Pyrimidine-biaryl compounds, preparation method therefor and use thereof as herbicides

Abstract

The present invention relates to herbicide technology, and aims to provide pyrimidine-biaryl compounds, a preparation method therefor and the use thereof as herbicides. The structural formula of the pyrimidine-biaryl compounds is shown as general formula (I). An application method of the compounds comprises applying a herbicidally active amount the compounds to leaves of pre-emergence or post-emergence weeds. Compared with the prior art, the compounds provided by the present invention can be used as pre-emergence and post-emergence herbicides, have wide weed control spectrums, and have wider herbicide application windows.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to herbicide technology, and more particularly to a pyrimidine-biaryl compound, a preparation method therefor, and the use thereof as a herbicide. BACKGROUND

[0002] In the process of grain cultivation, the use of herbicides is an essential means to increase yield per unit area and crop quality, ensuring grain production to meet the demands of population growth. On the other hand, the use of herbicides also brings certain negative impacts to the environment, such as increased weed resistance leading to higher herbicide application rates, thereby posing significant risks to ecosystems. Therefore, the development of high-efficiency, low-toxicity, readily degradable, and environmentally friendly herbicides has become an important direction for innovative research.

[0003] Pyrimidinylsalicylate herbicides are widely used for weed control in rice fields and cotton fields. To date, five herbicides have been registered in relevant countries and are used for the control of important weeds in farmland, the structural formulas of which are respectively: pyrithiobac-sodium H3CO OCH3    R2 pyrimidine-biphenyl hybrids

[0004] Due to the widespread use of these herbicides, weed resistance has increased and threatens the continued use of these herbicides. Previous studies have shown that the target of pyrimidinylsalicylate herbicides is acetohydroxyacid synthase (AHAS), and the resistance mechanisms of weeds to these herbicides are mainly manifested in two aspects: target-site mutation and metabolic resistance in non-target-site resistance (increased metabolic capacity toward herbicides). Therefore, designing resistancebreaking inhibitors will become a major challenge.

[0005] To overcome this challenge, a class of pyrimidine-biphenyl compounds has been found to be effective against Descurainia sophia and Ammannia arenaria that have developed resistance to AHAS inhibitors. These pyrimidine-biphenyl compounds were discovered based on structural optimization of pyrimidinylsalicylate herbicides, retaining the pyrimidine skeleton and the carboxylic acid group, while introducing a phenyl or heteroaryl group at the 6-position of the benzene ring, among which the 6-phenyl compounds are effective against weeds resistant to AHAS.

[0006] Biaryl compounds are fundamental skeletons of natural products; they are also common molecular substructures in medicinal chemistry, and due to their internal rotational flexibility, they can adapt to various drug targets. Moreover, this skeleton is an important structural component in pesticide molecules; it is also a significant class of scaffolds in materials science. Therefore, molecules containing such skeletons have broad application prospects. Furthermore, the Suzuki-Miyaura cross-coupling reaction can be used to rapidly construct these compounds, effectively expanding new chemical space.

[0007] Pyrimidinylsalicylate herbicides all contain a pyrimidine skeleton and a carboxyl group or its ester. Previous studies have consistently held that both of these substructures must be retained in the design of inhibitors to maintain herbicidal activity. Consequently, those skilled in the art have always directed their research toward new herbicide development along this line of thinking, which has prevented the continuous introduction of products with newer chemical structures and better resistance-breaking properties.

[0008] Therefore, the development of this novel type of pyrimidine-biaryl compounds for weed control is of great urgency and significant importance. SUMMARY

[0009] The present disclosure addresses the deficiencies of the prior art by providing a pyrimidine-biaryl compound, a preparation method therefor, and the use thereof as a herbicide. The compound can be used as an agrochemical herbicide for weed control in agriculture, exhibiting excellent post-emergence and pre-emergence herbicidal activity.

[0010] To achieve the above objective, the present disclosure provides the following solution.

[0011] The present disclosure provides a pyrimidine-biaryl compound having a structural formula as shown in Formula (I): O. ,N^ / O N (I) O

[0012] In Formula (I), Ar is selected from any one of Ar1 to Ar31 as shown below: Ar2 Ar29 O O Ar30

[0013] where, Ri is hydrogen, halogen, amino, hydroxy, cyano, trifluoromethyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl or C1-C2 alkyl;

[0014] R2 is hydrogen, halogen, amino, methoxy or C1-C2 alkyl;

[0015] R3 is hydrogen, halogen, C1-C2 alkyl, C1-C2 alkoxy, acetyl, benzoyl, carboxy or methoxycarbonyl;

[0016] R4 is hydrogen, halogen, methoxy or C1-C2 alkyl; and

[0017] Rs is hydrogen or fluoro.

[0018] In a preferred embodiment of the present disclosure, the halogen is fluoro, chloro, or bromo; the C1-C2 alkyl is methyl (Me, CH3) or ethyl (Et, C2Hs); and the C1-C2 alkoxy is methoxy (MeO, CH3O) or ethoxy (EtO, C2HsO). The pyrimidine-biaryl compounds described in the present disclosure can be specifically represented as compounds I-1 to I-78 by combining Formula (I) with the specific structures of the 78 Ar groups listed in Table 1, but the present disclosure is not limited to these compounds. Table 1: Compound No: Ar Compound No: Ar I-1 b I-2 ch3 I-3 H3C.^ bb I-4 h3c^^ I-5 OCH3 b' I-6 H3CO^ / by I-7 h3co^^ I-8 nh2 I-9 h2n^^ by I-10 by" h2n^^ I-11 OH er I-12 I 0 I-13 F I-14 Q I-15 Cl ■i' I-16 yy Cl I-17 Br d' I-18 cf3 I-19 ry f3c / '^ I-20 CN I-21 sch3 (^y I-22 soch3 I-23 SO2CH3 I-24 H3C^jO^ 0 I-25 Ph.^ 0 I-26 Hsco^y^e^ 0 I-27 HO^y 0 I-28 ch3 H3C.,X I-29 ch3 xy ch3 I-30 h3c.^ ch3 I-31 och3 H3C0.^;.:: / ^ yy I-32 och3 0' och3 I-33 ch3 xy och3 I-34 och3 ch3 I-35 0 0 I-36 och3 h3c^X^ I-37 Br 'r' OCH3 I-38 och3 Br I-39 Br I-40 Br h3c^X^ I-41 Br '■r ' ch3 I-42 ch3 •y Br I-43 Ck.^ I J I-44 Ck^ J J h3co^^^ I-45 Cl.^^ IT C2H5O^^ I-46 cf3 h3c^XT^ I-47 OH ¢-ch3 I-48 F h3co.A I I cr I-49 oi I-50 0^) F I-51 (J I-52 [I 1 I-53 h I-54 n'NY^ [I 1 I-55 I-56 I-57 1 co I-58 I-59 I-60 H I-61 ki I-62 H IN I-63 -pi H I-64 <6 I-65 O'Z^Z I I-66 ¢3 I-67 d) I-68 I w o-y° I-69 *6 I-70 co I-71 ci I-72 ci I-73 d> I-74 ¢6 I-75 I-76 r0^ L0XJ I-77 ddY I-78 o—\ z d

[0019] The present disclosure further provides a method for preparing the previously mentioned pyrimidine-biaryl compound, which is accomplished by Synthetic Route 1 or Synthetic Route 2 as set forth below.

[0020] Synthetic Route 1: (B)

[0021] In Formula (B), LG1 represents a boron-containing substituent.

[0022] Synthetic Route 2:

[0023] In Formula (C), LG2 represents a boron-containing substituent; and in Formula (D), X2 represents a leaving group.

[0024] In a preferred embodiment of the present disclosure, the preparation method based on Synthetic Route 1 comprises: reacting an intermediate of Formula (A) with a compound of Formula (B) in the presence of potassium carbonate and a palladium catalyst in a solvent, at a molar ratio of 1:1.3:6:0.05, at a temperature of 100°C for 1 hour, to obtain a crude reaction product; and purifying the crude reaction product by silica gel column chromatography to obtain the compound of Formula (I).

[0025] In a preferred embodiment of the present disclosure, the preparation method based on Synthetic Route 2 comprises:

[0026] (a) reacting a compound of Formula (C) with a compound of Formula (D) in the presence of sodium carbonate and a palladium catalyst in a solvent, at a molar ratio of 1:1.3:5:0.05, at 100°C for 1 hour, to obtain a compound of Formula (E);

[0027] (b) reacting the compound of Formula (E) with salicylaldehyde in methanol at room temperature for 0.5 hour, followed by addition of sodium borohydride and continuing the reaction at room temperature for 0.5 hour, to obtain a compound of Formula (F); wherein the molar ratio of the compound of Formula (E), salicylaldehyde, and sodium borohydride is 1:1.5:1.5; and

[0028] (c) reacting the compound of Formula (F) with 2-(methylsulfonyl)-4,6-dimethoxypyrimidine in the presence of cesium carbonate in 1,4-dioxane, at a molar ratio of 1:1.2:1.5, at 110°C for 4 hours, to obtain a crude product; and

[0029] (d) purifying the crude product by silica gel column chromatography to obtain the compound of Formula (I).

[0030] The disclosure further provides a herbicidal composition, comprising a herbicidally effective amount of the abovementioned pyrimidine-biaryl compound and at least one formulation adjuvant.

[0031] The disclosure further provides a method for preparing a herbicidal composition, comprising mixing a herbicidally effective amount of the abovementioned pyrimidine-biaryl compound with at least one formulation adjuvant.

[0032] The disclosure also provides use of the pyrimidine-biaryl compound as an agrochemical herbicide.

[0033] The disclosure also provides a method for controlling weeds, comprising applying a herbicidally effective amount of the pyrimidine-biaryl compound to leaves of the weeds at a pre-emergence or post-emergence stage; where the weeds are selected from the group consisting of barnyardgrass (Echinochloa crus-galli), crabgrass (Digitaria sanguinalis), redroot pigweed (Amaranthus retroflexus), velvetleaf (Abutilon theophrasti), and sicklepod (Senna obtusifolia).

[0034] The following advantages are associated with the pyrimidine-biaryl compound, a preparation method therefor, and the use thereof as a herbicide of the disclosure.

[0035] 1. The present disclosure breaks through the previously prevailing design approach and adopts a completely new design concept: retaining the pyrimidine skeleton while removing the carboxyl group, and utilizing the biaryl skeleton to design a class of pyrimidine-biaryl compounds with entirely new structures. This type of compound has the following characteristics: (1) in this structure, the aryl group is located at the ortho position of the benzylamine moiety, and due to its internal rotational flexibility, it can effectively adapt to relevant targets; (2) this structure does not contain a carboxyl group and has strong lipophilicity, which facilitates absorption by plants; and (3) the lipophilicity of the compound may enable its interaction with the target enzyme in a hydrophobically driven manner, which is distinct from existing pyrimidinylsalicylate herbicides.

[0036] 2. The pyrimidine-biaryl compound provided in the present disclosure can be used as an agrochemical herbicide for controlling various weeds in agricultural fields.

[0037] 3. The pyrimidine-biaryl compound provided in the present disclosure can be used as a post-emergence herbicide, and is particularly effective against barnyardgrass, crabgrass, and redroot pigweed; some of the compounds can effectively control barnyardgrass, crabgrass, redroot pigweed, sicklepod, and velvetleaf, exhibiting a broad herbicidal spectrum.

[0038] 4. The pyrimidine-biaryl compound provided in the present disclosure can be used as a pre-emergence herbicide, and is particularly effective against barnyardgrass, crabgrass, and redroot pigweed; some of the compounds can effectively control barnyardgrass, crabgrass, redroot pigweed, and velvetleaf, exhibiting a broad herbicidal spectrum.

[0039] 5. The pyrimidine-biaryl compound provided in the present disclosure can be used as both a post-emergence and a pre-emergence herbicide, providing a wider application window.

[0040] 6. The pyrimidine-biaryl compound I-5 provided in the present disclosure can be used as both a post-emergence and a pre-emergence herbicide; its post-emergence and pre-emergence herbicidal activities are comparable to those of the AHAS inhibitor P, but its post-emergence activity is superior to that of the commercial herbicide pretilachlor; for the control of the troublesome weed barnyardgrass, the compound provides a wider application window than pretilachlor. DETAILED DESCRIPTION

[0041] To further illustrate the disclosure, embodiments detailing a pyrimidinebiaryl compound, a preparation method therefor, and the use thereof as a herbicide are described below. It should be noted that the following embodiments are intended to describe and not to limit the disclosure.

[0042] Part 1: Overview of Preparation Methods

[0043] The compounds of the present disclosure having the structure shown in Formula (I) can be prepared via two main synthetic routes.

[0044] Synthetic Route 1:

[0045] Compounds I-1 to I-22, I-24 to I-26, I-28 to I-39, I-43 to I-45, I-47 to I-50, I-55 to I-64, and I-74 to I-78 in Table 1 are prepared using Synthetic Route 1.

[0046] In this route, the compound of Formula (A) can be synthesized according to the method reported by Meng et al. in Org. Chem. Front. 2020, 7, 267-272. One molar equivalent of the compound of Formula (A) can be converted into the compound of Formula (I) by reacting with 1.3 molar equivalents of a compound of Formula (B) (wherein LG1 represents a suitable boron-containing substituent, such as boronic acid or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, preferably boronic acid), optionally in the presence of 6 molar equivalents of potassium carbonate and 0.05 molar equivalents of tetrakis(triphenylphosphine)palladium(0), in a suitable solvent (which may include N,N-dimethylformamide or 1,4-dioxane, preferably N,N-dimethylformamide), at 100°C for 1 hour. The product is purified by silica gel column chromatography.

[0047] Synthetic Route 2:

[0048] Compounds I-23, I-40 to I-42, I-46, I-51 to I-54, and I-65 to I-73 in Table 1 are prepared using Synthetic Route 2.

[0049] In this route, one molar equivalent of a compound of Formula (C) (wherein LG2 represents a suitable boron-containing substituent, such as boronic acid or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, preferably 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) can be converted into a compound of Formula (E) by reacting with 1.3 molar equivalents of a compound of Formula (D) (wherein X2 represents a suitable leaving group, such as bromo or iodo, preferably iodo), optionally in the presence of 5 molar equivalents of sodium carbonate and 0.05 molar equivalents of a suitable palladium catalyst (which may include tetrakis(triphenylphosphine)palladium(0) or [1,1‘-bis(diphenylphosphino)ferrocene]dichloropalladium(II), preferably tetrakis(triphenylphosphine)palladium(0)), in N,N-dimethylformamide, at 100°C for 1 hour.

[0050] One molar equivalent of the compound of Formula (E) can be converted into a compound of Formula (F) by reacting with 1.5 molar equivalents of salicylaldehyde in methanol at room temperature for 0.5 hours, and further with 1.5 molar equivalents of sodium borohydride at room temperature for 0.5 hours.

[0051] One molar equivalent of the compound of Formula (F) can be converted into the compound of Formula (I) by reacting with 1.2 molar equivalents of 2-(methylsulfonyl)-4,6-dimethoxypyrimidine in the presence of 1.5 molar equivalents of cesium carbonate in 1,4-dioxane at 110°C for 4 hours. The product is purified by silica gel column chromatography.

[0052] In addition, compound I-27 in Table 1 is derived from further modification of compound I-26 and is not encompassed by the above two synthetic routes.

[0053] In this preparation method, one molar equivalent of compound I-26 can be reacted with 5 molar equivalents of sodium hydroxide in a 1:1 (v / v) methanol / water solution at 80°C for 1 hour, and then acidified with 0.5 mol / L dilute hydrochloric acid to obtain compound I-27.

[0054] Part 2: Preparation Examples of the Compounds Example 1

[0055] This example illustrates the synthesis of target compound I-1 according to Synthetic Route 1 of the present disclosure.

[0056] Synthesis of intermediate N-(2-((4,6-dimethoxypyrimidin-2-yl)oxy)benzyl)-2-iodoaniline (A) (A)

[0057] The intermediate (A) can be synthesized according to the method reported by Meng et al. in Org. Chem. Front. 2020, 7, 267-272.

[0058] Synthesis of target product I-1:

[0059] Phenylboronic acid (B-1) (79.2 mg, 0.65 mmol) and N-(2-((4,6-dimethoxypyrimidin-2-yl)oxy)benzyl)-2-iodoaniline (A) (231.6 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide (4 mL). Under argon protection, tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) was added, followed by aqueous potassium carbonate solution (2 mL, 1.5 mol / L). The resulting mixture was heated at 100°C for 1 hour. After cooling to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude I-1. The crude product was purified by silica gel column chromatography [V(petroleum ether) / V(ethyl acetate) = 10 / 1] to give waxy product I-1. Example 2

[0060] This example illustrates the synthesis of target compound I-8 according to Synthetic Route 1 of the present disclosure. (1-8)

[0061] (2-Aminophenyl)boronic acid pinacol ester (C-1) (142.4 mg, 0.65 mmol) and N-(2-((4,6-dimethoxypyrimidin-2-yl)oxy)benzyl)-2-iodoaniline (A) (231.6 mg, 0.5 mmol) were dissolved in N,N-dimethylformamide (4 mL). Under argon, tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) was added, followed by aqueous potassium carbonate solution (2 mL, 1.5 mol / L). The mixture was heated at 100°C for 1 hour. After cooling, saturated brine was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give crude I-8, which was purified by silica gel column chromatography [V(petroleum ether) / V(ethyl acetate) = 10 / 1] to afford waxy product I-8. Example 3

[0062] This example illustrates the synthesis of target compound I-63 according to Synthetic Route 1 of the present disclosure.

[0063] 1H-Indazol-4-ylboronic acid (B-2) (105.3 mg, 0.65 mmol) and N-(2-((4,6-dimethoxypyrimidin-2-yl)oxy)benzyl)-2-iodoaniline (A) (231.6 mg, 0.5 mmol) were dissolved in 1,4-dioxane (4 mL). Under argon protection, tetrakis(triphenylphosphine)palladium(0) (28.9 mg, 0.025 mmol) was added, followed by aqueous potassium carbonate solution (2 mL, 1.5 mol / L). The resulting mixture was heated at 100°C for 1 hour. After cooling to room temperature, saturated brine was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give crude I-63. The crude product was purified by silica gel column chromatography [V(petroleum ether) / V(ethyl acetate) = 10 / 1] to afford waxy product I-63.

[0064] The synthesis of the following compounds can be carried out with reference to Examples 1 to 3, and detailed descriptions are omitted here.

[0065] Characterization data for compounds I-1 to I-22, I-24 to I-26, I-28 to I-39, I-43 to I-45, I-47 to I-50, I-55 to I-64, and I-74 to I-78 are as follows:

[0066] I-1: waxy; XH NMR (400 MHz, CDCh) 8 7.45 - 7.38 (m, 5H), 7.37 - 7.24 (m, 2H), 7.21 - 7.06 (m, 4H), 6.78 (t, J = 7.1 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.33 (s, 2H), 3.77 (s, 6H). (No NH)

[0067] I-2: waxy; XH NMR (400 MHz, CDCh) 8 7.35 (d, J = 7.6 Hz, 1H), 7.30 -7.21 (m, 4H), 7.20 - 7.08 (m, 4H), 6.98 (dd, J = 7.4, 1.5 Hz, 1H), 6.75 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.31 (s, 2H), 3.78 (s, 6H), 2.15 (s, 3H). (No NH)

[0068] I-3: waxy; XH NMR (400 MHz, CDCh) 8 7.44 (d, J = 7.5 Hz, 1H), 7.37 -7.21 (m, 4H), 7.23 - 7.07 (m, 5H), 6.75 (td, J = 7.4, 1.1 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.78 (s, 1H), 4.35 (s, 2H), 3.78 (s, 6H), 2.41 (s, 3H). (No NH)

[0069] I-4: solid, m.p. 82.6-83.9°C; XH NMR (400 MHz, CDCh) 8 7.44 - 7.37 (m, 1H), 7.32 - 7.24 (m, 3H), 7.22 (d, J = 7.9 Hz, 2H), 7.20 - 7.15 (m, 1H), 7.14 - 7.08 (m, 2H), 7.06 (dd, J = 7.4, 1.5 Hz, 1H), 6.74 (td, J = 7.4, 1.0 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.32 (s, 2H), 3.76 (s, 6H), 2.39 (s, 3H). (No NH)

[0070] I-5: waxy; XH NMR (400 MHz, CDCh) 8 7.45 (d, J = 7.5 Hz, 1H), 7.36 (td, J = 8.2, 1.7 Hz, 1H), 7.30 - 7.22 (m, 2H), 7.20 - 6.96 (m, 6H), 6.76 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 7.8 Hz, 1H), 5.78 (s, 1H), 4.35 (d, J = 4.1 Hz, 2H), 3.82 (s, 3H), 3.80 (s, 6H). (No NH)

[0071] I-6: solid, m.p. 118.5-120.1°C; XH NMR (400 MHz, CDCh) 8 7.43 - 7.39 (m, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.27 (td, J = 7.7, 1.7 Hz, 1H), 7.18 (td, J = 7.5, 1.1 Hz, 1H), 7.15 - 7.06 (m, 3H), 7.03 - 6.95 (m, 2H), 6.90 - 6.86 (m, 1H), 6.74 (td, J = 7.4, 0.9 Hz, 1H), 6.60 (d, J = 8.0 Hz, 1H), 5.76 (s, 1H), 4.33 (s, 2H), 3.83 (s, 3H), 3.77 (s, 6H). (No NH)

[0072] I-7: solid, m.p. 104.8-105.3°C; XH NMR (400 MHz, CDCh) 8 7.40 (dd, J = 7.6, 1.1 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.27 (td, J = 7.9, 1.6 Hz, 1H), 7.17 (td, J = 7.5, 1.0 Hz, 1H), 7.14 - 7.08 (m, 2H), 7.05 (dd, J = 7.4, 1.5 Hz, 1H), 6.95 (d, J = 8.7 Hz, 2H), 6.75 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.32 (s, 2H), 3.84 (s, 3H), 3.76 (s, 6H). (No NH)

[0073] I-8: solid, m.p. 84.8-87.0°C; XH NMR (400 MHz, CDCh) 8 7.39 (d, J = 7.6 Hz, 1H), 7.26 (dd, J = 7.7, 1.6 Hz, 1H), 7.21 - 7.06 (m, 6H), 6.82 (td, J = 7.4, 1.0 Hz, 1H), 6.80 - 6.72 (m, 2H), 6.62 (d, J = 8.1 Hz, 1H), 5.78 (s, 1H), 4.33 (d, J = 1.8 Hz, 2H), 3.78 (s, 6H). (No NH, no NH2)

[0074] I-9: solid, m.p. 51.7-53.8°C; XH NMR (400 MHz, CDCh) 8 7.43 - 7.38 (m, 1H), 7.27 (td, J = 7.7, 1.6 Hz, 1H), 7.23 - 7.15 (m, 2H), 7.13 - 7.06 (m, 3H), 6.80 (d, J = 7.5 Hz, 2H), 6.74 - 6.65 (m, 2H), 6.57 (d, J = 8.0 Hz, 1H), 5.76 (s, 1H), 4.31 (s, 2H), 3.78 (s, 6H). (No NH, no NH2)

[0075] I-10: waxy; XH NMR (400 MHz, CDCh) 8 7.41 (dd, J = 7.5, 1.3 Hz, 1H), 7.27 (td, J = 7.8, 1.7 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.18 (td, J = 7.5, 1.1 Hz, 1H), 7.14 - 7.02 (m, 3H), 6.80 (d, J = 8.3 Hz, 2H), 6.72 (td, J = 7.4, 1.0 Hz, 1H), 6.57 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.31 (s, 2H), 3.78 (s, 6H).

[0076] I-11: waxy; XH NMR (400 MHz, CDCh) 8 7.34 - 7.13 (m, 7H), 7.12 (d, J = 8.0 Hz, 1H), 7.05 - 6.95 (m, 2H), 6.90 (td, J = 7.5, 0.9 Hz, 1H), 6.77 (d, J = 9.1 Hz, 1H), 5.77 (s, 1H), 4.26 (s, 2H), 3.75 (s, 6H).

[0077] I-12: solid, m.p. 52.4-54.2°C; XH NMR (400 MHz, CDCh) 8 7.42 - 7.36 (m, 1H), 7.30 - 7.22 (m, 3H), 7.17 (td, J = 7.5, 1.1 Hz, 1H), 7.13 - 7.07 (m, 2H), 7.04 (dd, J = 7.4, 1.5 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H), 6.74 (t, J = 7.4 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.31 (s, 2H), 3.77 (s, 6H).

[0078] I-13: solid, m.p. 101.2-102.4°C; XH NMR (400 MHz, CDCh) 8 7.43 (dd, J = 7.5, 1.0 Hz, 1H), 7.40 - 7.31 (m, 2H), 7.27 (td, J = 7.7, 1.5 Hz, 1H), 7.24 - 7.05 (m, 6H), 6.76 (dd, J = 7.4, 0.7 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.36 (s, 2H), 3.78 (s, 6H).

[0079] I-14: solid, m.p. 89.9-91.9°C; XH NMR (400 MHz, CDCh) 8 7.45 - 7.34 (m, 3H), 7.29 (td, J = 7.8, 1.5 Hz, 1H), 7.23 - 7.08 (m, 5H), 7.05 (dd, J = 7.4, 1.5 Hz, 1H), 6.75 (dd, J = 7.4, 0.7 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 5.78 (s, 1H), 4.34 (s, 2H), 3.77 (s, 6H).

[0080] I-15: solid, m.p. 126.2-127.2°C; XH NMR (400 MHz, CDCh) 8 7.53 - 7.47 (m, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.35 - 7.23 (m, 4H), 7.17 (t, J = 7.7 Hz, 2H), 7.11 (d, J = 8.0 Hz, 1H), 7.02 (dd, J = 7.4, 1.3 Hz, 1H), 6.76 (td, J = 7.4, 0.6 Hz, 1H), 6.62 (d, J = 8.2 Hz, 1H), 5.78 (s, 1H), 4.35 (s, 2H), 3.78 (s, 6H).

[0081] I-16: solid, m.p. 105.1-106.2°C; XH NMR (400 MHz, CDCh) 8 7.41 - 7.27 (m, 6H), 7.22 - 7.08 (m, 3H), 7.03 (dd, J = 7.5, 1.5 Hz, 1H), 6.75 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.32 (s, 2H), 3.75 (s, 6H).

[0082] I-17: solid, m.p. 39.5-42.1°C; XH NMR (400 MHz, CDCh) 8 7.69 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 6.9 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.33 - 7.20 (m, 3H), 7.17 (t, J = 7.6 Hz, 2H), 7.11 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 7.4, 1.4 Hz, 1H), 6.76 (t, J = 7.3 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 5.78 (s, 1H), 4.35 (s, 2H), 3.78 (s, 6H).

[0083] I-18: solid, m.p. 150.6-151.7°C; XH NMR (400 MHz, CDCh) 8 7.79 (d, J = 7.8 Hz, 1H), 7.58 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 7.5 Hz, 2H), 7.26 (td, J = 7.7, 1.5 Hz, 1H), 7.20 - 7.12 (m, 2H), 7.09 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.73 (td, J = 7.4, 0.7 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.31 (s, 2H), 3.77 (s, 6H).

[0084] I-19: solid, m.p. 112.2-114.2°C; XH NMR (400 MHz, CDCh) 8 7.68 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 7.5 Hz, 1H), 7.30 (t, J = 7.6 Hz, 1H), 7.24 - 7.10 (m, 3H), 7.05 (dd, J = 7.4, 1.1 Hz, 1H), 6.77 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 5.77 (s, 1H), 4.35 (s, 2H), 3.75 (s, 6H).

[0085] I-20: waxy; XH NMR (400 MHz, CDCh) 8 8.60 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 8.2 Hz, 1H), 8.27 (dd, J = 7.9, 0.9 Hz, 1H), 7.83 - 7.76 (m, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.39 - 7.32 (m, 1H), 7.30 - 7.23 (m, 3H), 7.20 (d, J = 7.3 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 5.79 (s, 1H), 5.64 (s, 2H), 3.85 (s, 6H).

[0086] I-21: waxy; XH NMR (400 MHz, CDCh) 8 7.46 (d, J = 6.9 Hz, 1H), 7.40 -7.33 (m, 1H), 7.30 - 7.12 (m, 6H), 7.10 (dd, J = 7.9, 0.8 Hz, 1H), 7.03 (dd, J = 7.4, 1.4 Hz, 1H), 6.76 (td, J = 7.3, 0.7 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.34 (s, 2H), 3.79 (s, 6H), 2.38 (s, 3H).

[0087] I-22: waxy; XH NMR (400 MHz, CDCh) 8 8.13 (t, J = 8.0 Hz, 1H), 7.69 -7.54 (m, 2H), 7.40 (d, J = 7.4 Hz, 1H), 7.33 - 7.06 (m, 6H), 6.72 - 6.65 (m, 1H), 6.57 (d, J = 8.2 Hz, 1H), 5.75 (s, 1H), 4.29 (q, J = 12.3 Hz, 2H), 3.76 (s, 6H), 2.41 (s, 3H).

[0088] I-24: waxy; XH NMR (400 MHz, CDCh) 8 7.99 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 7.40 (dd, J = 7.5, 1.3 Hz, 1H), 7.29 (td, J = 7.6, 1.3 Hz, 1H), 7.23 -7.09 (m, 3H), 7.06 (dd, J = 7.5, 1.4 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 8.2 Hz, 1H), 5.75 (s, 1H), 4.33 (s, 2H), 3.74 (s, 6H), 2.62 (s, 3H).

[0089] I-25: waxy; XH NMR (400 MHz, CDCh) 8 7.92 - 7.79 (m, 4H), 7.65 - 7.57 (m, 1H), 7.56 - 7.47 (m, 4H), 7.39 (dd, J = 7.5, 1.1 Hz, 1H), 7.29 (td, J = 7.7, 1.4 Hz, 1H), 7.22 - 7.08 (m, 4H), 6.80 (t, J = 7.1 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 5.74 (s, 1H), 4.35 (s, 2H), 3.75 (s, 6H).

[0090] I-26: waxy; XH NMR (400 MHz, CDCh) 8 8.07 (d, J = 8.3 Hz, 2H), 7.48 (d, J = 8.3 Hz, 2H), 7.39 (dd, J = 7.5, 1.3 Hz, 1H), 7.29 (td, J = 7.7, 1.5 Hz, 1H), 7.21 -7.09 (m, 3H), 7.06 (dd, J = 7.5, 1.5 Hz, 1H), 6.76 (td, J = 7.4, 0.7 Hz, 1H), 6.67 (d, J = 8.1 Hz, 1H), 5.75 (s, 1H), 4.32 (s, 2H), 3.94 (s, 3H), 3.74 (s, 6H).

[0091] I-28: waxy; XH NMR (400 MHz, CDCh) 8 7.38 (d, J = 7.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.22 - 7.04 (m, 6H), 7.00 (d, J = 7.2 Hz, 1H), 6.75 (t, J = 7.2 Hz, 1H), 6.59 (d, J = 8.0 Hz, 1H), 5.79 (s, 1H), 4.33 (s, 2H), 3.80 (s, 6H), 2.36 (s, 3H), 2.09 (s, 3H).

[0092] I-29: waxy; XH NMR (400 MHz, CDCh) 8 7.37 (d, J = 7.6 Hz, 1H), 7.27 (td, J = 7.8, 1.6 Hz, 1H), 7.21 - 7.07 (m, 5H), 7.02 (s, 1H), 6.98 (dd, J = 7.4, 1.5 Hz, 1H), 6.75 (td, J = 7.3, 0.7 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.78 (s, 1H), 4.33 (s, 2H), 3.79 (s, 6H), 2.35 (s, 3H), 2.12 (s, 3H).

[0093] I-30: waxy; XH NMR (400 MHz, CDCh) 8 7.39 (d, J = 6.6 Hz, 1H), 7.27 (td, J = 7.7, 1.7 Hz, 1H), 7.18 (td, J = 7.5, 1.0 Hz, 1H), 7.13 - 7.08 (m, 2H), 7.06 (dd, J = 7.5, 1.5 Hz, 1H), 7.01 (s, 2H), 6.97 (s, 1H), 6.76 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 5.75 (s, 1H), 4.34 (s, 2H), 3.77 (s, 6H), 2.35 (s, 6H).

[0094] I-31: waxy; XH NMR (400 MHz, CDCh) 8 7.45 (d, J = 7.4 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 7.18 - 7.07 (m, 5H), 6.94 (d, J = 8.1 Hz, 1H), 6.86 (d, J = 7.5 Hz, 1H), 6.73 (t, J = 7.3 Hz, 1H), 6.57 (d, J = 7.9 Hz, 1H), 5.77 (s, 1H), 4.35 (s, 2H), 3.91 (s, 3H), 3.80 (s, 6H), 3.61 (s, 3H).

[0095] I-32: waxy; XH NMR (400 MHz, CDCh) 8 7.45 (d, J = 7.1 Hz, 1H), 7.26 (td, J = 7.7, 1.6 Hz, 1H), 7.20 - 7.06 (m, 4H), 6.96 - 6.81 (m, 3H), 6.75 (t, J = 7.3 Hz, 1H), 6.59 (d, J = 7.0 Hz, 1H), 5.77 (s, 1H), 4.35 (d, J = 3.9 Hz, 2H), 3.80 (s, 6H), 3.79 (s, 3H), 3.75 (s, 3H).

[0096] I-33: solid, m.p. 95.3-97.2°C; XH NMR (400 MHz, CDCh) 8 7.36 (dd, J = 7.6, 1.3 Hz, 1H), 7.26 (td, J = 7.7, 1.6 Hz, 1H), 7.21 - 7.11 (m, 3H), 7.11 (dd, J = 8.1, 1.1 Hz, 1H), 6.99 (dd, J = 7.4, 1.6 Hz, 1H), 6.83 (dd, J = 8.4, 2.8 Hz, 1H), 6.78 - 6.72 19 (m, 2H), 6.61 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.32 (s, 2H), 3.79 (s, 3H), 3.78 (s, 6H), 2.07 (s, 3H).

[0097] I-34: waxy; XH NMR (600 MHz, CDCh) 8 7.45 (d, J = 7.3 Hz, 1H), 7.26 (td, J = 7.6, 1.2 Hz, 1H), 7.19 - 7.13 (m, 2H), 7.11 (t, J = 7.6 Hz, 2H), 7.07 (dd, J = 7.5, 1.4 Hz, 2H), 6.89 (d, J = 8.3 Hz, 1H), 6.75 (t, J = 6.8 Hz, 1H), 6.57 (s, 1H), 5.77 (s, 1H), 4.34 (q, J = 16.3 Hz, 2H), 3.80 (s, 6H), 3.78 (s, 3H), 2.33 (s, 3H).

[0098] I-35: solid, m.p. 103.6-105.3°C; XH NMR (400 MHz, CDCh) 8 7.40 (d, J = 7.6 Hz, 1H), 7.27 (td, J = 7.8, 1.7 Hz, 1H), 7.18 (td, J = 7.5, 1.1 Hz, 1H), 7.14 - 7.05 (m, 3H), 6.84 - 6.67 (m, 4H), 6.63 (d, J = 8.0 Hz, 1H), 5.75 (s, 1H), 4.34 (s, 2H), 3.81 (s, 3H), 3.77 (s, 6H), 2.37 (s, 3H).

[0099] I-36: waxy; XH NMR (400 MHz, CDCh) 8 7.47 - 7.40 (m, 1H), 7.26 (td, J = 7.6, 1.5 Hz, 1H), 7.22 - 7.01 (m, 7H), 6.75 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 7.4 Hz, 1H), 5.77 (s, 1H), 4.36 (s, 2H), 3.80 (s, 6H), 3.45 (s, 3H), 2.35 (s, 3H).

[0100] I-37: waxy; XH NMR (400 MHz, CDCL) 8 7.54 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 7.5 Hz, 1H), 7.26 (td, J = 7.7, 1.5 Hz, 1H), 7.16 (t, J = 7.7 Hz, 2H), 7.10 (d, J = 7.9 Hz, 1H), 7.00 (dd, J = 7.4, 1.5 Hz, 1H), 6.86 (d, J = 3.0 Hz, 1H), 6.82 - 6.71 (m, 2H), 6.61 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.34 (s, 2H), 3.79 (s, 3H), 3.78 (s, 6H).

[0101] I-38: waxy; XH NMR (400 MHz, CDCL) 8 7.47 - 7.34 (m, 3H), 7.27 (td, J = 7.7, 1.6 Hz, 1H), 7.21 - 7.08 (m, 3H), 7.03 (dd, J = 7.5, 1.5 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.75 (t, J = 7.3 Hz, 1H), 6.60 (d, J = 6.6 Hz, 1H), 5.78 (s, 1H), 4.34 (d, J = 5.6 Hz, 2H), 3.80 (s, 6H), 3.79 (s, 3H).

[0102] I-39: solid, m.p. 51.2-53.4°C; XH NMR (400 MHz, CDCh) 8 7.45 (d, J = 7.5 Hz, 1H), 7.33 (t, J = 7.9 Hz, 1H), 7.25 (td, J = 7.7, 1.5 Hz, 1H), 7.19 - 7.12 (m, 2H), 7.10 (dd, J = 8.0, 0.9 Hz, 1H), 6.99 (dd, J = 7.4, 1.5 Hz, 1H), 6.91 (d, J = 7.9 Hz, 2H), 6.75 (t, J = 7.4 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.33 (s, 2H), 3.94 (s, 3H), 3.78 (s, 6H).

[0103] I-43: waxy; XH NMR (400 MHz, CDCh) 8 7.40 (dd, J = 7.5, 1.2 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.28 (td, J = 7.6, 1.5 Hz, 1H), 7.24 - 7.16 (m, 2H), 7.14 -7.08 (m, 2H), 7.04 (d, J = 8.3 Hz, 1H), 7.01 (dd, J = 7.5, 1.5 Hz, 1H), 6.72 (dd, J = 7.4, 0.8 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.33 (s, 2H), 3.76 (s, 6H).

[0104] I-44: waxy; ih nmr (400 MHz, CDCl3) 8 7.41 - 7.36 (m, 2H), 7.33 - 7.22 (m, 2H), 7.18 (td, J = 7.5, 1.0 Hz, 1H), 7.12 (td, J = 8.2, 1.2 Hz, 2H), 7.02 (dd, J = 7.5, 1.5 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.33 (s, 2H), 3.94 (s, 3H), 3.76 (s, 6H).

[0105] I-45: waxy; XH NMR (400 MHz, CDCI3) 8 7.43 - 7.36 (m, 2H), 7.28 (td, J = 7.6, 1.6 Hz, 1H), 7.23 (dd, J = 8.4, 2.1 Hz, 1H), 7.18 (td, J = 7.5, 1.1 Hz, 1H), 7.14 -7.08 (m, 2H), 7.02 (dd, J = 7.5, 1.5 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.73 (t, J = 7.4 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.33 (s, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.76 (s, 6H), 1.50 (t, J = 7.0 Hz, 3H).

[0106] I-47: waxy; XH NMR (400 MHz, CDCI3) 8 7.33 (d, J = 7.6 Hz, 1H), 7.29 (td, J = 7.7, 1.7 Hz, 1H), 7.21 - 7.16 (m, 3H), 7.13 (d, J = 8.0 Hz, 1H), 7.09 (dd, J = 8.2, 2.2 Hz, 1H), 7.06 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.89 (td, J = 7.4, 1.2 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 5.77 (s, 1H), 4.27 (s, 2H), 3.75 (s, 6H), 2.32 (s, 3H).

[0107] I-48: waxy; XH NMR (400 MHz, CDCI3) 8 7.41 (d, J = 6.7 Hz, 1H), 7.28 (td, J = 7.6, 1.1 Hz, 1H), 7.23 - 7.14 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H), 7.05 (d, J = 7.4 Hz, 1H), 7.01 - 6.94 (m, 1H), 6.75 (t, J = 7.4 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 5.77 (s, 1H), 4.34 (s, 2H), 3.99 (d, J = 1.0 Hz, 3H), 3.77 (s, 6H).

[0108] I-49: waxy; XH NMR (400 MHz, CDCl3) 8 7.90 (t, J = 9.3 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.58 - 7.48 (m, 2H), 7.46 - 7.39 (m, 2H), 7.29 (d, J = 7.6 Hz, 1H), 7.25 - 7.19 (m, 2H), 7.15 - 7.10 (m, 2H), 7.07 (dd, J = 8.0, 1.0 Hz, 1H), 6.82 (td, J = 7.4, 0.9 Hz, 1H), 6.68(d, J = 8.1 Hz, 1H), 5.74 (s, 1H), 4.27 (s, 2H), 3.75 (s, 6H).

[0109] I-50: waxy; XH NMR (400 MHz, CDCl3) 8 8.17 (d, J = 8.3 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.57 (t, J = 7.2 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.35 (dd, J = 7.7, 5.5 Hz, 1H), 7.31 - 7.17 (m, 4H), 7.16 - 7.04 (m, 3H), 6.80 (dd, J = 7.4, 0.6 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 5.74 (s, 1H), 4.27 (s, 2H), 3.75 (s, 6H).

[0110] I-55: waxy; XH NMR (400 MHz, CDCl3) 8 7.61 - 7.57 (m, 1H), 7.49 (t, J = 1.6 Hz, 1H), 7.43 (dd, J = 7.5, 1.3 Hz, 1H), 7.29 (td, J = 7.8, 1.6 Hz, 1H), 7.19 (td, J = 7.5, 1.1 Hz, 1H), 7.17 - 7.07 (m, 3H), 6.71 (td, J = 7.4, 1.0 Hz, 1H), 6.62 (d, J = 8.1 Hz, 1H), 6.58 (dd, J = 1.7, 0.7 Hz, 1H), 5.75 (s, 1H), 4.35 (s, 2H), 3.77 (s, 6H).

[0111] I-56: waxy; XH NMR (400 MHz, CDCl3) 8 7.49 - 7.44 (m, 2H), 7.41 (dd, J = 7.7, 1.5 Hz, 1H), 7.29 (td, J = 7.8, 1.6 Hz, 1H), 7.19 (td, J = 7.5, 1.2 Hz, 1H), 7.13 (dd, J = 8.0, 1.1 Hz, 1H), 7.10 - 7.04 (m, 1H), 6.73 - 6.66 (m, 1H), 6.62 (d, J = 8.2 Hz, 1H), 6.55 - 6.51 (m, 1H), 6.50 - 6.44 (m, 1H), 5.73 (s, 1H), 4.44 (s, 2H), 3.76 (s, 6H).

[0112] I-57: waxy; XH NMR (400 MHz, CDCh) 8 7.43 (d, J = 7.6 Hz, 1H), 7.40 (dd, J = 4.9, 3.0 Hz, 1H), 7.34 (dd, J = 2.9, 1.3 Hz, 1H), 7.29 (td, J = 7.8, 1.6 Hz, 1H), 7.23 - 7.08 (m, 5H), 6.72 (td, J = 7.4, 1.0 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 5.76 (s, 1H), 4.35 (s, 2H), 3.78 (s, 6H).

[0113] I-58: waxy; XH NMR (400 MHz, CDCh) 8 7.43 (d, J = 7.5 Hz, 1H), 7.33 (dd, J = 5.1, 1.1 Hz, 1H), 7.29 (td, J = 7.8, 1.6 Hz, 1H), 7.25 - 7.17 (m, 2H), 7.16 - 7.06 (m, 4H), 6.71 (td, J = 7.4, 0.9 Hz, 1H), 6.61 (d, J = 8.2 Hz, 1H), 5.76 (s, 1H), 4.36 (s, 2H), 3.78 (s, 6H).

[0114] I-59: waxy; XH NMR (400 MHz, CDCh) 8 7.44 (dd, J = 7.7, 1.7 Hz, 1H), 7.29 (td, J = 7.8, 1.7 Hz, 1H), 7.26 - 7.19 (m, 3H), 7.18 (dd, J = 3.6, 1.1 Hz, 1H), 7.16 - 7.10 (m, 3H), 7.06 - 7.01 (m, 2H), 6.73 (td, J = 7.5, 1.1 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.74 (s, 1H), 4.39 (s, 2H), 3.75 (s, 6H).

[0115] I-60: waxy; XH NMR (400 MHz, CDCh) 8 8.32 (s, 1H), 7.39 (d, J = 8.0 Hz, 2H), 7.30 - 7.07 (m, 8H), 6.79 (t, J = 7.3 Hz, 1H), 6.65 (d, J = 8.0 Hz, 1H), 6.43 (s, 1H), 5.76 (s, 1H), 4.31 (s, 2H), 3.77 (s, 6H).

[0116] I-61: waxy; XH NMR (400 MHz, CDCh) 8 8.61 (s, 1H), 7.67 (dd, J = 7.1, 1.9 Hz, 1H), 7.32 - 7.08 (m, 9H), 6.78 (td, J = 7.4, 1.2 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 6.58 (dd, J = 3.2, 2.0 Hz, 1H), 5.76 (d, J = 0.9 Hz, 1H), 4.30 (dd, J = 47.3, 13.3 Hz, 2H), 3.75 (s, 6H).

[0117] I-62: waxy; XH NMR (400 MHz, CDCh) 8 11.13 (s, 1H), 8.36 (d, J = 4.7 Hz, 1H), 7.47 - 7.30 (m, 2H), 7.31 - 7.13 (m, 5H), 7.10 (d, J = 7.9 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 6.46 (d, J = 3.5 Hz, 1H), 5.73 (s, 1H), 4.34 (s, 2H), 3.74 (s, 6H).

[0118] I-63: waxy; XH NMR (600 MHz, CDCh) 8 8.00 (s, 1H), 7.48 (d, J = 8.3 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.38 (d, J = 7.4 Hz, 1H), 7.31 - 7.12 (m, 5H), 7.10 (d, J = 8.0 Hz, 1H), 6.80 (t, J = 7.4 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 5.73 (s, 1H), 4.33 (s, 2H), 3.75 (s, 6H).

[0119] I-64: waxy; XH NMR (500 MHz, CDCh) 8 8.03 (s, 1H), 7.73 (dd, J = 8.1, 1.0 Hz, 1H), 7.34 (dd, J = 7.0, 1.0 Hz, 1H), 7.25 - 7.13 (m, 5H), 7.11 - 7.04 (m, 2H), 6.77 (td, J = 7.4, 1.1 Hz, 1H), 6.68 (dd, J = 8.3, 1.1 Hz, 1H), 5.72 (s, 1H), 4.27 (s, 2H), 3.70 (s, 6H).

[0120] I-74: waxy; XH NMR (400 MHz, CDCh) 8 8.92 (dd, J = 4.2, 1.7 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.00 (dd, J = 8.5, 0.7 Hz, 1H), 7.78 (dd, J = 8.5, 7.1 Hz, 1H), 7.51 (dd, J = 7.0, 1.0 Hz, 1H), 7.35 (dd, J = 8.5, 4.2 Hz, 1H), 7.25 - 7.20 (m, 3H), 7.14 - 7.09 (m, 1H), 7.08 - 7.05 (m, 2H), 6.80 (td, J = 7.4, 0.9 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 5.72 (s, 1H), 4.25 (s, 2H), 3.72 (s, 6H).

[0121] I-75: waxy; XH NMR (400 MHz, CDCh) 8 9.29 (s, 1H), 8.45 (d, J = 5.9 Hz, 1H), 7.99 (t, J = 4.7 Hz, 1H), 7.66 (d, J = 5.0 Hz, 2H), 7.47 (d, J = 5.9 Hz, 1H), 7.30 -7.17 (m, 3H), 7.12 (td, J = 7.5, 1.0 Hz, 1H), 7.09 - 7.01 (m, 2H), 6.80 (td, J = 7.4, 0.8 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 5.72 (s, 1H), 4.26 (s, 2H), 3.72 (s, 6H).

[0122] I-76: waxy; XH NMR (400 MHz, CDCh) 8 7.46 (d, J = 7.6 Hz, 1H), 7.28 (td, J = 7.6, 1.5 Hz, 1H), 7.20 - 7.08 (m, 4H), 6.94 - 6.87 (m, 2H), 6.87 - 6.81 (m, 1H), 6.76 (t, J = 7.2 Hz, 1H), 6.61 (d, J = 8.0 Hz, 1H), 5.78 (s, 1H), 4.35 (s, 2H), 4.27 (s, 4H), 3.80 (s, 6H).

[0123] I-77: waxy; XH NMR (400 MHz, CDCh) 8 7.45 - 7.39 (m, 1H), 7.27 (td, J = 7.7, 1.6 Hz, 1H), 7.18 (td, J = 7.5, 1.1 Hz, 1H), 7.13 - 7.01 (m, 3H), 6.94 - 6.85 (m, 3H), 6.72 (t, J = 7.4 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.33 (s, 2H), 4.29 (s, 4H), 3.77 (s, 6H).

[0124] I-78: waxy; XH NMR (600 MHz, CDCh) 8 7.59 (d, J = 7.5 Hz, 1H), 7.38 -7.28 (m, 3H), 7.25 (td, J = 7.8, 1.7 Hz, 1H), 7.20 (dd, J = 7.5, 1.6 Hz, 1H), 7.17 - 7.09 (m, 3H), 6.97 (dd, J = 7.3, 1.6 Hz, 1H), 6.72 (td, J = 7.3, 1.2 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.29 (qd, J = 16.2, 4.3 Hz, 2H), 3.91 (s, 1H), 3.78 (s, 6H), 3.61 (q, J = 4.7 Hz, 4H), 3.33 (dd, J = 63.5, 13.7 Hz, 2H), 2.32 (s, 4H). Example 4

[0125] This example illustrates the synthesis of target compound I-41 according to Synthetic Route 2.

[0126] Step 1: Synthesis of intermediate 2'-bromo-5'-methyl-[1,1'-biphenyl]-2-amine (E-1) (D-1)                         (E-1)

[0127] (2-Aminophenyl)boronic acid pinacol ester (C-1) (131.5 mg, 0.6 mmol) and 4-bromo-3-iodotoluene (D-1) (231.6 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (4 mL). Under argon, tetrakis(triphenylphosphine)palladium(0) (34.7 mg, 0.03 mmol) was added, followed by aqueous potassium carbonate solution (2 mL, 1.5 mol / L). The mixture was heated at 100°C for 1 hour. After cooling, saturated brine was added and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were washed with brine, dried over NaaSO^ filtered, and concentrated to give 2'-bromo-5'-methyl-[1,1'-biphenyl]-2-amine (E-1).

[0128] Step 2: Synthesis of intermediate 2-(((2'-bromo-5'-methyl-[1,1'-biphenyl]-2- yl)amino)methyl)phenol (F-1) (E-1)                                                   (F-1)

[0129] 2'-Bromo-5'-methyl-[1,1'-biphenyl]-2-amine (E-1) (131.1 mg, 0.5 mmol) was dissolved in methanol (6 mL), and salicylaldehyde (91.6 mg, 0.75 mmol) was added. The mixture was stirred at room temperature for 0.5 hours until the starting material was completely consumed. Then, sodium borohydride (28.4 mg, 0.75 mmol) was slowly added, and stirring continued at room temperature for another 0.5 hours. After completion, the solvent was removed under reduced pressure to give 2-(((2'-bromo-5'-methyl-[1,1'-biphenyl]-2-yl)amino)methyl)phenol (F-1).

[0130] Step 3: Synthesis of target product I-41 (1-41)

[0131] 2-(((2'-Bromo-5'-methyl-[1,1'-biphenyl]-2-yl)amino)methyl)phenol (F-1) (184.2 mg, 0.5 mmol) was dissolved in 1,4-dioxane (6 mL), and cesium carbonate (244.3 mg, 0.75 mmol) and 2-(methylsulfonyl)-4,6-dimethoxypyrimidine (131.0 mg, 0.6 mmol) were added. The solution was heated to 110°C and stirred for 4 hours. After cooling, saturated brine was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over NaaSO^ filtered, and concentrated to give a crude product, which was purified by silica gel column chromatography [V(petroleum ether) / V(ethyl acetate) = 10 / 1] to afford light yellow waxy product I-41. Example 5

[0132] This example illustrates the synthesis of target compound I-70 according to Synthetic Route 2

[0133] Step 1: Synthesis of intermediate 2-(benzo[d]thiazol-7-yl)aniline (E-2)

[0134] (2-Aminophenyl)boronic acid (C-2) (82.8 mg, 0.6 mmol) and 7-bromobenzo[d]thiazole (D-2) (167.0 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (4 mL). Under argon, [1,1‘-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (22.0 mg, 0.03 mmol) was added, followed by aqueous potassium carbonate solution (2 mL, 1.5 mol / L). The mixture was heated at 100°C for 1 hour. After cooling, saturated brine was added and extracted with ethyl acetate (3 x 10 mL). The combined organic layers were dried over NaaSO4, filtered, and concentrated to give 2-(benzo[d]thiazol-7-yl)aniline (E-2).

[0135] Step 2: Synthesis of intermediate 2-(((2-(benzo[d]thiazol-7-yl)phenyl)amino)methyl)phenol (F-2) (E-2)                                                     (F-2)

[0136] 2-(Benzo[d]thiazol-7-yl)aniline (E-2) (113.2 mg, 0.5 mmol) was dissolved in methanol (6 mL), and salicylaldehyde (91.6 mg, 0.75 mmol) was added. The mixture was stirred at room temperature for 0.5 hours until the starting material was consumed. Then sodium borohydride (28.4 mg, 0.75 mmol) was slowly added, and stirring continued for another 0.5 hours. The solvent was removed under reduced pressure to give 2-(((2-(benzo[d]thiazol-7-yl)phenyl)amino)methyl)phenol (F-2).

[0137] Step 3: Synthesis of target product I-70 (F-2)                                                                           (1-70)

[0138] 2-(((2-(Benzo[d]thiazol-7-yl)phenyl)amino)methyl)phenol (F-2) (166.2 mg, 0.5 mmol) was dissolved in 1,4-dioxane (6 mL), and cesium carbonate (244.3 mg, 0.75 mmol) and 2-(methylsulfonyl)-4,6-dimethoxypyrimidine (131.0 mg, 0.6 mmol) were added. The solution was heated to 110°C for 4 hours. After work-up as above, the crude product was purified by silica gel column chromatography [V(petroleum ether) / V(ethyl acetate) = 10 / 1] to give light yellow waxy product I-70.

[0139] The synthesis of the following compounds can be carried out with reference to Examples 4 and 5, and detailed descriptions are omitted here.

[0140] Characterization data for compounds I-23, I-40 to I-42, I-46, I-51 to I-54, and I-65 to I-73 are as follows:

[0141] I-23: waxy; XH NMR (500 MHz, CDCh) 8 8.24 (dd, J = 8.0, 1.3 Hz, 1H), 7.65 (td, J = 7.5, 1.4 Hz, 1H), 7.56 (td, J = 7.7, 1.4 Hz, 1H), 7.39 (dd, J = 7.6, 1.6 Hz, 1H), 7.34 (dd, J = 7.5, 1.3 Hz, 1H), 7.25 (td, J = 7.7, 1.7 Hz, 1H), 7.24 - 7.17 (m, 1H), 26 7.15 (td, J = 7.5, 1.2 Hz, 1H), 7.08 (dd, J = 8.0, 1.2 Hz, 1H), 7.06 (dd, J = 7.5, 1.6 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.66 (dd, J = 8.3, 1.0 Hz, 1H), 5.76 (s, 1H), 4.30 (q, J = 15.6 Hz, 2H), 3.76 (s, 6H), 2.78 (s, 3H).

[0142] I-40: waxy; XH NMR (400 MHz, CDCh) 8 7.45 (dd, J = 7.6, 1.2 Hz, 1H), 7.31 - 7.23 (m, 3H), 7.21 - 7.07 (m, 4H), 6.99 (dd, J = 7.4, 1.5 Hz, 1H), 6.77 (td, J = 7.4, 0.9 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.78 (s, 1H), 4.35 (s, 2H), 3.80 (s, 6H), 2.50 (s, 3H).

[0143] I-41: waxy; XH NMR (400 MHz, CDCh) 8 7.55 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.27 (td, J = 7.7, 1.5 Hz, 1H), 7.21 - 7.09 (m, 4H), 7.04 (dd, J = 8.1, 1.8 Hz, 1H), 6.98 (dd, J = 7.4, 1.5 Hz, 1H), 6.75 (t, J = 7.4 Hz, 1H), 6.60 (d, J = 8.1 Hz, 1H), 5.77 (s, 1H), 4.35 (d, J = 1.9 Hz, 2H), 3.79 (s, 6H), 2.34 (s, 3H).

[0144] I—42: waxy; xr NMR (400 MHz, CDCL) 8 7.38 (dd, J = 8.1, 2.1 Hz, 1H), 7.36 - 7.32 (m, 2H), 7.27 (td, J = 7.7, 1.5 Hz, 1H), 7.21 - 7.08 (m, 4H), 6.93 (dd, J = 7.4, 1.5 Hz, 1H), 6.74 (t, J = 7.4 Hz, 1H), 6.61 (d, J = 8.1 Hz, 1H), 5.78 (s, 1H), 4.32 (s, 2H), 3.78 (s, 6H), 2.08 (s, 3H).

[0145] I-46: solid, m.p. 113.5-115.2°C; XH NMR (600 MHz, CDCh) 8 7.43 (t, J = 7.7 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.31 (d, J = 7.6 Hz, 1H), 7.27 (td, J = 7.7, 1.7 Hz, 1H), 7.18 (td, J = 7.6, 1.3 Hz, 1H), 7.15 - 7.11 (m, 3H), 6.94 (dd, J = 7.4, 1.6 Hz, 1H), 6.72 (td, J = 7.4, 1.1 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 5.79 (s, 1H), 4.34 (s, 2H), 3.79 (s, 6H), 2.59 (d, J = 2.5 Hz, 3H).

[0146] I-51: waxy; XH NMR (400 MHz, CDCh) 8 8.55 (d, J = 4.8 Hz, 1H), 7.75 (td, J = 7.9, 1.8 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.19 - 7.04 (m, 4H), 6.78 - 6.67 (m, 2H), 5.69 (s, 1H), 4.49 (s, 2H), 3.75 (s, 6H).

[0147] I-52: waxy; XH NMR (500 MHz, CDCh) 8 8.68 (d, J = 1.7 Hz, 1H), 8.57 (d, J = 4.7 Hz, 1H), 7.75 (dt, J = 7.8, 2.0 Hz, 1H), 7.39 (dd, J = 7.7, 1.6 Hz, 1H), 7.34 (dd, J = 7.8, 4.9 Hz, 1H), 7.28 (dd, J = 7.7, 1.7 Hz, 1H), 7.20 - 7.14 (m, 2H), 7.11 (dd, J = 8.0, 1.0 Hz, 1H), 7.04 (dd, J = 7.4, 1.7 Hz, 1H), 6.76 (t, J = 7.4 Hz, 1H), 6.64 (dd, J = 8.2, 1.1 Hz, 1H), 5.75 (s, 1H), 4.32 (s, 2H), 3.75 (s, 6H).

[0148] I-53: waxy; XH NMR (400 MHz, CDCh) 8 8.64 (d, J = 5.1 Hz, 2H), 7.44 (d, J = 5.4 Hz, 2H), 7.39 (dd, J = 7.5, 1.5 Hz, 1H), 7.29 (td, J = 7.8, 1.6 Hz, 1H), 7.23 - 7.16 (m, 2H), 7.12 (dd, J = 8.0, 1.1 Hz, 1H), 7.06 (dd, J = 7.5, 1.5 Hz, 1H), 6.77 (td, J = 7.4, 0.9 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 5.75 (s, 1H), 4.33 (s, 2H), 3.75 (s, 6H).

[0149] I-54: waxy; XH NMR (400 MHz, CDCh) 8 9.03 (dd, J = 4.8, 1.4 Hz, 1H), 7.88 (dd, J = 8.9, 1.3 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.47 (d, J = 7.5 Hz, 1H), 7.25 (td, J = 7.7, 1.5 Hz, 1H), 7.20 - 7.09 (m, 3H), 6.74 - 6.66 (m, 2H), 5.67 (s, 1H), 4.53 (s, 2H), 3.76 (s, 6H).

[0150] I-65: waxy; XH NMR (500 MHz, CDCh) 8 7.78 (dd, J = 8.1, 1.1 Hz, 1H), 7.76 (s, 1H), 7.29 (dd, J = 8.2, 7.2 Hz, 1H), 7.25 - 7.21 (m,2H), 7.21 - 7.16 (m, 1H), 7.14 - 7.05 (m, 4H), 6.74 (td, J = 7.4, 1.1 Hz, 1H), 6.64 (d, J = 8.1 Hz, 1H), 5.74 (s, 1H), 4.28 (s, 2H), 3.72 (s, 6H), 3.34 (s, 3H).

[0151] I-66: waxy; XH NMR (600 MHz, CDCh) 8 8.11 (s, 1H), 7.57 (dd, J = 7.9, 1.1 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 1H), 7.42 (dd, J = 7.4, 0.9 Hz, 1H), 7.24 (d, J = 7.6 Hz, 2H), 7.20 - 7.14 (m, 2H), 7.09 (d, J = 7.8 Hz, 1H), 6.81 (t, J = 7.3 Hz, 1H), 6.69 (d, J = 7.3 Hz, 1H), 5.74 (s, 1H), 4.36 (s, 2H), 3.76 (s, 6H).

[0152] I-67: waxy; XH NMR (500 MHz, CDCh) 8 8.11 (s, 1H), 7.79 - 7.74 (m, 1H), 7.46 - 7.40 (m, 3H), 7.29 - 7.24 (m, 1H), 7.23 - 7.14 (m, 3H), 7.13 - 7.06 (m, 1H), 6.80 (t, J = 7.5 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 5.73 (s, 1H), 4.34 (s, 2H), 3.74 (s, 6H).

[0153] I-68: waxy; XH NMR (500 MHz, CDCL) 8 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 7.46 (dd, J = 7.5, 1.7 Hz, 1H), 7.39 - 7.31 (m, 2H), 7.28 - 7.21 (m, 2H), 7.19 - 7.13 (m, 2H), 7.10 (d, J = 7.9 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 7.7 Hz, 1H), 5.74 (s, 1H), 4.35 (s, 2H), 3.77 (s, 6H), 2.64 (s, 3H).

[0154] I-69: waxy; XH NMR (400 MHz, CDCh) 8 9.02 (s, 1H), 8.03 - 7.91 (m, 1H), 7.62 - 7.41 (m, 3H), 7.25 - 7.12 (m, 4H), 7.08 (d, J = 7.9 Hz, 1H), 6.82 (td, J = 7.4, 0.7 Hz, 1H), 6.69 (d, J = 8.1 Hz, 1H), 5.75 (s, 1H), 4.33 (s, 2H), 3.77 (s, 6H).

[0155] I-70: waxy; XH NMR (400 MHz, CDCh) 8 9.01 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.59 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.5 Hz, 1H), 7.30 -7.16 (m, 3H), 7.16 (dd, J = 7.5, 1.0 Hz, 1H), 7.08 (dd, J = 8.0, 1.0 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.70 (d, J = 8.1 Hz, 1H), 5.73 (s, 1H), 4.31 (s, 2H), 3.74 (s, 6H).

[0156] I-71: waxy; XH NMR (400 MHz, CDCh) 8 7.62 (d, J = 2.1 Hz, 1H), 7.50 (d, J = 8.2 Hz, 1H), 7.36 (dt, J = 10.6, 5.3 Hz, 2H), 7.31 - 7.22 (m, 2H), 7.21 - 7.13 (m, 3H), 7.09 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.3 Hz, 1H), 6.73 - 6.63 (m, 2H), 5.74 (s, 1H), 4.32 (s, 2H), 3.75 (s, 6H).

[0157] I-72: waxy; XH NMR (400 MHz, CDCh) 8 7.89 (d, J = 8.0 Hz, 1H), 7.46 -7.38 (m, 2H), 7.37 - 7.32 (m, 2H), 7.28 - 7.23 (m, 1H), 7.21 - 7.13 (m, 4H), 7.10 (d, J = 8.0 Hz, 1H), 6.79 (t, J = 7.4 Hz, 1H), 6.66 (d, J = 8.1 Hz, 1H), 5.76 (s, 1H), 4.31 (s, 2H), 3.77 (s, 6H).

[0158] I-73: waxy; XH NMR (400 MHz, CDCh) 8 7.67 (d, J = 7.9 Hz, 1H), 7.34 -6.98 (m, 9H), 6.94 (d, J = 7.9 Hz, 1H), 6.63 (t, J = 7.4 Hz, 1H), 6.50 (d, J = 8.2 Hz, 1H), 5.59 (s, 1H), 4.16 (s, 2H), 3.61 (s, 6H). Example 6

[0159] This example illustrates the preparation method of target compound I-27.

[0160] The starting material methyl 2'-((2-((4,6-dimethoxypyrimidin-2- yl)oxy)benzyl)amino)-[1,1'-biphenyl]-4-carboxylate (I-26) was synthesized according to the method disclosed in Example 1.

[0161] Synthesis of target compound I-27.

[0162] Methyl 2'-((2-((4,6-dimethoxypyrimidin-2-yl)oxy)benzyl)amino)-[1,1'-biphenyl]-4-carboxylate (I-26) (287.1 mg, 0.6 mmol) was dissolved in a 1:1 (v / v) methanol / water solution (6 mL), and sodium hydroxide (120.0 mg, 3 mmol) was added. The solution was heated to 80°C and stirred for 1 hour. After cooling, saturated brine was added, and the mixture was extracted with ethyl acetate (3 x 10 mL). The aqueous layer was collected, concentrated under reduced pressure, and then 0.5 mol / L dilute hydrochloric acid was slowly added dropwise to precipitate a solid. The solid was filtered, washed with distilled water, and dried to give target compound I-27 as a light yellow waxy solid.

[0163] I-27: waxy; XH NMR (400 MHz, DMSO-*d*6) 8 8.00 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.3 Hz, 2H), 7.41 (dd, J = 7.4, 1.0 Hz, 1H), 7.30 (td, J = 7.7, 1.5 Hz, 1H), 7.22 (dd, J = 7.4, 0.7 Hz, 1H), 7.16 (dd, J = 7.9, 1.0 Hz, 1H), 7.00 (dd, J = 7.5, 1.4 Hz, 1H), 6.65 (t, J = 7.4 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 5.99 (s, 1H), 5.34 (s, 1H), 4.18 (d, J = 3.2 Hz, 2H), 3.74 (s, 6H).

[0164] Part 3: Performance Testing and Conclusions of the Compounds Example 7

[0165] This example illustrates the post-emergence herbicidal activity of the compounds of Formula (I) provided in the present disclosure.

[0166] Test agents: Compounds of Formula (I) provided in the present disclosure (see Table 3).

[0167] Test targets: barnyardgrass (Echinochloa crus-galli), crabgrass (Digitaria sanguinalis), velvetleaf (Abutilon theophrasti), redroot pigweed (Amaranthus retroflexus), and sicklepod (Senna obtusifolia).

[0168] Planting method: Test soil was prepared by mixing sand, silt, and clay at a mass ratio of 1:1:1, and homogenized as special test soil. Plastic pots with a diameter of 8 cm were filled with soil to three-quarters of the pot volume, and the pots were placed in a large stainless steel pan containing 5 cm deep water. After the soil was completely wetted, 10-15 seeds of the above target weeds were sown in each pot. After sowing, the seeds were covered with 0.2-0.5 cm of soil and placed in a greenhouse for cultivation. Water was replenished daily to maintain soil moisture at about 80% (relative humidity), with a growth temperature of 25±8°C and air humidity above 60%.

[0169] Application method: A greenhouse pot culture method was used. When the weeds reached the 2-leaf stage, post-emergence spray treatment was carried out. Each treatment had two replicates, and a blank control (distilled water) was set up. After spraying, the pots were left to stand indoors to allow the herbicide solution to be absorbed by the leaves, then transferred to the greenhouse for cultivation at 25±8°C.

[0170] Criteria for visual evaluation of herbicidal activity (Table 2). Table 2 Growth inhibition rate (%) Herbicidal activity evaluation 0 Same as control, no activity, no effect on target growth 0-30 Low activity, slight effect on target growth 30-60 Moderate activity, obvious effect on target growth 60-80 Good activity, can inhibit target growth 80-100 Particularly good activity, severely inhibits target growth 100 Particularly good activity, complete plant death

[0171] Survey method: The growth and response symptoms of weeds were observed regularly after treatment. At 21 days after treatment, the herbicidal activity was evaluated by visual inspection. The results are shown in Table 3. Table 3 Compoun d No. Inhibition rate (%) (2-leaf stage) Dosag e (g a.i / ha) Barnyardgras s Crabgras s Velvetlea f Redroot pigwee d Sicklepo d I-1 60 85 85 85 85 750 I-2 98 100 45 0 98 750 I-3 100 85 45 0 80 750 I-4 100 90 60 0 80 750 I-5 100 100 50 0 88 750 I-6 100 100 40 40 85 750 I-7 100 100 70 30 88 750 I-8 100 80 65 0 20 750 I-9 100 82 65 0 90 750 I-10 100 95 25 0 88 750 I-11 100 80 50 0 85 550 I-12 92 65 35 0 75 750 I-13 92 75 40 0 82 750 I-14 98 90 45 0 70 750 I-15 100 80 40 30 80 750 I-16 95 98 55 50 70 750 I-17 100 100 50 30 45 750 I-18 98 100 60 0 80 750 I-19 100 78 45 0 90 750 I-20 50 30 5 90 NT 750 I-21 95 95 40 100 NT 750 I-22 95 95 100 100 NT 750 I-23 95 98 55 100 NT 750 I-24 100 98 30 0 20 750 I-25 98 85 72 0 78 750 I-26 100 92 20 40 72 750 I-27 70 95 85 95 NT 750 I-28 90 90 65 100 65 750 I-29 85 90 65 100 65 750 I-30 90 88 65 100 65 750 I-31 85 88 65 100 65 750 I-32 85 88 65 100 65 750 I-33 80 88 40 100 65 750 I-34 90 92 65 100 65 750 I-35 80 88 40 90 60 750 I-36 85 88 50 100 65 750 I-37 85 90 65 100 75 750 I-38 90 90 65 100 65 750 I-39 85 85 65 100 60 750 I-40 85 88 65 100 60 750 I-41 90 95 65 100 70 750 I-42 85 95 50 100 65 750 I-43 90 85 55 0 68 750 I-44 100 90 65 10 70 750 I-45 95 90 40 0 68 750 I-46 95 40 60 100 40 750 I-47 100 85 60 100 60 750 I-48 92 98 55 100 NT 750 I-49 80 90 90 100 NT 750 I-50 75 100 70 100 NT 750 I-51 100 85 20 0 70 750 I-52 100 90 85 100 95 750 I-53 100 85 65 0 50 750 I-54 95 92 80 100 NT 750 I-55 90 65 20 0 68 750 I-56 90 65 40 0 90 750 I-57 100 100 75 80 98 750 I-58 95 20 60 70 85 750 I-59 100 85 75 0 80 750 I-60 70 85 70 70 NT 750 I-61 70 100 75 100 NT 750 I-62 100 95 70 100 NT 750 I-63 95 98 75 100 NT 750 I-64 88 92 55 100 NT 750 I-65 90 75 65 100 80 750 I-66 88 90 55 95 NT 750 I-67 NT NT NT NT NT 750 I-68 100 80 70 100 80 750 I-69 70 88 90 85 NT 750 I-70 70 100 85 100 NT 750 I-71 90 90 40 100 NT 750 I-72 90 90 40 100 NT 750 I-73 95 92 55 100 NT 750 I-74 65 95 55 50 NT 750 I-75 70 100 70 100 NT 750 I-76 70 100 75 50 NT 750 I-77 100 90 58 0 80 750 I-78 90 90 65 100 85 750

[0172] From Table 3, it can be seen that the compounds of Formula (I) generally exhibit strong post-emergence herbicidal activity, particularly against barnyardgrass, crabgrass, and redroot pigweed, indicating effective post-emergence control of grassy weeds and Amaranthaceae weeds. Among them, compound I-22 showed inhibition rates >95% against all four tested weed targets, not only effectively controlling grassy weeds and Amaranthaceae weeds but also achieving 100% control of velvetleaf. Compound I-52 was effective against all five weed targets, providing good control of grassy weeds and Amaranthaceae weeds, while also achieving 95% and 85% control of sicklepod and velvetleaf, respectively, demonstrating a broad herbicidal spectrum. Example 8

[0173] This example illustrates the pre-emergence herbicidal activity of the compounds of Formula (I) provided in the present disclosure.

[0174] Test agents: Compounds of Formula (I) provided in the present disclosure (see Table 4).

[0175] Test targets: barnyardgrass, crabgrass, velvetleaf, redroot pigweed, and sicklepod.

[0176] Planting method: Test soil was prepared by mixing sand, silt, and clay at a mass ratio of 1:1:1, and homogenized as special test soil. Plastic pots with a diameter of 8 cm were filled with soil to three-quarters of the pot volume, and the pots were placed in a large stainless steel pan containing 5 cm deep water. After the soil was completely wetted, seeds of the above target weeds were sown in each pot, ensuring 10-15 seeds per weed species, and covered with 0.2-0.5 cm of soil, then placed in a greenhouse for cultivation. The growth temperature was 25±8°C and air humidity was above 60%..

[0177] Application method: A greenhouse pot culture method was used. 24 hours after sowing, the test agents were applied to the soil surface. Each treatment had two replicates, and a blank control (distilled water) was set up. After soil treatment, the pots were transferred to the greenhouse for cultivation at 25±8°C.

[0178] Survey method: The growth and response symptoms of weeds were observed regularly after treatment. At 21 days after treatment, the herbicidal activity was evaluated by visual inspection. The results are shown in Table 4. Table 4: Compoun d No. Inhibition rate (%) (2-leaf stage) Dosag e (g a.i / ha) Barnyardgras s Crabgras s Velvetlea f Redroot pigwee d Sicklepo d I-1 30 80 30 15 30 750 I-2 60 90 70 95 35 750 I-3 65 90 75 0 30 750 I-4 85 87 72 90 55 750 I-5 90 92 72 0 50 750 I-6 60 90 72 0 35 750 I-7 88 90 75 92 50 750 I-8 30 87 70 0 50 750 I-9 40 92 72 55 48 750 I-10 65 90 75 0 45 750 I-11 55 87 68 0 40 550 I-12 65 92 75 0 40 750 I-13 65 87 80 0 30 750 I-14 55 87 70 92 30 750 I-15 55 87 60 88 30 750 I-16 60 90 60 90 40 750 I-17 55 92 65 95 30 750 I-18 60 90 78 92 30 750 I-19 80 92 80 0 45 750 I-20 20 20 15 70 25 750 I-21 85 90 65 95 35 750 I-22 45 85 60 100 40 750 I-23 45 75 65 100 30 750 I-24 70 87 20 0 45 750 I-25 55 90 78 0 40 750 I-26 50 90 72 0 35 750 I-27 30 55 75 85 NT 750 I-28 45 65 65 95 30 750 I-29 55 90 50 100 70 750 I-30 50 85 60 100 45 750 I-31 65 95 45 100 50 750 I-32 30 85 20 95 30 750 I-33 40 90 20 100 30 750 I-34 50 90 45 100 50 750 I-35 90 100 60 100 55 750 I-36 85 100 40 100 50 750 I-37 70 85 20 100 40 750 I-38 50 90 20 100 20 750 I-39 50 85 50 100 10 750 I-40 40 95 50 100 45 750 I-41 85 98 30 100 45 750 I-42 60 95 60 100 25 750 I-43 30 87 20 0 15 750 I-44 85 84 20 0 10 750 I-45 55 87 60 0 10 750 I-46 65 85 65 100 20 750 I-47 80 100 50 100 0 750 I-48 50 80 60 90 30 750 I-49 70 60 30 60 NT 750 I-50 20 55 20 70 NT 750 I-51 82 90 70 92 45 750 I-52 90 95 80 100 0 750 I-53 20 82 65 0 10 750 I-54 75 60 65 95 50 750 I-55 20 82 30 0 0 750 I-56 40 87 50 0 50 750 I-57 82 87 75 0 55 750 I-58 80 82 75 0 45 750 I-59 50 87 60 0 40 750 I-60 30 85 30 75 NT 750 I-61 40 75 30 75 NT 750 I-62 55 90 70 85 65 750 I-63 80 90 75 100 60 750 I-64 55 80 30 90 65 750 I-65 75 95 75 100 0 750 I-66 75 90 80 100 50 750 I-67 85 100 60 100 55 750 I-68 90 95 85 100 20 750 I-69 30 55 70 60 NT 750 I-70 20 60 75 85 NT 750 I-71 80 95 75 100 70 750 I-72 80 90 65 100 60 750 I-73 80 98 75 100 60 750 I-74 20 50 10 65 NT 750 I-75 30 55 20 70 NT 750 I-76 30 65 20 65 NT 750 I-77 60 87 65 0 40 750 I-78 70 90 40 100 40 750

[0179] From Table 4, it can be seen that the compounds of Formula (I) generally exhibit strong pre-emergence herbicidal activity, particularly against barnyardgrass, crabgrass, and redroot pigweed, indicating effective pre-emergence control of grassy weeds and Amaranthaceae weeds. Among them, compound I-35 showed inhibition rates >90% against three tested weed targets, effectively controlling grassy weeds and Amaranthaceae weeds. Compounds I-52 and I-68 not only effectively controlled grassy weeds and Amaranthaceae weeds with inhibition rates >90%, but also achieved 80% and 85% control of velvetleaf, respectively, demonstrating a broad herbicidal spectrum.

[0180] From Tables 3 and 4, it is evident that among the pyrimidine-biaryl compounds provided herein, some have excellent post-emergence herbicidal activity and can be used as post-emergence herbicides. Some compounds also have excellent pre-emergence herbicidal activity and can be used as pre-emergence herbicides. Certain compounds exhibit both excellent post-emergence and pre-emergence activities, and can be used as both pre- and post-emergence herbicides, providing a wider application window. Example 9

[0181] This example illustrates the dose-response tests for post-emergence and preemergence herbicidal activities of the compounds of Formula (I) provided in the present disclosure.

[0182] Test agents: Compounds of Formula (I) provided in the present disclosure (see Table 5).

[0183] Test targets: barnyardgrass and crabgrass.

[0184] Reference agents: Pretilachlor; AHAS inhibitor P: 2-((4,6-dimethoxypyrimidin-2-yl)oxy)benzoic acid.

[0185] Planting method: Post-emergence test same as Example 7; pre-emergence test same as Example 8.

[0186] Application method: Post-emergence test same as Example 7; pre-emergence test same as Example 8.

[0187] Survey method: The growth and response symptoms of weeds were observed regularly after treatment. At 21 days after treatment, the herbicidal activity was evaluated by visual inspection. The results are shown in Table 5. Table 5: Compound No. Dosage (g a.i / ha) Inhibition rate (%) (2-leaf stage) post-emergence pre-emergence Barnyardgrass Crabgrass Barnyardgrass Crabgrass I-2 187.5 85 70 NT NT 375 90 80 NT NT I-5 187.5 85 80 100 70 375 90 85 100 80 I-6 187.5 75 60 NT NT 375 80 70 NT NT I-7 187.5 75 70 NT NT 375 80 75 NT NT I-11 187.5 70 70 NT NT 375 70 80 NT NT I-17 187.5 75 60 NT NT 375 85 70 NT NT I-18 187.5 70 65 NT NT 375 80 85 NT NT I-24 187.5 75 75 NT NT 375 80 85 NT NT I-53 187.5 70 60 NT NT 375 85 70 NT NT I-57 187.5 70 70 NT NT 375 80 85 NT NT AHAS inhibitor P 187.5 85 85 100 85 375 90 90 100 95 pretilachlor 300 40 0 100 100

[0188] From Table 5, it can be seen that at a dosage of 375 g a.i / ha, most of the compounds of Formula (I) still exhibit good post-emergence herbicidal activity. When the dosage was reduced to 187.5 g a.i / ha, compounds I-2 and I-5 showed postemergence activity comparable to the reference AHAS inhibitor P, and superior to the commercial herbicide pretilachlor. The pre-emergence activity of I-5 was also tested, and it still showed good pre-emergence activity comparable to AHAS inhibitor P, while its activity against barnyardgrass was equivalent to that of pretilachlor, achieving 100% inhibition. Compound I-5 exhibits good both post-emergence and pre-emergence herbicidal activity and can be used as both a post-emergence and preemergence herbicide. For the control of the troublesome weed barnyardgrass, the compound provides a wider application window than pretilachlor.

[0189] The pyrimidine-biaryl compounds of the present disclosure can be used as active ingredients in herbicides. By adding various formulation adjuvants such as organic solvents, surfactants, carriers, etc., according to conventional pesticide formulation processing methods, they can be formulated into various formulations such as emulsions, granules, etc., for weed control in crops. Example 10

[0190] Emulsion concentrate

[0191] 5% of the pyrimidine-biaryl compound, 5% of agricultural emulsifier 500# (calcium salt), 5% of agricultural emulsifier 602#, 5% of N-methyl-2-pyrrolidone, and 80% of solvent oil 330# were heated and stirred uniformly to obtain an emulsion concentrate.

[0192] In field application, spray according to the dosages of the pyrimidine-biaryl compound as referenced in the examples. Example 11

[0193] Wettable powder

[0194] 10% of the pyrimidine-biaryl compound, 5% of magnesium lignosulfonate, 1% of fatty alcohol polyoxyethylene ether (JFC), 40% of diatomaceous earth, and 44% of light calcium carbonate were uniformly mixed and ground to obtain a wettable powder.

[0195] In field application, spray according to the dosages of the pyrimidine-biaryl compound as referenced in the examples.

Claims

1. A pyrimidine-biaryl compound having a structural formula as shown inFormula (I):wherein:in Formula (I), Ar is selected from any one of Ar1 to Ar31 as shown below:H3Ar17Ar25Ar29OAr30Ri is hydrogen, halogen, amino, hydroxy, cyano, trifluoromethyl, methoxy, methylthio, methylsulfinyl, methylsulfonyl or C1-C2 alkyl;R2 is hydrogen, halogen, amino, methoxy or C1-C2 alkyl;R3 is hydrogen, halogen, C1-C2 alkyl, C1-C2 alkoxy, acetyl, benzoyl, carboxy or methoxycarbonyl;R4 is hydrogen, halogen, methoxy or C1-C2 alkyl; andRs is hydrogen or fluoro.

2. The compound of claim 1, wherein the halogen is fluoro, chloro, or bromo; the C1-C2 alkyl is methyl (Me, CH3) or ethyl (Et, C2H5); and the C1-C2 alkoxy is methoxy (MeO, CH3O) or ethoxy (EtO, C2H5O).

3. A method for preparing the pyrimidine-biaryl compound of claim 1, the method comprising a synthetic route 1 or a synthetic route 2 as set forth below:synthetic route 1:(B)wherein in Formula (B), LG1 represents a boron-containing substituent;synthetic route 2:wherein in Formula (C), LG2 represents a boron-containing substituent; and inFormula (D), X2 represents a leaving group.

4. The method of claim 3, wherein the synthetic route 1 comprises: reacting an intermediate of Formula (A) with a compound of Formula (B) in the presence of potassium carbonate and a palladium catalyst in a solvent, at a molar ratio of 1:1.3:6:0.05, at a temperature of 100°C for 1 hour, to obtain a crude reaction product; and purifying the crude reaction product by silica gel column chromatography to obtain the compound of Formula (I).

5. The method of claim 3, wherein the synthetic route 2 comprises:a) reacting a compound of Formula (C) with a compound of Formula(D) in the presence of sodium carbonate and a palladium catalyst in a solvent,at a molar ratio of 1:1.3:5:0.05, at 100°C for 1 hour, to obtain a compound of Formula (E);b) reacting the compound of Formula (E) with salicylaldehyde in methanol at room temperature for 0.5 hour, followed by addition of sodium borohydride and continuing the reaction at room temperature for 0.5 hour, to obtain a compound of Formula (F); wherein the molar ratio of the compound of Formula (E), salicylaldehyde, and sodium borohydride is 1:1.5:1.5; andc) reacting the compound of Formula (F) with 2-(methylsulfonyl)-4,6-dimethoxypyrimidine in the presence of cesium carbonate in 1,4-dioxane, at a molar ratio of 1:1.2:1.5, at 110°C for 4 hours, to obtain a crude product;purifying the crude product by silica gel column chromatography to obtain the compound of Formula (I).

6. A herbicidal composition, comprising a herbicidally effective amount of the pyrimidine-biaryl compound of claim 1 and at least one formulation adjuvant.

7. A method for preparing a herbicidal composition, comprising mixing a herbicidally effective amount of the pyrimidine-biaryl compound of claim 1 with at least one formulation adjuvant.

8. Use of the pyrimidine-biaryl compound of claim 1 as an agrochemical herbicide.

9. A method for controlling weeds, comprising applying a herbicidally effective amount of the pyrimidine-biaryl compound of claim 1 to leaves of the weeds at a pre-emergence or post-emergence stage; where the weeds are selected from the group consisting of barnyardgrass, crabgrass, redroot pigweed, velvetleaf, and sicklepod.