A 2,7-disubstituted benzothiazole compound and its application

Abstract

The present invention provides a 2,7-disubstituted benzothiazole compound and its application. The 2,7-disubstituted benzothiazole compound provided by the present invention, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, can be used as a novel highly selective PI3Kα inhibitor, which while retaining high activity against PI3Kα, weakens its inhibitory effects on PI3Kβ, PI3Kδ, and PI3Kγ; the present invention also provides the application of the 2,7-disubstituted benzothiazole compound or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof in the preparation of anti-tumor drugs.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceuticals, and relates to a 2,7-disubstituted benzothiazole compound and its use as a novel phosphatidylinositol-3-kinase α (PI3Kα) inhibitor, as well as its preparation method and uses. Technical Background

[0002] The PI3K / Akt / mTOR signaling pathway, as an important intracellular signaling pathway, plays important biological functions in processes such as cell growth, survival, proliferation, and apoptosis. However, the disorder of this pathway can cause a series of diseases, including cancers, immune system and hematopoietic system diseases, etc. Relevant studies have shown that the key regulatory site PI3K on this pathway is closely related to the occurrence and development of tumors. Therefore, the development of anti-tumor drugs targeting PI3K has been a research hotspot in recent years (Vanhaesebroeck B, Stephens L, Hawkins P, Nature Reviews Molecular Cell Biology 2012, 13: 195-203).

[0003] Phosphoinositide 3-kinase (PI3K) is a class of lipid kinases that includes multiple members. According to differences in structural characteristics, activation mechanisms, and lipid substrate selectivity, PI3K kinases can be mainly divided into three classes: I, II, and III. Among them, class I PI3K has been the most thoroughly studied. Class I PI3K kinases contain four subtypes: PI3Kα, PI3Kβ, PI3Kδ, and PI3Kγ. Class I PI3K kinases can be further divided into two subclasses: IA and IB. Class IA PI3K includes three subtypes: PI3Kα, PI3Kβ, and PI3Kδ, while class IB PI3K only contains one subtype, PI3Kγ. All class I PI3K kinases are composed of a catalytic subunit and a regulatory subunit. The catalytic subunits include p110α, p110β, p110δ, and p110γ, which are encoded by the genes PIK3CA, PIK3CB, PIK3CD, and PIK3CG, respectively. The regulatory subunits of class IA PI3K include p85α, p85β, p55α, and p55γ, and their functions are related to the expression, activation, and localization of the kinase. The regulatory subunit of class IB PI3K, namely PI3Kγ, includes p101 and p87. Class I PI3K kinases can phosphorylate the hydroxyl group at the 3 position of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) to generate phosphatidylinositol-3,4,5-triphosphate (PtdIns(3,4,5)P3), and the latter acts as an important second messenger in the cell to interact with the downstream serine / threonine protein kinase Akt (also known as protein kinase B, PKB). The activated Akt further acts on downstream effector proteins including mammalian target of rapamycin (mTOR) to regulate various life activities in the cell (Liu PX, Cheng HL, Roberts TM, et al., Nature Reviews Drug Discovery 2009, 8: 627-644).

[0004] Among the four subtypes of class I PI3K, PI3Kα and PI3Kβ are expressed in various organs, while PI3Kδ and PI3Kγ are mainly distributed in bone marrow cells (Kong D, Yamori T; Cancer Science, 2008, 99: 1734-1740). Among them, PI3Kα has the closest connection with the occurrence and development of tumors. The PIK3CA gene encoding p110α is one of the most easily mutated oncogenes [46-51]. Its mutations mainly occur at three sites with the highest mutation frequencies: glutamic acid E542 and E545 on the helical domain PI3Ka and histidine H1047 on the kinase catalytic domain PI3Kc. Usually, glutamic acid E542 and E545 mutate into lysine, while histidine H1047 mutates into arginine. Tumors caused by these three mutation sites account for about 30% of all solid tumors. PI3Kα mutations cause abnormal activation of the PI3K / Akt / mTOR signaling pathway, leading to excessive cell proliferation and then the occurrence of various malignant tumors, including breast cancer, colon cancer, endometrial cancer, gastric cancer, ovarian cancer, and lung cancer, etc. (Steelman LS, Chappell WH, Abrams SL, Aging, 2011, 3: 192-222). Although the other three subtypes, PI3Kβ, PI3Kδ, and PI3Kγ, play roles in thrombosis, immune function, and allergy and inflammatory responses respectively, they also play important roles in the process of tumorigenesis by affecting catalytic activity, physical and chemical properties, interactions, and recognition, etc.

[0005] So far, more than 38 ATP-competitive PI3K inhibitors have successively entered clinical studies, including pan-Class I PI3Ks inhibitors, PI3K / mTOR dual inhibitors, and a new generation of Class I PI3K subtype-selective inhibitors. Among them, subtype-selective inhibitors only target one or two Class I PI3K subtypes, so significantly reducing the toxic and side effects of pan-Class I PI3Ks inhibitors. Currently, the PI3Kδ-selective inhibitor Idelalisib, the PI3Kδ / γ dual inhibitor Duvelisib, and the PI3Kα / δ dual inhibitor Copanlisib have been approved for marketing and are all used for the treatment of hematological tumors: This is mainly due to the fact that the expression of the PI3Kδ subtype is only limited to the hematopoietic system.

[0006] Therefore, there is an urgent need to search for and discover novel highly selective PI3Kα inhibitors that, while retaining high activity against PI3Kα, weaken their inhibitory effects on PI3Kβ, PI3Kδ, and PI3Kγ. SUMMARY OF THE INVENTION

[0007] In view of the deficiencies of existing target - oriented PI3Kα inhibitors, the present invention provides a novel highly selective PI3Kα inhibitor, which while retaining high activity against PI3Kα, weakens its inhibitory effects on PI3Kβ, PI3Kδ, and PI3Kγ.

[0008] To achieve the above - mentioned purpose, the present invention adopts the following technical solutions:

[0009] The present invention provides a 2,7 - disubstituted benzothiazole compound represented by formula (I) or (II), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0010]

[0011] In formula (I):

[0012] X is CH or N;

[0013] R 1 is selected from hydrogen, amino, C 1-5 alkylamide group, C 1-5 alkylsulfonamide group, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C containing N and O 3-8 heterocyclic group;

[0014] In formula (II):

[0015] R 2 is selected from hydrogen, halogen, cyano, C 1-6 alkoxy;

[0016] R 3 is selected from hydrogen, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy.

[0017] Furthermore, R 1 is hydrogen, amino, C 1-3 alkylamide group, C 1-3 alkylsulfonamide group, C 1-4 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, C 1-3 haloalkoxy or C containing N and O 3-6 heterocyclic group; R 2 is hydrogen, halogen, cyano or C 1-3 alkoxy; R 3 is hydrogen, C 1-3 alkoxy, C 1-2 haloalkyl or C 1-2Halogenated alkoxy group.

[0018] Further, R 1 is hydrogen, amino group, methyl group, isopropyl group, tert-butyl group, methoxy group, trifluoromethyl group, difluoromethoxy group, formamido group, N-methylformamido group, N-methylmethanesulfonamido group or 2-oxazolidinonyl group; R 2 is hydrogen, chlorine, cyano group or methoxy group; R 3 is hydrogen, methoxy group, trifluoromethyl group or trifluoromethoxy group.

[0019] More specifically, the 2,7-disubstituted benzothiazole compounds represented by formula (I) or (II) provided by the present invention, or pharmaceutically acceptable salts, stereoisomers, solvates thereof, and the 2,7-disubstituted benzothiazole compounds represented by formula (I) or (II) are selected from any one of the following compounds:

[0020]

[0021]

[0022] On the other hand, the present invention provides the use of the 2,7-disubstituted benzothiazole compounds having the structure of formula (I) or (II) or pharmaceutically acceptable salts, stereoisomers or solvates thereof in the preparation of anti-tumor drugs. The tumors include lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colorectal cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma / glioblastoma, endometrial cancer, melanoma, renal and renal pelvic cancer, bladder cancer, corpus cancer of uterus, cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, small intestine cancer, non-Hodgkin lymphoma, melanoma and villous colon adenoma, etc.

[0023] Preferably, the 2,7-disubstituted benzothiazole compound is compound T-10, T-17, T-19, T-22, T23 or T-24.

[0024] More preferably, the 2,7-disubstituted benzothiazole compound is compound T-17.

[0025] The present invention also provides a pharmaceutical composition, which comprises at least one active ingredient and at least one pharmaceutically acceptable carrier, and the active ingredient can be arbitrarily selected from any one or more of the 2,7-disubstituted benzothiazole compounds represented by formula (I) or (II) or pharmaceutically acceptable salts, stereoisomers, solvates thereof.

[0026] Furthermore, the application of the 2,7-disubstituted benzothiazole compounds represented by formula (I) or (II) in the preparation of anti-tumor drugs includes the application of pharmaceutically acceptable salts and solvates of the compounds in the preparation of anti-tumor drugs. The drug is composed of the 2,7-disubstituted benzothiazole compound or its pharmaceutically acceptable salt, stereoisomer, solvate and a pharmaceutically acceptable carrier. The tumors include lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon and rectal cancer, thyroid cancer, liver and intrahepatic bile duct cancer, hepatocellular carcinoma, gastric cancer, glioma / glioblastoma, endometrial cancer, melanoma, kidney and renal pelvis cancer, bladder cancer, corpus cancer of uterus, cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myeloid leukemia, chronic myeloid leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, small intestine cancer, non-Hodgkin lymphoma, melanoma and villous colonic adenoma, etc.

[0027] The "pharmaceutically acceptable carrier" refers to conventional pharmaceutical carriers in the pharmaceutical field, including conventional diluents in the pharmaceutical field, excipients such as water, fillers such as starch, binders such as cellulose derivatives, gelatin, etc., wetting agents such as glycerol, disintegrants such as agar, calcium carbonate, etc., absorption promoters such as quaternary ammonium compounds, surfactants such as cetyl alcohol, adsorption carriers such as kaolin and saponite clay, lubricants such as talc powder, etc. If necessary, flavoring agents, sweetening agents, etc. can also be added.

[0028] The pharmaceutical preparation is suitable for administration by any appropriate route, such as oral (including buccal or sublingual administration), rectal administration, nasal administration, topical administration (including buccal, sublingual or transdermal administration), vaginal administration or parenteral administration (including subcutaneous injection, intramuscular injection, intravenous injection or intradermal injection) routes. These preparations can be prepared by any method known in the pharmaceutical field. For example, by mixing the active ingredient with a carrier or excipient.

[0029] The preparation method of the 2,7-disubstituted benzothiazole compounds and their structural analogs provided by the present invention is as follows: in terms of the side chain, first, 4-amino-2-bromopyrimidine is used as a raw material for acetylation under the condition of acetic anhydride or sulfonamidation with NaH as a base, and then CS2CO3 is used as a base to react with methyl iodide. In terms of the parent nucleus, first, 2-amino-7-bromobenzothiazole is used as the parent nucleus for the protection of the amino group with tert-butoxycarbonyl, then the bromine at the 7-position undergoes Suzuki-Miyaura borylation reaction under anhydrous and anaerobic conditions, and then different aromatic derivatives are coupled at this site by Suzuki coupling. Secondly, the deprotection of the amino protecting group is carried out under the conditions of dichloromethane and trifluoroacetic acid. Finally, it first reacts with phenyl chloroformate, and then undergoes ester aminolysis to form a urea structure. The target compound is prepared, and the specific steps are as follows, but not limited to the following methods:

[0030] Detailed implementation mode

[0031] The specific embodiments included below are for illustrative purposes and should not be construed as limiting the scope of the present invention. In addition, it should be understood that after reading the teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

[0032] Example 1

[0033] 2-Bromo-4-aminopyrimidine (900.0 mg, 5.17 mmol) and 4-dimethylaminopyridine (125.6 mg, 1.03 mmol) were added to acetic anhydride (3 mL). The temperature was raised to 60 °C and the reaction was carried out for 13 h. After the reaction was completed, the solvent was evaporated, and after concentration, it was purified by silica gel column chromatography. Elution was carried out with a mixed solution of dichloromethane and methanol with a volume ratio of 50:1 as the eluent. The eluate containing the target product was collected, the organic solvent was evaporated, and dried to obtain 538.9 mg of a yellow solid with a yield of 48.3%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.27 (s, 1H, NH), 8.47 (d, J = 5.7 Hz, 1H, Ar-H), 8.03 (d, J = 5.6 Hz, 1H, Ar-H), 2.10 (s, 3H, CH3). (ESI) m / z: [M+H] + 214.97.

[0034] Example 2

[0035] N-(2-Bromopyrimidin-4-yl)acetamide (217.6 mg, 0.87 mmol) and Cs2CO3 (561.6 mg, 1.73 mmol) were dissolved in N,N-dimethylformamide (4.0 mL). Methyl iodide (107.8 μL, 1.73 mmol) was added dropwise at 0 °C and the reaction was maintained at 0 °C for 9 h. Then, ethyl acetate (20 mL) and water (15 mL) were added to the reaction solution. The organic layer was separated and dried over anhydrous sodium sulfate. After concentration, it was purified by silica gel column chromatography. Elution was carried out with a mixed solution of dichloromethane and methanol with a volume ratio of 100:1 as the eluent. The eluate containing the target product was collected, and the organic solvent was evaporated to obtain 401.4 mg of a white oil with a yield of 86.9%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 8.48 (d, J = 3.2 Hz, 1H, Ar-H), 7.92 (d, J = 3.1 Hz, 1H, Ar-H), 3.37 (s, 3H, CH3), 2.34 (s, 3H, CH3). (ESI) m / z: [M+H]+ 228.99。

[0036] Example 3

[0037] 2-Bromo-4-aminopyrimidine (900.0 mg, 5.17 mmol) and NaH (248.3 mg, 10.3 mg) were added to tetrahydrofuran solvent (20 mL). Methanesulfonyl chloride (803.8 μL, 10.3 mmol) was added dropwise at 0 °C, and the reaction was carried out in an ice bath for 12 h. After the reaction was completed, it was dried over anhydrous sodium sulfate, and the solvent was evaporated. After concentration, it was purified by silica gel column chromatography, eluted with a mixed solution of dichloromethane and methanol with a volume ratio of 25:1 as the eluent, the eluent containing the target product was collected, and the organic solvent was evaporated to obtain 573.4 mg of a white oil, with a yield of 53.4%. 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 5.7 Hz, 1H, Ar-H), 7.15 (d, J = 5.4 Hz, 1H, Ar-H), 3.31 (s, 3H, CH3). (ESI) m / z: [M + H] + 250.94。

[0038] Example 4

[0039] N-(2-Bromopyrimidin-4-yl)methanesulfonamide (435.5 mg, 1.73 mmol) and Cs2CO3 (123.3 mg, 3.46 mmol) were dissolved in DMF (5 mL), and iodomethane (215.5 μL, 3.46 mmol) was added dropwise at 0 °C. The reaction was carried out in an ice bath for 9 h. After the reaction was completed, ethyl acetate (30 mL) and water (10 mL) were added, and liquid separation was carried out. The organic phase was dried over anhydrous sodium sulfate. After concentration, it was purified by silica gel column chromatography, eluted with a mixed solution of dichloromethane and methanol with a volume ratio of 100:3 as the eluent, the organic solvent containing the target product was evaporated and collected to obtain 401.4 mg of a white oil, with a yield of 86.9%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d, J = 5.8 Hz, 1H, Ar-H), 7.50 (d, J = 5.8 Hz, 1H, Ar-H), 3.39 (s, 3H, CH3), 3.33 (s, 3H, CH3). (ESI) m / z: [M + H] + : 264.95。

[0040] Example 5

[0041] 2,4 - Dichloropyrimidine (900 mg, 6.08 mmol), oxazolidin - 2 - one (1.1 g, 12.07 mmol), and NaH (420.0 mg, 17.5 mmol) were dissolved in DMF (5 mL), and the reaction was carried out at 0 °C for 6 h. After the reaction was completed, ethyl acetate (30 mL) and water (10 mL) were added. After liquid - liquid separation, the organic layer was dried over anhydrous sodium sulfate. After concentration, it was purified by silica gel column chromatography. Elution was carried out with a mixed solution of petroleum ether and ethyl acetate = 4:1 as the eluent. The organic solvent containing the target solvent was collected, rotary - evaporated, and dried to obtain 912.3 mg of a white solid with a yield of 75.8%. 1 H NMR (400 MHz, DMSO - d6) δ 8.56 (d, J = 5.8 Hz, 1H), 8.04 (d, J = 5.8 Hz, 1H), 4.47 (t, J = 8.0 Hz, 2H), 4.09 (t, J = 7.9 Hz, 2H). (ESI) m / z: [M + H] + : 199.01。

[0042] Example 6

[0043] 2 - Amino - 7 - bromobenzothiazole (15.0 g, 65.50 mmol), 4 - dimethylaminopyridine (30.0 mg, 0.25 mmol) were dissolved in dichloromethane (150 mL). Di - tert - butyl dicarbonate (11 mL, 78.6 mmol) was added dropwise at 0 °C, and the mixture was stirred for 16 h. After the reaction was completed, water (35 mL) was added. After liquid - liquid separation, the organic layer was dried over anhydrous sodium sulfate. After concentration, it was purified by silica gel column chromatography. Elution was carried out with a mixed solution of petroleum ether and ethyl acetate with a volume ratio of 6:1 as the eluent. The eluent containing the target product was collected, the organic solvent was rotary - evaporated, and dried to obtain 18.6 g of a white solid with a yield of 86%. 1 H NMR (400 MHz, CDCl3) δ 10.74 (s, 1H, NH), 7.81 (d, J = 8.0 Hz, 1H, Ar - H), 7.40 (d, J = 7.8 Hz, 1H, Ar - H), 7.28 (m, J = 8.0 Hz, 1H, Ar - H), 1.60 (s, 9H, CH3×3). (ESI) m / z: [M + H] + : 327.99。

[0044] Example 7

[0045] tert-Butyl (7-bromobenzo[d]thiazol-2-yl)carbamate (3.0 g, 9.12 mmol), bis(pinacolato)diboron (2.8 g, 10.95 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (665.2 mg, 0.91 mmol), and potassium acetate (2.7 g, 27.36 mmol) were added to a two-necked flask, and the gas in the flask was replaced with N2 three times. Distilled 1,4-dioxane (30 mL) was added. The reaction was carried out at 100 °C for 5 h. After the reaction was completed and cooled, dichloromethane (100 mL) was added, and the organic layer was washed with water twice. The dichloromethane layer was dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography. A mixed solution of dichloromethane and methanol with a volume ratio of 100:3 was used as the eluent for rapid elution. The organic solvent containing the target product was collected, dried by rotary evaporation, and 2.84 g of a black solid crude product was obtained. (2.84 g, 6.48 mmol, 70.1% yield), with a yield of 70.1%. 1 H NMR(400MHz,DMSO-d 6 )δ11.68(s,1H,NH),7.80(d,J=7.1Hz,1H,Ar-H),7.59(dd,J=7.2,1.0Hz,1H,Ar-H),7.44–7.38(m,1H,Ar-H),1.52(s,9H,CH3×3),1.35(s,12H,CH3×3).(ESI)m / z:[M+H] + :376.16。

[0046] Example 8

[0047] tert-Butyl (7-(3,3,4,4-tetramethyl-1,3,2,5-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)carbamate (150.0 mg, 0.40 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (29.2 mg, 0.91 mmol), and potassium carbonate (165.6 mg, 1.20 mmol) were added to a two-necked flask, and the gas in the flask was replaced with N2 three times. 1,4-Dioxane / water (8 mL v / v 3:1) was added, and after stirring for several minutes, bromobenzene (62.4 mg, 0.40 mmol) was added. The reaction was carried out at 100 °C overnight. After the reaction was completed, dichloromethane (20 mL) was added to the reaction solution, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate. After concentration, it was purified by silica gel column chromatography. A mixed solution of petroleum ether and ethyl acetate with a volume ratio of 4:1 was used as the eluent for elution. The organic solvent containing the target product was collected, dried by rotary evaporation, and 64.4 mg of a white product was obtained, with a yield of 49.3%. 1 H NMR(400MHz,DMSO-d 6)δ 11.82 (s, 1H, NH), 7.74–7.67 (m, 3H, Ar-H), 7.57 (t, J = 7.6 Hz, 2H, Ar-H), 7.52 (t, J = 7.8 Hz, 1H, Ar-H), 7.47 (t, J = 7.4 Hz, 1H, Ar-H), 7.36 (dd, J = 7.6, 4.8 Hz, 1H, Ar-H), 1.51 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 326.11。

[0048] Example 9

[0049] 7-Phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) was added to tetrahydrofuran (2 mL), and N,N-diisopropylethylamine (60.9 μL, 0.35 mmol) was added. The reaction was placed at 0 °C, and a solution of phenyl chloroformate (24 mg, 0.15 mmol) in tetrahydrofuran (1 mL) was added dropwise. The reaction was stirred at room temperature for 2 h, the solvent was evaporated, tetrahydrofuran (2 mL), N,N-diisopropylethylamine (60.9 μL, 0.35 mmol) and L-prolinamide (20 mg, 0.17 mmol) were added, and the reaction was stirred at 60 °C overnight. The reaction solution was concentrated by evaporation, purified by silica gel column chromatography, eluted with a mixture of dichloromethane and methanol with a volume ratio of 50:1 as the eluent, the organic solvent containing the target product was collected by evaporation, and dried to obtain 27.4 mg of a white solid with a yield of 52.4%. 1 1H NMR (400 MHz, DMSO-d 6 )δ 11.11 (s, 1H, NH), 7.70 (d, J = 7.5 Hz, 2H, Ar-H), 7.63 (s, 1H, NH), 7.56 (t, J = 7.6 Hz, 2H, Ar-H), 7.48 (dt, J = 14.9, 7.5 Hz, 2H, Ar-H), 7.42 (d, J = 7.1 Hz, 1H, Ar-H), 7.33 (t, J = 8.1 Hz, 1H, Ar-H), 6.98 (s, 1H, NH), 4.33–4.18 (m, 1H, CH), 3.70–3.60 (m, 1H, CH), 3.56–3.47 (m, 1H, CH), 2.16–2.05 (m, 1H, CH), 1.95–1.79 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 366.12。

[0050] Example 10

[0051] This example adopts the same implementation method as Example 8, with the difference that bromobenzene (62.4 mg, 0.40 mmol) is replaced by 1-bromo-3-(trifluoromethyl)benzene (96.3 mg, 0.43 mmol), and the product obtained is tert-butyl 7-(3-(trifluoromethyl)benzo[d]thiazol-2-yl)carbamate with a mass of 66.9 mg and a yield of 40.5%. 1 H NMR(400MHz,DMSO-d 6 )δ11.93(s,1H,NH),8.10(d,J=7.2Hz,1H,Ar-H),8.04(s,1H,Ar-H),7.89(dd,J=11.4,7.7Hz,2H,Ar-H),7.83–7.78(m,1H,Ar-H),7.61(t,J=7.8Hz,1H,Ar-H),7.49(dd,J=7.5,0.9Hz,1H,Ar-H),1.56(s,9H,CH3×3).(ESI)m / z:[M+H] + :394.10。

[0052] Example 11

[0053] This example adopts the same implementation method as Example 9, with the difference that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced by 7-(3-(trifluoromethyl)phenyl)benzo[d]thiazol-2-amine (31.6 mg, 0.11 mmol), and the product obtained is (S)-N 1 -(7-(trifluoromethyl)benzo[d]thiazol-2-yl)pyrrolidine-1,2-dicarboxamide with a mass of 28.6 mg and a yield of 60.8%. 1 H NMR(400MHz,DMSO-d 6 )δ11.14(s,1H,NH),8.03(d,J=7.0Hz,1H,Ar-H),7.98(s,1H,Ar-H),7.88–7.76(m,2H,Ar-H),7.69(s,1H,NH),7.53(t,J=7.7Hz,1H,Ar-H),7.39(dd,J=17.0,9.4Hz,2H,Ar-H),6.98(s,1H,NH),4.36–4.28(m,1H,CH),3.62–3.73(m,1H,CH),3.57–3.49(m,1H,CH),2.17–2.04(m,1H,CH),1.94–1.87(m,3H,CH×3).(ESI)m / z:[M+H] + :434.10。

[0054] Example 12

[0055] This example adopts the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 1-bromo-3-(trifluoromethoxy)benzene (95.0 mg, 0.40 mmol), and 65.9 mg of tert-butyl (7-(3-(trifluoromethoxy)phenyl)benzo[d]thiazol-2-yl)carbamate is obtained, with a yield of 40.2%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.88 (s, 1H, NH), 8.90 (s, 1H, Ar-H), 8.67 (d, J = 4.2 Hz, 1H, Ar-H), 8.13 (d, J = 7.9 Hz, 1H, Ar-H), 7.75 (d, J = 7.9 Hz, 1H, Ar-H), 7.62–7.52 (m, 2H, Ar-H), 7.41 (d, J = 7.4 Hz, 1H, Ar-H), 1.50 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 410.09。

[0056] Example 13

[0057] This example adopts the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(3-methoxyphenyl)benzothiazol-2-amine (31.6 mg, 0.11 mmol), and 28.6 mg of (S)-N 1 -7-(3-(trifluoromethoxy)phenyl)benzothiazol-2-yl)pyrrolidine-1,2-dicarboxamide is obtained, with a yield of 60.8%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.14 (s, 1H, NH), 7.77 (d, J = 7.6 Hz, 1H, Ar-H), 7.71 (t, J = 7.9 Hz, 2H, Ar-H), 7.65 (s, 1H, NH), 7.57–7.46 (m, 2H, Ar-H), 7.42 (d, J = 8.4 Hz, 1H, Ar-H), 7.37 (d, J = 7.2 Hz, 1H, Ar-H), 6.99 (s, 1H, NH), 4.36–4.26 (m, 1H, CH), 3.73–3.65 (m, 1H, CH), 3.58–3.48 (m, 1H, CH), 2.25–2.01 (m, 1H, CH), 1.93–1.99 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 450.10。

[0058] Example 14

[0059] This example adopts the same implementation method as Example 8, with the difference that bromobenzene (62.4 mg, 0.40 mmol) is replaced by 1-bromo-2-methoxybenzene (74.4 mg, 0.40 mmol), and the obtained product, tert-butyl (7-(3-methoxypyridin-2-yl)benzo[d]thiazol-2-yl)carbamate, has a mass of 82.6 mg and a yield of 46.1%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.56 (s, 1H, NH), 8.40 (dd, J = 4.6, 1.2 Hz, 1H, Ar-H), 8.16 (d, J = 7.7 Hz, 1H, Ar-H), 7.70 (t, J = 7.3 Hz, 2H, Ar-H), 7.52–7.44 (m, 2H, Ar-H), 3.94 (s, 3H, OCH3), 1.52 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 357.11.

[0060] Example 15

[0061] This example adopts the same implementation method as Example 9, with the difference that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced by 7-(3-methoxypyridin-2-yl)benzo[d]thiazol-2-amine (49.4 mg, 0.19 mmol), and the obtained product, (S)-N 1 -(7-(3-methoxypyridin-2-yl)benzo[d]thiazol-2-yl)pyrrolidine-1,2-dicarboxamide, has a mass of 28.6 mg and a yield of 59.9%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.14 (s, 1H, NH), 7.56 (s, 1H, NH), 7.49–7.37 (m, 3H, Ar-H), 7.37–7.31 (m, 1H, Ar-H), 7.16 (t, J = 8.1 Hz, 2H, Ar-H), 7.07 (t, J = 7.4 Hz, 1H, Ar-H), 6.97 (s, 1H, NH), 4.35–4.25 (m, 1H, CH), 3.74 (s, 3H, OCH3), 3.68–3.57 (m, 1H, CH), 3.57–3.46 (m, 1H, CH), 2.14–3.03 (m, 1H, CH), 1.96–1.84 (m, CH×3). (ESI) m / z: [M+H] + : 396.13.

[0062] Example 16

[0063] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.4 mmol) is replaced with 3-bromoanisole (74.4 mg, 0.40 mmol), and the mass of tert-butyl (7-(3-methoxyphenyl)benzo[d]thiazol-2-yl)carbamate obtained is 82.6 mg, with a yield of 58.2%. 1 H NMR(400MHz,DMSO-d 6 )δ11.62(s,1H,NH),8.00(d,J=7.4Hz,1H,Ar-H),7.89(t,J=7.8Hz,1H,Ar-H),7.83(d,J=7.5Hz,1H,Ar-H),7.75(d,J=7.8Hz,1H,Ar-H),7.53(t,J=7.8Hz,1H,Ar-H),6.88(d,J=8.0Hz,1H,Ar-H),4.17(s,3H,OCH3),1.53(s,9H,CH3×3).(ESI)m / z:[M+H] + :356.12。

[0064] Example 17

[0065] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(3-methoxyphenyl)benzothiazol-2-amine (31.6 mg, 0.12 mmol), and the product (S)-N 1 -7-(3-methoxyphenyl)benzothiazol-2-ylpyrrolidine-1,2-dicarboxamide has a mass of 58.6 mg and a yield of 59.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.92(s,1H,NH),7.93(d,J=7.7Hz,1H,Ar-H),7.86(t,J=7.8Hz,1H,Ar-H),7.78(d,J=7.5Hz,1H,Ar-H),7.68(s,1H,NH),7.48(dd,J=13.3,5.4Hz,2H,Ar-H),7.04(s,1H,NH),6.85(d,J=8.1Hz,1H,Ar-H),4.38–4.30(m,1H,CH),4.23(s,3H,OCH3),3.74–3.68(m,1H,CH),3.58–3.47(m,1H,CH),2.17–2.01(m,1H,CH),1.96–1.89(m,3H,CH×3).(ESI)m / z:[M+H] + :396.13。

[0066] Example 18

[0067] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-chlorobromobenzene (76.0 mg, 0.40 mmol), and the product (tert-butyl 7-(2-chlorophenyl)benzothiazol-2-ylcarbamate) has a mass of 90.7 mg and a yield of 63.4%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.83 (s, 1H, NH), 7.72 (d, J = 7.5 Hz, 1H, Ar-H), 7.68–7.60 (m, 1H, Ar-H), 7.51 (dt, J = 9.4, 4.9 Hz, 4H, Ar-H), 7.24–7.16 (m, 1H, Ar-H), 1.47 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 360.07

[0068] Example 19

[0069] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(2-chlorophenyl)benzothiazol-2-amine (48.1 mg, 0.19 mmol), and the product (S)-N 1 -7-chlorophenylbenzothiazol-2-ylpyrrolidine-1,2-dicarboxamide has a mass of 31.8 mg and a yield of 43.6%. 1 HNMR (400 MHz, DMSO-d 6 ) δ 11.25 (s, 1H, NH), 7.68–7.58 (m, 2H, Ar-H), 7.54–7.44 (m, 4H, Ar-H), 7.36 (s, 1H, NH), 7.16 (d, J = 7.4 Hz, 1H, Ar-H), 6.94 (s, 1H, NH), 4.36–4.16 (m, 1H, CH), 3.72–3.65 (m, 1H, CH), 3.58–3.64 (m, 1H, CH), 2.15–2.03 (m, 1H, CH), 1.96–1.86 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 400.08

[0070] Example 20

[0071] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 1-bromo-2-chloro-3-methoxybenzene (88.0 mg, 0.40 mmol), and the product obtained is tert-butyl 7-(2-chloro-3-methoxyphenyl)benzothiazol-2-ylcarbamate with a mass of 72.7 mg and a yield of 42.3%. 1 H NMR(400MHz,DMSO-d 6 )δ11.83(s,1H,NH),7.72(dd,J=8.1,0.7Hz,1H,Ar-H),7.51–7.37(m,2H,Ar-H),7.27(dd,J=8.4,1.2Hz,1H,Ar-H),7.19(dd,J=7.4,0.8Hz,1H,Ar-H),7.06(dd,J=7.6,1.3Hz,1H,Ar-H),3.94(s,3H,OCH3),1.48(s,9H,CH3×3).(ESI)m / z:[M+H] + :390.08。

[0072] Example 21

[0073] This example uses the same implementation method as Example 9, except that 7-phenylbenzothiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(2-chloro-3-methoxyphenyl)benzothiazol-2-amine (30.1 mg, 0.11 mmol), and the product obtained is (S)-N 1 -7-chloro-3-methoxybenzothiazol-2-ylpyrrolidine-1,2-dicarboxamide with a mass of 23.6 mg and a yield of 54.5%. 1 H NMR(400MHz,DMSO-d 6 )δ11.10(s,1H,NH),7.66(s,1H,NH),7.54–7.35(m,3H,Ar-H),7.31–7.24(m,1H,Ar-H),7.16(d,J=7.3Hz,1H,Ar-H),7.07(d,J=7.4Hz,1H,Ar-H),6.97(s,1H,NH),4.29–4.17(m,1H,CH),3.95(s,3H,OCH3),3.71–3.68(m,1H,CH),3.58–3.49(m,1H,CH),2.19–2.04(m,1H,CH),1.94–1.87(m,3H,CH×3).(ESI)m / z:[M+H] + :430.09。

[0074] Example 22

[0075] This example adopts the same implementation method as Example 8, with the difference that bromobenzene (62.4 mg, 0.40 mmol) is replaced by 2-bromobenzonitrile (72.8 mg, 0.40 mmol), and the mass of the product tert-butyl (7-(2-isocyanophenyl)benzo[d]thiazol-2-yl)carbamate is 77.3 mg, with a yield of 54.5%. 1 H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H, NH), 8.05 (dd, J = 7.8, 0.8 Hz, 1H, Ar-H), 7.85–7.90 (m, 1H, Ar-H), 7.79 (d, J = 7.9 Hz, 2H, Ar-H), 7.68–7.71 (m, 1H, Ar-H), 7.60–7.50 (m, 1H, Ar-H), 7.36 (dd, J = 7.4, 0.9 Hz, 1H, Ar-H), 1.48 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 351.10.

[0076] Example 23

[0077] This example adopts the same implementation method as Example 9, with the difference that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced by 2-(2-aminobenzothiazol-7-yl)benzonitrile (30.1 mg, 0.12 mmol), and the mass of the product (S)-N 1 -7-(2-cyanophenyl)benzothiazol-2-ylpyrrolidine-1,2-dicarboxamide is 30.6 mg, with a yield of 64.8%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H, NH), 8.03 (d, J = 7.1 Hz, 1H, Ar-H), 7.87 (td, J = 7.7, 1.2 Hz, 1H, Ar-H), 7.77 (d, J = 7.6 Hz, 1H, Ar-H), 7.68 (td, J = 7.7, 1.1 Hz, 2H, Ar-H), 7.54 (t, J = 7.8 Hz, 1H, Ar-H), 7.39 (s, 1H, NH), 7.31 (d, J = 7.4 Hz, 1H, Ar-H), 6.95 (s, 1H, NH), 4.29–4.36 (m, 1H, CH), 3.69–3.58 (m, 1H, CH), 3.59–3.50 (m, 1H, CH), 2.16–2.03 (m, 1H, CH), 1.94–1.87 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 391.11.

[0078] Example 24

[0079] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromo-6-methoxybenzonitrile (84.8 mg, 0.40 mmol), and the mass of the product tert-butyl (7-(2-cyano-3-methoxyphenyl)benzo[d]thiazol-2-yl)carbamate obtained is 84.8 mg, and the yield is 50.0%. 1 H NMR (400 MHz, DMSO-d6) δ 11.92 (s, 1H, NH), 7.82 (dd, J = 17.0, 8.5 Hz, 2H, Ar-H), 7.60–7.54 (m, 1H, Ar-H), 7.40 (d, J = 8.4 Hz, 1H, Ar-H), 7.35 (d, J = 6.7 Hz, 1H, Ar-H), 7.32 (d, J = 7.6 Hz, 1H, Ar-H), 4.03 (s, 3H, OCH3), 1.51 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 381.11

[0080] Example 25

[0081] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 2-(2-aminobenzo[d]thiazol-7-yl)-6-methoxybenzonitrile (33.1 mg, 0.18 mmol), and the product (S)-N 1 -(7-(2-cyano-3-methoxyphenyl)benzo[d]thiazol-2-yl)pyrrolidine-1,2-dicarboxamide has a mass of 30.6 mg and a yield of 41.6%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.14 (s, 1H, NH), 7.79 (t, J = 8.1 Hz, 1H, Ar-H), 7.70 (s, 1H, NH), 7.51 (t, J = 7.8 Hz, 1H, Ar-H), 7.36 (d, J = 8.6 Hz, 2H, Ar-H), 7.28 (dd, J = 7.3, 3.9 Hz, 2H, Ar-H), 6.94 (s, 1H, NH), 4.32–4.24 (m, 1H, CH), 4.00 (s, 3H, OCH3), 3.69–3.58 (m, 1H, CH), 3.58–3.48 (m, 1H, CH), 2.19–2.02 (m, 1H, CH), 1.93–1.86 (m, 3H, CH×3). (ESI) m / z: [M+H] +: 421.12.

[0082] Example 26

[0083] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromopyridine (62.8 mg, 0.40 mmol), and the mass of the obtained product tert-butyl (7-(pyridin-2-yl)benzo[d]thiazol-2-yl)carbamate is 55.9 mg, with a yield of 43.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.58 (s, 1H, NH), 8.83 (d, J = 4.3 Hz, 1H, Ar-H), 8.28 (d, J = 8.1 Hz, 1H, Ar-H), 8.05 (d, J = 7.6 Hz, 1H, Ar-H), 7.99 (td, J = 8.0, 1.6 Hz, 1H, Ar-H), 7.76 (d, J = 7.8 Hz, 1H, Ar-H), 7.55 (t, J = 7.8 Hz, 1H, Ar-H), 7.44 (dd, J = 7.1, 5.0 Hz, 1H, Ar-H), 1.54 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 327.10.

[0084] Example 27

[0085] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(pyridin-2-yl)benzo[d]thiazol-2-amine (27.6 mg, 0.12 mmol), and the obtained product is (S)-N 1 -7-(pyridin-2-yl)benzo[d]thiazol-2-ylpyrrolidine-1,2-dicarboxamide with a mass of 24.6 mg and a yield of 42.0%. 1 HNMR (400 MHz, DMSO-d 6)δ 10.91 (s, 1H, NH), 8.84 (d, J = 4.1 Hz, 1H, Ar-H), 8.26 (d, J = 8.2 Hz, 1H, Ar-H), 8.07–7.86 (m, 2H, Ar-H), 7.72 (s, 1H, NH), 7.54 (t, J = 7.8 Hz, 1H, Ar-H), 7.50–7.40 (m, 2H, Ar-H), 7.02 (s, 1H, NH), 4.39–4.26 (m, 1H, CH), 3.73–3.82 (m, 1H, CH), 3.59–3.50 (m, 1H, CH), 2.20–2.07 (m, 1H, CH), 1.97–1.89 (m, J = 5.9 Hz, 3H, CH×3). (ESI) m / z: [M+H] + : 367.11。

[0086] Example 28

[0087] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromo-6-methylpyridine (68.4 mmol, 0.4 mmol), and the mass of the obtained product tert-butyl (7-(6-methylpyridin-2-yl)benzo[d]thiazol-2-yl)carbamate is 71.7 mg, and the yield is 52.6%. 1 H NMR (400 MHz, DMSO-d 6 )δ 11.51 (s, 1H, NH), 8.05 (dd, J = 16.5, 7.7 Hz, 2H, Ar-H), 7.87 (t, J = 7.8 Hz, 1H, Ar-H), 7.74 (d, J = 7.6 Hz, 1H, Ar-H), 7.53 (t, J = 7.8 Hz, 1H, Ar-H), 7.29 (d, J = 7.6 Hz, 1H, Ar-H), 2.66 (s, 3H, CH3), 1.54 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 341.12。

[0088] Example 29

[0089] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(6-methylpyridin-2-yl)benzo[d]thiazol-2-amine (40.1 mg, 0.17 mmol), and the obtained product (S)-N 1 -(7-(6-methylpyridin-2-yl)benzo[d]thiazol-2-yl)pyrrolidine-1,2-dicarboxamide has a mass of 36.5 mg and a yield of 56.4%. 11H NMR (400 MHz, DMSO-d 6 ) δ 10.81 (s, 1H, NH), 8.02 (d, J = 8.0 Hz, 1H, Ar-H), 7.96 (d, J = 7.7 Hz, 1H, Ar-H), 7.85 (t, J = 7.8 Hz, 1H, Ar-H), 7.67 (s, 1H, NH), 7.50 (t, J = 7.8 Hz, 1H, Ar-H), 7.43 (d, J = 8.0 Hz, 1H, Ar-H), 7.27 (d, J = 7.6 Hz, 1H, Ar-H), 7.00 (s, 1H, NH), 4.43–4.35 (m, 1H, CH), 3.72–3.61 (m, 1H, CH), 3.58–3.47 (m, 1H, CH), 2.73 (s, 3H, CH3), 2.18–2.02 (m, 1H, CH), 1.95–1.83 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 381.13。

[0090] Example 30

[0091] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromo-6-isopropylpyridine (79.6 mg, 0.40 mmol), and the mass of the product tert-butyl (7-(6-isopropylpyridin-2-yl)benzo[d]thiazol-2-yl)carbamate obtained is 96.2 mg, and the yield is 65.2%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.51 (s, 1H, NH), 8.07 (d, J = 7.9 Hz, 1H, Ar-H), 8.02 (d, J = 7.4 Hz, 1H, Ar-H), 7.88 (t, J = 7.8 Hz, 1H, Ar-H), 7.74 (d, J = 7.6 Hz, 1H, Ar-H), 7.53 (t, J = 7.8 Hz, 1H, Ar-H), 7.30 (d, J = 7.6 Hz, 1H, Ar-H), 3.20 (dd, J = 13.8, 6.9 Hz, 1H, CH), 1.54 (s, 9H, CH3×3), 1.43 (d, J = 6.9 Hz, 6H, CH3×2). (ESI) m / z: [M+H] + : 369.15。

[0092] Example 31

[0093] This example is implemented in the same way as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(6-isopropylpyridin-2-yl)benzo[d]thiazol-2-amine (47.8 mg, 0.18 mmol) to obtain the product (S)-N 1 -(7-(6-isopropylpyridin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide with a mass of 42.6 mg and a yield of 58.8%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.80 (s, 1H, NH), 8.04 (d, J = 8.0 Hz, 1H, Ar-H), 7.97 (d, J = 7.6 Hz, 1H, Ar-H), 7.87 (t, J = 7.8 Hz, 1H, Ar-H), 7.69 (s, 1H, NH), 7.51 (t, J = 7.8 Hz, 1H, Ar-H), 7.47 (s, 1H, Ar-H), 7.29 (d, J = 7.6 Hz, 1H, Ar-H), 7.05 (s, 1H, NH), 4.47–4.28 (m, 1H, CH), 3.77–3.65 (m, 1H, CH), 3.58–3.68 (m, 1H, CH), 3.25 (q, J = 13.6, 6.8 Hz, 1H, CH), 2.17–2.04 (m, 1H, CH), 1.95–1.82 (m, 3H, CH×3), 1.41 (d, J = 6.9, 2.3 Hz, 6H, CH3×2). (ESI) m / z: [M+H] + : 409.16.

[0094] Example 32

[0095] This example is implemented in the same way as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromo-6-(tert-butyl)pyridine (85.2 mg, 0.40 mmol) to obtain the product tert-butyl (7-(6-(tert-butyl)pyridin-2-yl)benzo[d]thiazol-2-yl]carbamate with a mass of 73.3 mg and a yield of 47.8%. 1 H NMR (400 MHz, DMSO-d 6)δ 11.54 (s, 1H, NH), 8.05 (d, J = 7.8 Hz, 1H, Ar-H), 7.99 (d, J = 7.2 Hz, 1H, Ar-H), 7.88 (t, J = 7.8 Hz, 1H, Ar-H), 7.72 (d, J = 7.3 Hz, 1H, Ar-H), 7.51 (t, J = 7.6 Hz, 1H, Ar-H), 7.41 (d, J = 7.5 Hz, 1H, Ar-H), 1.49 (d, J = 11.2 Hz, 18H, CH3×6). (ESI) m / z: [M+H] + : 383.17。

[0096] Example 33

[0097] This example was carried out in the same manner as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) was replaced with 7-(6-(tert-butyl)pyridin-2-yl)benzo[d]thiazol-2-amine (38.0 mg, 0.14 mmol) to obtain the product (S)-N 1- (7-(6-(tert-butyl)pyridin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide with a mass of 28.4 mg and a yield of 49.4%. 1 H NMR (400 MHz, DMSO-d 6 )δ 10.78 (s, 1H, NH), 7.99 (d, J = 7.7 Hz, 1H, Ar-H), 7.92 (d, J = 7.2 Hz, 1H, Ar-H), 7.86 (t, J = 7.7 Hz, 1H, Ar-H), 7.66 (s, 1H, NH), 7.54–7.42 (m, 2H, Ar-H), 7.38 (d, J = 7.7 Hz, 1H, Ar-H), 7.04 (s, 1H, NH), 4.46–4.56 (m, 1H, CH), 3.74–3.83 (m, 1H, CH), 3.57–3.46 (m, 1H, CH), 2.15–2.02 (m, 1H, CH), 1.94–1.83 (m, 3H, CH×3), 1.46 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 423.17。

[0098] Example 34

[0099] This example adopts the same implementation method as Example 8, with the difference that bromobenzene (62.4 mg, 0.40 mmol) is replaced by 2-bromo-6-(trifluoromethyl)pyridine (90.4 mg, 0.40 mmol), and the mass of the product tert-butyl (7-(6-(trifluoromethyl)pyridin-2-yl)benzo[d]thiazol-2-yl)carbamate is 64.0 mg, with a yield of 41.8%. 1 HNMR(400MHz,DMSO-d 6 )δ11.57(s,1H,NH),8.58(d,J=8.2Hz,1H,Ar-H),8.27(t,J=7.9Hz,1H,Ar-H),8.14(d,J=7.6Hz,1H,Ar-H),7.93(d,J=7.7Hz,1H,Ar-H),7.83(d,J=7.8Hz,1H,Ar-H),7.63–7.54(m,1H,Ar-H),1.54(s,9H,CH3×3).(ESI)m / z:[M+H] + :395.09。

[0100] Example 35

[0101] This example adopts the same implementation method as Example 9, with the difference that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced by 7-(6-(trifluoromethyl)pyridin-2-yl)benzo[d]thiazol-2-amine (27.1 mg, 0.09 mmol), and the mass of the product (S)-N 1 -(7-(6-(trifluoromethyl)pyridin-2-yl)benzo[d]thiazol-2-yl)pyrrolidine-1,2-dicarboxamide is 20.6 mg, with a yield of 55.6%. 1 H NMR(400MHz,DMSO-d 6 )δ10.89(s,1H,NH),8.50(d,J=8.0Hz,1H,Ar-H),8.22(t,J=7.1Hz,1H,Ar-H),8.04(d,J=6.8Hz,1H,Ar-H),7.88(d,J=6.7Hz,1H,Ar-H),7.73(s,1H,Ar-H),7.54(d,J=7.2Hz,1H,Ar-H),7.46(s,1H,NH),7.01(s,1H,NH),4.46–4.37(m,1H,CH),3.72–3.81(m,1H,CH),3.57–3.45(m,1H,CH),2.15–2.23(m,1H,CH),1.93–1.84(m,3H,CH×3).(ESI)m / z:[M+H] +: 435.10.

[0102] Example 36

[0103] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromo-6-(difluoromethoxy)pyridine (89.2 mg, 0.40 mmol), and the mass of the obtained product 2-bromo-6-(difluoromethoxy)pyridine is 66.3 mg, with a yield of 42.1%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.69 (s, 1H, NH), 8.12 (dd, J = 7.5, 5.1 Hz, 2H, Ar-H), 8.06 (d, J = 7.0 Hz, 1H, CH), 7.96 (s, 1H, Ar-H), 7.82–7.74 (m, 1H, Ar-H), 7.56 (t, J = 7.8 Hz, 1H, Ar-H), 7.14 (dd, J = 6.3, 2.4 Hz, 1H, Ar-H), 1.53 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 393.10.

[0104] Example 37

[0105] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(6-(difluoromethoxy)pyridin-2-yl)benzo[d]thiazol-2-amine (50.3 mg, 0.17 mmol), and the mass of the obtained product (S)-N 1 -(7-(6-(difluoromethoxy)pyridin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide is 39.6 mg, with a yield of 52.7%. 1 H NMR (400 MHz, DMSO-d 6)δ 10.97 (s, 1H, NH), 8.09 (d, J = 15.7 Hz, 2H, Ar-H, CH), 8.01–7.90 (m, 1H, Ar-H), 7.73 (d, J = 12.2 Hz, 1H, Ar-H), 7.58–7.49 (m, 1H, Ar-H), 7.45 (s, 1H, NH), 7.35 (s, 1H, Ar-H), 7.15–7.08 (m, 1H, Ar-H), 7.02 (s, 1H, NH), 4.38–4.25 (m, 1H, CH), 3.73–3.63 (m, 1H, CH), 3.56–3.65 (m, 1H, CH), 2.17–2.28 (m, 1H, CH), 1.95–1.87 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 433.10。

[0106] Example 38

[0107] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromo-6-methoxypyridine (74.8 mg, 0.40 mmol), and the mass of the obtained product tert-butyl (7-(6-methoxypyridin-2-yl)benzo[d]thiazol-2-yl)carbamate is 76.2 mg, and the yield is 53.4%. 1 H NMR (400 MHz, DMSO-d 6 )δ 11.62 (s, 1H, NH), 8.00 (d, J = 7.4 Hz, 1H, Ar-H), 7.89 (t, J = 7.8 Hz, 1H, Ar-H), 7.83 (d, J = 7.5 Hz, 1H, Ar-H), 7.75 (d, J = 7.8 Hz, 1H, Ar-H), 7.53 (t, J = 7.8 Hz, 1H, Ar-H), 6.88 (d, J = 8.0 Hz, 1H, Ar-H), 4.17 (s, 3H, OCH3), 1.53 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 357.11。

[0108] Example 39

[0109] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(6-methoxypyridin-2-yl)benzo[d]thiazol-2-amine (47.7 mg, 0.23 mmol), and the obtained product is (S)-N 1The mass of [-(7-(6-methoxypyridin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide was 40.7 mg, and the yield was 45.7%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.92 (s, 1H, NH), 7.93 (d, J = 7.7 Hz, 1H, Ar-H), 7.86 (t, J = 7.8 Hz, 1H, Ar-H), 7.78 (d, J = 7.5 Hz, 1H, Ar-H), 7.68 (s, 1H, NH), 7.48 (dd, J = 13.3, 5.4 Hz, 2H, Ar-H), 7.04 (s, 1H, NH), 6.85 (d, J = 8.1 Hz, 1H, Ar-H), 4.45–4.32 (m, 1H, CH), 4.15 (s, 3H, OCH3), 3.75–3.62 (m, 1H, CH), 3.58–3.45 (m, 1H, CH), 2.17–2.01 (m, 1H, CH), 1.96–1.87 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 397.12.

[0110] Example 40

[0111] This example adopted the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) was replaced with 2-bromopyrimidine (63.2 mg, 0.40 mmol), and the mass of the obtained product [7-(pyrimidin-2-yl)benzo[d]thiazol-2-yl]carbamic acid tert-butyl ester was 59.2 mg, and the yield was 45.1%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.66 (s, 1H, NH), 9.05 (d, J = 4.7 Hz, 2H, Ar-H), 8.46 (d, J = 7.7 Hz, 1H, Ar-H), 7.84 (d, J = 7.9 Hz, 1H, Ar-H), 7.58 (t, J = 7.8 Hz, 1H, Ar-H), 7.51 (t, J = 4.7 Hz, 1H, Ar-H), 1.52 (s, 9H, CH3×3).

[0112] (ESI) m / z: [M+H] + : 328.10.

[0113] Example 41

[0114] This example is implemented in the same way as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(pyrimidin-2-yl)benzo[d]thiazol-2-amine (30.1 mg, 0.13 mmol) to obtain the product (S)-N 1 -(7-(pyrimidin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide with a mass of 21.3 mg and a yield of 44.4%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.94 (s, 1H, NH), 9.03 (d, J = 4.7 Hz, 2H, Ar-H), 8.42 (d, J = 7.4 Hz, 1H, Ar-H), 7.78 (s, 1H, Ar-H), 7.60–7.38 (m, 3H, Ar-H, NH), 7.00 (s, 1H, NH), 4.38–4.26 (m, 1H, CH), 3.74–3.65 (m, 1H, CH), 3.59–3.46 (m, 1H, CH), 2.17–2.08 (m, 1H, CH), 1.94–1.85 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 368.11.

[0115] Example 42

[0116] This example is implemented in the same way as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromo-4-methoxypyrimidine (75.2 mg, 0.40 mmol) to obtain the product tert-butyl (7-(4-methoxypyrimidin-2-yl)benzo[d]thiazol-2-yl]carbamate with a mass of 75.2 mg and a yield of 52.5%. 1 H NMR (400 MHz, DMSO-d6) δ 11.67 (s, 1H, NH), 8.77 (d, J = 5.8 Hz, 1H, Ar-H), 8.47 (d, J = 7.7 Hz, 1H, Ar-H), 7.86 (d, J = 7.9 Hz, 1H, Ar-H), 7.59 (t, J = 7.8 Hz, 1H, Ar-H), 6.96 (d, J = 5.8 Hz, 1H, Ar-H), 4.16 (s, 3H, OCH3), 1.53 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 358.11.

[0117] Example 43

[0118] This example is implemented in the same manner as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(4-methoxypyrimidin-2-yl)benzo[d]thiazol-2-amine (29.8 mg, 0.12 mmol) to obtain the product (S)-N 1 -(7-(4-methoxypyrimidin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide with a mass of 23.3 mg and a yield of 50.0%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.93 (s, 1H, NH), 8.73 (d, J = 5.7 Hz, 1H, Ar-H), 8.40 (d, J = 7.7 Hz, 1H, Ar-H), 7.77 (s, 1H, NH), 7.54 (t, J = 7.8 Hz, 1H, Ar-H), 7.43 (s, 1H, Ar-H), 7.00 (s, 1H, NH), 6.92 (d, J = 5.8 Hz, 1H, Ar-H), 4.39–4.28 (m, 1H, CH), 4.13 (s, 3H, OCH3), 3.73–3.65 (m, 1H, CH), 3.58–3.48 (s, 1H, CH), 2.16–2.05 (m, 1H, CH), 1.94–1.85 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 398.12.

[0119] Example 44

[0120] This example is implemented in the same manner as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 2-bromo-4-methylpyrimidine (68.8 mg, 0.40 mmol) to obtain the product tert-butyl (7-(4-methylpyrimidin-2-yl)benzo[d]thiazol-2-yl]carbamate with a mass of 61.0 mg and a yield of 44.6%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.62 (s, 1H, NH), 8.90 (d, J = 5.1 Hz, 1H, Ar-H), 8.46 (dd, J = 7.7, 1.0 Hz, 1H, Ar-H), 7.85 (dd, J = 7.9, 1.0 Hz, 1H, Ar-H), 7.58 (t, J = 7.8 Hz, 1H, Ar-H), 7.40 (d, J = 5.1 Hz, 1H, Ar-H), 2.63 (s, 3H, CH3), 1.55 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 342.12.

[0121] Example 45

[0122] This example is implemented in the same manner as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(4-methylpyrimidin-2-yl)benzo[d]thiazol-2-amine (45.7 mg, 0.19 mmol) to obtain the product (S)-N 1 -(7-(4-methylpyrimidin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide with a mass of 33.8 mg and a yield of 46.9%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.92 (s, 1H, NH), 8.89 (d, J = 4.9 Hz, 1H, Ar-H), 8.43 (d, J = 7.2 Hz, 1H, Ar-H), 7.80 (s, 1H, NH), 7.56 (t, J = 7.7 Hz, 1H, Ar-H), 7.48 (s, 1H, Ar-H), 7.39 (d, J = 4.8 Hz, 1H, Ar-H), 7.03 (s, 1H, NH), 4.46–3.32 (m, 1H, CH), 3.74–3.61 (m, 1H, CH), 3.62–3.46 (m, 1H, CH), 2.63 (s, 3H, CH3), 2.19–2.10 (m, 1H, CH), 1.99–1.86 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 382.12。

[0123] Example 46

[0124] This example is implemented in the same manner as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with N-(2-bromopyrimidin-4-yl)acetamide (86.0 mg, 0.40 mmol) to obtain the product tert-butyl (7-(4-acetamidopyrimidin-2-yl)benzo[d]thiazol-2-yl]carbamate with a mass of 84.5 mg and a yield of 54.9%. 1 H NMR (400 MHz, DMSO-d 6)δ 11.62 (s, 1H, NH), 10.98 (s, 1H, NH), 8.87 (d, J = 5.6 Hz, 1H, Ar-H), 8.37 (d, J = 7.7 Hz, 1H, Ar-H), 8.00 (d, J = 5.7 Hz, 1H, Ar-H), 7.82 (d, J = 7.9 Hz, 1H, Ar-H), 7.56 (t, J = 7.8 Hz, 1H, Ar-H), 2.18 (s, 3H, CH3), 1.51 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 385.12。

[0125] Example 47

[0126] In this example, the same implementation method as in Example 9 was adopted. The difference is that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) was replaced with N-(2-(2-aminobenzo[d]thiazol-7-yl)pyrimidin-4-yl)acetamide (13.4 mg, 0.04 mmol) to obtain the product (S)-N 1 -(7-(4-acetylaminopyrimidin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide with a mass of 13.6 mg and a yield of 63.7%. 1 H NMR (400 MHz, DMSO-d 6 )δ 11.00 (s, 1H, NH), 8.90 (d, J = 5.7 Hz, 1H, Ar-H), 8.37 (d, J = 7.7 Hz, 1H, Ar-H), 8.03 (d, J = 5.8 Hz, 1H, Ar-H), 7.79 (d, J = 7.6 Hz, 1H, Ar-H), 7.57 (t, J = 7.8 Hz, 1H, Ar-H), 7.46 (s, 1H, NH), 7.01 (s, 1H, NH), 4.38–3.25 (m, 1H, CH), 3.73–3.65 (m, 1H, CH), 3.57–3.45 (m, 1H, CH), 2.22 (s, 3H, CH3), 2.17–2.05 (m, 1H, CH), 1.96–1.86 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 425.13。

[0127] Example 48

[0128] This example uses the same implementation method as Example 8. The difference is that bromobenzene (62.4 mg, 0.40 mmol) is replaced with N-(2-bromopyrimidin-4-yl)-N-methylacetamide (91.6 mg, 0.40 mmol), and the mass of the product tert-butyl [7-(4-(N-methylacetamido)pyrimidin-2-yl)benzo[d]thiazol-2-yl]carbamate is 76.1 mg, with a yield of 47.7%. 1 H NMR(400MHz,DMSO-d 6 )δ11.00(s,1H,NH),8.87(d,J=5.8Hz,1H,Ar-H),8.39(d,J=7.5Hz,1H,Ar-H),8.00(d,J=5.8Hz,1H,Ar-H),7.90(d,J=8.1Hz,1H,Ar-H),7.58(t,J=7.8Hz,1H,Ar-H),3.56(s,3H,CH3),2.18(s,3H,CH3),1.56(s,9H,CH3×3).(ESI)m / z:[M+H] + :399.14。

[0129] Example 49

[0130] This example uses the same implementation method as Example 9. The difference is that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with N-(2-(2-aminobenzo[d]thiazol-7-yl)pyrimidin-4-yl)-N-methylacetamide (38.6 mg, 0.16 mmol), and the mass of the product (S)-N 1 -(7-(4-(N-methylacetamido)pyrimidin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide is 32.6 mg, with a yield of 60.4%. 1 H NMR(400MHz,DMSO-d 6)δ10.91(s,1H,NH),8.87(d,J=5.4Hz,1H,Ar-H),8.38(d,J=7.2Hz,1H,Ar-H),7.81(d,J=5.5Hz,2H,Ar-H),7.53(t,J=7.5Hz,1H,Ar-H),7.42(s,1H,NH),6.98(s,1H,NH),4.37–4.26(m,1H,CH),3.74–3.65(m,1H,CH),3.59(s,3H,CH3),3.57–3.46(m,1H,CH),2.39(s,3H,CH3),2.15–2.06(m,1H,CH),1.94–1.85(m,3H,CH×3).(ESI)m / z:[M+H] + :439.14。

[0131] Example 50

[0132] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with tert-butyl (2-bromopyrimidin-4-yl)carbamate (109.2 mg, 0.40 mmol), and the mass of the product tert-butyl [(7-(4-(tert-butoxycarbonyl)amino)pyrimidin-2-yl)benzo[d]thiazol-2-yl]carbamate obtained is 92.5 mg, and the yield is 52.2%. 1 H NMR(400MHz,DMSO-d 6 )δ11.67(s,1H,NH),7.85(t,J=7.1Hz,2H,Ar-H),7.74(d,J=8.0Hz,1H,Ar-H),7.68(d,J=7.5Hz,1H,Ar-H),7.53(t,J=7.7Hz,1H,Ar-H),6.78(d,J=8.1Hz,1H,Ar-H),1.63(s,9H,CH3×3),1.52(s,9H,CH3×3).(ESI)m / z:[M+H] + :443.16。

[0133] Example 51

[0134] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 7-(4-aminopyrimidin-2-yl)benzo[d]thiazol-2-amine (30.1 mg, 0.13 mmol), and the mass of the product [(7-(4-aminopyrimidin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide obtained is 31.3 mg, and the yield is 61.5%. 11H NMR (400 MHz, DMSO-d 6 ) δ 10.77 (s, 1H, NH), 8.33–8.12 (m, 2H, Ar-H), 7.70 (s, 1H, NH), 7.43 (d, J=23.7 Hz, 2H, Ar-H), 6.96 (s, 3H, NH), 6.40 (d, J=4.2 Hz, 1H, Ar-H), 4.35–4.23 (m, 1H, CH), 3.67–3.57 (m, 1H, CH), 3.57–3.46 (m, 1H, CH), 2.14–2.19 (m, 1H, CH), 1.94–1.85 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 383.12。

[0135] Example 52

[0136] This example uses the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) is replaced with 3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (97.2 mg, 0.40 mmol), and the mass of the product tert-butyl [7-(4-(2-oxooxazolin-3-yl)pyrimidin-2-yl)benzo[d]thiazol-2-yl]carbamate obtained is 32.1 mg, and the yield is 19.4%. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.64 (s, 1H, NH), 8.88 (d, J=6.0 Hz, 1H, Ar-H), 8.41 (d, J=8.0 Hz, 1H, Ar-H), 8.03 (d, J=5.7 Hz, 1H, Ar-H), 7.83 (d, J=8.1 Hz, 1H, Ar-H), 7.56 (t, J=7.7 Hz, 1H, Ar-H), 4.57 (t, J=7.7 Hz, 2H, CH2), 4.41 (t, J=7.8 Hz, 2H, CH2), 1.51 (s, 9H, CH3×3). (ESI) m / z: [M+H] + : 413.12。

[0137] Example 53

[0138] This example uses the same implementation method as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with 3-(2-(2-aminobenzo[d]thiazol-7-yl)pyrimidin-4-yl)oxazol-2-one (13.2 mg, 0.04 mmol), and the product (S)-N 1The mass of [[ID=]], -(7-(4-(2-oxooxazolin-3-yl)pyrimidin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide was 8.9 mg and the yield was 49.6%. 1 H NMR(400 MHz, DMSO-d 6 )δ 10.98(s, 1H, NH), 8.90(d, J = 5.8 Hz, 1H, Ar-H), 8.40(d, J = 7.7 Hz, 1H, Ar-H), 8.05(d, J = 5.8 Hz, 1H, Ar-H), 7.80(s, 1H, Ar-H), 7.56(t, J = 7.8 Hz, 1H Ar-H), 7.44(s, 1H, NH), 7.01(s, 1H, NH), 4.59(t, J = 8.1 Hz, 2H, CH2), 4.44(t, J = 8.1 Hz, 2H, CH2), 4.37–4.29(m, 1H, CH2), 3.75–3.64(m, 1H, CH), 3.57–3.47(m, 1H, CH), 2.16–2.04(m, 1H, CH), 1.98–1.90(m, 3H, CH×3). (ESI) m / z: [M+H] + : 453.12.

[0139] Example 54

[0140] This example used the same implementation method as Example 8, except that bromobenzene (62.4 mg, 0.40 mmol) was replaced with N-(2-bromopyrimidin-4-yl)-N-methylmethanesulfonamide (100.4 mg, 0.40 mmol), and the mass of the product [[ID=]], -(7-(4-(N-methylsulfamoyl)pyrimidin-2-yl)benzo[d]thiazol-2-yl]carbamic acid tert-butyl ester was 74.3 mg and the yield was 44.1%. 1 H NMR(400 MHz, DMSO-d 6 )δ 11.71(s, 1H, NH), 8.87(d, J = 5.7 Hz, 1H, Ar-H), 8.39(d, J = 6.8 Hz, 1H, Ar-H), 7.84(d, J = 7.3 Hz, 1H, Ar-H), 7.67(m, 1H, Ar-H), 7.61–7.54(m, 1H, Ar-H), 7.46(d, J = 6.1 Hz, 1H, Ar-H), 3.54(s, 3H, CH3), 3.45(s, 3H, CH3), 1.51(s, 9H, CH3×3). (ESI) m / z: [M+H] + : 435.10.

[0141] Example 55

[0142] This example is implemented in the same manner as Example 9, except that 7-phenylbenzo[d]thiazol-2-amine (30.3 mg, 0.14 mmol) is replaced with N-(2-(2-aminobenzo[d]thiazol-7-yl)pyrimidin-4-yl)-N-methylmethanesulfonamide (43.1 mg, 0.13 mmol) to obtain the product (S)-N 1 The mass of -(7-(4-(N-methylsulfamoyl)pyrimidin-2-yl)benzo[d]thiazol-2-yl]pyrrolidine-1,2-dicarboxamide is 31.3 mg, and the yield is 58.8%. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.92 (s, 1H, NH), 8.85 (d, J = 5.5 Hz, 1H, Ar-H), 8.35 (d, J = 7.1 Hz, 1H, Ar-H), 7.78 (s, 1H, NH), 7.54 (t, J = 7.5 Hz, 1H, Ar-H), 7.49–7.36 (m, 2H, Ar-H), 6.98 (s, 1H, NH), 4.38–4.26 (s, 1H, CH), 3.74–3.64 (m, 1H, CH), 3.63–3.56 (m, 1H, CH), 3.51 (s, 1H, CH3), 3.44 (s, 3H, CH3), 2.17–2.06 (m, 1H, CH), 1.95–1.85 (m, 3H, CH×3). (ESI) m / z: [M+H] + : 475.11.

[0143] Example 56: PI3Kα inhibitory activity of the compound (2,7-disubstituted benzothiazole compound) of the present invention

[0144] The inhibitory activity of the compounds of the present invention against PI3Kα was determined by Kinase-Glo Plus Luminescent Kinase Assay. First, the test compounds were diluted to a series of concentrations required for the test, and 2.5 μL of each was added to a 384-well plate. Subsequently, PI3Kα was diluted to 1.65 nM with kinase buffer solution (50 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) pH 7.5, 3 mM MgCl2, 1 mM ethylene glycol-bis(2-aminoethylether)-N,N,N',N'-tetraacetic acid (EGTA), 100 mM NaCl, 0.03% 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS), 2 mM dithiothreitol (DTT)), and then 2.5 μL of it was added to the 384-well plate per well; similarly, the substrates PIP2 and ATP were diluted to 50 μM and 25 μM respectively with kinase buffer solution, and 5 μL of each was added to the above 384-well plate per well. After reacting for 1 hour, 10 μL of Kinase-Glo reagent was added to each well of the 384-well plate to terminate the reaction. After the samples were centrifuged and other treatments, the RLU value was read using a microplate reader. The inhibition rate was calculated according to the following formula: Inhibition rate (%) = (sample RLU - min) / (max - min) × 100, where "min" represents the RL of the enzyme-free control well, and "max" represents the RLU of the DMSO-containing control well.

[0145] Table 1 PI3Kα inhibitory activity of the compounds of the present invention (2,7-disubstituted benzothiazole compounds)

[0146] Compound <![CDATA[PI3Kα(IC 50 , nM)]]> Compound <![CDATA[PI3Kα(IC 50 , nM)]]> T-1 ++(439) T-14 +(1281) T-2 ++(239) T-15 ++(325) T-3 ++(867) T-16 ++(289) T-4 ++(851) T-17 +++(52) T-5 ++(157) T-18 ++(193) T-6 +(1091) T-19 +++(70) T-7 +(1213) T-20 ++(131) T-8 ++(771) T-21 ++(149.9) T-9 ++(241) T-22 +++(56) T-10 +++(64) T-23 +++(98) T-11 ++(451) T-24 +++(56.4) T-12 +(1465) Alpelisib +++(5) T-13 +(>2000)

[0147] "+++" represents 0 - 100 nM; "++" represents 100 - 1000 nM; "+" represents > 1000 nM;

[0148] From the enzyme inhibition activity data in Table 1, it can be seen that most compounds showed strong PI3Kα inhibitory activity, and the enzyme inhibition activity of some compounds was comparable to that of Alpelisib, having good application prospects.

[0149] Example 57: Selectivity of the preferred compounds of the present invention for Class I PI3Ks

[0150] The selectivity data (Table 2) of the preferred compounds of the present invention for Class I PI3Ks are as follows to further illustrate their selective effect on PI3Kα. Other compounds of the present invention also have similar effects, and this should not be understood as only these several compounds of the present invention having the following effects.

[0151] Table 2 Selectivity of the preferred compounds for Class I PI3Ks

[0152]

[0153]

[0154] Example 58: Comparison of the compound of the present invention (2,7-disubstituted benzothiazole compounds) with patent data

[0155] A certain similar structure to the patented compound was reported in a US patent (US20100075965A1). Firstly, there are essential differences between this patent and it. This patent mainly conducts derivatization at the 7-position of the parent nucleus, which is different from the 6-position derivatization of some of its compounds. Secondly, in the patent disclosure data, we compared their inhibitory activities against PI3Kα.

[0156]

[0157] Table 3 Comparison of data of the preferred compound and the 25 similar compounds in the patent

[0158] Compound T17 25 PI3Kα (nM) 52 <1000

Claims

1. A 2,7-disubstituted benzothiazole compound represented by formula (I) or (II), or a pharmaceutically acceptable salt or stereoisomer thereof, In formula (I): X is CH or N; In formula (I), R 1 is hydrogen, amino, methyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, difluoromethoxy, formamido, N -methylformamido, N -methylmethanesulfonamido or 2-oxazolidinonyl; in formula (II), R 2 is hydrogen, chlorine, cyano or methoxy; R 3 is hydrogen, methoxy, trifluoromethyl or trifluoromethoxy.

2. The 2,7-disubstituted benzothiazole compound represented by formula (I) or (II) according to claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that The 2,7-disubstituted benzothiazole compounds represented by the formula (I) or (II) are selected from any one of the following compounds: 。 3. Use of the 2,7-disubstituted benzothiazole compound represented by formula (I) or (II) according to any one of claims 1 to 2, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of an anti-tumor drug.

4. The use according to claim 3, characterized in that The tumor is selected from lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colorectal cancer, thyroid cancer, liver and intrahepatic bile duct cancer, gastric cancer, glioma, glioblastoma, endometrial cancer, melanoma, renal and renal pelvic cancer, bladder cancer, corpus cancer of uterus, cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, lymphocytic leukemia, myeloid leukemia, brain cancer, oral and pharyngeal cancer, laryngeal cancer, small intestine cancer, non-Hodgkin lymphoma, melanoma and villous colonic adenoma.

5. The use according to claim 3, characterized in that The 2,7-disubstituted benzothiazole compound is compound T-10, T-17, T-19, T-22, T23 or T-24. 。 6. The use according to claim 5, characterized in that The 2,7-disubstituted benzothiazole compound described above is compound T-17 .

7. The use according to claim 3, characterized in that: The anti-tumor drug is a pharmaceutical composition, which is composed of the 2,7-disubstituted benzothiazole compound or its pharmaceutically acceptable salt, stereoisomer and a pharmaceutically acceptable carrier.

8. The use according to claim 7, characterized in that: The pharmaceutically acceptable carrier is a diluent, excipient, filler, binder, wetting agent, disintegrant, absorption promoter, surfactant, adsorption carrier or lubricant.

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