4.8 Hz, 0.5H), 8.72 (d, J = 4.8 Hz, 0.5H), 8.02 (s, 0.5H), 8.01 (s, 0.5H), 7.59 (s, 0.5H), 7.58 (s, 0.5H), 7.37 - 7.29 (m, 1H), 4.82 (s, 2H), 3.67 - 3.42 (m, 3H), 3.31 - 3.22 (m, 2H), 3.20 - 3.08 (m, 1H), 3.02 - 2.90 (m, 1H), 2.89 - 2.70 (m, 1H), 2.59 (s, 2H), 1.82 - 1.23 (m, 2H), 1.16 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 28 H26 ClN4O4S2[M+H] + 581.1079, found 581.1080.

[0418] Example 106

[0419] 1-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)benzo[d]thiazole-7-carbonyl)piperidin-4-yl acetate (I-434)

[0420] The compound I-434 was prepared according to the procedure described in Reference Example 53, replacing compound H8 with piperidin-4-yl acetate, as a yellow solid in 31.1% yield. 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 0.5H), 9.67 (s, 0.5H), 8.72 (d, J = 4.8 Hz, 1H), 7.99 (s, 0.5H), 7.97 (s, 0.5H), 7.58 (s, 0.5H), 7.56 (s, 0.5H), 7.29 (d, J = 4.8 Hz, 0.5H), 7.23 (d, J = 4.8 Hz, 0.5H), 7.22 (s, 0.5H), 7.06 (s, 0.5H), 6.78 (s, 0.5H), 6.67 (s, 0.5H), 4.82 (s, 2H), 4.31 - 4.10 (m, 1H), 3.31 - 3.09 (m, 1H), 2.93 - 2.77 (m, 1H), 2.64 - 2.56 (m, 2H), 2.47 - 2.40 (m, 1H), 2.22 - 2.10 (m, 1H), 1.72 - 1.58 (m, 1H), 1.47 - 1.25 (m, 3H), 1.17 (s, 1.5H), 1.16 (s, 1.5H), 1.03 (s, 1.5H), 1.02 (s, 1.5H). HRMS (ESI) calcd. for C 29 H 27 ClN5O4S2[M+H] + 608.1187, found 608.1190.

[0421] Example 107

[0422] 1-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)benzo[d]thiazole-7-carbonyl)piperidin-4-yl acetate (I-434)

[0423] The compound H8 was replaced with azetidine-3-carboxamide according to the method of Example 53 to give compound I-436 (brown-yellow solid, yield 31.1%). 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.38 - 7.32 (m, 1H), 7.22 - 6.92 (m, 1H), 4.82 (s, 1H), 4.70 (s, 1H), 4.03 - 3.76 (m, 1H), 3.68 - 3.49 (m, 1H), 3.15 - 3.03 (m, 2H), 2.59 (s, 1H), 2.58 (s, 1H), 1.18 (s, 1.5H), 1.15 (s, 1.5H), 1.01 (s, 1.5H), 0.97 (s, 1.5H). HRMS (ESI) calcd. for C 27 H 23 ClN5O4S2[M+H] + 580.0874, found 580.0863.

[0424] Example 108

[0425] 4-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)benzo[d]thiazole-7-carbonyl)piperazine-1 -carboxamide (I-437)

[0426] The compound H8 was replaced with azetidine-3-carboxamide according to the method of Example 53 to give compound I-436 (brown-yellow solid, yield 31.1%). 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.73 (d, J = 4.8 Hz, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 7.38 - 7.32 (m, 1H), 7.22 - 6.92 (m, 1H), 4.82 (s, 1H), 4.70 (s, 1H), 4.03 - 3.76 (m, 1H), 3.68 - 3.49 (m, 1H), 3.15 - 3.03 (m, 2H), 2.59 (s, 1H), 2.58 (s, 1H), 1.18 (s, 1.5H), 1.15 (s, 1.5H), 1.01 (s, 1.5H), 0.97 (s, 1.5H). HRMS (ESI) calcd. for C 13C NMR (101 MHz, DMSO-d6) δ 173.51, 165.56, 160.59, 157.98, 156.35, 150.70, 148.39, 144.86, 140.40, 135.41, 133.26, 132.68, 128.95, 128.46, 127.04, 125.63, 119.65, 46.57, 43.57, 41.70, 36.98, 36.10, 33.44, 25.97, 15.86. HRMS (ESI) calcd. for C 28 H 26 ClN6O4S2[M+H] + 609.1140, found 609.1132.

[0427] Example 109

[0428] 4-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)benzo[d]thiazole-7-carbonyl)-1,4-diazepane-1-carboxamide (I-438)

[0429] Following the procedure for Reference Example 79, I-94 was reacted with trimethylsilyl isocyanate to give compound I-438 (white solid, yield 57.2%). 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 0.3H), 9.67 (s, 0.7H), 8.75 - 8.71 (m, 1H), 8.01 (s, 0.3H), 7.99 (s, 0.7H), 7.58 (s, 1H), 7.30 (d, J = 4.8 Hz, 0.3H), 7.25 (d, J = 4.8 Hz, 0.7H), 5.83 (s, 2H), 4.82 (s, 2H), 3.78 - 3.43 (m, 2H), 3.24 - 3.05 (m, 3H), 2.97 - 2.68 (m, 3H), 2.59 (s, 2H), 1.84 - 1.68 (m, 1H), 1.53 - 1.39 (m, 1H), 1.16 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 29 H 28 ClN6O4S2[M+H] + 623.1296, found 623.1287.

[0430] Example 110

[0431] 3-((7-(4-chloro-7-(6-hydroxy-2-azaspiro[3.3]heptane-2-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-439)

[0432] Compound I-439 (yellow solid, yield 53%) was prepared according to the method of Reference Example 53, replacing compound H8 with 2-azaspiro[3.3]heptan-6-ol hydrochloride. 1 H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.97 (s, 1H), 7.60 (s, 1H), 7.30 - 7.25 (m, 1H), 4.95 (s, 1H), 4.83 (s, 2H), 3.85 - 3.59 (m, 3H), 3.45 (s, 1H), 3.39 - 3.35 (m, 1H), 2.58 (s, 2H), 2.17 - 2.05 (m, 1H), 2.01 - 1.89 (m, 1H), 1.84 - 1.73 (m, 1H), 1.58 - 1.47 (m, 1H), 1.16 (s, 3H), 0.99 (s, 3H). HRMS (ESI) calcd. for C 29 H 26 ClN4O4S2[M+H] + 593.1079, found 593.1082.

[0433] Example 111

[0434] 3-(7-(4-chloro-7-(1-oxo-2,9-diazaspiro[5.5]undecane-9-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-440)

[0435] Compound I-440 (yellow solid, yield 34.5%) was prepared according to the method of Reference Example 53, replacing compound H8 with 2,9-diazaspiro[5.5]undecan-1-one hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 0.6H), 9.67 (s, 0.4H), 8.73 (d, J = 4.8 Hz, 0.6H), 8.71 (d, J = 4.8 Hz, 0.4H), 7.99 (s, 0.6H), 7.96 (s, 0.4H), 7.58 (s, 0.6H), 7.56 (s, 0.4H), 7.29 - 7.19 (m, 2H), 4.85 - 4.78 (m, 2H), 3.78 - 3.54 (m, 1H), 3.24 (m, 1H), 3.08 - 2.96 (m, 3H), 2.76 - 2.64 (m, 1H), 2.60 - 2.56 (m, 2H), 1.87 - 1.50 (m, 4H), 1.49 - 1.41 (m, 1H), 1.36 - 1.25 (m, 2H), 1.16 (s, 3H), 1.04 - 0.96 (m, 4H). HRMS (ESI) calcd. for C 32 H 31 ClN5O4S2[M+H] + 648.1501, found 648.1507.

[0436] Example 112

[0437] 3-(7-(7-(4-(Aminomethyl)-4-fluoropiperidine-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-441)

[0438] Following the procedure of Reference Example 53, replacing compound H8 with 4-[(tert-butoxycarbonylamino)methyl]-4-fluoropiperidine, compound I-441 was prepared (white solid, yield 47.2%). 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.74 (m, 0.5H), 8.72 (m, 0.5H), 8.03 (m, 0.5H), 7.99 (s, 0.5H), 7.59 (s, 0.5H), 7.58 (s, 0.5H), 7.30 (d, J = 4.8 Hz, 0.5H), 7.24 (d, J = 4.8 Hz, 0.5H), 4.82 (s, 2H), 4.16 - 4.07 (m, 1H), 3.22 - 2.88 (m, 3H), 2.70 - 2.55 (m, 4H), 2.39 - 2.06 (m, 3H), 1.77 - 1.50 (m, 2H), 1.47 - 1.27 (m, 1H), 1.17 (s, 1.5H), 1.16 (s, 1.5H), 1.05 (s, 1.5H), 0.99 (s, 1.5H). HRMS (ESI) calcd. for C 29 H 28 ClFN5O3S2[M+H] + 612.1301, found 612.1290.

[0439] Example 113

[0440] 3-(7-(4-chloro-7-(1-oxo-2,8-diazaspiro[4.5]decane-8-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-442)

[0441] Following the procedure of Reference Example 53, replacing compound H8 with 2,8-diazaspiro[4.5]-1-decanone hydrochloride, compound I-441 was prepared (light brown solid, yield 33.6%). 1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 0.6H), 9.68 (s, 0.4H), 8.76 - 8.69 (m, 1H), 7.98 (s, 1H), 7.60 - 7.54 (m, 2H), 7.29 (d, J = 4.8 Hz, 0.4H), 7.26 (d, J = 4.8 Hz, 0.6H), 4.82 (s, 1H), 4.80 (s, 1H), 4.10 - 4.04 (m, 0.6H), 3.94 - 3.85 (m, 0.4H), 3.25 - 2.79 (m, 5H), 2.59 (s, 1H), 2.58 (s, 1H), 1.88 - 1.73 (m, 2H), 1.69 - 1.53 (m, 2H), 1.40 - 1.28 (m, 2H), 1.16 (s, 3H), 1.01 (s, 2H), 0.99 (s, 1H). HRMS (ESI) calcd. for C 31 H 29 ClN5O4S2[M+H] + 634.1344, found 634.1330.

[0442] Example 114

[0443] 3-(7-(7-(3-(1-aminocyclopropyl)azetidine-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-443)

[0444] Following the procedure of Reference Example 53, replacing compound H8 with tert-butyl N-(1-(azetidin-3-yl)cyclopropyl)carbamate hydrochloride, compound I-443 was prepared (white solid, yield 59.0%). 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.74 (d, J = 4.8 Hz, 1H), 7.96 (s, 1H), 7.59 (s, 1H), 7.33 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.80 - 3.73 (m, 1H), 3.58 - 3.52 (m, 1H), 3.43 - 3.38 (m, 1H), 3.26 - 3.17 (m, 1H), 2.58 (s, 2H), 2.32 - 2.25 (m, 1H), 1.15 (s, 3H), 0.99 (s, 3H), 0.27 - 0.20 (m, 2H), 0.08 - 0.00 (m, 2H). 13C NMR (101 MHz, DMSO-d6) δ 172.46, 172.39, 165.84, 160.16, 155.29, 149.52, 147.33, 143.49, 139.79, 134.67, 132.28, 131.96, 127.83, 126.58, 126.20, 124.67, 118.88, 52.02, 49.86, 35.88, 35.01, 34.74, 33.02, 32.31, 32.26, 24.87, 14.77, 10.86. HRMS (ESI) calcd. for C 29 H 27 ClN5O3S2[M+H] + 592.1238, found 592.1231.

[0445] Example 115

[0446] 3-(7-(7-(3-(2-aminopropan-2-yl)azetidine-l-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-444)

[0447] Following the procedure of Reference Example 53, replacing compound H8 with tert-butyl (2-(azetidin-3-yl)propan-2-yl)carbamate hydrochloride, compound I-443 was prepared (white solid, yield 54.1%). 1 H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 7.96 (s, 1H), 7.58 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.73 - 3.65 (m, 2H), 3.40 - 3.34 (m, 2H), 2.57 (s, 2H), 2.29 - 2.21 (m, 1H), 1.15 (s, 3H), 1.01 (s, 3H), 0.71 (s, 3H), 0.63 (s, 3H). 13C NMR (101 MHz, DMSO-d6) δ 172.45, 172.36, 165.80, 160.11, 155.30, 149.51, 147.32, 143.49, 139.79, 134.62, 132.30, 131.93, 127.78, 126.70, 126.19, 124.61, 118.91, 50.79, 48.50, 47.89, 35.90, 34.98, 32.32, 32.26, 28.38, 26.01, 25.64, 24.86, 14.80. HRMS (ESI) calcd. for C 29 H 29 ClN5O3S2[M+H] + 594.1395, found 594.1385.

[0448] Example 116

[0449] 3-(7-(7-(3-(1-aminoethyl)azetidine-1-carbonyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-445)

[0450] Referring to the method of Example 53, the compound H8 was replaced with tert-butyl (1-(azetidin-3-yl)ethyl)carbamate hydrochloride to prepare compound I-443 (white solid, yield 37.4%). HRMS (ESI) calcd. for C 28 H 27 ClN5O3S2[M+H] + 580.1238, found 580.1231.

[0451] Example 117

[0452] 3-(7-(7-(3-(aminomethyl)azetidine-1-carbonyl)-4-(trifluoromethyl)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-446)

[0453] Compound M2 (1 g, 4 mmol) was dissolved in 16 mL of acetone, and benzoyl isothiocyanate (707 mg, 4.3 mmol) was added. The reaction was refluxed for 3 hours. After TLC showed that the starting material almost completely disappeared, 472 mg of sodium hydroxide in 10 mL of water was added dropwise into the reaction bottle, heated to 70 °C for about 4 hours, then cooled to room temperature, most of the solvent was removed under reduced pressure, then diluted with 40 mL of water, extracted with ethyl acetate (25 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by 20 mL of n-hexane to obtain compound M3 as a light yellow solid 930 mg, with a yield of 75.5%. 1 H NMR (400 MHz, Chloroform-d) δ 7.54 (s, 1H), 6.63 (s, 1H), 2.32 (s, 3H).

[0454] Compound M2 (1 g, 4 mmol) was dissolved in 16 mL of acetone, and benzoyl isothiocyanate (707 mg, 4.3 mmol) was added. The reaction was refluxed for 3 hours. After TLC showed that the starting material almost completely disappeared, 472 mg of sodium hydroxide in 10 mL of water was added dropwise into the reaction bottle, heated to 70 °C for about 4 hours, then cooled to room temperature, most of the solvent was removed under reduced pressure, then diluted with 40 mL of water, extracted with ethyl acetate (25 mL x 3), the combined organic phase was washed with saturated brine (30 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by 20 mL of n-hexane to obtain compound M3 as a light yellow solid 930 mg, with a yield of 75.5%. 1 H NMR (400 MHz, Chloroform-d) δ 7.54 (s, 1H), 6.63 (s, 1H), 2.32 (s, 3H).

[0455] Compound M3 (920 mg, 2.94 mmol) was added to 12 mL of chloroform, and liquid bromine (0.3 mL, 5.88 mmol) was added dropwise under ice bath, and the reaction was carried out at 60 °C. After TLC showed that the reaction was complete, the reaction was cooled to room temperature, and saturated sodium thiosulfate solution was added to quench the residual liquid bromine, then extracted with dichloromethane (20 mL x 3), the combined organic phase was washed with saturated brine (20 mL x 2), and the solvent was removed under reduced pressure to obtain compound M4 as a light yellow solid 880 mg, which was used directly in the next step without purification.

[0456] Compound M4 (880 mg, 2.83 mmol) was added to 14 mL of tetrahydrofuran, and isopentylnitrite (0.57 mL, 4.24 mmol) was added dropwise under ice bath, and the reaction was allowed to proceed at 60°C. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, and the reaction solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 50: 1) to obtain compound M5 as a yellow solid (0.55 g, 63.2% yield for two steps). 1 H NMR (400 MHz, Chloroform-d) δ 9.14 (s, 1H), 8.00 (s, 1H), 2.74 (s, 3H).

[0457] Compound M5 (520 mg, 1.76 mmol) was added to a mixture of 15 mL of pyridine and 5 mL of water, and potassium permanganate (2.25 g, 14.23 mmol) was added portionwise under stirring at room temperature, and the reaction was allowed to proceed at 100°C for 6 hours. After the reaction was completed as monitored by TLC, the reaction solution was cooled to room temperature, and the filtrate was filtered on celite, and the filter cake was washed with ethyl acetate. Most of the filtrate was removed under reduced pressure, and 20 mL of ethyl acetate was added to dilute the residue, and the reaction was back-extracted with 4 mol / L aqueous sodium hydroxide solution (15 mL x 2). The aqueous phase was combined and then adjusted to a pH of about 2 with 6 mol / L hydrochloric acid, and a large amount of solid was precipitated. The solid was filtered, washed with water, and dried to obtain compound M6 as a white solid (416 mg, 72.6% yield of crude product), which was used directly in the next reaction without purification.

[0458] Compound M6 (130 mg, 0.4 mmol), 3-Boc-aminomethylazetidine (M7) (82 mg, 0.44 mmol), EDCI (115 mg, 0.6 mmol), HOBt (81 mg, 0.6 mmol), and triethylamine (167 μL, 1.2 mmol) were sequentially added to 2 mL of N,N-dimethylformamide, and the reaction was allowed to proceed at 70°C for 5 hours. After the reaction was completed as monitored by TLC, the system was cooled to room temperature, 20 mL of water was added, and the reaction was extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain compound M8 as a light yellow oil (120 mg, 60.7% yield).

[0459] Compound M8 (116 mg, 0.235 mmol), compound A8 (145 mg, 0.352 mmol), dichlorobis-(4-dimethylaminophenyl) palladium(II) (8.3 mg, 0.012 mmol) and potassium phosphate (74.7 mg, 0.352 mmol) were added into 3 mL of 1.4-dioxane and 0.5 mL of water, replaced by argon for 3 times, heated at 90 °C for 4 hours. TLC monitoring showed that the reaction was completed, the reaction solvent was removed directly under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:3) to obtain compound M9 as a light yellow oil (130 mg, crude yield 79.0%), which was directly used in the next step.

[0460] Compound M9 (130 mg, 0.186 mmol) was dissolved in 2 mL of dichloromethane, and trifluoroacetic acid (213 μL, 2.79 mmol) was slowly added dropwise under ice bath, and then the reaction was allowed to react at room temperature for 4 hours. TLC monitoring showed that the reaction was completed, 5 mL of dichloromethane was added to dilute, then saturated aqueous sodium bicarbonate solution was added for neutralization, and then dichloromethane (5 mL x 2) was used for extraction, the combined organic phase was washed with saturated brine (5 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 15:1) to obtain compound I-446 as a white solid (58 mg, yield 52.1%). HRMS (ESI) calcd for C 28 H 25 F3N5O3S2[M+H] + 600.1345, found 600.1335.

[0461] Example 118

[0462] 3-(7-(7-(5-oxa-2,8-diazaspiro[3.5]nonane-2-carbonyl)-4-(trifluoromethyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-447)

[0463] Referring to the method of Example 117, compound M7 was replaced with 5-oxa-2,8-diazaspiro[3,5]nonane-8-carboxylic acid tert-butyl ester to prepare compound I-447 (white solid, yield 66.5%). 1H NMR (400 MHz, DMSO-d6) δ 9.82 (s, 1H), 8.77 (d, J = 4.8 Hz, 1H), 8.20 (s, 1H), 7.61 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 4.83 (s, 2H), 3.80 - 3.72 (m, 1H), 3.65 - 3.56 (m, 1H), 3.39 - 3.34 (m, 2H), 3.27 - 3.17 (m, 2H), 2.58 (s, 2H), 2.49 - 2.42 (m, 2H), 2.40 - 2.25 (m, 2H), 1.15 (s, 3H), 0.99 (s, 3H). HRMS (ESI) calcd. for C 30 H 27 F3N5O4S2[M+H] + 642.1451, found 642.1442.

[0464] Example 119

[0465] Methyl (1-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3- yl)methyl)thieno[3,2-b]pyridin-7-yl)benzo[d]thiazol-7-carbonyl)piperidin-4- yl)carbamate (I-448)

[0466] Compound I-417 (63 mg, 0.1 mmol) and triethylamine (30 μL, 0.22 mmol) were dissolved in 0.6 mL of dichloromethane, dimethyl pyrocarbonate (16 mg, 0.12 mmol) was added dropwise under ice bath, and the mixture was allowed to react at room temperature for 2 hours. The reaction was monitored by TLC, 5 mL of water was added, and the mixture was extracted with dichloromethane (5 mL x 2). The combined organic phase was washed with saturated brine (5 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to obtain compound I-448 as a white solid (37 mg, yield 56.8%). 1H NMR(400MHz, DMSO-d6)δ9.66(s,1H),8.73(d,J=4.8Hz,0.5H),8.71(d,J=4.8Hz,0.5H),8.02(s,0.5H),7.96(s,0.5H),7.59(s,0.5H),7 .57(s,0.5H),7.30(d,J=4.8Hz,0.5H),7.21(d,J=4.8Hz,0.5H),7.14(t,J=6.0Hz,0.5H),7.00(d,J=6.0Hz,0.5H),4.82(s,1H),4.81(s, 1H),4.31–4.20(m,1H),3.48(s,1.5H),3.47(s,1.5H),3.28–3.21(m,0.5H),3.11–3.03(m,0.5H),2.85–2.74(m,1.5H),2.68–2.55(m,3 H),2.43–2.31(m,1.5H),1.64–1.51(m,1H),1.49–1.32(m,2H),1.17(s,3H),1.06–0.95(m,4H),0.89–0.78(m,1H).HRMS(ESI)calcd.for C 31 H 31 ClN5O5S2[M+H] + 652.1450, found 652.1440.

[0467] Example 120

[0468] Ethyl (1-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)benzo[d]thiazole-7-carbonyl)piperidin-4-yl)methyl)carbamate (I-449)

[0469] Referring to the method of Example 119, dimethyl pyrocarbonate was replaced with diethyl pyrocarbonate to prepare compound I-449 (white solid, yield 61.4%). 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.74 (d, J = 4.8 Hz, 0.5H), 8.71 (d, J = 4.8 Hz, 0.5H), 8.02 (s, 0.5H), 7.96 (s, 0.5H), 7.59 (s, 0.5H), 7.57 (s, 0.5H), 7.30 (d, J = 4.8 Hz, 0.5H), 7.22 (d, J = 4.8 Hz, 0.5H), 7.10 (t, J = 6.0 Hz, 0.5H), 6.96 (t, J = 5.9 Hz, 0.5H), 4.82 (s, 1H), 4.82 (s, 1H), 4.31 - 4.21 (m, 1H), 3.99 - 3.88 (m, 2H), 3.29 - 3.21 (m, 0.5H), 3.09 - 3.05 (m, 0.5H), 2.85 - 2.76 (m, 1.5H), 2.69 - 2.56 (m, 3H), 2.44 - 2.30 (m, 1.5H), 1.65 - 1.51 (m, 1H), 1.51 - 1.35 (m, 1H), 1.19 - 1.09 (m, 7H), 1.06 - 0.95 (m, 4H), 0.92 - 0.81 (m, 1H). HRMS (ESI) calcd. for C 32 H 33 ClN5O5S2[M+H] + 666.1606, found 666.1593.

[0470] Example 121

[0471] 3-(7-(4-chloro-7-(3-(((2,2,2-trifluoroethyl)amino)methyl)azetidine-1-carbonyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-450)

[0472] Compound I-416 (60.2 mg, 0.1 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (34.8 mg, 0.15 mmol) and triethylamine (42 μL, 0.3 mmol) were added into 0.5 mL of tetrahydrofuran, heated at 60 °C for 6 hours. TLC monitoring reaction was completed, added 5 mL of water, extracted with ethyl acetate (5 mL x 2), combined organic phase was washed with saturated brine (5 mL x 2), the solvent was removed under reduced pressure, the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to give compound I-450 as a white solid (40 mg, yield 61.8%). 1H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.98 (s, 1H), 7.59 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 4.82 (s, 2H), 3.87 - 3.78 (m, 1H), 3.55 - 3.44 (m, 2H), 3.13 - 3.01 (m, 3H), 2.58 (s, 2H), 2.43 - 2.34 (m, 3H), 1.15 (s, 3H), 0.97 (s, 3H). HRMS (ESI) calcd. for C 29 H 26 ClF3N5O3S2[M+H] + 648.1112, found 648.1102.

[0473] Example 122

[0474] 3-(7-(4-chloro-7-(3-(((2,2,2-difluoroethyl)amino)methyl)azetidine-l- carbonyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2,4-dione (I-451)

[0475] Compound I-451 was prepared (white solid, yield 59.3%) according to the method of Reference Example 121, replacing 2,2,2-trifluoroethyl trifluoromethanesulfonate with 2,2,2-difluoroethyl trifluoromethanesulfonate. 1 H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.97 (s, 1H), 7.59 (s, 1H), 7.30 (d, J = 4.8 Hz, 1H), 6.04 - 5.67 (m, 1H), 4.82 (s, 2H), 3.91 - 3.77 (m, 1H), 3.58 - 3.39 (m, 2H), 3.14 - 2.98 (m, 1H), 2.81 - 2.66 (m, 1H), 2.58 (s, 2H), 2.44 - 2.25 (m, 3H), 1.15 (s, 4H), 0.98 (s, 3H). HRMS (ESI) calcd. for C 29 H 27 ClF2N5O3S2[M+H] + 630.1206, found 630.1198.

[0476] Example 123

[0477] N-(1-(6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)-4-(trifluoromethyl)benzo[d]thiazol-7-carbonyl)azetidin-3-yl)methyl)-2,2,2- trifluoroacetamide (I-452)

[0478] Compound I-446 (30 mg, 0.05 mmol), triethylamine (21 μL, 0.15 mmol) was added to 1 mL of anhydrous dichloromethane, trifluoroacetic anhydride (21 μL, 0.15 mmol) was added dropwise slowly under ice-bath, after the dropwise addition was completed, the reaction was carried out at room temperature for 2 hours. TLC monitoring showed that the reaction was completed, 10 mL of saturated aqueous sodium bicarbonate solution was added and stirred for 5 minutes, extracted with dichloromethane (5 mL x 2), the combined organic phase was washed with saturated brine (5 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by preparative silica gel plate to obtain compound I-452 as a white solid (15 mg, yield 43%). 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.50 - 9.40 (m, 1H), 8.78 (d, J = 4.8 Hz, 1H), 8.19 (s, 1H), 7.61 (s, 1H), 7.36 (d, J = 4.8 Hz, 1H), 4.89 - 4.78 (m, 2H), 3.96 - 3.82 (m, 1H), 3.67 - 3.46 (m, 2H), 3.34 - 3.26 (m, 1H), 3.20 - 3.02 (m, 2H), 2.61 - 2.53 (m, 3H), 1.15 (s, 3H), 0.98 (s, 3H). HRMS (ESI) calcd. for C 30 H 24 F6N5O4S2[M+H] + 696.1168, found 696.1160.

[0479] Example 124

[0480] N-(1-(6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2- b]pyridin-7-yl)-4-(trifluoromethyl)benzo[d]thiazol-7-carbonyl)azetidin-3-yl)methyl)-2,2,2- trifluoroacetamide (I-452)

[0481] Referring to the method of Example 123, compound I-453 (white solid, yield 45%) was prepared by replacing trifluoroacetic anhydride with difluoroacetic anhydride. 1H NMR (400MHz, DMSO-d6) δ9.84 (s, 1H), 8.87–8.81 (m, 1H), 8.78 (d, J = 4.8Hz, 1H),8.18(s,1H),7.61(s,1H),7.35(d,J=4.8Hz,1H),6.33–6.01(m,1H),4 .83(s,2H),3.94–3.82(m,1H),3.67–3.47(m,1H),3.30–3.21(m,1H),3.17 –2.99(m,2H),2.58(s,2H),1.15(s,3H),0.97(s,3H).HRMS(ESI)calcd.for C 30 H 25 F5N5O4S2[M+H]+678.1263,found 678.1254.

[0482] Example 125

[0483] N-(1-(4-chloro-6-(2-((6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)benzo[d]thiazole-7-carbonyl)azetidin-3-yl)methyl ester)-2,2,2-trifluoroacetamide (I-454)

[0484] Referring to the method of Example 123, the raw material I-446 was replaced with I-416 to prepare compound I-454 (white solid, yield 46%). 1 H NMR (400MHz, DMSO-d6) δ9.84(s,1H),9.50–9.39(m,1H),8.78(d,J=4.8Hz,1H),8.18(s,1H),7.61(s,1H),7.35(d,J=4.8Hz,1H),3.96–3 .81(m,1H),3.66–3.46(m,1H),3.33–3.26(m,4H),3.19–3.01(m,0H),2.61–2.52(m,3H),1.15(s,4H),0.97(s,3H).HRMS(ESI)calcd.for C 29 H 24 ClF3N5O4S2[M+H] + 662.0905,found 662.0894.

[0485] Example 126

[0486] (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl(1-(4-chloro-6-(2-(6,6-dimethyl-2,4-dioxo-3-azabicyclo[3.1.0]hexan-3-yl)methyl)thieno[3,2-b]pyridin-7-yl)benzo[d]thiazole-7-carbonyl)azetidin-3-yl)methyl)carbamate (I-455)

[0487] Compound I-416 (60 mg, 0.1 mmol), DIPEA (32 mg, 0.25 mmol), and (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-4-nitrophenyl carbonate (33 mg, 0.11 mmol) were added sequentially to 1 mL of tetrahydrofuran and stirred at room temperature overnight. After completion of the reaction, monitored by TLC, 5 mL of water was added and the mixture was extracted with ethyl acetate (5 mL x 2). The combined organic phases were washed with saturated brine (5 mL x 2). The solvent was evaporated under reduced pressure, and the residue was purified on a preparative silica gel plate to afford compound I-455 as a white solid (39 mg, 54.0% yield). 1 H NMR (400MHz, DMSO-d6) δ9.70 (s, 1H), 8.75 (d, J = 4.8Hz, 1H), 7.96 (s, 1H), 7.59 (s ,1H),7.47(t,J=5.9Hz,1H),7.30(d,J=4.8Hz,1H),4.85–4.81(m,4H),3.86–3.7 8(m,1H),3.59–3.46(m,2H),3.26–3.17(m,1H),3.02–2.81(m,2H),2.58(s,2H), 2.47–2.39(m,1H),2.13(s,3H),1.15(s,3H),0.98(s,3H).HRMS(ESI)calcd.for C 33 H 29 ClN5O8S2[M+H] + 722.1141, found 722.1126.

[0488] Example 127

[0489] 3-((7-(7-((1s,3s)-3-aminocyclobutyloxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-456)

[0490] Referring to the method of Example 31, compound F7 was reacted with N-Boc-trans-3-aminocyclobutanol to prepare compound I-456 (white solid, yield 52.1%). 1 H NMR (400MHz, DMSO-d6) δ9.60(s,1H),8.75(d,J=4.8Hz,1H),7.74(s,1H),7.55(s,1H),7.45(d,J=4.8Hz,1H),4.80(s,2H),3 .94–3.84(m,1H),2.60–2.56(m,3H),2.16–2.03(m,2H),1.55–1.44(m,2H),1.16(s,3H),1.01(s,3H).HRMS(ESI)calcd.for C 26 H 24 ClN4O3S2[M+H] + 539.0973,found 539.0974.

[0491] Example 128

[0492] 3-(7-(7-((1s,3s)-3-(aminomethyl)cyclobutyloxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-457)

[0493] Referring to the method of Example 31, compound F7 was reacted with trans-3-(Bocaminomethyl)cyclobutanol to prepare compound I-456 (white solid, yield 46.6%). 1 H NMR(400MHz, DMSO-d6)δ9.60(s,1H),8.75(d,J=4.8Hz,1H),7.75(s,1H),7.55(s,1H),7.46(d,J=4.8Hz,1H),4.80(s,2H),4.22–4 .06(m,1H),2.58(s,2H),2.36–2.28(m,2H),1.92–1.82(m,2H),1.58–1.38(m,3H),1.15(s,3H),1.00(s,3H).HRMS(ESI)calcd.for C 27 H 26 ClN4O3S2[M+H] + 553.1129, found 553.1130.

[0494] Example 129

[0495] 3-(7-(7-((1r,3r)-3-(aminomethyl)cyclobutyloxy)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-458)

[0496] Compound I-458 (white solid, yield 55.3%) was prepared by the method described in Reference Example 31, using compound F7 and cis-3-(Bocaminomethyl)cyclobutanol. 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.75 (d, J = 4.8 Hz, 1H), 7.74 (s, 1H), 7.55 (s, 1H), 7.45 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.50 - 4.43 (m, 1H), 2.58 (s, 2H), 2.31 (d, J = 7.0 Hz, 2H), 1.95 - 1.86 (m, 1H), 1.83 - 1.76 (m, 2H), 1.74 - 1.67 (m, 2H), 1.16 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 27 H 26 ClN4O3S2[M+H] + 553.1129, found 553.1132.

[0497] Example 130

[0498] 3-(7-(4-chloro-7-((6,6-difluoroazepan-4-yl)oxy)benzo[d]thiazol-6-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-459)

[0499] Compound I-459 (white solid, yield 48.5%) was prepared by the method described in Reference Example 31, using compound F7 and 3,3-difluoro-5-hydroxyazepane-1-carboxylic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ 9.62 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.78 (s, 1H), 7.56 (s, 1H), 7.48 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 4.02 - 3.94 (m, 1H), 2.92 - 2.79 (m, 1H), 2.59 - 2.55 (m, 3H), 2.47 - 2.40 (m, 1H), 2.31 - 2.14 (m, 2H), 2.08 - 1.95 (m, 1H), 1.61 - 1.53 (m, 1H), 1.52 - 1.43 (m, 1H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. for C 28 H 26 ClF2N4O3S2[M+H] + 603.1097, found 603.1101.

[0500] Example 131

[0501] 3-(7-(7-((1-Oxa-4,9-diazaspiro[5.5]undec-9-yl)methyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-460)

[0502] Compound I-460 was prepared (white solid, yield 46.7%) by the method of Reference Example 57, using compound H11 and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate. 1 H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.74 (d, J = 4.7 Hz, 1H), 7.61 (s, 1H), 7.57 (s, 1H), 7.32 (d, J = 4.8 Hz, 1H), 4.78 (s, 2H), 3.54 - 3.40 (m, 4H), 2.60 - 2.55 (m, 4H), 2.31 - 2.08 (m, 4H), 1.81 - 1.69 (m, 2H), 1.49 - 1.38 (m, 2H), 1.15 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 31 H 33 ClN5O3S2[M+H] + 622.1708, found 622.1711.

[0503] Example 132

[0504] 3-(7-(7-((5-oxa-2,8-diazaspiro[3.5]nonan-2-yl)methyl)-4-chlorobenzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-461)

[0505] Compound I-461 (white solid, yield 46.7%) was prepared according to the method of Reference Example 57 by reacting compound H11 with tert-butyl 5-oxa-2,8-diazaspiro[3,5]nonane-8-carboxylate hydrochloride. 1 H NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 7.62 (s, 1H), 7.59 (s, 1H), 7.34 (d, J = 4.8 Hz, 1H), 4.79 (s, 2H), 3.83 - 3.68 (m, 1H), 3.58 - 3.46 (m, 3H), 3.40 - 3.33 (m, 2H), 3.05 (s, 2H), 2.87 - 2.74 (m, 3H), 2.69 - 2.62 (m, 1H), 2.57 (s, 2H), 1.15 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 29 H 29 ClN5O3S2[M+H] + 594.1395, found 594.1399.

[0506] Example 133

[0507] 3-(7-(7-(3-((cyclopropylamino)methyl)azetidine-1-carbonyl)-4-(trifluoromethyl)benzo[d]thiazol-6-yl)thieno[3,2-b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione hydrochloride (I-462)

[0508] tert-Butyl 3-formylazetidine-1-carboxylate (N1) (1.8 g, 9.7 mmol) and cyclopropylamine (N2) (0.555 g, 9.7 mmol) were dissolved in 47 mL of anhydrous dichloromethane, 1.1 mL of acetic acid was added, stirred at room temperature for 3 h, then cooled to 0 °C, sodium triacetoxyborohydride (5.12 g, 24.25 mmol) was added in portions, and after the addition was completed, it was raised to room temperature and stirred overnight. TLC monitoring showed that the reaction was complete, 30 mL of saturated aqueous sodium bicarbonate solution was added to quench, extracted with dichloromethane (40 mL x 2), the combined organic phase was washed with saturated brine (30 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 50:1) to give compound N3 as a light yellow oil (1.12 g, yield 53.6%). 1 H NMR (400 MHz, Chloroform-d) δ 4.04-3.95 (m, 2H), 3.62-3.54 (m, 2H), 2.93-2.85 (m, 2H), 2.69-2.60 (m, 1H), 2.11-2.04 (m, 1H), 1.43 (s, 9H), 0.46-0.42 (m, 2H), 0.34-0.26 (m, 2H).

[0509] Compound N3 (1.12 g, 5.2 mmol) and potassium carbonate (2.2 g, 15.6 mmol) were added to a mixture of 26 mL of ether and 9 mL of water, and benzyl chloroformate (2.3 mL, 15.6 mmol) was slowly added dropwise under vigorous stirring in an ice bath. After the dropwise addition was completed, it was stirred at room temperature overnight. TLC monitoring showed that the reaction was complete, 20 mL of water was added, extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (20 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1) to give compound N4 as a colorless oil (1.6 g, yield 85.4%). 1 H NMR (400 MHz, Chloroform-d) δ 7.39-7.28 (m, 5H), 5.14 (s, 2H), 4.01-3.89 (m, 2H), 3.71-3.60 (m, 2H), 3.53-3.46 (m, 1H), 2.88-2.78 (m, 1H), 2.55-2.44 (m, 1H), 1.43 (s, 9H), 0.86-0.77 (m, 2H), 0.69-0.61 (m, 2H).

[0510] Compound N4 (0.3 g, 0.83 mmol) was dissolved in 10 mL of methanol, and oxalyl chloride (0.21 mL, 2.50 mmol) was slowly added dropwise at room temperature. After the dropwise addition was completed, the mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC, and the solvent was removed under reduced pressure. The residue was slurried in 5 mL of diethyl ether for 0.5 hours, and then filtered. The crude compound N5 was used directly in the next step.

[0511] Compound N5 (160 mg, 0.54 mmol), compound M6 (147 mg, 0.45 mmol), EDCI (129 mg, 0.68 mmol), HOBt (91 mg, 0.68 mmol), and triethylamine (250 μL, 1.8 mmol) were sequentially added to 2.5 mL of N,N-dimethylformamide, and the mixture was heated to 70°C for 5 hours. The reaction was monitored by TLC, and the mixture was cooled to room temperature. Then, 20 mL of water was added, and the mixture was extracted with ethyl acetate (15 mL x 2). The combined organic phase was washed with saturated brine (10 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 2:1) to obtain compound N6 as a light yellow oil (132 mg, 51.9% yield). 1 H NMR (400 MHz, Chloroform-d) δ 9.18 (s, 1H), 8.00 (s, 1H), 7.35-7.27 (m, 5H), 5.11 (s, 2H), 4.41-4.34 (m, 1H), 4.08-4.01 (m, 1H), 4.01-3.92 (m, 1H), 3.80-3.69 (m, 1H), 3.66-3.58 (m, 1H), 3.57-3.49 (m, 1H), 3.10-3.00 (m, 1H), 2.55-2.48 (m, 1H), 0.85-0.79 (m, 2H), 0.69-0.64 (m, 2H).

[0512] Compound M8 (128 mg, 0.23 mmol), compound A8 (139 mg, 0.34 mmol), dichlorobis-(4-dimethylaminophenyl) palladium(II) (8 mg, 0.012 mmol), and potassium phosphate (71.7 mg, 0.34 mmol) were added to 3 mL of a mixture of 1.4-dioxane and 0.5 mL of water, and the mixture was replaced with argon three times. The mixture was heated at 90°C for 4 hours. The reaction was monitored by TLC, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 1:3) to obtain compound M9 as a light yellow oil (168 mg, 96.4% yield of crude product), which was used directly in the next step.

[0513] Compound M9 (168 mg, 0.22 mmol) was dissolved in 2.5 mL of dichloromethane, cooled to -10 °C, and trimethylsilyl iodide (220 mg, 1.1 mmol) was added dropwise slowly. After 10 minutes of dropping, the reaction was allowed to warm to room temperature for 1 hour. After the reaction was completed as monitored by TLC, 3 mL of methanol and 3 mL of saturated sodium thiosulfate solution were added and stirred for 5 minutes. The organic phase was extracted with dichloromethane (5 mL x 3), combined and washed with saturated brine (5 mL x 2). The solvent was removed under reduced pressure, and the residue was purified by preparative silica gel plate. Finally, the separated product was dissolved in 2 mL of ethyl acetate, and hydrogen chloride ethyl acetate solution was added to precipitate the hydrochloride salt solid. After filtration and drying, compound I-462 (55 mg, yield 37.5%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 1H), 9.24 (s, 2H), 8.83 (d, J = 4.9 Hz, 1H), 8.20 (s, 1H), 7.65 (s, 1H), 7.44 (d, J = 4.9 Hz, 1H), 4.84 (s, 2H), 4.01 - 3.92 (m, 1H), 3.80 - 3.72 (m, 1H), 3.71 - 3.62 (m, 1H), 3.47 - 3.38 (m, 1H), 3.02 - 2.86 (m, 2H), 2.85 - 2.75 (m, 1H), 2.60 (s, 2H), 1.17 (s, 3H), 1.02 (s, 3H), 0.81 - 0.76 (m, 2H), 0.68 - 0.62 (m, 2H). HRMS (ESI) calcd. for C 31 H 29 F3N5O3S2[M+H] + 640.1658, found 640.1646.

[0514] Example 134

[0515] 3-((7-(7-chloro-4-(1,4-diazepane-1-carbonyl)-1H-indol-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-182)

[0516] Compound 2-bromo-4-chlorobenzoic acid (01) (1 g, 4.3 mmol) and potassium nitrate (449 mg, 4.5 mmol) were added slowly to stirring concentrated sulfuric acid (98%, 18 mL) at 0 °C, and the reaction was allowed to warm to room temperature for 3 hours after 5 minutes. After the reaction was substantially complete as monitored by TLC, the reaction solution was slowly added to 15 mL of ice water, filtered, and the filter cake was washed with water and dried to obtain compound 02 as a white powdery solid (1.08 g, yield 90.6%).1 H NMR (400 MHz, DMSO) δ 14.14 (br, 1H), 8.44 (s, 1H), 8.29 (s, 1H).

[0517] Compound O2 (561 mg, 2.0 mmol) was dissolved in thionyl chloride (6 mL), heated at 80 °C until compound O2 was completely converted to acyl chloride (about 3 hours), the solvent was removed under reduced pressure, 1-BOC-homopiperazine (O3) (401 mg, 2.0 mmol) was dissolved in anhydrous dichloromethane (3 mL), triethylamine (558 μL, 2 mmol) was added, the acyl chloride was dissolved in anhydrous dichloromethane (3 mL) at 0 °C, and was added dropwise to the above reaction system. After the reaction was basically complete, monitored by TLC, water was added to quench the reaction, extracted with dichloromethane (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain compound O4 as a yellow sticky solid (723 mg, yield 78.1%). 1 H NMR (300 MHz, CDCl3) δ 7.86-7.82 (m, 1H), 7.82-7.77 (m, 1H), 4.09-3.68 (m, 2H), 3.67-3.53 (m, 3H), 3.46-3.21 (m, 4H), 2.11-1.66 (m, 2H), 1.47 (s, 9H).

[0518] Compound O4 (620 mg, 1.3 mmol) was dissolved in anhydrous tetrahydrofuran (15 mL), replaced with argon for 3 times, then slowly added dropwise with vinylmagnesium bromide (1.0 M in THF) (4.7 mL, 4.7 mmol) at -50 °C, continued to stir at -50 °C for 1 hour after dropwise addition, the reaction was complete, monitored by TLC, added saturated aqueous ammonium chloride solution to quench the reaction, extracted with ethyl acetate (15 mL x 3), the combined organic phase was washed with saturated sodium chloride (20 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1: 1) to obtain compound O5 as a light yellow oil (167 mg, yield 27.28%). 1 H NMR (300 MHz, CDCl3) δ 7.86-7.82 (m, 1H), 7.82-7.77 (m, 1H), 4.09-3.68 (m, 2H), 3.67-3.53 (m, 3H), 3.46-3.21 (m, 4H), 2.11-1.66 (m, 2H), 1.47 (s, 9H).

[0519] Compound O5 (165 mg, 0.35 mmol), compound A8 (293 mg, 0.71 mmol), [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium (13 mg, 0.0177 mmol) and potassium carbonate (98 mg, 0.71 mmol) were added into a mixed solvent of 1.4-dioxane (4 mL) and water (0.7 mL), replaced by argon for 3 times, heated at 100 °C for 4 h. TLC monitoring showed that the reaction was completed. The reaction solution was cooled to room temperature, 15 mL of water was added, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated sodium chloride aqueous solution (10 mL x 2), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain compound O6 as a light yellow oil (98 mg, crude yield 95.2%), which was directly used in the next step reaction.

[0520] Compound O6 (98 mg, 0.15 mol) was dissolved in dichloromethane (2 mL), and hydrogen chloride solution in 1.4-dioxane (0.6 mL, 2.22 mmol) was slowly added dropwise in an ice bath. After dropping, the reaction was carried out at room temperature for 4 h. TLC monitoring showed that the reaction was completed. Dichloromethane (5 mL) was added to dilute the solution, then saturated sodium bicarbonate aqueous solution was added to neutralize, extracted with dichloromethane (8 mL x 3), the combined organic phase was washed with saturated sodium chloride aqueous solution (15 mL), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (DCM / MeOH = 15 / 1) to obtain compound I-182 as a white solid (25 mg, yield 12.7%). 1 H NMR (300 MHz, DMSO) δ 12.04 (s, 1H), 8.76-8.57 (m, 1H), 7.63 (s, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 7.33-7.23 (m, 1H), 6.62-6.50 (m, 1H), 4.80 (s, 2H), 3.73-3.44 (m, 2H), 3.20-3.04 (m, 2H), 3.03-2.63 (m, 3H), 2.59 (s, 2H), 2.46-2.03 (m, 2H), 1.79-1.29 (m, 2H), 1.16 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. for C 29 H 29 ClN5O3S[M+H] + 562.1675, found 562.1677.

[0521] Example 135

[0522] 3-((7-(7-chloro-4-(piperazin-1-ylcarbonyl)-1H-indol-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-181)

[0523] Compound I-181 was prepared (white solid, yield 23.9%) by reacting compound O2 with 1-BOC-piperazine according to the procedure of Reference Example 134. 1 H NMR (400 MHz, DMSO) δ 12.03 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 7.63 (m, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.23 (d, J = 4.8 Hz, 1H), 6.51 (s, 1H), 4.80 (s, 2H), 3.45 - 3.39 (m, 3H), 2.96 - 2.87 (m, 1H), 2.80 - 2.65 (m, 2H), 2.59 (s, 2H), 2.37 - 2.24 (m, 2H), 1.80 - 1.69 (br, 1H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. For C 28 H 27 ClN5O3S [M+H] + 548.1518, found 548.1522.

[0524] Example 136

[0525] 3-((7-(7-chloro-4-(2,9-diazaspiro[5.5]undecane-9-carbonyl)-1H-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-463)

[0526] Compound O2 (2.0 g, 7.13 mmol) was dissolved in anhydrous dichloromethane (36 mL), 1,3-dicyclohexylcarbodiimide (1.6 g, 7.84 mmol), 4-dimethylaminopyridine (436 mg, 3.57 mmol) were added slowly at 0 °C, stirred for 15 min, then n-butanol (1 mL, 10.70 mmol) was added, and the reaction was allowed to proceed at room temperature for 5 h. TLC monitoring showed that the reaction was complete. The solvent was removed under reduced pressure, and the reaction was neutralized with saturated aqueous sodium bicarbonate solution. The organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated aqueous sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. The filtrate was collected and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4: 1) to give compound P1 as a light yellow sticky solid (1.2 g, yield 48.8%). 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.87 (s, 1H), 1.62 (s, 9H).

[0527] Compound P1 (400 mg, 1.2 mmol) was dissolved in 12 mL of anhydrous tetrahydrofuran, and argon was replaced for 3 times. At -50 °C, vinylmagnesium bromide (1.0 M in THF) (4.2 mL, 4.2 mmol) was added slowly dropwise, and the reaction was allowed to proceed at -50 °C for 1 h. TLC monitoring showed that the reaction was complete. The reaction was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (15 mL x 3), washed with saturated aqueous sodium chloride (20 mL), and dried over anhydrous sodium sulfate. The filtrate was collected and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 30: 1) to give compound P2 as a white solid (175 mg, yield 44.5%). 1 H NMR (400 MHz, DMSO) δ 11.98 (s, 1H), 7.57 (m, 1H), 7.47 (s, 1H), 6.54 (m, 1H), 1.59 (s, 9H).

[0528] Compound P2 (145 mg, 0.44 mmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (TFA) (373 μL, 4.84 mmol) was added dropwise. The reaction was allowed to proceed at room temperature for 3 h. TLC monitoring showed that the reaction was complete. The solvent was removed under reduced pressure, and the pH of the system was adjusted to 8-9 with 1 N NaOH. The aqueous phase was extracted with ethyl acetate (20 mL x 3), and the pH of the aqueous phase was adjusted to 2-3 with 1 N HCl. The organic phase was extracted with ethyl acetate (20 mL x 3), washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. The solvent was removed under reduced pressure to give compound P3 as a yellow-brown solid (106 mg, yield 87.7%). 1H NMR (300 MHz, DMSO) δ 11.96 (s, 1H), 7.56 (m, 1H), 7.48 (s, 1H), 6.60 (m, 1H).

[0529] Compound P3 (200 mg, 0.73 mmol) was dissolved in N,N-dimethylformamide (3.5 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (211 mg, 1.10 mmol), 1-hydroxybenzotriazole (149 mg, 1.10 mmol) and triethylamine (254 μL, 1.83 mmol) were added slowly at 0 °C, after the addition was completed, the system was warmed to room temperature and stirred for 1 hour, then tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate (P4) (224 mg, 0.87 mmol) was added, and the system was warmed to 60 °C and reacted for 5 hours. TLC monitoring showed that the reaction was complete, the system was cooled to room temperature, water (10 mL) was added, and the organic phase was extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL x 2), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain compound P5 as a green sticky substance (253 mg, yield 67.3%). 1 H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 7.39 (s, 1H), 7.26 (s, 1H), 3.67-3.34 (m, 4H), 3.33-3.27 (m, 1H), 3.25-3.08 (m, 3H), 1.54-1.47 (m, 4H), 1.42 (s, 9H), 1.25-1.01 (m, 4H).

[0530] Compound P5 (250 mg, 0.49 mmol), compound A8 (280 mg, 0.68 mmol), dichlorobis-(4-dimethylaminophenyl) palladium (II) (17 mg, 0.024 mmol) and potassium phosphate (156 mg, 0.74 mmol) were added to a mixed solvent of 1.4-dioxane (3.5 mL) and water (0.6 mL), replaced with argon for 3 times, heated at 100 °C for 4 hours. TLC monitoring showed that the reaction was complete, the reaction liquid was cooled to room temperature, water (15 mL) was added, and the organic phase was extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL), the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:5) to obtain compound P6 as a yellow-brown oily substance (317 mg, crude product yield 90.1%), which was directly used in the next step reaction.

[0531] Compound P6 (317 mg, 0.44 mol) was dissolved in dichloromethane (3.5 mL), hydrogen chloride 1.4-dioxane solution (1.6 mL, 6.62 mmol) was added dropwise slowly at 0 °C, and the reaction was allowed to proceed at room temperature for 4 h after the dropwise addition was completed. The reaction was monitored by TLC, diluted with dichloromethane (5 mL), neutralized with saturated aqueous sodium bicarbonate solution, extracted with dichloromethane (10 mL x 3), washed with saturated aqueous sodium chloride solution (20 mL), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 12:1) to obtain compound I-463 as a white solid (70 mg, yield 23.1%). 1 H NMR (400 MHz, DMSO) δ 11.98 (s, 1H), 8.71-8.60 (m, 1H), 7.60 (s, 1H), 7.54-7.50 (m, 1H), 7.48-7.41 (m, 1H), 7.29-7.20 (m, 1H), 6.51-6.43 (m, 1H), 4.79 (s, 2H), 3.67-3.41 (m, 3H), 3.28-3.18 (m, 2H), 3.14-2.84 (m, 2H), 2.81-2.70 (m, 1H), 2.57 (s, 2H), 2.46-2.30 (m, 1H), 2.14 (s, 1H), 1.47-1.13 (m, 8H), 1.02 (s, 3H), 0.99-0.73 (m, 3H). HRMS (ESI) calcd. for C 33 H 35 ClN5O3S[M+H] + 616.2144, found 616.2136.

[0532] Example 137

[0533] 3-((7-(7-chloro-4-(1,4-oxazepan-4-carbonyl)-1H-indol-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-464)

[0534] Compound I-464 (white solid, yield 50.7%) was prepared according to the method of Example 136 using compound P3 and homomorpholine. 1H NMR (400 MHz, DMSO) δ 12.00 (s, 1H), 8.70 - 8.58 (m, 1H), 7.66 - 7.59 (m, 1H), 7.53 (s, 1H), 7.46 (s, 1H), 7.35 - 7.26 (m, 1H), 6.52 - 6.46 (m, 1H), 4.79 (s, 2H), 3.72 - 3.49 (m, 3H), 3.32 - 2.70 (m, 5H), 2.57 (s, 2H), 1.79 - 1.70 (m, 0.5H), 1.62 - 1.51 (m, 0.5H), 1.48 - 1.31 (m, 0.5H), 1.15 (s, 3H), 1.13 - 1.06 (m, 0.5H), 1.00 (s, 3H). HRMS (ESI) calcd. For C 29 H 28 ClN4O4S[M+H] + 563.1515, found 563.1506.

[0535] Example 138

[0536] 3-((7-(4-(4-aminopiperidine-1-carbonyl)-7-chloro-1H-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-465)

[0537] Compound I-465 (white solid, yield 39.4%) was prepared according to the method described in Reference Example 136 by reacting compound P3 with 4-tert-butoxycarbonylamino piperidine. 1H NMR (400 MHz, DMSO) δ 8.66 (d, J = 4.8 Hz, 0.5H), 8.63 (d, J = 4.7 Hz, 0.5H), 7.62 (d, J = 3.1 Hz, 0.5H), 7.60 (d, J = 3.1 Hz, 0.5H), 7.53 (s, 0.5H), 7.51 (s, 0.5H), 7.44 (s, 0.5H), 7.41 (s, 0.5H), 7.25 (d, J = 4.8 Hz, 0.5H), 7.17 (d, J = 4.8 Hz, 0.5H), 6.50 (d, J = 3.1 Hz, 0.5H), 6.43 (d, J = 3.1 Hz, 0.5H), 4.79 (s, 2H), 4.22 - 4.05 (m, 1H), 3.23 - 3.03 (m, 3.5H), 2.95 - 2.78 (m, 1.5H), 2.66 - 2.61 (m, 1H), 2.61 - 2.56 (m, 3H), 1.65 - 1.56 (m, 1H), 1.23 - 1.13 (m, 5H), 1.04 - 0.94 (m, 4H). HRMS (ESI) calcd. For C 29 H 29 ClN5O3S[M+H] + 562.1675, found 562.1667.

[0538] Example 139

[0539] 3-((7-(7-chloro-4-(1-oxo-2,9-diazaspiro[5.5]undecane-9-carbonyl)-1H-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-466)

[0540] Compound I-466 (white solid, yield 36.7%) was prepared according to the method of Reference Example 136 by reacting compound P3 with 2,9-diazaspiro[5.5]-1-undecanone hydrochloride. 1H NMR (400 MHz, DMSO) δ 12.00 (s, 0.6H), 11.98 (s, 0.4H), 8.67 - 8.61 (m, 1H), 7.64 - 7.60 (m, 1H), 7.53 (s, 0.6H), 7.50 (s, 0.4H), 7.44 (s, 0.6H), 7.41 (s, 0.4H), 7.27 - 7.21 (m, 2H), 6.53 - 6.50 (m, 0.4H), 6.48 - 6.45 (m, 0.6H), 4.84 - 4.76 (m, 2H), 3.85 - 3.80 (m, 0.6H), 3.73 - 3.64 (m, 0.4H), 3.53 - 3.44 (m, 0.5H), 3.25 - 3.15 (m, 1.5H), 3.06 - 2.98 (m, 2.5H), 2.77 - 2.71 (m, 0.5H), 2.58 - 2.55 (m, 2H), 1.88 - 1.79 (m, 0.7H), 1.74 - 1.51 (m, 3.3H), 1.51 - 1.43 (m, 1.5H), 1.41 - 1.33 (m, 1.5H), 1.29 - 1.21 (m, 1H), 1.15 (s, 3H), 1.02 - 0.95 (m, 3H). HRMS (ESI) calcd. For C 33 H 33 CIN5O4S [M+H] + 630.1937, found 630.1928.

[0541] Example 140

[0542] 3-((7-(4-(Aminomethyl)piperidine-1-carbonyl)-7-chloro-1H-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-467)

[0543] Compound I-467 (white solid, yield 27.6%) was prepared according to the method described in Reference Example 136 by reacting compound P3 with 4-Boc-aminomethylpiperidine. 1H NMR (400 MHz, DMSO) δ 8.65 (d, J = 4.8 Hz, 0.5H), 8.63 (d, J = 4.8 Hz, 0.5H), 7.61 (d, J = 3.1 Hz, 0.5H), 7.59 (d, J = 3.1 Hz, 0.5H), 7.52 (s, 0.5H), 7.51 (s, 0.5H), 7.47 (s, 0.5H), 7.41 (s, 0.5H), 7.28 (d, J = 4.8 Hz, 0.5H), 7.16 (d, J = 4.8 Hz, 0.5H), 4.79 (s, 2H), 4.44 - 4.30 (m, 1H), 3.13 - 2.99 (m, 2H), 2.78 - 2.65 (m, 1H), 2.64 - 2.53 (m, 3H), 2.48 - 2.31 (m, 2H), 2.03 - 1.91 (m, 1H), 1.71 - 1.53 (m, 1H), 1.40 - 1.24 (m, 1H), 1.18 - 1.12 (m, 4H), 1.10 - 0.91 (m, 5H). HRMS (ESI) calcd. For C 30 H 31 ClN5O3S[M+H] + 576.1831, found 576.1823.

[0544] Example 141

[0545] 3-((7-(4-(3-aminomethyl)azetidine-1-carbonyl)-7-chloro-1H-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-468)

[0546] Compound I-468 (white solid, yield 40.50%) was prepared by the method described in Reference Example 136, using compound P3 and 3-Boc-aminomethylazetidine. 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 4.8 Hz, 1H), 7.66 (d, J = 4.8 Hz, 1H), 7.53 (s, 1H), 7.39 (s, 1H), 7.24 (d, J = 3.1 Hz, 1H), 6.62 (m, 1H), 4.81 (s, 2H), 4.05 - 3.67 (m, 4H), 3.25 - 2.96 (m, 2H), 2.88 - 2.70 (m, 1H), 2.58 (s, 2H), 1.16 (s, 3H), 1.00 (s, 3H). HRMS (ESI) calcd. For C 30 H 31 ClN5O3S[M+H]+ 548.1518, found 548.1511.

[0547] Example 142

[0548] 3-((7-(4-(3-aminopyrrolidine-1-carbonyl)-7-chloro-1H-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-469)

[0549] Compound I-469 was prepared according to the procedure described in Reference Example 136 by reacting compound P3 with 3-(Boc-amino)pyrrolidine to give compound I-469 (white solid, yield 44.2%). 1 H NMR (400 MHz, DMSO) δ 11.98 (s, 1H), 8.66 - 8.56 (m, 1H), 7.65 - 7.60 (m, 1H), 7.54 - 7.49 (m, 1H), 7.47 - 7.40 (m, 1H), 7.38 - 7.24 (m, 0.5H), 7.19 - 7.15 (m, 0.5H), 6.56 - 6.51 (m, 0.5H), 6.51 - 6.47 (m, 0.5H), 4.80 (s, 2H), 3.64 - 3.47 (m, 1H), 3.26 - 2.95 (m, 3H), 2.90 - 2.77 (m, 1H), 2.58 (m, 2H), 2.00 - 1.84 (m, 1H), 1.82 - 1.66 (m, 1H), 1.58 - 1.41 (m, 1H), 1.31 - 1.10 (m, 4H), 1.06 - 1.02 (m, 1H), 1.01 - 0.98 (m, 2H). 1.31 - 1.10 (m, 4H), 1.06 - 1.02 (m, 1H), 1.01 - 0.98 (m, 2H). HRMS (ESI) calcd. For C 28 H 27 ClN5O3S [M+H] + 548.1518, found 548.1509.

[0550] Example 143

[0551] 3-((7-(7-chloro-4-(4-(methylamino)piperidine-1-carbonyl)-1H-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-470)

[0552] Compound I-470 (white solid, 34.3% yield) was prepared by the method described in Reference Example 136 using compound P3 and 4-N-tert-butoxycarbonyl-4-N-methylaminopiperidine. 1 H NMR (400 MHz, DMSO) δ 12.00 (s, 0.8H), 11.57 (s, 0.2H), 8.69-8.59 (m, 1H), 7.64-7.58 (m, 1H), 7.54-7.50 (m, 1H), 7.47-7.33 (m, 1H), 7.24 (m, 0.5H), 7.18 (m, 0.5H), 6.50-6.42 (m, 0.8H), 6.38-6.32 (m, 0.2H), 4.83-4.75 (m, 2H), 4.17-3.99 (m, 1H), 3.19-2.69 (m, 3H), 2.58 (m, 3H), 2.39-2.28 (m, 1H), 2.18 (s, 1.5H), 2.08 (s, 1.5H), 1.73-1.58 (m, 1H), 1.29-1.19 (m, 2H), 1.16 (s, 3H), 1.04-0.98 (m, 3H), 0.96-0.69 (m, 1H). HRMS (ESI) calcd. For C 30 H 31 ClN5O3S[M+H] + 576.1831, found 576.1821.

[0553] Example 144

[0554] 3-((7-(7-chloro-4-(4-(hydroxymethyl)piperidine-l-carbonyl)-lH-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-471)

[0555] Compound I-471 (white solid 55 mg, 28.0% yield) was prepared by the method described in Reference Example 136 using compound P3 and 4-hydroxymethylpiperidine. 1H NMR (400 MHz, DMSO) δ 12.13 - 11.88 (m, 0.4 H), 11.65 - 11.45 (m, 0.6 H), 8.71 - 8.57 (m, 1 H), 7.66 - 7.57 (m, 1 H), 7.54 - 7.49 (m, 1 H), 7.49 - 7.26 (m, 1.5 H), 7.22 - 7.12 (m, 0.5 H), 6.53 - 6.41 (m, 0.4 H), 6.40 - 6.28 (m, 0.6 H), 4.84 - 4.74 (m, 2 H), 4.50 - 4.26 (m, 2 H), 3.27 - 3.06 (m, 2 H), 2.93 - 2.64 (m, 2 H), 2.61 - 2.57 (m, 2 H), 2.51 - 2.31 (m, 1 H), 1.75 - 1.23 (m, 3 H), 1.23 - 1.03 (m, 4 H), 1.03 - 0.99 (m, 3 H), 0.93 - 0.81 (m, 1 H). HRMS (ESI) calcd. For C 30 H 30 ClN4O4S[M+H] + 577.1671, found 577.1659.

[0556] Example 145

[0557] 3-((7-(7-chloro-4-(4-((methylamino)methyl)piperidine-l-carbonyl)-lH-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-472)

[0558] Following the procedure of Reference Example 136, compound P3 was reacted with tert-butyl methyl(piperidin-4-ylcarbamate) to give compound I-472 (white solid 60 mg, yield 33.9%). 1H NMR (400 MHz, DMSO) δ 12.12 - 11.94 (m, 1H), 8.71 - 8.61 (m, 1H), 7.66 - 7.60 (m, 1H), 7.57 - 7.50 (m, 1H), 7.47 - 7.40 (m, 1H), 7.32 - 7.23 (m, 0.5H), 7.17 - 7.13 (m, 0.5H), 6.59 - 6.51 (m, 0.5H), 6.50 - 6.43 (m, 0.5H), 4.80 (s, 2H), 4.40 - 4.27 (m, 1H), 3.31 - 3.11 (m, 1.5H), 2.95 - 2.64 (m, 2.5H), 2.64 - 2.57 (m, 2H), 2.48 - 2.45 (m, 3H), 2.44 - 2.32 (m, 1H), 1.89 - 1.68 (m, 2H), 1.53 - 1.44 (m, 0.5H), 1.26 - 1.15 (m, 4.5H), 1.10 - 0.84 (m, 4H). HRMS (ESI) calcd. For C 31 H 33 ClN5O3S[M+H] + 590.1987, found 590.1993.

[0559] Example 146

[0560] 3-((7-(4-(4-aminoazepine-l-carbonyl)-7-chloro-lH-indol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-473)

[0561] Compound I-473 (white solid, yield 45.0%) was prepared according to the method described in Reference Example 136 using compound P3 and 4-tert-butoxycarbonyl-lH-azepine. 1H NMR (400 MHz, DMSO) δ 8.73 - 8.61 (m, 1H), 7.66 - 7.59 (m, 1H), 7.55 - 7.50 (m, 1H), 7.49 - 7.42 (m, 1H), 7.33 - 7.21 (m, 1H), 6.54 - 6.40 (m, 1H), 4.87 - 4.74 (m, 2H), 3.75 - 3.54 (m, 1H), 3.17 - 2.78 (m, 3H), 2.74 - 2.65 (m, 1H), 2.58 (s, 2H), 1.75 - 1.62 (m, 1H), 1.61 - 1.29 (m, 2H), 1.28 - 1.20 (m, 2H), 1.18 - 1.13 (m, 3H), 1.02 - 0.96 (m, 3H), 0.92 - 0.80 (m, 1H). HRMS (ESI) calcd. For C 30 H 31 ClN5O3S[M+H] + 576.1831, found 576.1832.

[0562] Example 147

[0563] 3-((7-(4-(3-aminopyrrolidine-1-carbonyl)-7-chloro-1H-indazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-474)

[0564] Methyl 3-amino-2-methylbenzoate (Q1) (2.0 g, 12.10 mmol) was dissolved in acetonitrile (10 mL), N-bromosuccinimide (2.2 g, 12.10 mmol) was added portionwise at 0 °C, and the reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC, and after completion, saturated aqueous sodium thiosulfate solution was added to quench the reaction. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL). The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 4: 1) to give compound Q2 as a yellow-brown oil (3.0 g, yield 95.1%). 1 H NMR (400 MHz, CDCl3) δ 7.19 (d, J = 8.5 Hz, 1H), 6.58 (d, J = 8.6 Hz, 1H), 3.94 (s, 3H), 2.08 (s, 3H).

[0565] Compound Q2 (2.5 g, 10.04 mmol) was dissolved in acetonitrile (50 mL), N- chlorosuccinimide (1.5 g, 11.04 mmol) was added portionwise, and the mixture was warmed to 65 °C for 7 h. The reaction was monitored by TLC, and after cooling to room temperature, the reaction was quenched with saturated aqueous sodium thiosulfate solution. After the addition of 15 mL of water, the mixture was extracted with ethyl acetate (20 mL x 3), and the combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL). The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 10: 1) to give compound Q3 as a yellow-brown oil (2.6 g, 88.0% yield). 1 H NMR (400 MHz, CDCl3) δ 7.36 (s, 1H), 4.13 (s, 2H), 3.94 (s, 3H), 2.13 (s, 3H).

[0566] Compound Q3 (1.6 g, 5.9 mmol) was dissolved in glacial acetic acid (30 mL), and a solution of nitrous acid (447 mg, 6.48 mmol) in water (3 mL) was added. The mixture was stirred at room temperature for 4 h. The reaction was monitored by TLC, and after cooling to room temperature, the solvent was removed under reduced pressure. The reaction was neutralized with saturated aqueous sodium bicarbonate solution, and after the addition of 15 mL of water, the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL). The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 8: 1) to give compound Q4 as a light yellow solid (1.0 g, 61.0% yield). 1 H NMR (400 MHz, DMSO) δ 14.13 (s, 1H), 8.30 (s, 1H), 7.86 (s, 1H), 3.98 (s, 3H).

[0567] Compound Q4 (1.0 g, 3.6 mmol) was dissolved in ethanol, and a solution of sodium hydroxide (575 mg, 14.4 mmol) in water (8.5 mL) was added. The mixture was warmed to 80 °C for 2 h. The reaction was monitored by TLC, and after cooling to room temperature, the solvent was removed under reduced pressure. The pH of the mixture was adjusted to 2-3 with 1N hydrochloric acid, and after the addition of 10 mL of water, the mixture was extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound Q5 as a light yellow solid (808 mg, 81.5% yield). 1 H NMR (300 MHz, DMSO) δ 14.06 (s, 1H), 8.26 (s, 1H), 7.80 (s, 1H).

[0568] Compound Q5 (550 mg, 2.0 mmol) was dissolved in anhydrous dichloromethane (5 mL), and anhydrous N,N-dimethylformamide (33 μL, 0.42 mmol), oxalyl chloride (339 μL, 4.0 mmol) were added slowly at 0 °C. After compound Q5 was completely converted to acyl chloride (about 3 hours), the solvent was removed under reduced pressure. 3-(Boc-amino)pyrrolidine (Q6) (372 mg, 2.0 mmol) was dissolved in anhydrous dichloromethane (4 mL), and triethylamine (555 μL, 4.0 mmol) was added. The acyl chloride was dissolved in anhydrous dichloromethane (5 mL) at 0 °C and added dropwise to the above reaction system. After the reaction was substantially complete, water was added to quench the reaction, and dichloromethane (10 mL x 3) was used to extract, and the combined organic phase was washed with saturated aqueous sodium chloride solution (30 mL). The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain compound O7 as a yellow sticky solid (469 mg, yield 53.1%). 1 H NMR (300 MHz, CDC13) δ 10.88 (s, 1H), 8.04-7.93 (m, 1H), 7.58-7.49 (m, 1H), 4.77-4.62 (m, 1H), 4.46-4.18 (m, 1H), 3.92-3.76 (m, 1H), 3.74-3.51 (m, 1H), 3.47-3.28 (m, 1H), 3.23-3.02 (m, 1H), 2.36-2.12 (m, 1H), 1.98-1.85 (m, 1H), 1.47 (m, 9H).

[0569] Compound Q7 (250 mg, 0.56 mmol), compound A8 (326 mg, 0.79 mmol), dichlorobis-(4-dimethylaminophenyl) palladium (II) (20 mg, 0.028 mmol), and potassium phosphate (178 mg, 0.84 mmol) were added to a mixed solvent of 1.4-dioxane (3.5 mL) and water (0.6 mL), and replaced with argon for 3 times. The reaction was heated at 100 °C for 8 hours. After the reaction was completed, the reaction liquid was cooled to room temperature, water (15 mL) was added, and ethyl acetate (10 mL x 3) was used to extract. The combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL), and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:8) to obtain compound Q8 as a yellow-brown oil (221 mg, crude yield 60.8%), which was directly used in the next step reaction.

[0570] Compound Q8 (221 mg, 0.34 mmol) was dissolved in dichloromethane (4 mL), hydrogen chloride solution in dioxane (1.3 mL, 5.10 mmol) was added dropwise slowly at 0 °C, and the mixture was stirred at room temperature for 4 h after the dropwise addition was completed. The reaction was monitored by TLC, and dichloromethane (5 mL) was added to dilute the reaction mixture, which was then neutralized with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (10 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (20 mL) and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane:methanol = 12:1) to give compound I-474 as a white solid (116 mg, 37.7% yield). 1 H NMR (400 MHz, DMSO) δ 8.71-8.59 (m, 1H), 8.33-8.23 (m, 1H), 7.77-7.67 (m, 1H), 7.57-7.51 (m, 1H), 7.41-7.18 (m, 1H), 4.80 (s, 2H), 3.67-3.41 (m, 2H), 3.44-3.32 (m, 2H), 3.26-3.04 (m, 2H), 2.94-2.76 (m, 1H), 2.61-2.56 (m, 2H), 2.03-1.50 (m, 2H), 1.20-1.12 (m, 3H), 1.09-0.95 (m, 3H). HRMS (ESI) calcd. For C 27 H 26 ClN6O3S[M+H] + 549.1470, found 549.1472.

[0571] Example 148

[0572] 3-((7-(7-chloro-4-(piperazin-1-carbonyl)-1H-indazol-5-yl)thieno[3,2-b]pyridin-2- yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-137)

[0573] Compound I-137 (white solid, yield 20.5%) was prepared according to the method of Reference Example 147 by reacting compound Q5 with N-Boc-piperazine. 1H NMR (400 MHz, CDC13) δ 8.70 (d, J = 4.8 Hz, 1H), 8.24 (s, 1H), 7.74 (s, 1H), 7.56 (s, 1H), 7.25 (d, J = 4.8 Hz, 1H), 4.80 (s, 2H), 3.47 - 3.37 (m, 3H), 2.96 - 2.88 (m, 1H), 2.80 - 2.66 (m, 2H), 2.59 (s, 2H), 2.32 - 2.20 (m, 2H), 1.72 - 1.54 (s, 1H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. For C 27 H 26 ClN6O3S [M+H] + 549.1470, found 549.1474.

[0574] Example 149

[0575] 3-((7-(7-chloro-4-(2,9-diazaspiro[5.5]undecane-9-carbonyl)-lH-indazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-475)

[0576] Compound I-475 (white solid, yield 22.3%) was prepared according to the method described in Reference Example 147, using compound Q5 and tert-butyl 2,9-diazaspiro[5.5]undecane-2-carboxylate. 1 H NMR (400 MHz, DMSO) δ 8.72 - 8.66 (m, 1H), 8.25 (d, J = 6.0 Hz, 1H), 7.74 (d, J = 6.3 Hz, 1H), 7.57 - 7.53 (m, 1H), 7.28 - 7.22 (m, 1H), 4.80 (s, 2H), 3.62 - 3.44 (m, 2H), 3.12 - 2.63 (m, 6H), 2.61 - 2.57 (m, 2H), 1.61 - 1.29 (m, 4H), 1.19 - 1.15 (m, 3H), 1.15 - 1.07 (m, 2H), 1.06 - 0.84 (m, 5H). HRMS (ESI) calcd. For C 32 H 34 ClN6O3S [M+H] + 617.2097, found 617.2098.

[0577] Example 150

[0578] 3-((7-(7-chloro-4-(1,4-diazepane-1-carbonyl)-1H-indazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-138)

[0579] Compound I-138 (white solid, yield 19.7%) was prepared by the method described in Reference Example 147 using compound Q5 and tert-butyl homopiperazine-1-carboxylate. 1 H NMR (400 MHz, DMSO) d 8.69 (d, J = 4.8 Hz, 0.5H), 8.65 (d, J = 4.8 Hz, 0.5H), 8.31 (s, 0.5H), 8.27 (s, 0.5H), 7.75 (s, 1H), 7.55 (s, 0.5H), 7.54 (s, 0.5H), 7.47 (d, J = 4.8 Hz, 0.5H), 7.30 (d, J = 4.8 Hz, 0.5H), 4.80 (s, 4H), 3.60 - 3.44 (m, 3H), 3.16 - 3.07 (m, 1H), 3.03 - 2.79 (m, 2H), 2.76 - 2.68 (m, 0.5H), 2.64 - 2.53 (m, 3.5H), 2.34 - 2.24 (m, 0.5H), 2.11 - 1.99 (m, 0.5H), 1.73 - 1.64 (m, 0.5H), 1.56 - 1.48 (m, 0.5H), 1.44 - 1.35 (m, 0.5H), 1.26 - 1.20 (m, 0.5H), 1.16 (s, 3H), 1.02 (s, 1.5H), 1.00 (s, 1.5H). HRMS (ESI) calcd. For C 28 H 28 ClN6O3S[M+H] + 563.1627, found 563.1632.

[0580] Example 151

[0581] 3-((7-(7-chloro-4-(1-oxa-4,9-diazaspiro[5.5]undecane-9-carbonyl)-1H-indazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-476)

[0582] Compound I-476 (white solid, yield 30.5%) was prepared by the method described in Reference Example 147 using compound Q5 and tert-butyl 1-oxa-4,9-diazaspiro[5.5]undecane-4-carboxylate.1 H NMR (400 MHz, DMSO) δ 8.70 (d, J = 4.8 Hz, 0.5H), 8.67 (d, J = 4.8 Hz, 0.5H), 8.34 (s, 0.5H), 8.21 (s, 0.5H), 7.75 (s, 0.5H), 7.70 (s, 0.5H), 7.55 (s, 0.5H), 7.54 (s, 0.5H), 7.26 (d, J = 4.8 Hz, 0.5H), 7.18 (d, J = 4.8 Hz, 0.5H), 4.80 (s, 2H), 4.09 - 3.93 (m, 1H), 3.66 - 3.46 (m, 3H), 3.12 - 2.96 (m, 2H), 2.85 - 2.69 (m, 4H), 2.62 - 2.57 (m, 2H), 2.45 - 2.32 (m, 1H), 2.01 - 1.93 (m, 0.5H), 1.90 - 1.82 (m, 0.5H), 1.68 - 1.59 (m, 0.5H), 1.57 - 1.47 (m, 0.5H), 1.37 - 1.27 (m, 1H), 1.17 (s, 1H), 1.16 (s, 2H), 1.04 (s, 1H), 1.00 (s, 2H). HRMS (ESI) calcd. For C 31 H 32 ClN6O4S [M+H] + 619.1889, found 619.1877.

[0583] Example 152

[0584] 3-((7-(4-(Aminomethyl)piperidine-1-carbonyl)-7-chloro-1H-indazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-477)

[0585] Following the procedure of Reference Example 147, compound I-477 was prepared by reacting compound Q5 with 4-Boc-aminomethylpiperidine (white solid, yield 38.8%). 1H NMR (400 MHz, DMSO) δ 8.70 (d, J = 4.8 Hz, 0.5H), 8.67 (d, J = 4.8 Hz, 0.5H), 8.31 (s, 0.5H), 8.19 (s, 0.5H), 7.75 (s, 0.5H), 7.70 (s, 0.5H), 7.55 (s, 0.5H), 7.54 (s, 0.5H), 7.26 (d, J = 4.8 Hz, 0.5H), 7.19 (d, J = 4.8 Hz, 0.5H), 4.80 (s, 2H), 4.45 - 4.25 (m, 1H), 3.30 - 3.11 (m, 3H), 2.95 - 2.83 (m, 0.5H), 2.78 - 2.65 (m, 1.5H), 2.63 - 2.56 (m, 2.5H), 2.48 - 2.32 (m, 1H), 2.27 - 2.14 (m, 0.5H), 1.77 - 1.54 (m, 2H), 1.47 - 1.12 (m, 5H), 1.10 - 0.80 (m, 4H). HRMS (ESI) calcd. For C 29 H 30 ClN6O3S[M+H] + 577.1784, found 577.1773.

[0586] Example 153

[0587] 3-((7-(4-(4-aminopiperidine-1-carbonyl)-7-chloro-1H-indazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-478)

[0588] Following the procedure of Reference Example 147, compound Q5 was reacted with 4-tert-butoxycarbonylamino piperidine to give compound I-478 (white solid, yield 33.8%). 1H NMR (400 MHz, DMSO) δ 8.69 (d, J = 4.8 Hz, 0.5H), 8.66 (d, J = 4.9 Hz, 0.5H), 8.22 (s, 0.5H), 8.18 (s, 0.5H), 7.73 (s, 0.5H), 7.70 (s, 0.5H), 7.55 (s, 0.5H), 7.54 (s, 0.5H), 7.26 (d, J = 4.8 Hz, 0.5H), 7.20 (d, J = 4.8 Hz, 0.5H), 4.80 (s, 2H), 4.19 - 4.04 (m, 1H), 3.32 - 2.99 (m, 3H), 3.00 - 2.80 (m, 1H), 2.73 - 2.55 (m, 4H), 1.69 - 1.55 (m, 1H), 1.33 - 1.19 (m, 2H), 1.16 (s, 3H), 1.05 - 0.90 (m, 4H). HRMS (ESI) calcd. For C 28 H 28 ClN6O3S[M+H] + 563.1627, found 563.1617.

[0589] Example 154

[0590] 3-((7-(4-(3-aminomethyl)azetidine-1-carbonyl)-7-chloro-1H-indazol-5-yl)thieno[3,2- b]pyridin-2-yl)methyl)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2,4-dione (I-479)

[0591] Compound I-479 was prepared (white solid, yield 43.7%) by referring to the method of Example 147, reacting compound Q5 with 3-Boc-aminomethylazetidine. 1 H NMR (400 MHz, DMSO) δ 8.70 (d, J = 4.8 Hz, 1H), 8.39 (s, 1H), 7.69 (s, 1H), 7.55 (s, 1H), 7.28 (d, J = 4.8 Hz, 1H), 4.81 (s, 2H), 4.11 - 3.56 (m, 4H), 2.97 - 2.62 (m, 3H), 2.59 (s, 2H), 1.16 (s, 3H), 1.01 (s, 3H). HRMS (ESI) calcd. For C 27 H 26 ClN6O3S[M+H] + 549.1470, found 549.1469.

[0592] The compounds not given specific examples in the present application can be synthesized by the above similar methods, and the mass spectrometry data of some compounds are shown in Table 2 below.

[0593] Table 2

[0594] Example 156

[0595] In vitro inhibitory activity of the compounds on USP7 enzyme

[0596] 1. Preparation

[0597] Enzyme activity test buffer: 50 mM HEPES, pH 7.5, 100 mM NaCl, 0.5 mM EDTA, 1 mM TCEP, 0.1 mg / mL BSA.

[0598] Preparation of the solution of the compound to be tested: an appropriate amount of the compound to be tested (I-1 to I-13, I-22 to I-28, I-37 to I-54, I-71 to I-94, I-97, I-101 to I-106, I-115 to I-117, I-134 to I-136, I-153, I-155, I-176 prepared in Examples 1-70) was weighed, dissolved with DMSO, and diluted by 3 times successively to obtain 8 concentrations of the solution of the compound to be tested. An appropriate amount of the positive compound was weighed, dissolved with DMSO, and diluted by 3 times successively to obtain 8 concentrations (the highest concentration was 250 μM) of the solution of the positive compound. The above compound solutions and DMSO (blank control) were diluted by 62.5 times with the enzyme activity test buffer to obtain the solution of the compound to be tested.

[0599] Preparation of the solution of USP7 protein: the commercially purchased USP7 solution (0.7 μg / μl, Recombinant USP7 Protein, Active Motif, Catalog No: 31525, Lot No: 08215001) was gradient diluted with the enzyme activity test buffer to 20 pM to obtain the solution of USP7 protein for testing.

[0600] Preparation of Ub-Rho solution: Commercially available Ub-Rho solution (2.490 mg / ml, Boston Biochem, U-555-050, Lot No: DBFH2322121) was diluted 500 times with enzyme activity test buffer to obtain Ub-Rho solution for testing.

[0601] 2. Sample loading and incubation

[0602] To the experimental wells of 384-well plates (Thermo Scientific, Lot No: 1207363), USP7 protein solution (10 μl) and different concentrations of the compound to be tested (5 μL) were added, 4 replicate wells for each concentration, and the resulting mixture was incubated at room temperature in the dark for 30 minutes. To 2 replicate wells of each concentration, Ub-Rho solution (5 μL) was added, and to the other 2 replicate wells, enzyme activity test buffer (5 μL) was added. After addition, the 384-well plate was incubated at 37°C in the dark for 2 h. The positive control used the USP7 inhibitor Compound 4 (CP4) reported in the literature (Nat Chem Bio 1, 2018, 14(2): 118).

[0603] 3. Reading and calculation

[0604] The fluorescence data was read with a multifunctional plate reader at an excitation wavelength of 485 nm and an emission wavelength of 535 nm.

[0605] Inhibition rate % = [(F 空白(Ub-Rho) -F 空白(缓冲液) )-(F 化合物(Ub-Rho) -F 化合物(缓冲液) )] / (F 空白(Ub-Rho) -F 空白 (缓冲液) )×100%

[0606] IC 50 The numerical value was calculated with GraphPad Prism software.

[0607] 4. Experimental results

[0608] The inhibitory activity of some compounds on USP7 is shown in Table 3 below. In Table 3, A indicates IC 50 ≤ 10 nM, B indicates 10 nM < IC 50 ≤ 50 nM, C indicates 50 nM < IC 50 ≤ 100 nM, D indicates IC 50 > 100 nM.

[0609] Table 3, Inhibitory activity of compounds on USP7 The inhibitory activity of some compounds on USP7 is shown in Table 3 below. In Table 3, A indicates IC 50 ≤ 10 nM, B indicates 10 nM < IC 50 ≤ 50 nM, C indicates 50 nM < IC 50 ≤ 100 nM, D indicates IC 50 > 100 nM.

[0609] Table 3, Inhibitory activity of compounds on USP7 The inhibitory activity of some compounds on USP7 is shown in Table 3 below. In Table 3, A indicates IC 50 ≤ 10 nM, B indicates 10 nM < IC 50 ≤ 50 nM, C indicates 50 nM < IC 50 ≤ 100 nM, D indicates IC 50 > 100 nM.

[0610] The experimental results (Table 3) show that the compounds of the present application have significant inhibitory activity against USP7. For example, compounds I-1, I-13, I-71, I-74, I-84, I-91, I-92, I-135 and I-155 have in vitro inhibitory IC50values against USP7 of less than 10 nM. 50 50 I-92, which has an IC50value of 0.7 nM, is the most active compound in the present application. The above results suggest that the compounds of the present application are potent USP7 inhibitors.

[0611] Example 15

[0612] Metabolic stability of compounds in human liver microsomes

[0613] 1. Main operation steps

[0614] The NADPH regenerating system and liver microsomes were added to PBS buffer and pre-incubated at 37 °C for 5 min, then the reaction was started by adding the compound (denoted as T0), immediately mixed and the timer was started. After certain time points (0, 10, 30, 60 min, adjusted flexibly according to the stability of the compound), 50 μL of the reaction solution was taken, 150 μL of pre-cooled acetonitrile was added to terminate the reaction, vortexed for 1 min, centrifuged at 4 °C for 10 min, and then the supernatant was taken for LC-MS / MS analysis.

[0615] 2. Experimental results

[0616] The half-lives of some compounds in the human liver microsome incubation system are shown in Table 4, wherein compounds I-416, I-417, I-440 and I-479 exhibit high in vitro metabolic stability, with half-lives of more than 60 min.

[0617] Table 4 Half-lives of compounds in the human liver microsome incubation system

[0618] Example 15

[0619] Inhibitory activity of compounds against hERG potassium ion channel

[0620] 1. Main operation steps

[0621] First, the DMSO solutions of the solvent control, positive control and test sample were prepared, and the test sample concentrations were 0.3 μM, 1 μM, 3 μM, 10 μM and 30 μM, and the positive control terfenadine concentration was 0.001 μM, 0.01 μM, 0.1 μM and 1 μM.

[0622] ​HEK-293-hERG cells were cultured to the appropriate state, then washed with PBS (or DPBS), digested and separated in Tryple solution, resuspended in culture medium and stored in centrifuge tubes, after centrifugation, the supernatant was discarded, the cells were resuspended in extracellular fluid and stored at 2-8°C. Before patch clamp recording, the cells were added dropwise to the culture dish to ensure that the cells had a certain density and that the cells were separated individually. The hERG current was recorded by whole-cell patch clamp technique. Take a small culture dish and add cell suspension to it, place it on the inverted microscope stage. After the cells adhere, perfuse with extracellular fluid, and the recommended flow rate is 1-2 mL / min. The glass microelectrode is two-step drawn by a microelectrode puller, and after filling the electrode with internal solution, the water resistance value is 2-5 MΩ.

[0623] After establishing the whole-cell recording mode, the clamping potential was maintained at -80 mV. A depolarization voltage of +60 mV was given for 850 ms, and then repolarized to -50 mV for 1275 ms to induce hERG tail current. This set of pulse programs was repeated every 15 seconds throughout the experiment.

[0624] After the current was stable, the drug was administered by continuous perfusion of the extracellular fluid from low concentration to high concentration. From low concentration, continuous perfusion was carried out until the drug effect was stable, and then the next concentration perfusion was carried out. Each concentration of the test sample and the positive control was tested for its blocking effect on hERG tail current (N≥2).

[0625] The drug effect was stable: the current value change of the last 5 stimulation bars in each concentration administration stage was less than 10% of the mean value (when the current was greater than or equal to 200 pA) or less than 30% of the mean value (when the current was less than 200 pA); if it was unstable, the data of that concentration would be discarded.

[0626] Finally, the PatchMaster software was used for stimulation and signal acquisition, the patch clamp amplifier was used for signal amplification, and the statistical software such as Graphpad Prism was used for data analysis and curve fitting.

[0627] 2. Experimental results

[0628] The inhibition activities of some compounds on hERG potassium ion channel are shown in Table 5, wherein compounds I-416, I-417, I-421, I-440 and I-479 have no significant inhibition on hERG (IC 50 >30 μM), suggesting that they have lower risk of cardiotoxic side effects.

[0629] Table 4 Inhibition activities of compounds on hERG

[0630] Example 159

[0631] Tablets

[0632] The compound prepared in Example 1 (50 g), hydroxypropyl methylcellulose E (150 g), starch (200 g), povidone K30 (appropriate amount), and magnesium stearate (1 g) were mixed, granulated, and tableted.

[0633] In addition, each of the compounds of the present application can be formulated into a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalant, an ointment, a solution, a cream, a gel, a powder, a lotion, a tincture, a suppository, or a patch, according to the pharmacopoeia 2015 edition general preparation method, by being given different pharmaceutical excipients.

Claims

1. A benzo-pentacyclic aromatic compound represented by formula (I) or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated compound or solvate thereof: in, L is selected from -(CR 5 R 6 ) n1 -、-O-、-S-、-NR 7 -、-(CO)-,-(CO)NR 7 -、-(CO)O-、-S(O) n2 -or-S(O) n2 NR 7 -; R 1 is a 5-12 membered heteroaryl, a 3-12 membered cycloalkyl or a 3-12 membered heterocycloalkyl, or the 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl is optionally replaced by R 8 or the 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl may be optionally fused with a 5-10 membered aromatic group or a 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl, and the 5-10 membered aromatic group or a 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl fused with a 5-12 membered heteroaryl, 3-12 membered cycloalkyl or 3-12 membered heterocycloalkyl may be optionally replaced by R 9 replace; R 8 and R 9 Each independently selected from (=O), halogen, NO2, -CN, OR 10 NR 10 R 11 、-(CO)NR 10 R 11 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl, or the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 6-10 membered aryl, 5-12 membered heteroaryl, C 3-8 Cycloalkyl or 3-8 membered heterocycloalkyl may be optionally substituted with (=O), halogen, -CN, -OR 12 、-NR 12 R 13 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Substituted by cycloalkyl or 3-8 membered heterocycloalkyl; R 3 and R 4 Each independently selected from H, halogen, -CN, -N3, -CO NR 14 R 15 、-(CO)OR 14 , OR 14 NR 14 R 15 、-NO2、SR 14 -、-S(O) n3 R 14 、-S(O) n3 NR 14 R 15 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-12 membered heteroaryl, or the C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl or 5-12 membered heteroaryl may be optionally substituted with halogen, -CN, -(CO)OR 16 、-(CO)NR 16 R 17 -、-NO2、OR 16 、-NR 16 R 17 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Substituted by cycloalkyl or 3-8 membered heterocycloalkyl; R 5 and R 6 are independently selected from H, halogen, OH, or C 1-6 alkyl; R 2 Selected from C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl, or the C 1-6 Alkyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl and 5-12 membered heteroaryl may be optionally substituted with (=O), halogen, -CN, -NO2, -OR 18 、-(CO)NR 18 R 19 、-(CO)OR 18 、-NR 18 R 19 、-SR 18 -、-S(O) n4 R 18 、-S(O) n4 NR 18 R 19 、C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Substituted by cycloalkyl or 3-8 membered heterocycloalkyl; R 7 、R 10 、R 11 、R 12 、R 13 、R 14 、R 15 、R 16 、R 17 、R 18 、R 19 Each independently selected from H, C 1-6 Alkyl or C 3-8 Cycloalkyl; n1 is 0, 1, 2, 3 or 4; n2, n3, n4 are selected from 1 or 2; X 1 、X 2 and X 3 Any one of them is selected from O, S, N or NH, and the remaining two are independently selected from O, S, N, NH or CH; The heterocycloalkyl or heteroaryl group refers to a group in which the ring atoms have 1 to 4 heteroatoms independently selected from oxygen, nitrogen or sulfur.

2. The benzo-pentacyclic aromatic heterocyclic compound or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof according to claim 1, characterized in that: described Select any one of the following structural fragments:

3. The benzo-pentacyclic aromatic heterocyclic compound or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof according to claim 1, characterized in that: The L is selected from O, NH, -(CO)- or -CH2-.

4. The benzo-5-membered aromatic heterocyclic compound or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof according to claim 1, characterized in that: The R 1 Select any one of the following structural fragments:

5. The benzo-5-membered aromatic heterocyclic compound or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof according to claim 1, characterized in that: The R 2 Select any one of the following structural fragments:

6. The benzo-5-membered aromatic heterocyclic compound or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof according to claim 1, characterized in that: The R 3 Selected from H, the R 4 Selected from halogen, -CN, -C≡CH, or -CF3.

7. The compound according to claims 1-6 or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof, characterized in that: The compound is selected from any one of the following:

8. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof in the preparation of a USP7 inhibitor.

9. Use of the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof in the preparation or treatment of a medicament for a disease mediated by USP7.

10. The use according to claim 9, characterized in that The USP7-mediated disease is a tumor, an infectious disease or an inflammatory disease.

11. A pharmaceutical composition for treating USP7-mediated diseases, characterized in that: The composition comprises the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt, ester, stereoisomer, deuterated substance or solvate thereof and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, characterized in that The pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.

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