A method for synthesizing n-borane benzazaborine based on modular gbb and applications thereof

Abstract

The application discloses a method for synthesizing N-BOH benzazaborine based on modular GBB and application thereof, and belongs to the technical field of medicinal chemistry. The method is as follows: a boron source and an amino pyridine are dissolved in an alcohol solvent, the mixture is stirred at room temperature, then an isonitrile is added dropwise, the stirring reaction is continued, and the solid separated in the reaction process is filtered and washed. The application proposes a novel three-component coupling reaction combining a GBB reaction and intramolecular cyclization, and a BN-nitazaborine skeleton with N-BOH functionalization is directly generated in an alcohol solvent through a one-pot process. The application can react under mild conditions and is simple to operate. The target product is usually precipitated from the reaction mixture in the form of a high-purity solid, and high-purity products can be obtained through simple filtration without chromatographic purification. This not only greatly improves the synthesis efficiency, but also provides a green, economical and practical method for large-scale preparation of BN-nitazaborine.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a method and application for synthesizing N-BOH benzozaborane based on modular GBB. Background Technology

[0002] Diverse modifications to the molecular skeleton are a key starting point for improving drug efficacy. Traditional methods typically rely on de novo, multi-step synthetic pathways, which are not only arduous and inefficient but also require significant resources and time. In recent years, the implementation of bioisosteric strategies has provided a new avenue for the efficient construction of bioactive molecules, significantly accelerating drug development. The development of novel boron-nitrogen (B–N) covalent bonds has gradually become a hot topic in international research due to its broad application potential in synthetic chemistry, medicinal chemistry, and materials science.

[0003] Benzoboranes, as a unique class of boron-nitrogen (BN) heterocycles, can serve as BN isosteres of phthalazine and isoquinoline. These substances typically contain an N–BOH functional group and exhibit significantly enhanced therapeutic potential compared to their all-carbon counterparts due to improved water solubility, metabolic stability, and target binding ability.

[0004] This advantage is partly attributed to the NH or BOH groups within the BN ring, which can act as hydrogen bond donors, enhancing specific interactions with biomacromolecules such as proteins. Currently, the synthetic chemistry of BN heterocycles derived from phthalazines is well-established and extensively studied. However, pathways for synthesizing structurally similar isoquinoline-derived BN heterocycles (especially 1,2-dihydrobenzo[c][1,2]azaboranes) remain limited.

[0005] Existing methods suffer from significant limitations in terms of reaction conditions, substrate versatility, and ease of operation. Established strategies primarily include: base-catalyzed one-pot, multi-step condensation of substituted isoindolinetones with 2-formylarylboronic acids; and the modular three-component synthesis via Wolff-type ring expansion reported by the Kumar team. While these important methods have made substantial progress in the synthesis of various N–BOH-containing BN heterocycles, the flexible construction and diversified derivatization of such BN skeletons under mild, environmentally friendly, and efficient conditions remains a key objective in medicinal chemistry. Summary of the Invention

[0006] To address the aforementioned shortcomings in the prior art, this invention provides a method for synthesizing N-BOH benzozaboranes based on modular GBB and its application.

[0007] To achieve the above objectives, the technical solution adopted by the present invention to solve its technical problem is as follows: The purpose of this invention is to provide a method for synthesizing N-BOH benzozaborane based on modular GBB. The method involves dissolving a boron source and aminopyridine in an alcohol solvent, mixing them under stirring at room temperature, then adding isonitriles dropwise, continuing stirring, and filtering and washing away the solids precipitated during the reaction. The reaction formula is as follows:

[0008] Furthermore, the molar ratio of boron source, aminopyridine, and isonitrile is 0.5~1:0.5~1:0.5~1.

[0009] Furthermore, the molar ratio of boron source, aminopyridine, and isonitrile is 1:1:1.

[0010] Furthermore, the alcohol solvent is methanol, ethanol, or an aqueous solution of ethanol.

[0011] Furthermore, the alcohol solvent is methanol.

[0012] Furthermore, the amount of alcohol solvent used is <5 mL, preferably 1 mL in the present invention, the final concentration of boron source in alcohol solvent is 0.5~1 mmol / mL, the final concentration of aminopyridine in alcohol solvent is 0.5~1 mmol / mL, and the final concentration of isonitrile in alcohol solvent is 0.5~1 mmol / mL.

[0013] Furthermore, the aminopyridine is an aminopyridine, 2-aminopyridine, or benzo[d]oxazol-2-amine that has halogen or methyl substitution.

[0014] Furthermore, the boron source is 2-formylarylboronic acid, naphthylformylboronic acid, or 2-formylarylboronic acid with methyl, methoxy, and / or halogen substitutions.

[0015] Furthermore, the isonitrile is n-butylisocyanate, benzylisocyanate, (2-isocyanoethyl)benzene, methyl isocyanate, or 2-morpholinoethylisocyanate.

[0016] Furthermore, the reaction time is 0.5 to 1 hour, preferably 1 hour.

[0017] Another object of the present invention is to provide an N-BOH benzozaborane prepared by the above method, the chemical structural formula of which is as follows: 、 、 , , , , , 、 , , 、 , , 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0018] Another object of the present invention is to provide the use of the above-mentioned N-BOH benzozaborane in the preparation of antitumor drugs.

[0019] Furthermore, the tumor is either small cell lung cancer or prostate cancer.

[0020] The beneficial effects of this invention are: This invention proposes a novel three-component coupling reaction combining the GBB reaction with intramolecular cyclization, directly generating an N-BOH-functionalized BN-azaborane skeleton in an alcohol solvent via a one-pot process. By seamlessly integrating the GBB reaction with subsequent boron cyclization, this invention achieves the direct conversion of a simple starting material into the target BN heterocycle without the need for intermediate separation.

[0021] This invention utilizes environmentally friendly methanol or other alcohols as solvents under mild conditions, and is simple to operate. Notably, the target product typically precipitates from the reaction mixture in high-purity solid form, eliminating the need for chromatographic purification; high-purity product can be obtained through simple filtration. This not only significantly improves synthetic efficiency but also provides a green, economical, and practical method for the large-scale preparation of BN-azaboranes. This invention not only provides a highly efficient new route for BN-azaboranes but also offers a practical and sustainable synthetic tool for the rapid derivatization of drug-like molecules based on bioisosteric strategies. Detailed Implementation

[0022] The specific embodiments of the present invention are described below to enable those skilled in the art to understand the present invention. However, it should be understood that the present invention is not limited to the scope of the specific embodiments. For those skilled in the art, various changes are obvious as long as they are within the spirit and scope of the present invention as defined and determined by the appended claims. All inventions utilizing the concept of the present invention are protected.

[0023] Example 1: Optimization and Determination of Preparation Process 1. Solvent selection First, we selected 2-formylarylboronic acid (1a), 2-aminopyridine (2a), and benzylisocyanate (3a) as initial reaction substrates, and obtained the target product (4a) in high yield using a standard volume of 5 mL of solvent.

[0024]

[0025] Notably, a white suspension appeared during the reaction. After concentration, a large amount of solid precipitated, facilitating direct separation of the high-purity product by filtration. Inspired by this phenomenon, the methanol volume was reduced to 1 mL. In this case, rapid precipitation formed a thick slurry, which could be directly filtered to obtain the high-purity product 4a. Ethanol and a 75% aqueous ethanol solution were subsequently investigated. When using 75% ethanol, additional impurities were detected, requiring column chromatography to achieve an 83% yield.

[0026] In addition, other solvents, such as dichloromethane (DCM), 1,4-dioxane, and acetone, were tested, but none improved the yield, mainly due to the poor solubility of the starting materials. It is worth noting that when using 1,4-dioxane as a solvent, the solvent absorbs water and becomes viscous due to the water produced in the reaction, making final separation difficult. Although N,N-dimethylformamide (DMF) yields a higher amount (item 6), it requires chromatographic purification, making post-processing more cumbersome than with the methanol system.

[0027] Table 1 Effect of different solvents on yield

[0028] Considering the yield, ease of operation, and environmental impact in Table 1, methanol was determined to be the optimal solvent, and its volume in the reaction system of this invention is 1 mL. It provides the highest yield with the fewest processing steps, and the reaction can be completed in just 1 hour.

[0029] 2. Selection of reaction substrate (1) Aminopyridine To expand the substrate selection to include a wider range of 2-aminopyridine substrates, this invention investigated a series of common substituted aminopyridines (Cl, Br, Me-substituted), all yielding the target products 4a-4f in excellent yields (88%–95%). Notably, benzo[d]oxazol-2-amine also exhibited significant reactivity, providing 4g of the compound in a high yield of 92%, and separation was achieved solely by filtration.

[0030] (2) Boron source For 2-formylarylboronic acid substrates, this invention evaluated five representative derivatives, demonstrating that substrates with different substitution modes (e.g., Me, OMe, and F) readily participated in the reaction, generating products 4h-4x in high yields (81%-98%). Detailed examination of the reaction process in the representative example 4x showed that the mixture transformed into a thick slurry within just one hour. Precipitation of the product significantly accelerated the reaction's completion. Simple filtration provided a pure product, greatly reducing the need for laborious chromatographic purification. Similarly, when using naphthylformylboronic acid (synthetic compound 4y), a solid gradually formed upon the addition of isonitriles, evolving into a similar white slurry after one hour.

[0031] (3) Isocyanates Regarding the choice of isonitrile substrates, n-butylisocyanate yielded compound 4z in up to 93% yield. Benzylisocyanate and (2-isocyanoethyl)benzene yielded compounds 4aa-4ac and 4ad-4ai, respectively, in yields ranging from 82% to 95% and 88% to 97%. Furthermore, methyl isocyanate was explored as a substrate. Similarly, the reaction mixture formed an easily handled slurry, which, after simple post-treatment, yielded compounds 4aj-4ao in 82% to 94% yield. This indicates that the introduction of methyl ester groups into these products offers a promising prospect for further derivatization.

[0032] 2-Morpholine ethyl isonitriles with important morpholine pharmacophores also exhibited excellent performance, efficiently synthesizing the compound 4ap-4au in yields between 79% and 88%. Among the tested groups, halogens (such as chlorine and bromine) provided the highest yields, followed by methyl and methoxy groups, with acceptable yields even in the absence of substituents. Similarly, high-purity products could be obtained with a simple separation procedure.

[0033] 3. Synthesis of N-BOH benzozaboranes (taking 4a as an example) 2-Formylarylboronic acid (1a, 1.0 mmol) and 2-aminopyridine (2a, 1.0 mmol) were dissolved in methanol (1.0 mL) and stirred at room temperature. Then, benzylisocyanate (3a, 1.0 mmol) was added dropwise. The mixture was stirred for 1 hour, during which a solid precipitated from the solution. The solid was then separated by filtration and washed with methanol to obtain the target compound 4a.

[0034]

[0035] Example 2 Compound 4a White solid (289 mg, 89%) 1 H NMR (400 MHz, DMSO- d 6) δ 8.97(s, 1H), 8.45 – 8.34 (m, 2H), 8.31 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.3 Hz,1H), 7.56 – 7.38 (m, 2H), 7.36 – 7.27 (m, 2H), 7.21 (t, J = 6.6 Hz, 3H), 7.02– 6.89 (m, 1H), 6.57 (t, J = 6.7 Hz, 1H), 5.65 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 140.76, 140.24, 138.31, 133.73, 131.40, 129.36, 127.83, 127.41, 126.78,125.92, 125.19, 124.76, 122.14, 121.95, 118.20, 111.50, 45.90. 11 B NMR (128MHz, DMSO- d 6) δ = 29.99. HRMS (ESI) calcd for C 20 H 17 BN3O + [M+H] + 326.1459, found: 326.1460. Example 3 Compound 4b White solid (337 mg, 95%) 1 H NMR (400 MHz, DMSO- d 6) δ 8.93(s, 1H), 8.40 – 8.24 (m, 2H), 7.97 (d, J = 2.7 Hz, 1H), 7.46 (d, J = 9.1 Hz,1H), 7.37 – 7.26 (m, 3H), 7.20 (d, J = 7.5 Hz, 3H), 6.93 (dd, J = 9.1, 6.5 Hz, 1H), 6.55 (t, J = 7.0 Hz, 1H), 5.64 (s, 2H), 3.88 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 157.54, 140.59, 140.29, 131.93, 129.33, 127.39, 127.05, 126.44,125.92, 124.42, 123.72, 121.64, 119.70, 117.90, 116.23, 111.35, 55.75,45.97. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.00. HRMS (ESI) calcd for C 21 H 19 BN3O2 + [M+H] + : 356.1565, found: 356.1565., Example 4 Compound 4c White solid (335 mg, 93%) 1 H NMR (400 MHz, DMSO- d 6) δ 9.10 (s, 1H), 8.39 (d, J = 8.3 Hz, 2H), 8.30 (d, J = 7.8 Hz, 1H), 7.73 (t, J = 7.5Hz, 1H), 7.54 (d, J= 9.6 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 7.34 (t, J = 7.5Hz, 2H), 7.23 (dd, J = 14.0, 7.3 Hz, 3H), 6.99 (dd, J = 9.6, 1.7 Hz, 1H), 5.66(s, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 140.08, 139.02, 133.72, 131.48, 129.46,128.37, 127.89, 127.53, 125.73, 122.69, 122.31, 122.00, 118.60, 45.66. 11 B NMR (128 MHz, DMSO- d 6) δ = 30.75. HRMS (ESI) calcd for C 20 H 16 BClN3O + [M+H] + 361.1069, found: 361.1073. Example 5 Compound 4d Yellow solid (339 mg, 90%) 1 H NMR (400 MHz, DMSO- d 6) δ 9.18 (s, 1H), 8.45 (dd, J = 8.5, 6.3 Hz, 1H), 8.39 (d, J = 1.4 Hz, 1H), 7.92 (dd, J =10.4, 2.6 Hz, 1H), 7.58 – 7.51 (m, 1H), 7.38 – 7.28 (m, 3H), 7.28 – 7.17 (m,3H), 7.06 – 6.98 (m, 1H), 5.64 (s, 2H). 13 C NMR (101 MHz, DMSO- d6) δ 166.15,163.68140.50, 139.98, 139.16, 137.04, 129.53, 129.20, 127.61, 127.07, 125.77,123.22, 122.52, 118.84, 113.49, 113.28, 107.44, 107.23, 45.69. 11 B NMR (128MHz, DMSO- d 6) δ = 30.64. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.36. HRMS (ESI)calcd for C 20 H 15 BClFN3O + [M+H] + : 378.0975, found: 378.0973. Example 6 Compound 4e Pale yellow solid (363 mg, 90%) 1 H NMR (400 MHz, DMSO- d 6) δ9.11 (s, 1H), 8.47 (s, 1H), 8.39 (d, J = 7.5 Hz, 1H), 8.31 (d, J = 7.9 Hz,1H), 7.74 (t, J = 7.2 Hz, 1H), 7.47 (dd, J = 11.9, 6.9 Hz, 2H), 7.34 (t, J =7.5 Hz, 2H), 7.23 (dd, J = 16.5, 7.5 Hz, 3H), 7.06 (dd, J = 9.6, 1.5 Hz, 1H), 5.65 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 140.14, 139.01, 137.88, 133.78,131.54, 129.52, 128.24, 127.68, 127.59, 125.78, 125.65, 124.71, 124.40,122.07, 118.96, 105.49, 45.76. 11 B NMR (128 MHz, DMSO- d6) δ = 31.30. HRMS (ESI)calcd for C 20 H 16 BBrN3O + [M+H] + : 404.0564, found: 404.0565. Example 7 Compound 4f White solid (310 mg, 88%) 1 H NMR (400 MHz, DMSO- d 6) δ 8.87(s, 1H), 8.17 (d, J = 8.2 Hz, 3H), 7.53 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 9.1Hz, 1H), 7.30 (d, J = 7.2 Hz, 2H), 7.22 (d, J = 7.0 Hz, 3H), 6.81 (d, J = 9.2Hz, 1H), 5.63 (s, 2H), 2.46 (s, 3H), 2.07 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ140.47, 139.80, 136.02, 133.98, 133.71, 132.46, 129.30, 127.40, 127.10,125.96, 124.92, 121.93, 120.11, 117.33, 45.89, 21.74, 18.39. 11 B NMR (128 MHz, DMSO- d 6) δ = 30.87. HRMS (ESI) calcd for C 22 H 21 BN3O + [M+H] + : 354.1772, found:354.1770. Example 8 Compound 4g White solid (335 mg, 92%) 1 H NMR (400 MHz, DMSO- d6) δ 8.82(s, 1H), 8.30 (d, J = 7.6 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.66 (t, J = 7.3Hz, 2H), 7.43 (d, J = 8.2 Hz, 1H), 7.36 – 7.14 (m, 8H), 5.57 (s, 2H). 13 C NMR (101 MHz, DMSO-) d 6) δ 151.19, 150.04, 139.82, 139.07, 133.64, 131.32, 129.25,127.29, 126.37, 125.97, 125.06, 124.33, 123.49, 121.42, 120.73, 113.90,112.76, 48.36. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.46. HRMS (ESI) calcd forC 22 H 17 BN3O2 + [M+H] + : 366.1408, found: 366.1410. Example 9 Compound 4h Pale yellow solid (256 mg, 88%) 1 H NMR (400 MHz, DMSO- d 6) δ 8.75(s, 1H), 8.60 (d, J = 7.3 Hz, 1H), 8.28 (dd, J = 19.6, 7.6 Hz, 2H), 7.70 –7.62 (m, 1H), 7.57 (d, J = 9.1 Hz, 1H), 7.42 – 7.34 (m, 1H), 7.09 (dd, J =9.1, 6.5 Hz, 1H), 6.91 – 6.81 (m, 1H), 4.35 (t, J = 7.1 Hz, 2H), 1.73 – 1.56(m, 2H), 1.38 (dd, J = 15.0, 7.4 Hz, 2H), 0.91 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-) d6) δ 140.76, 138.06, 133.50, 131.10, 127.87, 126.66, 124.97,124.81, 122.03, 121.87, 121.82, 118.38, 112.13, 42.65, 34.51, 19.56, 14.23. 11 BNMR (128 MHz, DMSO- d 6) δ = 29.75. HRMS (ESI) calcd for C 17 H 19 BN3O + [M+H] + :292.1616, found: 292.1617. Example 10 Compound 4i Yellow solid (308 mg, 95%) 1 H NMR (400 MHz, DMSO- d 6) δ 8.87(s, 1H), 8.62 (s, 1H), 8.28 (dd, J = 22.6, 6.9 Hz, 2H), 7.77 – 7.56 (m, 2H),7.41 (s, 1H), 7.13 (d, J = 8.8 Hz, 1H), 4.35 (s, 2H), 1.65 (s, 2H), 1.38 (d,J = 6.7 Hz, 2H), 0.94 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 139.06, 137.66,133.53, 131.26, 128.44, 127.84, 125.44, 122.59, 122.15, 121.91, 119.05,118.96, 41.49, 34.29, 19.61, 14.15. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.69. HRMS(ESI) calcd for C 17 H 18 BClN3O + [M+H] + : 326.1226, found: 326.1225. Example 11 Compound 4j Pale yellow solid (248 mg, 81%) 1 H NMR (400 MHz, DMSO- d 6) δ 9.11(s, 1H), 8.41 – 8.27 (m, 3H), 7.70 (t, J = 7.6 Hz, 1H), 7.56 (d, J = 9.0 Hz,1H), 7.40 (t, J = 7.4 Hz, 1H), 7.07 (dd, J = 9.2, 6.5 Hz, 1H), 6.78 (t, J =6.9 Hz, 1H), 5.26 (s, 2H), 3.73 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 171.92,140.77, 138.32, 133.61, 131.50, 127.68, 126.48, 125.20, 124.18, 122.19,121.94, 118.33, 111.92, 52.90, 44.95. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.68.HRMS (ESI) calcd for C 16 H 15 BN3O3 + [M+H] + : 308.1201, found: 308.1200. Example 12 Compound 4k Pale yellow solid (323 mg, 95%) 1 H NMR (400 MHz, DMSO- d 6) δ9.26 (s, 1H), 8.47 (d, J = 1.2 Hz, 1H), 8.30 (dd, J = 19.0, 7.6 Hz, 2H), 7.76– 7.68 (m, 1H), 7.63 (d, J = 9.6 Hz, 1H), 7.43 (td, J = 7.5, 1.0 Hz, 1H), 7.13 (dd, J = 9.6, 1.8 Hz, 1H), 5.30 (s, 2H), 3.74 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 172.00, 139.04, 137.88, 133.67, 131.69, 128.19, 127.68, 125.98,125.70, 122.80, 122.03, 121.78, 118.93, 52.97, 44.69. 11 B NMR (128 MHz, DMSO- d 6) δ = 32.09. HRMS (ESI) calcd for C 16 H 14 BClN3O3 + [M+H] + : 342.0811, found:342.0811. Example 13 Compound 4l Pale yellow solid (370 mg, 96%) 1 H NMR (400 MHz, DMSO- d 6) δ9.27 (s, 1H), 8.51 (s, 1H), 8.30 (dd, J = 19.1, 7.7 Hz, 2H), 7.72 (t, J = 7.5Hz, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.43 (t, J = 7.3 Hz, 1H), 7.19 (d, J = 9.6Hz, 1H), 5.30 (s, 2H), 3.75 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 172.00,139.04, 137.85, 133.67, 131.68, 128.01, 127.43, 125.70, 124.83, 123.77,122.05, 119.20, 105.95, 52.99, 44.74. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.31.HRMS (ESI) calcd for C 16 H 14 BBrN3O3 + [M+H] + : 386.0306, found: 386.0305. Example 14 Compound 4m Yellow solid (318 mg, 94%) 1 H NMR (400 MHz, DMSO- d 6) δ8.78 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.18 – 8.10 (m, 2H), 7.60 (d, J = 9.6Hz, 1H), 7.50 (dd, J = 8.1, 1.8 Hz, 1H), 7.11 (dd, J = 9.6, 1.8 Hz, 1H), 4.33(t, J = 7.2 Hz, 2H), 2.44 (s, 3H), 1.63 (p, J = 7.2 Hz, 2H), 1.44 – 1.30 (m,2H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 141.08, 137.45,136.57, 135.70, 134.49, 130.26, 130.09, 128.74, 124.34, 124.14, 124.07,121.09, 120.97, 44.97, 36.51, 23.93, 21.79, 16.31. 11 B NMR (128 MHz, DMSO- d 6) δ= 30.88. HRMS (ESI) calcd for C 18 H 20 BClN3O + [M+H] + : 340.1382, found: 340.1385. Example 15 Compound 4n Yellow solid (364 mg, 95%) 1 H NMR (400 MHz, DMSO- d6) δ8.78 (s, 1H), 8.66 –8.62 (m, 1H), 8.18 – 8.10 (m, 2H), 7.58 – 7.46 (m, 2H),7.17 (dd, J = 9.5, 1.6 Hz, 1H), 4.31 (t, J = 7.3 Hz, 2H), 2.44 (s, 3H), 1.64(p, J = 7.3 Hz, 2H), 1.38 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.3 Hz, 3H). 13 CNMR (101 MHz, DMSO- d 6) δ 138.88, 135.23, 134.36, 133.49, 132.28, 127.81,127.74, 126.53, 124.17, 123.83, 121.97, 119.06, 105.97, 41.56, 34.34, 21.75,19.63, 14.15. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.22. HRMS (ESI) calcd forC 18 H 20 BBrN3O + [M+H] + : 384.0877, found: 384.0878. Example 16 Compound 4o Yellow solid (281 mg, 88%) 1 H NMR (400 MHz, DMSO- d 6) δ 9.04(s, 1H), 8.36 (ddd, J = 7.9, 4.5, 3.4 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.13(d, J = 1.7 Hz, 1H), 7.58 – 7.49 (m, 2H), 7.05 (ddd, J = 9.1, 6.6, 1.0 Hz,1H), 6.77 (td, J = 6.9, 1.4 Hz, 1H), 5.24 (s, 2H), 3.73 (s, 3H), 2.44 (s,3H). 13 C NMR (101 MHz, DMSO- d6) δ 171.96, 140.60, 135.89, 134.15, 133.59,132.60, 127.14, 126.61, 125.92, 124.04, 121.95, 118.19, 111.82, 52.88, 44.90,21.71. 11 B NMR (128 MHz, DMSO- d 6) δ = 32.46. HRMS (ESI) calcd for C 17 H 17 BN3O3 + [M+H] + : 322.1357, found: 322.1355. Example 17 Compound 4p Yellow solid (315 mg, 94%) 1 H NMR (400 MHz, DMSO- d 6) δ 9.01(s, 1H), 8.15– 8.11 (m, 3H), 7.46 - 7.44 (m, 2H), 6.93 - 6.91 (m, 1H), 5.25(s, 2H), 3.74 (s, 3H), 2.44 (s, 3H), 2.25 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ172.01, 139.79, 136.00, 133.97, 133.57, 132.54, 126.95, 126.69, 125.84,124.98, 121.87, 121.11, 120.72, 117.56, 52.85, 44.94, 21.70, 18.57. 11 B NMR (128 MHz, DMSO- d 6) δ = 32.56. HRMS (ESI) calcd forC 18 H 19 BN3O3 + [M+H] + 336.1514, found: 336.1515. Example 18 Compound 4q Yellow solid (330 mg, 93%) 1H NMR (400 MHz, DMSO- d 6) δ8.82 (s, 1H), 8.60 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.89 (d, J= 2.6 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.29 (dd, J = 8.7, 2.6 Hz, 1H), 7.10(dd, J = 9.6, 1.8 Hz, 1H), 4.34 (t, J = 7.3 Hz, 2H), 3.86 (s, 3H), 1.64 (p, J= 7.2 Hz, 2H), 1.38 (h, J = 7.3 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (101MHz, DMSO- d 6) δ 157.69, 138.88, 131.22, 128.20, 127.09, 123.69, 121.96,121.77, 119.47, 118.87, 118.61, 116.07, 55.72, 41.53, 34.34, 19.59, 14.14. 11 BNMR (128 MHz, DMSO- d 6) δ = 31.69. HRMS (ESI) calcd for C 18 H 20 BClN3O2 + [M+H] + :356.1332, found: 356.1335. Example 19 Compound 4r Yellow solid (380 mg, 95%) 1 H NMR (400 MHz, DMSO- d6) δ8.83 (s, 1H), 8.65 (d, J = 1.8 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H), 7.89 (d, J= 2.6 Hz, 1H), 7.54 (d, J = 9.5 Hz, 1H), 7.29 (dd, J = 8.6, 2.7 Hz, 1H), 7.17(dd, J = 9.5, 1.6 Hz, 1H), 4.33 (t, J = 7.3 Hz, 2H), 3.86 (s, 3H), 1.64 (p, J= 7.3 Hz, 2H), 1.39 (h, J = 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR (101MHz, DMSO- d 6) δ 157.68, 138.89, 131.21, 127.97, 126.93, 123.99, 123.75,123.71, 119.48, 118.92, 116.07, 105.91, 55.72, 41.61, 34.35, 19.62, 14.17. 11 BNMR (128 MHz, DMSO- d 6) δ = 31.97. HRMS (ESI) calcd for C 18 H 20 BBrN3O2 + [M+H] + :400.0826, found: 400.0825. Example 20 Compound 4s Yellow solid (365 mg, 94%) 1 H NMR (400 MHz, DMSO- d 6) δ9.07 (s, 1H), 8.39 – 8.34 (m, 1H), 8.23 ​​(d, J = 8.6 Hz, 1H), 7.97 (d, J = 2.7Hz, 1H), 7.51 (d, J = 9.5 Hz, 1H), 7.38 – 7.29 (m, 3H), 7.27 – 7.17 (m, 3H), 6.96 (dd, J = 9.6, 1.8 Hz, 1H), 5.64 (s, 2H), 3.88 (s, 3H). 13C NMR (101 MHz, DMSO- d 6) δ 160.05, 142.42, 141.07, 133.66, 131.73, 130.48, 129.79, 129.25,128.01, 126.05, 124.28, 122.00, 120.58, 118.47, 57.99, 47.94. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.99. HRMS (ESI) calcd for C 21 H 18 BClN3O2 + [M+H] + : 390.1775, found:390.1775. Example 21 Compound 4t Pale yellow solid (416 mg, 96%) 1 H NMR (400 MHz, DMSO- d 6) δ9.05 (s, 1H), 8.44 (d, J = 0.9 Hz, 1H), 8.23 ​​(d, J = 8.7 Hz, 1H), 7.97 (d, J= 2.6 Hz, 1H), 7.45 (d, J = 9.5 Hz, 1H), 7.38 – 7.30 (m, 3H), 7.22 (dd, J =19.4, 7.3 Hz, 3H), 7.02 (dd, J = 9.5, 1.6 Hz, 1H), 5.64 (s, 2H), 3.88 (s,3H). 13 C NMR (101 MHz, DMSO- d 6) δ 157.82, 140.19, 138.84, 131.42, 129.50,128.02, 127.56, 126.87, 125.77, 124.11, 124.01, 123.83, 119.75, 118.61,116.26, 105.30, 55.76, 45.83. 11 B NMR (128 MHz, DMSO- d 6) δ = 32.67. HRMS (ESI)calcd for C 21 H 18 BBrN3O2+ [M+H] + : 434.0670, found: 434.0671. Example 22 Compound 4u Pale yellow solid (277 mg, 81%) 1 H NMR (400 MHz, DMSO- d 6) δ 9.06(s, 1H), 8.45 (dd, J = 8.4, 6.2 Hz, 1H), 8.35 (d, J = 7.3 Hz, 1H), 7.93 (dd,J = 10.5, 2.6 Hz, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.30 (q, J = 9.2, 8.5 Hz, 3H), 7.21 (d, J = 7.6 Hz, 3H), 6.99 (dd, J = 9.2, 6.5 Hz, 1H), 6.58 (t, J =6.9 Hz, 1H), 5.64 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 166.16, 163.71, 140.93,140.83, 140.10, 136.99, 136.90, 129.36, 128.70, 128.67, 127.72, 127.43,127.26, 126.01, 125.97, 125.90, 124.87, 122.60, 118.31, 113.04, 112.83,111.65, 107.32, 107.11, 45.92. 11 B NMR (128 MHz, DMSO- d 6) δ = 32.33. 19 F NMR (377MHz, DMSO- d 6) δ = -108.60. HRMS (ESI) calcd for C 20 H 16 BFN3O + [M+H] + : 344.1365, found: 344.1366. Example 23 Compound 4v Yellow solid (390 mg, 93%) 1H NMR (400 MHz, DMSO- d 6) δ 9.18 (s, 1H), 8.43 (d, J = 8.7 Hz, 2H), 7.90 (d, J = 9.5 Hz, 1H), 7.47 (d, J = 9.6Hz, 1H), 7.27 (ddd, J = 26.3, 17.1, 7.4 Hz, 6H), 7.07 (d, J = 9.5 Hz, 1H), 5.63 (s, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 166.15, 163.70, 140.49, 140.40, 139.99,139.16, 137.05, 136.96, 129.54, 129.05, 127.62, 126.83, 126.80, 125.78,125.26, 124.58, 119.10, 113.50, 113.28, 107.46, 107.25, 105.69, 45.77. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.70. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.36. HRMS(ESI) calcd for C 20 H 15 BBrFN3O + [M+H] + : 422.0470, found: 422.0468. Example 24 Compound 4w Yellow solid (332 mg, 97%) 1 H NMR (400 MHz, DMSO- d6) δ 8.96(s, 1H), 8.61 (d, J = 1.8 Hz, 1H), 8.37 (dd, J = 8.5, 6.3 Hz, 1H), 7.86 (dd,J = 10.5, 2.6 Hz, 1H), 7.63 (d, J = 9.6 Hz, 1H), 7.26 – 7.14 (m, 2H), 4.33(t, J = 7.3 Hz, 2H), 1.65 (p, J = 7.3 Hz, 2H), 1.38 (h, J = 7.4 Hz, 2H), 0.94(t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 140.27, 140.18, 139.24,136.83, 129.29, 127.00, 126.96, 123.18, 122.42, 119.24, 119.16, 113.31,107.26, 107.05, 40.67, 34.23, 19.61, 14.14. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.22. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.78. HRMS (ESI) calcd for C 17 H 17 BClFN3O + [M+H] + : 344.1337, found: 344.1334. Example 25 Compound 4x Yellow solid (380 mg, 98%) 1 H NMR (400 MHz, DMSO- d6) δ 8.96(s, 1H), 8.66 (d, J = 1.7 Hz, 1H), 8.37 (dd, J = 8.5, 6.3 Hz, 1H), 7.86 (dd,J = 10.4, 2.6 Hz, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.29 – 7.18 (m, 2H), 4.32(t, J = 7.3 Hz, 2H), 1.65 (p, J = 7.3 Hz, 2H), 1.39 (h, J = 7.4 Hz, 2H), 0.95(t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 166.00, 163.55, 140.24,139.23, 136.82, 129.12, 126.74, 125.20, 124.38, 119.42, 113.31, 113.09,107.07, 106.31, 41.59, 34.23, 19.63, 14.16. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.12. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.76. HRMS (ESI) calcd for C 17 H 17 BBrFN3O + [M+H] + : 388.0632, found: 388.0636. Example 26 Compound 4y Yellow solid (331 mg, 88%) 1 H NMR (400 MHz, DMSO- d 6) δ9.61 (d, J = 8.5 Hz, 1H), 8.72 (d, J = 11.0 Hz, 2H), 8.48 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 7.3 Hz, 1H), 7.69 (d, J= 9.6 Hz, 1H),7.64 – 7.58 (m, 1H), 7.52 (t, J = 6.9 Hz, 1H), 7.19 (dd, J = 9.6, 1.7 Hz, 1H), 4.45 (t, J = 7.4 Hz, 2H), 1.75 – 1.60 (m, 2H), 1.40 (dd, J = 14.9, 7.5 Hz, 2H), 0.94 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 139.39, 138.04, 137.71,132.20, 128.91, 128.34, 126.96, 125.27, 123.03, 122.45, 121.20, 119.08,119.06, 49.06, 42.27, 34.22, 19.48, 14.17. 11 B NMR (128 MHz, DMSO- d 6) δ =32.46. HRMS (ESI) calcd forC 21 H 20 BClN3O + [M+H] + : 376.1382, found: 376.1383. Example 27 Compound 4z Yellow solid (343 mg, 93%) 1 H NMR (400 MHz, DMSO- d 6) δ 8.88(s, 1H), 8.67 (s, 1H), 8.31 (d, J = 7.5 Hz, 1H), 8.26 (d, J = 7.8 Hz, 1H), 7.71– 7.64 (m, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 7.19 (dd, J = 9.6, 1.5 Hz, 1H), 4.33 (t, J= 7.3 Hz, 2H), 1.77 – 1.56 (m, 2H), 1.40 (dd, J = 14.7, 7.4 Hz, 2H), 0.95 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ139.05, 137.65, 133.53, 131.25, 128.28, 127.60, 125.43, 124.60, 124.13,121.93, 119.26, 106.11, 41.57, 34.30, 19.63, 14.18. 11 B NMR (128 MHz, DMSO- d 6)δ = 31.69. HRMS (ESI) calcd forC 17 H 18 BBrN3O + [M+H] + : 370.0721, found: 370.0719. Example 28 Compound 4aa White solid (277 mg, 82%) 1 H NMR (400 MHz, DMSO- d 6) δ 8.89 (s, 1H), 8.35 (d, J = 7.3 Hz, 1H), 8.20 (d, J = 8.3 Hz, 2H), 7.63 – 7.43 (m,1H), 7.24 (dd, J = 40.8, 7.7 Hz, 4H), 6.99 – 6.90 (m, 1H), 6.56 (t, J = 6.8 Hz,1H), 5.63 (s, 2H), 2.46 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 140.64, 140.30,135.93, 134.16, 133.74, 132.51, 129.33, 127.38, 127.30, 126.97, 125.90,124.59, 122.03, 121.87, 118.06, 111.41, 45.90, 21.76. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.57. HRMS (ESI) calcd for C 21 H 19 BN3O + [M+H] + : 340.1616, found:340.1615. Example 29 Compound 4ab Yellow solid (343 mg, 92%) 1 H NMR (400 MHz, DMSO- d 6) δ9.02 (s, 1H), 8.39 (s, 1H), 8.20 (d, J = 6.5 Hz, 2H), 7.54 (dd, J = 18.1, 8.8Hz, 2H), 7.26 (dd, J = 51.2, 7.6 Hz, 4H), 6.98 (d, J = 9.7 Hz, 1H), 5.64 (s, 2H), 2.47 (s, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 140.19, 138.89, 135.51, 134.68,133.79, 132.63, 129.49, 128.17, 127.87, 127.55, 125.76, 122.36, 122.20,122.09, 118.56, 118.31, 45.66, 21.78. 11 B NMR (128 MHz, DMSO- d 6) δ = 32.33.HRMS (ESI) calcd for C 21 H 18 BClN3O + [M+H] +: 374.1226, found: 374.1225. Example 30 Compound 4ac Yellow solid (397 mg, 95%) 1 H NMR (400 MHz, DMSO- d 6) δ9.02 (s, 1H), 8.45 (s, 1H), 8.20 (d, J = 7.0 Hz, 2H), 7.56 (d, J = 8.2 Hz, 1H), 7.46 (d, J = 9.5 Hz, 1H), 7.34 (t, J = 7.4 Hz, 2H), 7.28 – 7.16 (m, 3H), 7.04(d, J = 9.6 Hz, 1H), 5.64 (s, 2H), 2.47 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ140.20, 138.89, 135.49, 134.67, 133.79, 132.62, 129.50, 127.91, 127.73,127.56, 125.77, 124.40, 124.23, 122.12, 118.82, 105.38, 45.76, 21.78. 11 B NMR (128 MHz, DMSO- d 6) δ = 30.51. HRMS (ESI) calcd for C 21 H 18 BBrN3O + [M+H] + :418.0721, found: 418.0720. Example 31 Compound 4ad Yellow solid (367 mg, 95%) 1 H NMR (400 MHz, DMSO- d6) δ8.82 (s, 1H), 8.69 (s, 1H), 8.16 (d, J = 8.0 Hz, 1H), 8.10 (s, 1H), 7.61 (d,J = 9.6 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.25 (dd, J = 24.1, 7.1 Hz, 5H), 7.13 (d, J = 9.6 Hz, 1H), 4.56 (t, J = 7.9 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 2.43 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 138.97, 138.63, 135.32, 134.44,133.52, 132.41, 129.13, 128.95, 128.13, 127.77, 126.93, 122.29, 122.07,122.00, 118.90, 118.77, 43.33, 37.87, 21.76. 11 B NMR (128 MHz, DMSO- d 6) δ =31.33. HRMS (ESI) calcd for C 22 H 20 BClN3O + [M+H] + : 388.1382, found: 388.1385. Example 32 Compound 4ae Yellow solid (397 mg, 92%) 1 H NMR (400 MHz, DMSO- d 6) δ8.83 (s, 1H), 8.76 (s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 8.11 (s, 1H), 7.59 –7.48 (m, 2H), 7.34 – 7.16 (m, 6H), 4.54 (t, J = 8.0 Hz, 2H), 2.98 (t, J = 7.9Hz, 2H), 2.43 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 141.19, 140.84, 137.53,136.64, 135.74, 134.61, 131.37, 131.23, 130.10, 129.82, 129.20, 126.50,126.17, 124.27, 121.29, 108.26, 45.71, 24.01. 11 B NMR (128 MHz, DMSO- d 6) δ =31.85. HRMS (ESI) calcd for C 22 H 20 BBrN3O + [M+H] + : 432.0877, found: 432.0880. Example 33 Compound 4af Yellow solid (387 mg, 96%) 1 H NMR (400 MHz, DMSO- d 6) δ8.86 (s, 1H), 8.67 (d, J = 1.9 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.87 (q, J= 2.6 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.32 – 7.26 (m, 3H), 7.22 (d, J =6.9 Hz, 3H), 7.11 (d, J = 9.6 Hz, 1H), 4.61 – 4.50 (m, 2H), 3.85 (s, 3H), 3.04 – 2.91 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 157.65, 138.89, 138.64,131.22, 129.11, 128.94, 128.21, 126.92, 123.70, 121.98, 121.81, 119.41,118.84, 118.55, 116.07, 55.68, 43.37, 38.58. 11 B NMR (128 MHz, DMSO- d 6) δ =31.10. HRMS (ESI) calcd for C 22 H 20 BClN3O2 +[M+H] + : 404.1332, found: 404.1331. Example 34 Compound 4ag Yellow solid (433 mg, 97%) 1 H NMR (400 MHz, DMSO- d 6) δ8.87 (s, 1H), 8.73 (d, J = 1.8 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.87 (d, J= 2.7 Hz, 1H), 7.54 (d, J = 9.5 Hz, 1H), 7.35 – 7.13 (m, 7H), 4.58 – 4.49 (m, 2H), 3.85 (s, 3H), 3.02 – 2.93 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 157.67,148.29, 139.68, 138.93, 138.62, 131.20, 129.21, 128.83, 127.94, 126.98,124.14, 123.87, 119.49, 118.87, 116.09, 110.47, 105.97, 105.50, 55.71, 43.49,38.62. 11 B NMR (128 MHz, DMSO- d 6) δ = 29.72. HRMS (ESI) calcd for C 22 H 20 BBrN3O2 + [M+H] + : 448.0826, found: 448.0825. Example 35 Compound 4ah Yellow solid (356 mg, 91%) 1 H NMR (400 MHz, DMSO- d6) δ 8.96(s, 1H), 8.69 (s, 1H), 8.34 (dd, J = 8.4, 6.4 Hz, 1H), 7.87 (dd, J = 10.4,2.5 Hz, 1H), 7.63 (d, J = 9.6 Hz, 1H), 7.30 – 7.15 (m, 7H), 4.62 – 4.49 (m, 2H), 3.02 – 2.94 (m, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 140.29, 140.20, 139.24,138.57, 136.77, 136.68, 129.13, 129.09, 128.93, 127.04, 127.00, 126.94,123.16, 122.44, 119.19, 119.07, 113.28, 113.07, 107.30, 107.09, 43.36,38.39. 11 B NMR (128 MHz, DMSO- d 6) δ = 30.27. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.73. HRMS (ESI) calcd for C 21 H 17 BClFN3O + [M+H] + 392.1132, found: 392.1133. Example 36 Compound 4ai Yellow solid (382 mg, 88%) 1 H NMR (400 MHz, DMSO- d 6) δ 8.98(s, 1H), 8.75 (d, J = 1.9 Hz, 1H), 8.35 (dd, J = 8.5, 6.3 Hz, 1H), 7.87 (dd,J = 10.4, 2.6 Hz, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.33 – 7.17 (m, 7H), 4.54(t, J = 7.9 Hz, 2H), 2.99 (t, J = 7.9 Hz, 2H). 13 C NMR (101 MHz, DMSO-d 6) δ165.98, 163.53, 140.26, 139.24, 138.54, 136.76, 129.13, 128.97, 126.97,126.76, 125.19, 124.36, 119.33, 113.28, 107.32, 107.11, 106.31, 43.48,37.45. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.98. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.70. HRMS (ESI) calcd for C 21 H 17 BBrFN3O + [M+H] + : 436.0627, found: 436.0630. Example 37 Compound 4aj Pale yellow solid (277 mg, 82%) 1 H NMR (400 MHz, DMSO- d 6) δ9.05 (s, 1H), 8.36 (d, J = 7.2 Hz, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.90 (d, J= 2.7 Hz, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.31 (dd, J = 8.7, 2.7 Hz, 1H), 7.04(dd, J = 9.2, 6.5 Hz, 1H), 6.80 – 6.73 (m, 1H), 5.24 (s, 2H), 3.86 (s, 3H), 3.73 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 171.93, 157.49, 140.57, 131.86,127.43, 126.68, 126.28, 123.87, 121.72, 119.65, 118.03, 116.23, 111.78,55.71, 52.88, 44.96. 11 B NMR (128 MHz, DMSO- d6) δ = 29.52. HRMS (ESI) calcd forC 17 H 17 BN3O4 + [M+H] + : 338.1307, found: 338.1306. Example 38 Compound 4ak Yellow solid (340 mg, 92%) 1 H NMR (400 MHz, DMSO- d 6) δ9.21 (s, 1H), 8.46 – 8.41 (m, 1H), 8.20 (d, J = 8.6 Hz, 1H), 7.90 (d, J = 2.7Hz, 1H), 7.59 (d, J = 9.7 Hz, 1H), 7.32 (dd, J = 8.7, 2.7 Hz, 1H), 7.09 (dd,J = 9.6, 1.8 Hz, 1H), 5.28 (s, 2H), 3.86 (s, 3H), 3.74 (s, 3H). 13 C NMR (101MHz, DMSO- d 6) δ 171.97, 157.79, 138.86, 131.39, 128.02, 127.58, 126.82,123.80, 122.16, 121.39, 119.72, 118.70, 116.30, 55.74, 52.93, 44.74. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.22. HRMS (ESI) calcd for C 17 H 16 BClN3O4 + [M+H] + 372.0917, found: 372.0920. Example 39 Compound 4al Yellow solid (390 mg, 94%) 1 H NMR (400 MHz, DMSO- d6) δ9.21 (s, 1H), 8.50 – 8.46 (m, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.90 (d, J = 2.7Hz, 1H), 7.54 (d, J = 9.6 Hz, 1H), 7.32 (dd, J = 8.7, 2.6 Hz, 1H), 7.15 (dd,J = 9.6, 1.7 Hz, 1H), 5.29 (s, 2H), 3.86 (s, 3H), 3.74 (s, 3H). 13 C NMR (101MHz, DMSO- d 6) δ 171.99, 157.80, 138.88, 131.36, 127.77, 126.65, 124.22,123.82, 123.39, 119.73, 118.87, 116.31, 105.75, 55.74, 52.95, 44.79. 11 B NMR (128 MHz, DMSO- d 6) δ = 30.11. HRMS (ESI) calcd for C 17 H 16 BBrN3O4 + [M+H] + :416.0412, found: 416.0415. Example 40 Compound 4am Yellow solid (282 mg, 87%) 1 H NMR (400 MHz, DMSO- d 6) δ 9.20(s, 1H), 8.37 (t, J = 7.0 Hz, 2H), 7.89 (dd, J = 10.4, 2.6 Hz, 1H), 7.56 (d,J = 9.1 Hz, 1H), 7.23 (td, J = 8.9, 2.6 Hz, 1H), 7.10 (dd, J = 9.2, 6.5 Hz, 1H), 6.80 (t, J = 6.9 Hz, 1H), 5.24 (s, 2H), 3.73 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ 171.81, 166.18, 163.73, 140.91, 136.86, 128.47, 125.65, 124.38,122.70, 118.43, 113.04, 112.83, 112.08, 107.32, 107.11, 52.92, 44.88. 11 B NMR (128 MHz, DMSO- d 6) δ = 30.99. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.38. HRMS(ESI) calcd for C 16 H 14 BFN3O3 + [M+H] + : 326.1107, found: 326.1107. Example 41 Compound 4an Pale yellow solid (298 mg, 83%). 1 H NMR (400 MHz, DMSO- d 6) δ9.32 (s, 1H), 8.47 (s, 1H), 8.38 (dd, J = 8.3, 6.4 Hz, 1H), 7.88 (dd, J =10.4, 2.4 Hz, 1H), 7.63 (d, J = 9.6 Hz, 1H), 7.27 (td, J = 9.0, 2.5 Hz, 1H), 7.15 (dd, J = 9.7, 1.6 Hz, 1H), 5.28 (s, 2H), 3.74 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 171.87, 166.19, 163.73, 140.50, 139.16, 136.91, 128.91, 126.83,123.30, 121.89, 119.11, 113.50, 113.29, 107.47, 52.96, 44.67. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.22. 19 F NMR (377 MHz, DMSO- d6) δ = -108.10. HRMS (ESI) calcdfor C 16 H 13 BClFN3O3 + [M+H] + 360.0717, found: 360.0713. Example 42 Compound 4ao Pale yellow solid (345 mg, 86%) 1 H NMR (400 MHz, DMSO- d 6) δ9.32 (s, 1H), 8.51 (d, J = 1.7 Hz, 1H), 8.38 (dd, J = 8.4, 6.2 Hz, 1H), 7.88(dd, J = 10.4, 2.6 Hz, 1H), 7.57 (d, J = 9.6 Hz, 1H), 7.31 – 7.18 (m, 2H), 5.29 (s, 2H), 3.47 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 171.87, 166.20,163.74, 140.50, 139.19, 136.95, 128.77, 126.60, 125.37, 123.95, 119.34,113.53, 107.50, 107.29, 106.15, 52.99, 44.73. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.22. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.09. HRMS (ESI) calcd forC 16 H 13 BBrFN3O3 + [M+H] + : 404.0212, found: 404.0215. Example 43 Compound 4ap Yellow solid (327 mg, 82%) 1 H NMR (400 MHz, DMSO- d6) δ 9.03- 8.99 (m, 2H), 8.35 (dd, J = 8.5, 6.3 Hz, 1H), 7.85 (dd, J = 10.4, 2.6 Hz, 1H), 7.60 (d, J = 9.6 Hz, 1H), 7.23 (td, J = 8.8, 2.6 Hz, 1H), 7.14 (dd, J =9.7, 1.7 Hz, 1H), 4.38 (t, J = 6.9 Hz, 2H), 3.58 (s, 4H), 2.76 – 2.62 (m,2H), 2.48 (s, 4H). 13 C NMR (101 MHz, DMSO- d 6) δ 165.93, 163.48, 140.26, 140.16,139.21, 136.64, 136.55, 129.31, 126.83, 126.79, 123.06, 122.80, 119.07,118.87, 113.15, 112.94, 107.22, 107.01, 66.60, 59.27, 54.05, 41.04. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.83. 19 F NMR (377 MHz, DMSO- d 6) δ = -108.82. HRMS(ESI) calcd for C 19 H 20 BClFN4O2 + [M+H] + : 401.1346, found: 401.1345. Example 44 Compound 4aq Yellow solid (358 mg, 81%) 1 H NMR (400 MHz, DMSO- d6) δ 9.04(d, J = 13.2 Hz, 2H), 8.35 (dd, J = 8.4, 6.4 Hz, 1H), 7.85 (dd, J = 10.4, 2.5Hz, 1H), 7.54 (d, J = 9.6 Hz, 1H), 7.29 – 7.17 (m, 2H), 4.37 (t, J = 6.9 Hz, 2H), 3.61 (d, J = 4.4 Hz, 4H), 2.74 – 2.63 (m, 2H), 2.48 (s, 4H). 13 C NMR (101MHz, DMSO- d 6) δ 165.94, 163.48, 140.22, 139.22, 136.65, 129.14, 126.55,125.12, 124.79, 122.84, 119.16, 113.16, 112.94, 107.25, 106.22, 66.60, 59.25,54.09, 41.14. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.57. 19 F NMR (377 MHz, DMSO- d 6) δ= -108.77. HRMS (ESI) calcd for C 19 H 20 BBrFN4O2 + [M+H] + : 445.0841, found:445.0840. Example 45 Compound 4ar Yellow solid (362 mg, 88%) 1 H NMR (400 MHz, DMSO- d6) δ8.98 (d, J = 1.8 Hz, 1H), 8.90 (s, 1H), 8.18 (d, J = 8.6 Hz, 1H), 7.87 (d, J= 2.7 Hz, 1H), 7.58 (d, J = 9.6 Hz, 1H), 7.29 (dd, J = 8.7, 2.7 Hz, 1H), 7.09(dd, J = 9.6, 1.8 Hz, 1H), 4.40 (t, J = 6.9 Hz, 2H), 3.86 (s, 3H), 3.58 (t, J= 4.6 Hz, 4H), 2.68 (t, J = 6.9 Hz, 2H). 13 C NMR (101 MHz, DMSO- d 6) δ 157.65,138.98, 131.31, 128.12, 127.24, 123.67, 122.38, 122.01, 119.43, 118.74,118.50, 116.05, 66.61, 59.54, 55.71, 54.12, 41.02. 11 B NMR (128 MHz, DMSO- d 6) δ= 31.23. HRMS (ESI) calcd for C 20 H 23 BClN4O3 + [M+H] + : 413.1546, found: 413.1545. Example 46 Compound 4as Pale yellow solid (386 mg, 85%) 1 H NMR (400 MHz, DMSO- d 6) δ9.03 (s, 1H), 8.86 (s, 1H), 8.18 – 8.06 (m, 2H), 7.50 (dd, J = 14.5, 5.5 Hz, 2H), 7.16 (dd, J = 9.6, 1.5 Hz, 1H), 4.37 (t, J = 7.0 Hz, 2H), 3.65 – 3.54(m, 4H), 2.68 (t, J = 6.9 Hz, 2H), 2.43 (s, 3H). 13 C NMR (101 MHz, DMSO- d6) δ139.01, 135.31, 134.34, 133.43, 132.30, 127.90, 127.70, 124.45, 124.28,121.97, 118.94, 105.94, 66.62, 59.47, 54.11, 41.12, 21.74. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.68. HRMS (ESI) calcd for C 20 H 23 BBrN4O3 + [M+H] + : 457.1041, found:457.1040. Example 47 Compound 4at Yellow solid (313 mg, 79%) 1 H NMR (400 MHz, DMSO- d 6) δ8.97 (s, 1H), 8.89 (s, 1H), 8.12 (dd, J = 11.6, 4.5 Hz, 2H), 7.58 (d, J = 9.6Hz, 1H), 7.54 – 7.47 (m, 1H), 7.15 – 7.05 (m, 1H), 4.38 (d, J = 6.8 Hz, 2H), 3.59 (d, J = 4.3 Hz, 4H), 2.72 – 2.63 (m, 2H), 2.48 (m, 4H), 2.43 (s, 3H). 13 CNMR (101 MHz, DMSO- d 6) δ 138.97, 135.29, 134.30, 133.40, 132.26, 128.00,126.48, 122.41, 122.18, 121.91, 118.78, 66.61, 59.43, 54.03, 40.96, 21.74. 11 BNMR (128 MHz, DMSO- d 6) δ = 32.67. HRMS (ESI) calcd for C 20 H 23 BClN4O2 + [M+H] + 397.1603, found: 397.1600. Example 48 Compound 4au Yellow solid (365 mg, 83%) 1 H NMR (400 MHz, DMSO- d 6) δ9.05 (s, 1H), 8.89 (s, 1H), 8.26 – 7.99 (m, 2H), 7.61 – 7.43 (m, 2H), 7.17(d, J = 9.7 Hz, 1H), 4.39 (s, 2H), 3.60 (d, J = 11.4 Hz, 4H), 2.68 (s, 2H), 2.43 (s, 3H). 13 C NMR (101 MHz, DMSO- d 6) δ 139.03, 135.31, 134.38, 133.46,132.36, 127.92, 127.68, 124.53, 124.34, 121.98, 118.97, 105.96, 66.62, 59.46,54.12, 41.10, 21.75. 11 B NMR (128 MHz, DMSO- d 6) δ = 31.98. HRMS (ESI) calcd forC 20 H 23 BBrN4O2 + [M+H] + : 441.1092, found: 441.1096. Antitumor activity assay of experimental cases The antitumor activity of compounds 4a-4au was detected using A549 and DU145 cells in DMEM culture medium containing fetal bovine serum and penicillin-streptomycin solution. The specific procedure is as follows: (1) After counting the cells using a hemocytometer, dilute them to 5 × 10⁻⁶ using DMEM low glucose culture medium. 4 cells / mL; (2) Add 100 μL of cell suspension to each well of a 96-well plate, mix well by pipetting, and incubate at 37°C for 24 h. (3) Dilute the compound to be tested, 4a-4au, to a seed concentration of 10 μM, add the drug sequentially according to this concentration, and incubate at 37 ℃ for 48 h. (4) Add MTT at a concentration of 5 mg / mL and incubate at 37 ℃ for 4 h; (5) Add DMSO to dissolve the cells, and measure the OD values ​​at 490 nm and 630 nm using an enzyme-linked immunosorbent assay (ELISA) reader; (6) Process the data and calculate the inhibition rate based on the OD value. The results are shown in Table 2.

[0036] Table 2. Results of antitumor activity of novel quinoxaline-azacyclobutanone compounds

[0037] According to the activity test results in Table 1, the novel boron-nitrogen heterocyclic compounds prepared in this invention can inhibit tumor cell proliferation and have clear anti-tumor activity. They can be used to prepare anti-tumor drugs for treating human small cell lung cancer and prostate cancer.

[0038] Finally, it should be noted that the above specific embodiments are only used to illustrate the technical solutions of the present invention and not to limit it. Although the present invention has been described in detail with reference to examples, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the claims of the present invention.

Claims

1. A method for synthesizing N-BOH benzozaboranes based on modular GBB, characterized in that, The boron source and aminopyridine were dissolved in an alcohol solvent and stirred at room temperature. Then, isonitriles were added dropwise, and the reaction was continued with stirring. The solid precipitated during the reaction was filtered and washed.

2. The method according to claim 1, characterized in that, The molar ratio of boron source, aminopyridine and isonitrile is 0.5~1:0.5~1:0.5~1.

3. The method according to claim 1 or 2, characterized in that, The alcohol solvent is methanol, ethanol, or an aqueous solution of ethanol.

4. The method according to claim 1 or 2, characterized in that, The final concentration of boron source in alcohol solvent is 0.5–1 mmol / mL; the final concentration of aminopyridine in alcohol solvent is 0.5–1 mmol / mL; the final concentration of isonitrile in alcohol solvent is 0.5–1 mmol / mL.

5. The method according to claim 1 or 2, characterized in that, Aminopyridine is an aminopyridine, 2-aminopyridine, or benzo[d]oxazol-2-amine that has halogen or methyl substitution.

6. The method according to claim 1 or 2, characterized in that, The boron source is 2-formylarylboronic acid, naphthylformylboronic acid, or 2-formylarylboronic acid with methyl, methoxy, and / or halogen substitutions.

7. The method according to claim 1 or 2, characterized in that, The isonitriles are n-butylisocyanate, benzylisocyanate, (2-isocyanoethyl)benzene, methyl isocyanate, and 2-morpholine ethylisocyanate.

8. The method according to claim 1, characterized in that, The reaction time is 0.5~1h.

9. The N-BOH benzozaborane prepared by the method according to any one of claims 1 to 8 has the following chemical structural formula: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 10. The use of the N-BOH benzozaborane according to claim 9 in the preparation of antitumor drugs.

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