Novel aryl heterocyclic compounds, processes for their preparation and uses thereof

Abstract

This invention discloses aryl heterocyclic compounds containing substituted unsaturated hydrocarbons, their preparation methods, and uses. The compounds have the chemical structure shown in Formula I. The compounds of this invention are used as insecticides, showing particularly good control efficacy against armyworms, diamondback moths, cotton bollworms, corn borers, and rice leaf rollers, and are expected to become novel insecticides.

Description

Technical Field

[0001] This invention relates to the field of pesticide science; more specifically, it relates to novel arylpyrazole compounds, their preparation methods and uses as insecticides, and methods and applications of using these compounds and their combinations in the control of pests in agricultural, forestry, and horticultural environments. Background Technology

[0002] Agricultural production is of paramount importance to human survival and development. Natural disasters and pests / diseases are two major factors causing agricultural losses. Agricultural pests reduce food yields by feeding on plant fruits, stems, and leaves, causing mechanical damage, absorbing plant nutrients, affecting photosynthesis, and spreading plant diseases. According to data from the Food and Agriculture Organization of the United Nations, losses to food crops alone amount to at least $70 billion annually. Furthermore, pests also cause serious damage to food storage, forestry and horticulture, cargo storage, power equipment, and public health. Among existing pest control methods, pesticides play a crucial role, especially chemical pesticides, which are the most convenient, economical, and rapid-acting method in integrated pest management.

[0003] my country is a major producer and consumer of pesticides. Insecticides account for approximately 40% of the pesticides consumed annually in my country, based on sales revenue. Currently, with the high-intensity and prolonged use of single-variety insecticides, insects are gradually developing resistance to most existing commercial insecticides. At the same time, climate change will increase the risk of pests spreading in agricultural and forestry ecosystems, especially in cold Arctic, northern, temperate, and subtropical regions. Pests such as the fall armyworm have already spread due to global warming. Therefore, the demand for green, highly effective, low-toxicity insecticides with novel modes of action is increasingly urgent.

[0004] o-Diamide insecticides are a novel class of insecticides that target ryanodine receptors in insects, exhibiting good control efficacy against lepidopteran and coleopteran pests. Insect ryanodine receptors differ significantly from those in mammals and fish, thus these insecticides have low toxicity to fish and mammals. WO200170671 (DuPont, USA) discloses a class of insecticidal o-diamide compounds, among which compound DP possesses excellent stomach poison activity and some contact activity, showing good control efficacy against lepidopteran insects, with particularly excellent effects on eggs and larvae. It has been developed into a commercial insecticide, with the common name chlorantraniliprole.

[0005]

[0006] DuPont has filed numerous patents for these compounds to protect their structures. Bayer, Syngenta, and other agrochemical companies have followed suit, filing a series of patents. Therefore, research and development of novel o-diamide compounds has become a key focus in the agrochemical field for the past decade or so. Developing highly efficient, broad-spectrum, low-toxicity, and structurally novel o-diamide insecticides is of great significance for the development of pesticide creation in my country and for competing for a leading position in pesticide innovation.

[0007] Furthermore, with prolonged use, resistance to o-diamid insecticides has become increasingly serious. Resistance to the diamondback moth has been reported in the Philippines, Brazil, and in Zhejiang and Yunnan provinces of my country. Bromnipotentiamide, chlorfenapyr, and tetrachlorantraniliprole all exhibit cross-resistance with chlorantraniliprole.

[0008] In summary, insecticides that act on insect ryanodine receptors exhibit high species selectivity and are suitable pesticide targets. However, given the issue of resistance, these pesticides require continuous innovation to reduce the emergence of cross-resistance. Summary of the Invention

[0009] The purpose of this invention is to develop a class of compounds containing arylpyrazole structures with substituted unsaturated hydrocarbons. These compounds break through the framework of previous diamide insecticide patents and, through certain chemical modifications, achieve good biological activity. They can serve as a novel, highly efficient, low-toxicity, and environmentally compatible chemical insecticide.

[0010] The compounds of this invention are used as insecticides, and are particularly effective against lepidopteran pests such as armyworms, diamondback moths, cotton bollworms, corn borers, and rice leaf rollers, and are expected to become novel insecticides.

[0011] In a first aspect, the present invention provides a compound having the structure shown in general formula (I), an optical isomer, a cis-trans isomer, or a pesticide-acceptable salt thereof.

[0012] I

[0013] In the formula,

[0014] A is an independent substituted carbon-carbon double bond or a substituted carbon-carbon triple bond, wherein the substituent is selected from: hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkylthio, cyano, nitro, carboxyl, C 1-4 alkyl carbonyl, C 1-4 alkoxycarbonyl;

[0015] m and n are independently 0 or 1, where m + n = 1 or 2;

[0016] B is independently selected from: 5- or 6-membered heteroaromatic rings or aromatic rings, 8, 9, or 10-membered fused heterobicyclic rings, wherein each ring of the heteroaromatic ring or aromatic ring or fused heterobicyclic ring is optionally divided by 1-4 R 2 replace;

[0017] V is selected from: -CH2-, -C(O)-, -NR 7 C(O)-、-NR 7 C(S)-、-NR 7 S(O)2-、-C(O)NR 7 -、-C(S)NR 7 -or none;

[0018] W is selected from: -CH2-, -C(O)-, -C(OH)-, -S-, -S(O-), -S(O)2-, -C(O)O-, -C(O)NR 8 -、-C(S)NR 8 -、-S(O)2NR 8 - Halogenated or absent;

[0019] R 1 R 2 R 8 Independently selected from the group consisting of: hydrogen, halogen (including F, Cl, Br or I), hydroxyl, mercapto, nitro, carboxyl, cyano, substituted or unsubstituted C. 1-8 Alkyl, substituted or unsubstituted C 1-8 Halogenated alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Halogenated alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 1-8 Haloalkylthio, substituted or unsubstituted C 1-8 Alkylamine group, substituted or unsubstituted C 1-8 Dialkylamine group, substituted or unsubstituted C 1-8 Halogenated alkylamine group, substituted or unsubstituted C 1-8 Halogenated dialkylamine, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 Haloalkenyl, substituted or unsubstituted C 2-8 Alkenyl group, substituted or unsubstituted C 2-8 Alkyne group, substituted or unsubstituted C 5-7 Cycloalkenyl, substituted or unsubstituted C 1-8 Alkyl thionyl, substituted or unsubstituted C 1-8 thionylalkyl, substituted or unsubstituted C 1-8 alkylsulfonyl, substituted or unsubstituted C1-8 sulfonylalkyl, substituted or unsubstituted C 2-8 Alkyl carbonyl, substituted or unsubstituted C 2-8 Carbonyl alkyl, substituted or unsubstituted C 2-8 alkoxycarbonyl, substituted or unsubstituted C 2-8 Carbonylalkoxy, substituted or unsubstituted C 2-8 Alkylamine carbonyl, substituted or unsubstituted C 2-8 Carbonyl alkylamine, substituted or unsubstituted C 2-8 Alkylamine thiocarbonyl, substituted or unsubstituted C 2-8 Thiocarbonyl alkylamine, substituted or unsubstituted C 3-6 Cycloalkoxy, substituted or unsubstituted C 3-6 Cycloalkylamino, substituted or unsubstituted (C 1-4 Alkyl)C 3-6 Cycloalkylamino, substituted or unsubstituted C 3-6 Trialkylsilyl, substituted or unsubstituted C 2-6 Phosphate group, substituted or unsubstituted C 2-6 Boron ester group, substituted or unsubstituted 5-7 membered non-aromatic heterocyclic group, substituted or unsubstituted phenyl group, substituted or unsubstituted benzyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted azoaryl group, substituted or unsubstituted phenoxy group, substituted or unsubstituted 5- or 6-membered heteroaromatic ring or aromatic ring, substituted or unsubstituted 8, 9 or 10-membered fused heterobicyclic system;

[0020] Where R 1 R 2 and R 8 The substituents are independently selected from: hydrogen, halogen, hydroxyl, mercapto, cyano, nitro, oxo (=O), C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Dialkylamine, C3-C6 cycloalkyl, C 2-6 alkenyl, C 2-6 Haloalkenyl, C 2-6 alkenyloxy group, C 2-6 alkynyl group, C 5-7 Cycloalkenyl, C 1-6 alkyl thionyl, C 1-6 thionylalkyl, C 1-6 alkylsulfonyl, C 1-6 sulfonylalkyl, C 2-6 alkyl carbonyl, C 2-6 carbonyl alkyl, C 2-6 alkoxycarbonyl, C2-6 carbonylalkoxy, C 2-6 amino carbonyl, C 2-6 carbonyl alkylamine group, C 2-6 alkylamine thiocarbonyl, C 2-6 Thiocarbonyl alkylamine group, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, (C 1-4 Alkyl)C 3-6 Alkylamino, C 3-6 Trialkylsilyl, C 2-6 Phosphate group, C 2-6 Boronyl ester, phenyl, benzyl, benzoyl, azoaryl, phenoxy, 5- or 6-membered heteroaryl ring or aromatic ring, 8-, 9- or 10-membered fused heterobicyclic ring;

[0021] R 3 Independently selected from the group consisting of: hydrogen, halogen, hydroxyl, mercapto, nitro, carboxyl, cyano, aldehyde, amino, substituted or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 Halogenated alkylamine group, substituted or unsubstituted C 2-6 Dialkylamino, substituted or unsubstituted C 2-6 Halogenated dialkylamino, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Haloalkylthio, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkenyl group, substituted or unsubstituted C 2-6 Haloalkenyl, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted C 2-6 Alkenyl group, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 1-6 Alkyl thionyl, substituted or unsubstituted C 1-6 thionylalkyl, substituted or unsubstituted C 1-6 alkylsulfonyl, substituted or unsubstituted C 1-6 sulfonylalkyl, substituted or unsubstituted C 2-6 Alkyl carbonyl, substituted or unsubstituted C 2-6 Carbonyl alkyl, substituted or unsubstituted C 2-6 alkoxycarbonyl, substituted or unsubstituted C 2-6 Carbonylalkoxy, substituted or unsubstituted C2-6 Alkylamine carbonyl, substituted or unsubstituted C 2-6 Carbonyl alkylamine, substituted or unsubstituted C 2-6 Alkylamine thiocarbonyl, substituted or unsubstituted C 2-6 Thiocarbonyl alkylamine, substituted or unsubstituted C 3-6 Cycloalkoxy, substituted or unsubstituted C 3-6 Cycloalkylamino, substituted or unsubstituted (C 1-4 Alkyl)C 3-6 Cycloalkylamino, substituted or unsubstituted C 3-6 Trialkylsilyl, substituted or unsubstituted C 2-6 Phosphate group, substituted or unsubstituted C 2-6 Boron ester group, substituted or unsubstituted 5-7 membered non-aromatic heterocyclic group, substituted or unsubstituted phenyl group, substituted or unsubstituted benzyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted azoaryl group, substituted or unsubstituted phenoxy group, substituted or unsubstituted 5- or 6-membered heteroaromatic ring or aromatic ring, substituted or unsubstituted 8-, 9- or 10-membered fused heterobicyclic ring; wherein R 3 The substituents on it are one or more R 5 ;

[0022] p is 0-4, preferably 1-3, and more preferably an integer of 2;

[0023] R 5 Selected from: halogen, hydroxyl, mercapto, nitro, carboxyl, cyano, aldehyde, amino, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 alkylamine group, C 1-4 Haloalkylamine group, C 2-6 Dialkylamino, C 2-6 Halogenated dialkylamino, C 1-4 Alkylthio, C 1-4 Haloalkylthio group, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkenyloxy group, C 2-6 Haloalkenyl, C 2-6 alkenyloxy group, C 2-4 alkynyl group, C 1-4 alkyl thionyl, C 1-4 alkylsulfonyl, C 2-4 alkyl carbonyl, C 2-4 alkoxycarbonyl, C 2-4 Alkylaminocarbonyl, C 3-6 Dialkylaminocarbonyl, C2-4 alkylamine thiocarbonyl, C 3-6 Cycloalkoxy, C 3-6 Cycloalkylamino, (C 1-4 Alkyl)C 3-6 Cycloalkylamino, C 3-6 Trialkylsilyl, 5-7 membered non-aromatic heterocyclic groups.

[0024] R 7 Selected from: substituted or unsubstituted C 1-6 Halogenated alkyl, substituted or unsubstituted C 1-6 Alkoxy, substituted or unsubstituted C 1-6 Halogenated alkoxy, substituted or unsubstituted C 1-6 Alkylamine group, substituted or unsubstituted C 1-6 Halogenated alkylamine group, substituted or unsubstituted C 2-6 Dialkylamino, substituted or unsubstituted C 2-6 Halogenated dialkylamino, substituted or unsubstituted C 1-6 alkylthio, substituted or unsubstituted C 1-6 Haloalkylthio, substituted or unsubstituted C 3-6 cycloalkyl, substituted or unsubstituted halogenated C 3-6 cycloalkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkenyl group, substituted or unsubstituted C 2-6 Haloalkenyl, substituted or unsubstituted C 2-6 Alkenyl group, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 2-6 Alkyl carbonyl, substituted or unsubstituted C 2-6 alkoxycarbonyl, substituted or unsubstituted C 2-6 Alkylamine carbonyl, substituted or unsubstituted C 2-6 Alkylamine thiocarbonyl, substituted or unsubstituted C 3-6 Cycloalkoxy, substituted or unsubstituted C 3-6 Cycloalkylamino, substituted or unsubstituted (C 1-4 Alkyl)C 3-6 Cycloalkylamino, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 4-8 membered heteroaryl or 4-8 membered heterocyclic group.

[0025] In a specific implementation, A is selected from the structure shown in Formula II.

[0026] II

[0027] The double bond in the formula can be in either cis or trans conformation;

[0028] R10 R 11 Independently selected from: hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 1-4 Haloalkylthio, cyano, nitro, carboxyl, C 1-4 alkyl carbonyl, C 1-4 alkoxycarbonyl, C 1-4 Alkylaminocarbonyl group.

[0029] In a preferred embodiment, B is selected from the 5- or 6-membered aromatic heterocyclic structures B-1, B-2, B-3, B-4, and B-5 shown below, and each B may optionally contain one or more R. 2 Substituent substitution.

[0030]

[0031] B 1 Selected from O, S, or NR 2 ;

[0032] B 2 B 3 B 4 B 5 Each is selected from N or CR 2 ;

[0033] In the formula, R 2 As stated above.

[0034] In specific embodiments, the compound of formula I has the structures shown in formulas Ia, Ib, and Ic:

[0035]

[0036] in,

[0037] V is selected from: -NHC(O)-, -NHC(S)-, -NHS(O)2-, -C(O)NH-, -C(S)NH- or none;

[0038] W is selected from: -CH2-, -C(O)-, -C(OH)-, -S-, -S(O-), -S(O)2-, -C(O)O-, -C(O)NR 8 -、-C(S)NR 8 -、-S(O)2NR 8 - Halogenated or absent;

[0039] R 1 R 3 R8 R 10 R 11 As mentioned above, B, p, R 12 R 13 With R 10 With R 11 The definitions are the same.

[0040] In specific embodiments, the compound has a structure as shown in formulas Id, Ie, and If.

[0041]

[0042] In the formula, R 3 B, R 8 R 10 R 11 R 12 R 13 As defined above;

[0043] X and Y are independently selected from O or S;

[0044] R 9 Independently selected from: hydrogen, hydroxyl, mercapto, carboxyl, cyano, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Halogenated alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Halogenated alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 1-8 Haloalkylthio, substituted or unsubstituted C 1-8 Alkylamine group, substituted or unsubstituted C 1-8 Dialkylamine group, substituted or unsubstituted C 1-8 Halogenated alkylamine group, substituted or unsubstituted C 1-8 Halogenated dialkylamine, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 Alkenyl group, substituted or unsubstituted C 2-8 Alkyne group, substituted or unsubstituted C 5-7 Cycloalkenyl, substituted or unsubstituted C 1-8 Alkyl thionyl, substituted or unsubstituted C 1-8 thionylalkyl, substituted or unsubstituted C 1-8 alkylsulfonyl, substituted or unsubstituted C 1-8 sulfonylalkyl, substituted or unsubstituted C 2-8 Alkyl carbonyl, substituted or unsubstituted C 2-8 Carbonyl alkyl, substituted or unsubstituted C2-8 alkoxycarbonyl, substituted or unsubstituted C 2-8 Carbonylalkoxy, substituted or unsubstituted C 2-8 Alkylamine carbonyl, substituted or unsubstituted C 2-8 Carbonyl alkylamine, substituted or unsubstituted C 2-8 Alkylamine thiocarbonyl, substituted or unsubstituted C 2-8 Thiocarbonyl alkylamine, substituted or unsubstituted C 3-6 Cycloalkoxy, substituted or unsubstituted C 3-6 Cycloalkylamino, substituted or unsubstituted (C 1-4 Alkyl)cycloalkylamino, substituted or unsubstituted C 3-6 Trialkylsilyl, substituted or unsubstituted C 2-6 Phosphate group, substituted or unsubstituted C 2-6 Boron ester group, substituted or unsubstituted 5-7 membered non-aromatic heterocyclic group, substituted or unsubstituted phenyl group, substituted or unsubstituted benzyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted azo aryl group, substituted or unsubstituted phenoxy group, substituted or unsubstituted 5- or 6-membered heteroaromatic ring or aromatic ring, substituted or unsubstituted 8-, 9- or 10-membered fused heterobicyclic system;

[0045] Where R 8 R 9 The substituents on the group are independently selected from: hydrogen, halogen, hydroxyl, mercapto, cyano, nitro, oxo (=O), C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Alkoxy, C 1-6 Alkylthio, C 1-6 alkylamine group, C 1-6 Dialkylamine group, C 3-6 cycloalkyl, C 2-6 alkenyl, C 2-8 Haloalkenyl, C 2-6 alkenyloxy group, C 2-6 alkynyl group, C 5-7 Cycloalkenyl, C 1-6 alkyl thionyl, C 1-6 thionylalkyl, C 1-6 alkylsulfonyl, C 1-6 sulfonylalkyl, C 2-6 alkyl carbonyl, C 2-6 carbonyl alkyl, C 2-6 alkoxycarbonyl, C 2-6 carbonylalkoxy, C 2-6 alkylamine carbonyl, C 2-6 carbonyl alkylamine group, C 2-6 alkylamine thiocarbonyl, C 2-6Thiocarbonyl alkylamine group, C 3-6 Cycloalkoxy; C 3-6 Cycloalkylamino, (C 1-4 Alkyl)C 3-6 Cycloalkylamino, C 3-6 Trialkylsilyl, C 2-6 Phosphate group, C 2-6 Boronyl ester, phenyl, benzyl, benzoyl, azoaryl, phenoxy, 5- or 6-membered heteroaryl ring or aromatic ring, 8-, 9- or 10-membered fused heterobicyclic ring;

[0046] Or, R 8 R 9 They can combine with the nitrogen they are attached to to form U;

[0047] U is a ring consisting of 2-6 carbon atoms, or optionally an additional nitrogen, sulfur, or oxygen atom, in addition to the bonded nitrogen atom, and optionally surrounded by 1-4 atoms selected from C. 1-3 Alkyl, halogen, cyano, nitro and C 1-3 Substitution of alkoxy groups.

[0048] In a specific embodiment, the 5- or 6-membered heteroaromatic ring is a group selected from the group consisting of a group that is connected to the main body of the compound through any connection point thereon and optionally bounded by 1-3 R groups. 2 Substituent substitution:

[0049] ;

[0050] Alternatively, the 5-7 membered non-aromatic heterocyclic group may optionally contain one or two 5- or 6-non-aromatic heterocycles selected from C(=O), S(=O), or S(=O)2, and this group may optionally be substituted by 1-4 substituents selected from the group consisting of: C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 cycloalkyl, halogen, cyano, nitro;

[0051] More preferably, the group is selected from the group consisting of any connection point thereon, and when selected from D-24 to D-31, D34, D35, Q is selected from O, S, NH, N(C) 1-2 alkyl):

[0052] .

[0053] In specific embodiments, the compounds of formulas Id, Ie, and If have structures as shown in formulas Ig and Ih:

[0054]

[0055] In the formula, X and Y are selected from O or S;

[0056] Z is selected from N and CR. 6 ;

[0057] p, R 2 R 3 R 8 R 9 R 10 R 11 R 12 R 13 As stated above;

[0058] R 4 R 6 As mentioned above.

[0059] In a specific implementation, R 2 Selected from the following groups: hydrogen, halogens, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Haloalkylthio group, C 2-4 alkenyl, C 2-4 Haloalkenyl, C1-C23, D1-D35;

[0060] R 3 R 4 Independently selected from the following groups: hydrogen, halogen, nitro, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 Haloalkenyl, C 3-6 Trialkylsilyl;

[0061] R 6 Selected from the following groups: hydrogen, halogen, nitro, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 Haloalkenyl, C 3-6 Trialkylsilyl;

[0062] R 8 R 9 Independently selected from the group consisting of: hydrogen, optionally substituted C. 1-6 Alkyl, optionally substituted C 1-6 Haloalkyl, C1-6 Alkoxy, optional substituted C 1-6 Halogenated alkoxy groups, optionally substituted C 1-6 Alkylthio, optional substituted C 1-6 Haloalkylthio group, optional substituted C 1-6 Alkylamine group, optionally substituted C 1-6 Dialkylamine group, optionally substituted C 1-6 Haloalkylamine group, optionally substituted C 3-6 cycloalkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 Haloalkenyl, optional substituted C 2-6 Alkyl carbonyl, optionally substituted C 2-6 Carbonyl alkyl, optionally substituted C 2-6 alkoxycarbonyl, optionally substituted C 2-6 Carbonylalkoxy, optionally substituted C 2-6 Alkylamine carbonyl, optionally substituted C 2-6 Carbonyl alkylamine group, optionally substituted C 2-6 Alkylamine thiocarbonyl, optionally substituted C 2-6 Thiocarbonyl alkylamine group, optionally substituted C 3-6 Cycloalkoxy, optionally substituted C 3-6 Cycloalkylamino, optionally substituted C1-23, optionally substituted D1-35, optionally substituted phenyl, optionally substituted benzyl, wherein the substituent is selected from: hydrogen, halogen, hydroxyl, oxo (=O), C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Alkoxy, C 1-4 Alkylthio, C 1-6 alkylamine group, C 3-6 cycloalkyl, C 2-6 alkenyl, or R 8 R 9 They can form U together with the nitrogen atoms they are attached to, where U is a ring consisting of 2-5 carbon atoms or optionally an additional nitrogen, sulfur, or oxygen atom in addition to the attached nitrogen atom, the ring optionally being bounded by 1-3 atoms selected from C. 1-3 Alkyl, halogen, cyano and C 1-3 Substitution of alkoxy groups;

[0063] R 10 R 11 R 12 R 13 Independently selected from: hydrogen, halogen, methyl, ethyl, cyano, trifluoromethyl, difluoromethyl, trifluoromethylthio, trifluoromethoxy.

[0064] In specific embodiments, the compounds of formulas Ig and Ih have structures as shown in formulas Ii and Ij:

[0065]

[0066] R 3 Selected from the following groups: hydrogen, halogen, nitro, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 Haloalkenyl, C 3-6 Trialkylsilyl;

[0067] R 8 R 9 As stated above;

[0068] R 10 R 11 R 12 R 13 Independently selected from: hydrogen, halogen, methyl, cyano, trifluoromethyl, difluoromethyl.

[0069] In a preferred embodiment, the compound is selected from the group consisting of (e.g., 1-1 represents compound No. 1 in Table 1): 4-1, 4-2, 4-12, 4-22, 4-179, 4-42, 4-52, 4-62, 4-72, 4-82, 5-1, 5-4, 5-14, 5-24, 5-39, 5-180, 5-54, 5-64, 5-74, 5-84.

[0070] In a second aspect, the present invention provides a pesticide composition comprising (1) 0.001-99.99 wt% of the compound of the first aspect, an optical isomer, a cis-trans isomer, or a pesticide-acceptable salt thereof, of the total weight of the pesticide composition; and (2) a pesticide-acceptable carrier or excipient.

[0071] In a preferred embodiment, the agricultural composition is a solution, emulsion, suspension, powder, foam, paste, granule; aerosol, natural and synthetic materials impregnated with active substances, microcapsules in polymers, seed coating compounds, preparations for use with combustion devices (e.g., smoke tubes, smoke cans and smoke trays), ULV cold or hot fog preparations; or the agricultural composition further comprises and (3) other active compounds selected from the group consisting of: insecticides, compound baits, fungicides, acaricides, nematicides, fungicides, and growth regulators.

[0072] In a preferred embodiment, it is used to kill or prevent agricultural pests, sanitary pests, and pests that endanger animal health; or it is used as an insecticide composition for killing or preventing agricultural pests, sanitary pests, and pests that endanger animal health.

[0073] In a preferred embodiment, the compound described in the first aspect, its optical isomer, cis-trans isomer, or a pesticide composition described in the second aspect may be applied to the environment, soil, or agricultural, forestry, and horticultural plants requiring control.

[0074] In a preferred embodiment, the pests are selected from: cotton bollworm, Asian corn borer, rice leaf roller, diamondback moth, and armyworm.

[0075] In a third aspect, the present invention provides a method for preparing the compound described in the first aspect, the synthesis method comprising the following steps:

[0076] Under catalytically alkaline, Lewis acid, or neutral conditions, at -40 to 60°C in a polar aprotic solvent, compound (a) is reacted with compound (b), (c), or (d) to obtain a compound having the characteristic structure of the above-described compound (Iaj).

[0077] (a) (b) (c) (d)

[0078] In the formula, R 1 R 3 R 10 As defined above, EWG is defined as an electron-withdrawing group, and R... 10 R 1 W and Ar are defined as aromatic rings or aromatic heterocycles.

[0079] In a preferred embodiment, the specific steps of the method are as follows:

[0080] In tetrahydrofuran, in the presence of a catalytic amount of base, at 0-30°C, the following reaction is carried out for 2-24 hours to obtain the compound of formula (A):

[0081] (Iaj);

[0082] In dichloromethane, the following reaction is carried out at -20 to 30°C for 2 to 24 hours to obtain the compound of formula (A):

[0083] (Iaj);

[0084] In dichloromethane, in the presence of a catalytic amount of base, at 0-30°C, the following reaction is carried out for 2-24 hours to obtain the compound of formula (A):

[0085] (Iaj).

[0086] It should be understood that, within the scope of this invention, the above-described technical features of this invention and the technical features specifically described below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be described in detail here. Detailed Implementation

[0087] The inventors of this application, through extensive and in-depth research, have developed a series of arylpyrazole compounds containing substituted unsaturated hydrocarbons. These compounds possess insecticidal activity, exhibiting significant inhibitory effects against armyworms and diamondback moths, and also demonstrating good insecticidal activity against armyworms, diamondback moths, cotton bollworms, corn borers, and rice leaf rollers. They can be used as pesticides in agricultural production. This invention was completed based on these findings.

[0088] the term

[0089] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0090] The term "halogenated" refers to a group that is substituted by one or more of the same or different halogen atoms described above, such as difluoromethyl, pentachloroethyl, heptafluoroisopropyl, or similar groups.

[0091] Term "C" 1-8 "" refers to having 1, 2, 3, 4, 5, 6, 7, or 8 ring atoms, and so on. "4-8 rings" refers to having 4-8 ring atoms, and so on. The term "C" 1-8 "Alkyl" refers to a straight-chain or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, isopropyl, tert-butyl, or similar groups. The term "C"... 2-8 "Alkenyl" refers to a straight-chain or branched alkenyl group having 2-8 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups. The term "C"... 2-8 "Alynyl" refers to a straight-chain or branched alkynyl group having 2-8 carbon atoms, such as ethynyl, propynyl, or similar groups. The term "C"... 3-8 "Alkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or similar groups.

[0092] The term "4-8 membered heterocyclic group" refers to a 4-8 membered cyclic group containing at least one cyclic heteroatom (e.g., N, O, or S), such as morpholino, hexahydroisoindolyl, tetrahydrofuranyl, tetrahydropyrroleyl, etc. Typically, the heterocycle contains no more than 4 nitrogen atoms, no more than 2 oxygen atoms, and / or no more than 2 sulfur atoms. Unless otherwise specified, the heterocycle can be saturated, partially unsaturated, or fully unsaturated. The term "C"... 6-10 "Aryl" refers to an aromatic cyclic group with 6 to 10 carbon atoms that does not contain heteroatoms on the ring, such as phenyl and naphthyl. The term "5-8 membered heteroaryl" refers to a 5-8 membered heteroaryl group that contains one or more heteroatoms on the ring, such as pyrrole, furanyl, thiophene, pyrazolyl, thiazolyl, imidazole, oxazolyl, isoxazolyl, pyridinyl, pyranyl, pyridazinyl, pyrimidinyl, benzoindole, benzofuran, benzimidazolyl, etc.

[0093] Term "C" 1-8 "Alkoxy" refers to a straight-chain or branched alkoxy group having 1-8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or similar groups. Alkenoxy, alkynoxy, cycloalkyloxy, aryloxy, heteroaryloxy, and so on. 1-8 "Alkylthio" refers to a straight-chain or branched alkylthio group with 1-8 carbon atoms, such as methylthio, ethylthio, isopropylthio, tert-butylthio, or similar groups; olefinic thio, alkynyl thio, cycloalkyl thio, aryl thio, heteroaryl thio, and so on.

[0094] Term "C" 1-8 "Alkylamine" refers to a straight-chain or branched alkylamine group having 1-8 carbon atoms, such as methylamine, ethylamine, isopropylamine, tert-butylamine, or similar groups. Enamine, acetylenamine, cycloalkylamine, aromaticamine, heteroaromaticamine, and so on.

[0095] The terms Me refer to methyl, Et to ethyl, i-Pr to isopropyl, t-Bu to tert-butyl, Ac to acetyl, and Bn to benzyl.

[0096] Insecticidal activity of the active substance of this invention

[0097] The terms "active substance of the present invention" or "active compound of the present invention" refer to compounds with the structure shown in general formula I or pesticide-acceptable salts. They contain arylpyrazole structures with substituted unsaturated hydrocarbons, exhibit significant insecticidal activity, and possess a broad insecticidal spectrum and strong stability.

[0098] The term "pesticide-acceptable salt" means that the anion of the salt is known and acceptable in forming an insecticide-pesticide-acceptable salt. Preferably, the salt is water-soluble. Suitable acid addition salts formed from compounds of formula (I) include salts formed from inorganic acids, such as hydrochlorides, phosphates, sulfates, and nitrates; and salts formed from organic acids, such as acetates, benzoates, etc.

[0099] The compounds involved in this invention have particularly good control effects on armyworms, diamondback moths, cotton bollworms, corn borers, and rice leaf rollers.

[0100] Insecticide compositions containing the active substances of the present invention

[0101] The active substances of the present invention can be prepared into insecticide compositions using conventional methods. These active compounds can be formulated into conventional formulations, such as solutions, emulsions, suspensions, powders, foams, pastes, granules, aerosols, natural and synthetic materials impregnated with the active substances, microcapsules in polymers, seed coating compounds, and formulations for use with combustion devices, such as fumigation cylinders, fumigation canisters and fumigation trays, as well as ULV cold mist and warm mist formulations.

[0102] These formulations can be produced using known methods, such as mixing the active compound with a expander, which can be a liquid, liquefied gas, or solid diluent or carrier, and can be any type of surfactant, i.e., emulsifier and / or dispersant and / or foaming agent. For example, when water is used as the expander, organic solvents can also be used as adjuvants.

[0103] Liquid solvents are generally suitable as diluents or carriers, such as: aromatic hydrocarbons, such as xylene, toluene, or alkylnaphthalene; chlorinated aromatic or chlorinated aliphatic hydrocarbons, such as chlorobenzene, vinyl chloride, or dichloromethane; aliphatic hydrocarbons, such as cyclohexane or paraffins, such as mineral oil fractions; alcohols, such as ethanol or ethylene glycol and their ethers and esters; ketones, such as acetone, methyl ethyl ketone, methyl isobutyl ketone, or cyclohexanone; or less commonly used polar solvents, such as dimethylformamide, dimethyl sulfoxide, and water.

[0104] A liquefied gas diluent or carrier refers to a liquid that will become a gas at normal temperature and pressure, such as aerosol propellants, halogenated hydrocarbons, and butane, propane, nitrogen, and carbon dioxide.

[0105] Solid carriers can be ground natural minerals such as kaolin, clay, talc, quartz, activated clay, montmorillonite, or diatomaceous earth; and ground synthetic minerals such as highly dispersed silica, alumina, and silicates. Solid carriers for granulation are crushed and graded natural zircon, such as calcite, marble, pumice, sepiolite, dolomite, inorganic and organic coarse powders synthesized into granules, and organic materials such as sawdust, coconut husks, corncobs, and tobacco stalks.

[0106] Nonionic and anionic emulsifiers can be used as emulsifiers and / or foam forming agents. Examples include polyoxyethylene-fatty acid esters, polyoxyethylene-fatty alcohol ethers, alkylaryl polyethylene glycol ethers, alkyl sulfonates, alkyl sulfates, aryl sulfonates, and albumin hydrolysates. Dispersants include lignin sulfite waste and methylcellulose.

[0107] Binders, such as carboxymethyl cellulose, and natural and synthetic polymers in the form of powders, granules, or emulsions, such as gum arabic, polyvinyl alcohol, and polyvinyl acetate, can be used in the formulation.

[0108] Coloring agents such as inorganic dyes, like iron oxide, cobalt oxide, and Prussian blue; organic dyes, like azo dyes or metallic phthalocyanine dyes; and trace nutrients, such as salts of iron, manganese, boron, copper, cobalt, aluminum, and zinc, can be used.

[0109] These active compounds of the present invention can be mixed with other active compounds and exist in their commercial formulations or in dosage forms prepared from these formulations. These other active compounds are insecticides, fungicides, herbicides, growth regulators, etc. Insecticides include, for example, phosphate esters, carbamates, chlorinated hydrocarbons, and substances produced by microorganisms, such as avermectin. Fungicides include methoxyacrylates, amides, triazoles, etc.

[0110] Furthermore, these active compounds of the present invention can also be mixed with synergists in their commercial formulations or in dosage forms prepared from these formulations. These synergists are compounds that enhance the activity of the active compounds. Since the active compounds themselves are active, it is not necessary to add synergists.

[0111] These formulations typically contain 0.001-99.99 wt%, preferably 0.01-99.9 wt%, and more preferably 0.05-90 wt% of the active compound of the present invention, based on the total weight of the bactericidal composition. The concentration of the active compound in commercial formulations or drug formulations can vary over a wide range. The concentration of the active compound in drug formulations can range from 0.0000001–100% (g / v), preferably between 0.0001 and 1% (g / v).

[0112] Preparation method of the compound of the present invention

[0113] The arylpyrazole compounds containing substituted unsaturated hydrocarbons of the present invention can be prepared by the following method; however, the conditions of this method, such as reactants, solvents, bases, amounts of compounds used, reaction temperatures, and reaction times, are not limited to those explained below. The compounds of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, such combinations being readily performed by those skilled in the art.

[0114] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0115] Example 1: Synthesis ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)acrylamide)-5-chloro-3-methylbenzamide (Compound 1 in Table 4)

[0116]

[0117]

[0118] Step 1: Synthesis of intermediate Ia-2,3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-methanol

[0119] Anhydrous tetrahydrofuran (50 mL) was added to a 250 mL single-necked flask containing intermediate Ia-1 (3.025 g, 10 mmol) under ice bath conditions, and the flask was purged with argon gas. Under ice bath stirring conditions, lithium aluminum tetrahydrofuran powder (total 455.4 mg, 12 mmol) was added to the reaction flask in three batches, with each addition 10 min apart, and the flask was purged with argon gas after each addition. After the addition was completed, the reaction was carried out under ice bath conditions for 3 h, and the reaction was confirmed to be complete by TLC.

[0120] Under ice bath conditions, ice water (0.46 mL), NaOH aqueous solution (1 M, 0.46 mL), and ice water (1.38 mL) were added dropwise in sequence while stirring rapidly to quench the reaction. An appropriate amount of ethyl acetate (90 mL) was added, and the mixture was stirred at room temperature for 20 min. The reaction solution was allowed to stand and filtered, and the filtrate (yellow) was collected. The filtrate was washed with saturated brine (50 mL × 3), and the organic phase was dried over anhydrous sodium sulfate. The organic phase was then purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ia-2 as a white solid (1.615 mg, yield 56%).

[0121] 1 H NMR (400 MHz, CDCl3): δ 8.43 (dd, J = 4.7, 1.6 Hz, 1H), 8.02 (dd, J = 8.0, 1.6 Hz, 1H), 7.41 (dd, J = 8.0, 4.8 Hz, 1H), 6.50 (s, 1H), 4.52 (s, 2H), 4.05 (s, 1H) ppm.

[0122] Step 2: Synthesis of intermediate Ia-3 3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxaldehyde

[0123] Under ice bath conditions, dichloromethane (30 mL) was added to a 250 mL single-necked flask containing intermediate Ia-2 (1.443 g, 5 mmol), followed by the slow addition of a dichloromethane suspension (15 mL) of pyridinium chlorochromate (PCC) (2.156 g, 10 mmol). The reaction solution turned deep orange. The reaction was then transferred to room temperature, and after 30 min, the reaction turned dark brown. The reaction was continued for 8 h, and TLC analysis confirmed the completion of the reaction.

[0124] Add 20 mL of saturated ammonium chloride aqueous solution, wash the filtrate with 30 mL of saturated ammonium chloride aqueous solution, dry the organic phase with anhydrous sodium sulfate, rotary evaporate the organic phase and purify by column chromatography (n-heptane: ethyl acetate = 4:1) to give a yellow solid of intermediate Ia-3 (1.045 g, yield 73%).

[0125] 1 H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.53 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (dd, J = 8.4, 1.6 Hz, 1H), 7.49 (dd, J = 8.4, 4.8 Hz, 1H), 7.13 (s,1H) ppm.

[0126] Step 3: Synthesize intermediate Ia-4 ( E ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-yl)acrylate

[0127] At room temperature, dichloromethane (12 mL) and ethoxyformylmethylenetriphenylphosphine (1.463 g, 4.2 mmol) were added to a 100 mL single-necked flask containing intermediate Ia-3 (1.003 g, 3.5 mmol). After the addition was completed, the reaction was allowed to proceed at room temperature for 2 h. The reaction was confirmed to be complete by TLC.

[0128] Rotary evaporation of the organic phase followed by column chromatography (n-heptane:ethyl acetate = 4:1) yielded intermediate Ia-4 as a white solid (1.155 g, 92% yield). E : Z >99:1).

[0129] 1 H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 7.97 (dd, J = 8.1, 1.6 Hz, 1H), 7.46 (dd, J = 8.1, 4.7 Hz, 1H), 7.25 (d, J = 15.9 Hz,1H), 6.77 (s, 1H), 6.33 (d, J = 15.9 Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.29(t, J = 7.1 Hz, 3H) ppm.

[0130] Step 4: Synthesize intermediate Ia-5 ( E 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)acrylic acid

[0131] Under ice bath conditions, ethanol (10 mL) and NaOH aqueous solution (1 M, 10 mL) were added sequentially to a 100 mL single-necked flask containing intermediate Ia-4 (1.155 g, 3.16 mmol). After the addition was completed, the reaction was carried out at room temperature for 4 h. The reaction was confirmed to be complete by TLC.

[0132] The reaction solution was concentrated by rotary evaporation, and dilute hydrochloric acid (2M, 6 mL) was slowly added under ice bath stirring. A white solid precipitated out. The reaction solution was filtered, washed with water (10 mL × 3), and the filter cake was recovered and dried to obtain a white solid intermediate Ia-5 (935.7 mg, yield 90%).

[0133] 1H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (dd, J = 8.1, 4.7 Hz, 1H), 7.33 (d, J = 15.9 Hz,1H), 6.82 (s, 1H), 6.31 (d, J = 15.9 Hz, 1H) ppm.

[0134] Step 5: Synthesize intermediate Ia-7 ( E 2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)acrylamide)-5-chloro-3-methylbenzoate

[0135] At room temperature, 12 mL of dichloromethane was added to a 50 mL single-necked flask containing intermediate Ia-5 (657.1 mg, 2 mmol); oxalyl chloride (0.23 mL, 2.5 mmol) and DMF (13.8 μL, 0.2 mmol) were added sequentially with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 30 min. The reaction was confirmed to be complete by TLC. The solvent was evaporated to obtain the acyl chloride corresponding to Ia-5, which was then stored dry for a short period of time.

[0136] Under ice bath conditions, dichloromethane (6 mL) and DIEA (0.94 mL, 7.2 mmol) were added sequentially to a 50 mL single-necked flask containing intermediate Ia-6 (479.1 mg, 2.4 mmol). The acyl chloride corresponding to Ia-5 prepared in the previous step was dissolved in 3 mL of dichloromethane and slowly added dropwise to the reaction flask under ice bath stirring. After the addition was complete, the flask was transferred to room temperature and reacted for 5 h. The reaction was confirmed to be complete by TLC.

[0137] The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL), washed with saturated brine (15 mL × 3), dried with anhydrous sodium sulfate, and purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 2:1) to give intermediate Ia-7 as a white solid (756.2 mg, yield 74%).

[0138] 1 H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 7.95 (dd, J= 8.1, 1.6 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.44 (dd, J =8.1, 4.7 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 15.5 Hz, 1H), 6.83(s, 1H), 6.60 (d, J = 15.5 Hz, 1H), 3.90 (s, 3H), 2.24 (s, 3H) ppm.

[0139] Step 6: Synthesize intermediate Ia-8 ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)acrylamide)-5-chloro-3-methylbenzoic acid

[0140] Under ice bath conditions, ethanol (5 mL) and NaOH aqueous solution (1 M, 5 mL) were added sequentially to a 100 mL single-necked flask containing intermediate Ia-7 (756.2 mg, 1.48 mmol). After the addition was completed, the reaction was carried out at room temperature for 2 h. The reaction was confirmed to be complete by TLC.

[0141] The reaction solution was concentrated by rotary evaporation, and dilute hydrochloric acid (2M, 3 mL) was slowly added under ice bath stirring. A white solid precipitated out. The reaction solution was filtered, washed with water (10 mL × 3), and the filter cake was recovered and dried to obtain a white solid of intermediate Ia-8 (634.7 mg, yield 86%).

[0142] 1 H NMR (400 MHz, CDCl3) δ 9.31 (s, 1H), 8.49 (dd, J = 4.7, 1.6 Hz, 1H), 7.93 (dd, J = 8.1, 1.6 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.42 (d, J =2.4 Hz, 1H), 7.41 (dd, J = 8.1, 4.7 Hz, 1H), 7.28 (d, J = 15.5 Hz, 1H), 6.80(s, 1H), 6.59 (d, J = 15.5 Hz, 1H), 2.23 (s, 3H) ppm.

[0143] Step 7: Synthesize intermediate Ia-9 ( E )-2-(2-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)vinyl)-6-chloro-8-methyl-4H-benzo[d][1,3]oxazin-4-one

[0144] Anhydrous acetonitrile (3 mL) was added to a 50 mL single-necked flask containing intermediate Ia-8 (496.1 mg, 1 mmol) at room temperature; oxalyl chloride (0.12 mL, 1.3 mmol) and DMF (6.9 μL, 0.1 mmol) were added sequentially with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. A large amount of pale yellow solid precipitated in the reaction solution. The reaction was confirmed to be complete by TLC.

[0145] The reaction solution was filtered, and the filter cake was washed with a small amount of acetonitrile (1 mL × 3). The filter cake was recovered and dried to give a pale yellow solid of intermediate Ia-9 (367.5 mg, yield 77%).

[0146] 1 H NMR (400 MHz, CDCl3) δ 8.58 (dd, J = 4.7, 1.6 Hz, 1H), 8.01 (dd, J = 8.1, 1.6 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.61 (d, J = 2.4 Hz, 1H), 7.51(dd, J = 8.1, 4.7 Hz, 1H), 7.33 (d, J = 16.1 Hz, 1H), 6.86 (s, 1H), 6.73 (d, J = 16.1 Hz, 1H), 2.54 (s, 3H) ppm.

[0147] Step 8: Synthesis of Example 1 ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)acrylamide)-5-chloro-3-methylbenzamide

[0148] Under ice bath conditions, anhydrous acetonitrile (3 mL) was added to a 50 mL single-necked flask containing intermediate Ia-9 (334.7 mg, 0.7 mmol). The mixture was stirred at 0°C and ammonia water (0.3 mL) was slowly added dropwise. After the addition was complete, the reaction was continued at 0°C for 1.5 h. The reaction was confirmed to be complete by TLC.

[0149] The reaction was terminated by adding saturated ammonium chloride aqueous solution (5 mL), followed by the addition of a small amount of dichloromethane (5 mL), and then washing with saturated ammonium chloride aqueous solution (10 mL × 3), deionized water and pure water (10 mL × 2). The organic phase was dried with anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a pale yellow crude product. Acetonitrile (3 mL) was added to the crude product, and the mixture was ultrasonically vibrated for 20 s. A large amount of white solid precipitated in the lower layer of the reaction flask. The reaction solution was filtered, and the filter cake was washed with a small amount of acetonitrile (1 mL × 3). The filter cake was recovered and dried to obtain a white solid of the target compound in Example 1 (285.7 mg, yield 82%).

[0150] 1 H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.44 (dd, J =8.1, 4.7 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.30 (d, J = 15.5 Hz, 1H), 6.83(s, 1H), 6.60 (d, J = 15.5 Hz, 1H), 5.81 (s, 2H). 2.24 (s, 3H) ppm.

[0151] Example 2: Synthesis ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)acrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 2 in Table 4)

[0152]

[0153] Referring to step 8 of Example 1, replace the ammonia with monomethylamine hydrochloride;

[0154] The other steps were similar to those in Example 1, resulting in a white solid of the target compound from Example 2.

[0155] 1 H NMR (400 MHz, CDCl3) δ 9.41 (s, 1H), 8.52 (dd, J= 4.7, 1.5 Hz, 1H), 7.95 (dd, J = 8.1, 1.5 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.44 (dd, J =8.1, 4.7 Hz, 1H), 7.42 (d, J = 2.4 Hz, 1H), 7.33 (d, J = 16.1 Hz, 1H), 6.86(s, 1H), 6.73 (d, J = 16.1 Hz, 1H), 6.71 (q, J = 4.9 Hz, 1H), 2.76 (d, J =4.8 Hz, 3H), 2.16 (s, 3H) ppm.

[0156] Example 3: Synthesis ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-methylacrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 12 in Table 4)

[0157]

[0158] Synthetic intermediate Ia-4-Me ( E ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-yl)-2-methacrylate

[0159] Dichloromethane (15 mL) and ethoxyformyl ethylidene triphenylphosphine (2.174 g, 6 mmol) were added to a 100 mL single-necked flask containing intermediate Ia-3 (1.433 g, 5 mmol) at room temperature. The reaction was allowed to proceed for 2 h at room temperature and was confirmed to be complete by TLC.

[0160] The organic phase was purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 4:1) to give the intermediate Ia-4-Me as a white solid (1.671 g, yield 90%, E:Z > 99:1).

[0161] 1 H NMR (400 MHz, CDCl3) δ 8.53 (dd, J = 4.7, 1.5 Hz, 1H), 7.95 (dd, J = 8.1, 1.5 Hz, 1H), 7.44 (dd,J = 8.1, 4.7 Hz, 1H), 7.18 (d, J = 0.8 Hz, 1H), 6.69 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.17 (d, J = 1.3 Hz, 3H), 1.26 (t, J = 7.1 Hz, 3H) ppm.

[0162]

[0163] Referring to step 4 of Example 1, Ia-4 is replaced with intermediate Ia-4-Me;

[0164] Referring to step 8 of Example 1, replace the ammonia with monomethylamine hydrochloride;

[0165] The remaining steps are similar to those in Example 1, yielding a white solid of the target compound in Example 3.

[0166] 1 H NMR (400 MHz, CDCl3) δ 9.82 (s, 1H), 8.53 (dd, J = 4.7, 1.5 Hz, 1H), 7.94 (dd, J = 8.1, 1.5 Hz, 1H), 7.41 (dd, J = 8.1, 4.7 Hz, 1H), 7.23 (d, J = 1.9 Hz, 1H), 7.12 (s, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.71 (q, J = 4.9 Hz,1H), 6.69 (s, 1H), 2.76 (d, J = 4.8 Hz, 3H), 2.31 (d, J = 1.0 Hz, 3H), 2.16(s, 3H) ppm.

[0167] Example 4: Synthesis ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-ethylacrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 22 in Table 4)

[0168]

[0169] Synthetic intermediate Ia-4-Et ( E ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-yl)-2-ethylacrylate

[0170] Under argon protection, NaH (144 mg, 6 mmol) and triethyl 2-phosphonobutyrate (1.387 g, 5.5 mmol) were added to a 100 mL three-necked flask containing anhydrous THF (25 mL). The mixture was stirred at room temperature for 0.5 h, and then Ia-3 (1.433 g, 5 mmol) was added. The reaction was carried out at room temperature for 8 h under argon protection. The reaction was confirmed to be complete by TLC.

[0171] The reaction was quenched with dilute hydrochloric acid aqueous solution, the solvent was removed by rotary evaporation, and the solution was redissolved in ethyl acetate (30 mL). The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), and the organic phase was dried with anhydrous sodium sulfate. The organic phase was then purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 3:1) to give the intermediate Ia-4-Et as a white solid (1.696 g, yield 88%, E:Z = 90:10).

[0172] 1 H NMR (400 MHz, CDCl3) δ 8.53 (dd, J = 4.7, 1.6 Hz, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 1H), 7.44 (dd, J = 8.0, 4.7 Hz, 1H), 7.11 (s, 1H), 6.67 (s,1H), 4.19 (q, J = 7.1 Hz, 2H), 2.63 (q, J = 7.5 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.5 Hz, 3H) ppm.

[0173]

[0174] Referring to step 4 of Example 1, Ia-4 is replaced with intermediate Ia-4-Et;

[0175] Referring to step 8 of Example 1, replace the ammonia with monomethylamine hydrochloride;

[0176] The remaining steps are similar to those in Example 1, yielding a white solid of the target compound in Example 4.

[0177] 1 H NMR (400 MHz, CDCl3) δ 8.53 (dd, J = 4.7, 1.6 Hz, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 1H), 7.44 (dd, J = 8.0, 4.7 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H),7.11 (s, 1H), 7.06 (d, J = 2.1 Hz, 1H), 6.67 (s, 1H), 2.77 (d, J = 4.8 Hz, 3H), 2.63 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H) ppm.

[0178] Example 5: Synthesis ( Z )-2-(3-(3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl)-2-fluoroacrylamide)-N-(tert-butyl)-3,5-dichlorobenzamide (Compound 179 in Table 4)

[0179]

[0180] Synthetic intermediate Ia-4-F ( Z ) ( Z Ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-fluoroacrylate

[0181] At room temperature, anhydrous TEA (1.3 mL, 10 mmol) was added to a 100 mL three-necked flask containing triethyl 2-fluoro-2-phosphorylacetate (1.331 g, 5.5 mmol). The flask was purged with argon gas, and anhydrous THF (25 mL) and anhydrous magnesium bromide (1.013 g, 5.5 mmol) were added. After stirring at room temperature for 1 min, intermediate Ia-3 (1.433 g, 5 mmol) was added. The reaction was carried out at room temperature for 2 h under argon protection. The reaction was confirmed to be complete by TLC.

[0182] The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the organic phase was purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 3:1) to give intermediate Ia-4-F. ZA white solid (1.118 g, yield 74%), E:Z = 19:81.

[0183] 1 H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (dd, J = 8.1, 4.7 Hz, 1H), 6.97 (d, J = 2.2 Hz, 1H), 6.70 (d, J = 31.3 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H)ppm.

[0184]

[0185] Referring to step 4 of Example 1, intermediate Ia-4-F ( Z Replace Ia-4;

[0186] Referring to step 5 of Example 1, Ia-6 was replaced with methyl 2-amino-3,5-dichlorobenzoate;

[0187] Referring to step 8 of Example 1, replace ammonia with tert-butylamine;

[0188] The remaining steps are similar to those in Example 1, yielding a white solid of the target compound in Example 5.

[0189] 1 H NMR (400 MHz, CDCl3) δ 9.69 (s, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 7.97 (dd, J = 8.1, 1.6 Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.86 (d, J = 2.0 Hz, 1H), 6.73 (s,1H), 6.71 (d, J= 33.2 Hz, 1H), 1.32 (s, 9H) ppm.

[0190] Example 6: Synthesis ( Z )-5-chloro-2-(3-(4-(3-chloropyridin-2-yl)-2-(trifluoromethyl)pyrimidin-5-yl)-2-fluoroacrylamide)-N,3-dimethylbenzamide (Compound 22 in Table 4)

[0191]

[0192] Replace tert-butylamine with monomethylamine hydrochloride and replace intermediate Ia-1 with 4-(3-chloropyridin-2-yl)-2-(trifluoromethyl)pyrimidine-5-carboxylic acid; the other steps are similar to those in Example 5, to obtain a white solid of the target compound of the example.

[0193] 1 H NMR (400 MHz, CDCl3) δ 9.36 (s, 1H), 8.79 (s, 1H), 7.88 (d, J = 2.4Hz, 1H), 7.71 – 7.61 (m, 2H), 7.61 – 7.57 (m, 1H), 7.39 – 7.35 (m, 2H), 6.61(q, J = 4.8 Hz, 1H), 6.48 (d, J = 33.6 Hz, 1H), 2.85 (d, J = 4.8 Hz, 3H),2.17 (s, 3H). ppm.

[0194] Example 7: Synthesis ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-fluoroacrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 42 in Table 4)

[0195]

[0196] Synthetic intermediate Ia-4-F ( E ) ( E Ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-fluoroacrylate

[0197] Under argon protection and at -78°C, 3.78 mL of 1.6 M butyllithium (6 mmol, 1.6 M in THF) was added to a 100 mL three-necked flask containing triethyl 2-fluoro-2-phosphorylacetate (6 mmol) and anhydrous THF (10 mL). A solution of intermediate Ia-3 (1.433 g, 5 mmol) in anhydrous THF (10 mL) was then added to the reaction mixture. The reaction was carried out at -78°C for 30 min. The reaction was confirmed to be complete by TLC.

[0198] The reaction was quenched with dilute hydrochloric acid aqueous solution, the solvent was removed by rotary evaporation, and the solution was redissolved in ethyl acetate (20 mL). The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), and the organic phase was dried with anhydrous sodium sulfate. The organic phase was then purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ia-4-F. E A white solid (1.495 g, yield 85%, E:Z = 94:6).

[0199] 1 H NMR (400 MHz, CDCl3) δ 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H), 7.27 (s, 1H), 6.49 (d, J = 20.8 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) ppm.

[0200]

[0201] Referring to step 4 of Example 1, intermediate Ia-4-F ( E Replace Ia-4;

[0202] Referring to step 8 of Example 1, replace the ammonia with monomethylamine hydrochloride;

[0203] The remaining steps are similar to those in Example 1, yielding a white solid of the target compound in Example 7.

[0204] 1 H NMR (400 MHz, CDCl3) δ 9.82 (d, J = 2.7 Hz, 1H), 8.55 (dd, J= 4.7, 1.5 Hz, 1H), 7.98 (dd, J = 8.1, 1.5 Hz, 1H), 7.57 (s, 1H), 7.46 (dd, J = 8.1, 4.7 Hz, 1H), 7.36 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 2.1 Hz, 1H), 6.41 (d, J =23.8 Hz, 1H), 6.24 (d, J = 4.6 Hz, 1H), 2.94 (d, J = 4.9 Hz, 3H), 2.28 (s, 3H) ppm.

[0205] Example 8: Synthesis ( Z )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-chloroacrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 52 in Table 4)

[0206]

[0207] Synthetic intermediate Ia-4-Cl ( Z Ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-chloroacrylate

[0208] At -20°C, dichloromethane (20 mL) was added to a 100 mL three-necked flask containing ethoxyformylmethylenetriphenylphosphine (2.090 g, 6 mmol), the flask was purged with argon, and NCS (801.2 mg, 6 mmol) was added at -20°C. The mixture was kept at -20°C for 1 h, and then heated to room temperature. At room temperature, intermediate Ia-3 (1.433 g, 5 mmol) and K2CO3 (1.728 g, 12.5 mmol) were added, and the mixture was reacted at room temperature for 10 h. The reaction was confirmed to be complete by TLC.

[0209] The reaction solution was washed with saturated brine (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the organic phase was rotary evaporated and purified by column chromatography (n-heptane: ethyl acetate = 2:1) to give the intermediate Ia-4-Cl as a white solid (1.434 g, yield 73%, E:Z < 1:99).

[0210] 1 H NMR (400 MHz, CDCl3) δ 8.54 (dd,J = 4.7, 1.6 Hz, 1H), 7.98 (dd, J = 8.1, 1.6 Hz, 1H), 7.55 (s, 1H), 7.47 (dd, J = 8.1, 4.7 Hz, 1H), 7.38 (s,1H), 4.28 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H) ppm.

[0211]

[0212] Referring to step 4 of Example 1, Ia-4 is replaced with intermediate Ia-4-Cl;

[0213] Referring to step 8 of Example 1, replace the ammonia with monomethylamine hydrochloride;

[0214] The remaining steps are similar to those in Example 1, yielding a white solid of the target compound in Example 8.

[0215] 1 H NMR (400 MHz, CDCl3) δ 10.23 (s, 1H), 8.52 (dd, J = 4.6, 1.2 Hz, 1H), 7.96 (dd, J = 8.1, 1.2 Hz, 1H), 7.68 (s, 1H), 7.44 (dd, J = 8.1, 4.7 Hz,1H), 7.37 (s, 1H), 7.32 (d, J = 1.9 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.21(q, J = 4.8 Hz, 1H), 2.93 (d, J = 4.8 Hz, 3H), 2.21 (s, 3H) ppm.

[0216] Example 9: Synthesis ( Z )-2-bromo-3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-bromoacrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 62 in Table 4)

[0217]

[0218] Synthetic intermediate Ia-4-Br ( Z Ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-bromoacrylate

[0219] At -20°C, dichloromethane (20 mL) was added to a 100 mL three-necked flask containing ethoxyformylmethylenetriphenylphosphine (2.090 g, 6 mmol), the flask was purged with argon, and NBS (1.078 g, 6 mmol) was added at -20°C. The mixture was kept at -20°C for 1 h, and then heated to room temperature. At room temperature, intermediate Ia-3 (1.433 g, 5 mmol) and K2CO3 (1.728 g, 12.5 mmol) were added, and the mixture was reacted at room temperature for 10 h. The reaction was confirmed to be complete by TLC.

[0220] The reaction solution was washed with saturated brine (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the organic phase was rotary evaporated and purified by column chromatography (n-heptane: ethyl acetate = 2:1) to give the intermediate Ia-4-Br as a white solid (1.755 g, yield 81%, E:Z < 1:99).

[0221] 1 H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (dd, J = 8.1, 1.6 Hz, 1H), 7.87 (s, 1H), 7.54 (s, 1H), 7.46 (dd, J = 8.1, 4.7 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H) ppm.

[0222]

[0223] Referring to step 4 of Example 1, Ia-4 is replaced with intermediate Ia-4-Br;

[0224] Referring to step 8 of Example 1, replace the ammonia with monomethylamine hydrochloride;

[0225] The remaining steps are similar to those in Example 1, yielding a white solid of the target compound in Example 9.

[0226] 1 H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.51 (dd,J = 4.7, 1.6 Hz,1H), 7.99 (s, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.51 (s, 1H), 7.43 (dd, J = 8.1, 4.7 Hz, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.27 (d, J = 2.1 Hz, 1H), 6.10(q, J = 4.8 Hz, 1H), 2.95 (d, J = 4.8 Hz, 3H), 2.21 (s, 3H) ppm.

[0227] Example 10: Synthesis ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-cyanoacrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 72 in Table 4)

[0228]

[0229] Synthetic intermediate Ia-4-CN ( E Ethyl 3-(3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl)-2-cyanoacrylate

[0230] Piperidine (425.8 mg, 5 mmol) was added to a 100 mL single-necked flask containing anhydrous intermediate (1.433 g, 5 mmol) and methyl cyanoacetate (545.0 mg, 5.5 mmol) at room temperature. The reaction was allowed to proceed for 5 h at room temperature, and the reaction was confirmed to be complete by TLC.

[0231] The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the organic phase was rotary evaporated and purified by column chromatography (n-heptane: ethyl acetate = 2:1) to give intermediate Ia-4-CN as a white solid (1.738 mg, yield 91%, E:Z > 99:1).

[0232] 1 H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.01 (dd, J= 8.1, 1.6 Hz, 1H), 7.89 (s, 1H), 7.66 (s, 1H), 7.50 (dd, J = 8.1, 4.7 Hz,1H), 3.90 (s, 3H) ppm.

[0233]

[0234] Referring to step 4 of Example 1, Ia-4 is replaced with intermediate Ia-4-CN;

[0235] Referring to step 8 of Example 1, replace the ammonia with monomethylamine hydrochloride;

[0236] The remaining steps are similar to those in Example 1, yielding a white solid of the target compound of Example 10.

[0237] 1 H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 8.52 (dd, J = 4.7 1.5 z, 1H), 7.98 (dd, J = 8.1 1.5 Hz, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 7.46 (dd, J = 8.1, 4.7 Hz, 1H), 7.34 (d, J = 1.7 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 6.17 (q, J =4.9 Hz, 1H), 2.96 (d, J = 4.9 Hz, 3H), 2.22 (s, 3H) ppm.

[0238] Example 11: Synthesis ( Z )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-trifluoromethylacrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 82 in Table 4)

[0239]

[0240] Under argon protection at room temperature, CuI (38.1 mg, 0.2 mmol) was added to a 50 mL three-necked flask containing compound 62 (588.1 mg, 1 mmol), anhydrous DMF (4 mL), and HMPA (0.5 mL). The mixture was heated to 75°C, and while stirring, an anhydrous DMF solution (1 mL) of methyl fluorosulfonyl difluoroacetate (384.2 mg, 2 mmol) was slowly added via syringe. The addition process lasted for 2 h. The reaction was carried out at 75°C for 14 h under argon protection, and the reaction was confirmed to be complete by TLC.

[0241] The reaction was quenched with saturated ammonium chloride aqueous solution (2 mL), diluted with dichloromethane (20 mL), and the organic phase was washed with saturated brine (30 mL × 5). The organic phase was dried with anhydrous sodium sulfate, and the organic phase was purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 1:1) to obtain the white solid of Example 11 (389.2 mg, yield 68%).

[0242]

[0243] 1 H NMR (400 MHz, CDCl3) δ 9.43 (s, 1H), 8.56 (dd, J = 4.7, 1.5 Hz, 1H), 7.98 (dd, J = 8.1, 1.5 Hz, 1H), 7.43 (dd, J = 8.1, 4.7 Hz, 1H), 7.39 (s,1H), 7.30 (d, J = 2.0 Hz, 1H), 7.20 (d, J = 2.2 Hz, 1H), 6.90 (s, 1H), 6.16(q, J = 4.4 Hz, 1H), 2.82 (d, J = 4.4 Hz, 3H), 2.20 (s, 3H) ppm.

[0244] Example 12: Synthesis ( Z )-N-(2-(ethylaminomethylthioyl)-4-bromo-6-methylphenyl)-3-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-2-fluoroacrylamide (Compound 167 in Table 4)

[0245]

[0246] Synthetic intermediate 2-amino-5-bromo-N-ethyl-3-methylphenylthioamide

[0247] At room temperature, Lawson's reagent (1.213 g, 3 mmol) was added to a 100 mL single-necked flask containing 2-amino-5-bromo-N-ethyl-3-methylbenzamide (1.286 g, 5 mmol) and toluene (20 mL). The flask was purged with argon gas and heated to 80°C for 6 h. The reaction was confirmed to be complete by TLC.

[0248] The solvent was removed by rotary evaporation, and the organic phase was redissolved in dichloromethane (30 mL). The organic phase was washed with saturated brine (30 mL × 3), dried with anhydrous sodium sulfate, and purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 3:1) to give the intermediate 2-amino-5-bromo-N-ethyl-3-methylphenylthioamide as a white solid (983.3 mg, yield 72%).

[0249] 1 H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.41 (d, J = 2.4 Hz, 1H), 7.38(d, J = 2.4 Hz, 1H) 4.91 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 2.16 (s, 3H), 1.31(t, J = 7.1 Hz, 3H) ppm.

[0250]

[0251] Referring to step 5 in Example 1,

[0252] Replace intermediate Ia-6 with 2-amino-5-bromo-N-ethyl-3-methylphenylthioamide;

[0253] Using intermediate Ia-4-F ( Z By replacing Ia-4, the white solid of the target compound of Example 12 was synthesized.

[0254] 1 H NMR (400 MHz, CDCl3) δ 10.10 (d, J = 2.2 Hz, 1H), 8.52 (dd, J =4.7, 1.6 Hz, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (dd, J= 8.1, 4.7 Hz, 1H), 7.43 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 2.3 Hz, 1H), 7.24 (t, J = 4.8 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.77 (d, J = 33.9 Hz, 1H), 3.31 (q, J = 6.2Hz, 2H), 2.22 (s, 3H), 1.15 (t, J = 6.2 Hz, 2H) ppm.

[0255] Example 13: Synthesis ( Z )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-fluoropropene thioamide)-5-chloro-3-methyl-N-cyclopropylbenzamide (Table 4 Compound 200)

[0256]

[0257] Referring to the synthesis method of Example 5, intermediate Ia-12-7 was synthesized. Z methyl 5-chlorobenzoate 3-bromo-2-(3-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-2-fluoroacrylamido)-5-chlorobenzoate.

[0258] At room temperature, Lawson's reagent (485.4 mg, 1.2 mmol) was added to a 100 mL single-necked flask containing intermediate Ia-12-7 (1.186 g, 2 mmol) and toluene (10 mL). The flask was purged with argon gas and heated to 110°C for 3 h. The reaction was confirmed to be complete by TLC.

[0259] The solvent was removed by rotary evaporation, and the organic phase was redissolved in dichloromethane (15 mL). The organic phase was washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 3:1) to obtain the intermediate. Z Methyl 3-bromo-2-(3-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-2-fluoropropenylthioamido)-5-chlorobenzoate is a white solid (670.7 mg, 55% yield).

[0260] 1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.54 (dd, J = 4.7, 1.5 Hz, 1H), 7.96 (dd, J = 8.1, 1.5 Hz, 1H), 7.88 (d, J = 2.3 Hz, 1H), 7.82 (d, J =2.3 Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H), 7.21 (d, J = 34.5 Hz, 1H), 7.08(d, J = 2.4 Hz, 1H), 3.89 (s, 3H) ppm.

[0261]

[0262] Referring to step 8 of Example 1, cyclopropylamine was used to replace ammonia.

[0263] The remaining steps are similar to those in Example 1, yielding a white solid of the target compound of Example 13.

[0264] 1 H NMR (400 MHz, CDCl3) δ 10.53 (s, 1H), 8.52 (dd, J = 4.7, 1.5 Hz, 1H), 7.98 (dd, J = 8.1, 1.5 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 7.68 (d, J =2.3 Hz, 1H), 7.39 (dd, J = 8.1, 4.7 Hz, 1H), 6.92 (d, J = 2.4 Hz, 1H), 6.81(d, J = 33.6 Hz, 1H), 2.79 (dt, J = 10.6, 3.4 Hz, 1H), 0.80-0.85 (m, 2H), 0.52-0.57 (m, 2H) ppm.

[0265] Example 14: Synthesis ( Z)-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-3-fluoroacrylamide)-5-chloro-3-bromo-N-acetylbenzamide (Compound 198 in Table 4)

[0266]

[0267]

[0268] Step 1: Synthesis of intermediate Ia-14-2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl) tert-butyl carbamate

[0269] At room temperature, tert-butanol (80 mL) and triethylamine (2.6 mL, 20 mmol) were added to a 250 mL three-necked flask containing intermediate Ia-1 (3.025 g, 10 mmol), and the mixture was stirred at room temperature for 30 min. The flask was then purged with argon, and diphenyl azidophosphate (total 4.864 g, 20 mmol) was slowly added to the reaction mixture. The mixture was heated to 85°C and reacted for 3 h. The reaction was confirmed to be complete by TLC.

[0270] Slowly add 10 mL of saturated ammonium chloride aqueous solution, stir for 5 min to quench the reaction, add ethyl acetate to dilute (100 mL), wash the organic phase with 3 x 80 mL of saturated ammonium chloride aqueous solution and 1 x 5% sodium bicarbonate aqueous solution, dry with anhydrous sodium sulfate, rotary evaporate the organic phase and purify by column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ia-14-2 as a white solid (3.021 g, yield 81%).

[0271] 1 H NMR (400 MHz, CDCl3): δ 8.51 (s, 1H), 8.42 (dd, J = 4.7, 1.6 Hz, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.31 (dd, J = 8.1, 4.7 Hz, 1H), 6.61 (s,1H), 1.51 (s, 9H) ppm.

[0272] Step 2: Synthesis of intermediate Ia-14-3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-amine

[0273] Under ice bath and stirring, dichloromethane (30 mL) and trifluoroacetic acid (TFA) (2 mL, 27 mmol) were added to a 250 mL single-necked flask containing Ia-14-2 (2.989 g, 8 mmol), and the mixture was heated to room temperature for 5 h. The reaction was confirmed to be complete by TLC.

[0274] Under ice bath and stirring, the reaction solution was adjusted to weakly alkaline by adding NaOH aqueous solution (2M), extracted with dichloromethane, and washed with saturated ammonium chloride aqueous solution (50 mL × 3) and 5% sodium bicarbonate aqueous solution (50 mL × 1). The solution was dried over anhydrous sodium sulfate, and the organic phase was purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 1:1) to give intermediate Ia-14-3 as a colorless, transparent liquid (2.079 g, 95% yield).

[0275] 1 H NMR (400 MHz, CDCl3) δ 8.38 (dd, J = 4.7, 1.6 Hz, 1H), 7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.27 (dd, J = 8.0, 4.7 Hz, 1H), 5.66 (s, 1H), 4.69 (s, 2H) ppm.

[0276] Step 3: Synthesis of intermediate Ia-14-4 2-(3-bromo-5-iodo-1H-pyrazol-1-yl)-3-chloropyridine

[0277] At room temperature, acetonitrile (80 mL) and tert-butyl nitrite (1.557 g, 15.1 mmol) were added to a 250 mL single-necked flask containing intermediate Ia-14-3 (2.079 g, 7.6 mmol) and CuI (1.447 g, 7.6 mmol). The flask was purged with argon gas and heated to 75°C for 2 h. The reaction was confirmed to be complete by TLC.

[0278] The reaction was quenched by adding sodium thiosulfate aqueous solution (10 mL), the solvent was removed by rotary evaporation, the organic phase was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL × 3), dried with anhydrous sodium sulfate, the organic phase was purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ia-14-4 as a white molten solid (2.601 g, yield 89%).

[0279] 1 H NMR (400 MHz, CDCl3) δ 8.55 (dd, J= 4.7, 1.6 Hz, 1H), 7.95 (dd, J = 8.1, 1.6 Hz, 1H), 7.47 (dd, J = 8.1, 4.7 Hz, 1H), 6.65 (s, 1H) ppm.

[0280] Step 4: Synthesize intermediate Ia-14-5 ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)propynate

[0281] At room temperature, anhydrous DME (30 mL) was added to a 100 mL three-necked flask containing ethyl propynate (706.3 mg, 7.2 mmol) to replace the argon gas in the flask. Intermediate Ia-14-4 (2.499 g, 6.5 mmol), CuI (11.43 mg, 0.06 mmol), (PPh3)2PdCl2 (84.23 mg, 0.12 mmol), and K2CO3 (1.797 mg, 13 mmol) were added sequentially. After the addition was completed, the mixture was heated to 85°C and reacted for 8 h. The reaction was confirmed to be complete by TLC.

[0282] The reaction was quenched by adding saturated ammonium chloride aqueous solution (2 mL), the solvent was removed by rotary evaporation, the organic phase was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL × 3), dried with anhydrous sodium sulfate, the organic phase was purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 2:1) to give intermediate Ia-14-5 as a white solid (1.083 g, yield 47%).

[0283] 1 H NMR (400 MHz, CDCl3) δ 8.51 (dd, J = 4.7, 1.5 Hz, 1H), 7.95 (dd, J = 8.1, 1.5 Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H), 6.90 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H) ppm.

[0284] Step 5: Synthesize intermediate Ia-14-6 ( Z Ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-3-fluoroacrylate

[0285] At room temperature, anhydrous acetonitrile (30 mL), water (0.3 mL), and AgF (761.2 mg, 6 mmol) were added to a 100 mL single-necked flask containing intermediate Ia-14-5 (1.064 g, 3 mmol). After the addition was completed, the mixture was heated to 80°C and reacted for 12 h. The reaction was confirmed to be complete by TLC.

[0286] The reaction mixture was removed by rotary evaporation, diluted with dichloromethane (30 mL), dried over anhydrous sodium sulfate, and purified by rotary evaporation of the organic phase followed by column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ia-14-6 as a white solid. (854.9 mg, yield 76%, E:Z < 1:99)

[0287] 1 H NMR (400 MHz, CDCl3) δ 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.01 (dd, J = 8.1, 1.6 Hz, 1H), 7.50 (dd, J = 8.1, 4.7 Hz, 1H), 7.18 (s, 1H), 5.84 (d, J = 33.6 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) ppm.

[0288] Referring to steps 5 to 8 of Example 1, Ia-4-Br was replaced with Ia-14-6, and Ia-6 was replaced with methyl 2-amino-3-bromo-5-chlorobenzoate to synthesize intermediate Ia-14-7.

[0289] Acetyl chloride (78.50 mg, 1 mmol) was slowly added to a 50 mL single-necked flask containing Ia-14-7 (578.0 mg, 1 mmol), THF (5 mL), and pyridine (0.324 mL, 4 mmol) under ice bath and stirring. The mixture was heated to room temperature and reacted for 10 h. The reaction was confirmed to be complete by TLC.

[0290] Add 2 mL of saturated ammonium chloride aqueous solution, dilute with 15 mL of dichloromethane, wash the organic phase with 20 mL × 3 saturated ammonium chloride aqueous solution, dry with anhydrous sodium sulfate, rotary evaporate the organic phase and purify by column chromatography (n-heptane: ethyl acetate = 2:1) to obtain the white solid of Example 14 (410.4 mg, yield 66%).

[0291] 1H NMR (400 MHz, CDCl3) δ 9.22 (d, J = 2.1 Hz, 1H), 8.54 (dd, J = 4.7, 1.6 Hz, 1H), 8.01 (dd, J = 8.1, 1.6 Hz, 1H), 7.67 (d, J = 2.2 Hz, 1H), 7.50 (dd, J = 8.1, 4.7 Hz, 1H), 7.37 (d, J = 2.2 Hz, 1H), 7.18 (s, 1H), 6.42 (s,1H), 5.84 (d, J = 33.6 Hz, 1H), 2.26 (s, 3H) ppm.

[0292] Example 15: Synthesis ( E )-N-benzyl-2--2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-3-fluoroacrylamide)-5-chloro-3-methylbenzamide (Compound 127 in Table 4)

[0293]

[0294]

[0295] Synthetic intermediate Ia-15 ( E Ethyl 3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-3-fluoroacrylate

[0296] At room temperature, anhydrous DMF (25 mL) was added to a 100 mL three-necked flask containing ethyl 2,2-difluoro-2-bromoacetate (1.522 g, 7.5 mmol) and activated zinc powder (496.9 mg, 7.6 mmol). The argon gas in the flask was then replaced. Intermediate Ia-14-4 (1.922 g, 5 mmol), CuI (190.5 mg, 1 mmol), and Pd(PPh3)4 (288.9 mg, 0.25 mmol) were added sequentially. After the addition was complete, the mixture was heated to 70°C and reacted for 2 h. The reaction was confirmed to be complete by TLC.

[0297] The reaction was quenched by adding saturated ammonium chloride aqueous solution (2 mL), the solvent was removed by rotary evaporation, the organic phase was diluted with ethyl acetate (50 mL), washed with saturated ammonium chloride aqueous solution (50 mL × 5), dried with anhydrous sodium sulfate, the organic phase was purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ia-14 as a white solid (646.6 mg, yield 44%, E:Z = 78:22).

[0298] 1 H NMR (400 MHz, CDCl3) δ 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H), 7.06 (s, 1H), 6.29 (d, J = 21.5 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H) ppm.

[0299] Referring to steps 5 to 8 of Example 1, replace Ia-4 with Ia-15 and replace ammonia with benzylamine to obtain the white solid of the target compound of Example 15.

[0300] 1 H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 8.52 (dd, J = 4.7, 1.5 Hz,1H), 8.17 (s, 1H), 7.96 (dd, J = 8.1, 1.5 Hz, 1H), 7.83 (d, J = 2.3 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H) 7.35-7.28 (m, 2H),7.28-7.23 (m, 3H), 7.06 (s, 1H), 6.78 (t, J = 4.6 Hz, 1H), 5.95 (d, J = 20.8Hz, 1H), 4.43 (t, J= 6.2 Hz, 1H), 2.22 (s, 3H) ppm.

[0301] Example 16: Synthesis ( Z )-2-(3-(3-bromo-1-(2,4-dichlorophenyl)-1H-pyrazol-5-yl)-2-fluoroacrylamide)-3,5-dichloro-N-methylbenzamide (Table 4, Compound 186)

[0302]

[0303] Referring to step 1 in Example 5, Ia-1 was replaced with 3-bromo-1-(2,4-dichlorophenyl)-1H-pyrazole-5-carboxylic acid;

[0304] Referring to step 8 of Example 5, tert-butylamine was replaced with monomethylamine hydrochloride;

[0305] The other steps are similar to those in Example 5, yielding a white solid of the target compound in Example 16.

[0306] 1 H NMR (400 MHz, CDCl3) δ 9.39 (d, J = 2.5 Hz, 1H), 7.83-7.75 (m, 2H), 7.59-7.53 (m, 1H), 7.50 (d, J = 2.3 Hz, 1H) 7.32 (d, J = 2.3 Hz, 1H), 6.99(d, J = 2.4 Hz, 1H), 6.80 (d, J = 34.0 Hz, 1H), 6.46 (d, J = 4.8 Hz, 1H), 2.89 (d, J = 4.9 Hz, 3H) ppm.

[0307] Example 17: Synthesis ( Z )-2-(3-(3-bromo-1-(2-chloro-4-nitrophenyl)-1H-pyrazol-5-yl)-2-fluoroacrylamide)-5-cyano-3-methyl-N-methylbenzamide (Compound 219 in Table 4)

[0308]

[0309] Referring to step 1 in Example 5, Ia-1 was replaced with 3-bromo-4-chloro-1-(2-chloro-4-nitrophenyl)-1H-pyrazole-5-carboxylic acid;

[0310] Referring to step 5 of Example 5, Ia-6 was replaced with methyl 2-amino-5-cyano-3-methylbenzoate;

[0311] Referring to step 8 of Example 5, tert-butylamine was replaced with monomethylamine hydrochloride;

[0312] The other steps were similar to those in Example 5, resulting in a white solid of the target compound from Example 17.

[0313] 1 H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.56-8.50 (m, 2H), 8.32 (d, J =2.2 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.63 (d, J = 2.0 Hz, 1H), 6.82 (d, J = 33.9 Hz, 1H), 6.00 (q, J = 7.3 Hz, 1H), 2.89 (d, J = 4.9 Hz, 3H), 2.33 (s, 3H) ppm.

[0314] Example 18: Synthesis ( Z )-5-(2-(3-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-yl)-2-fluoroacrylamide)-5-chloro-3-methylphenyl)-N-methyl-1,2,4-oxadiazole-3-carboxamide (Compound 32 in Table 1)

[0315]

[0316] Referring to step 5 in Example 5, intermediate Ia-18-1 was synthesized.

[0317] Synthetic intermediate Ia-18-2 ( Z )-5-(2-(3-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazol-5-yl)-2-fluoroacrylamide)-5-chloro-3-methylphenyl)-1,2,4-oxadiazole-3-methyl ester

[0318] At room temperature, intermediate Ia-17-1 (1.104 g, 2 mmol) was added to a 100 mL flask containing 5 mL of tetrahydrofuran, followed by tert-butyl nitrite (309.4 mmol, 3 mmol) and 4 mol / L hydrogen chloride methanol solution (2 mL). The reaction was allowed to proceed for 2 h. The reaction was confirmed to be complete by TLC. The organic phase was purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ia-18-2 as a yellow solid (840.6 mg, yield 71%).

[0319] 1 H NMR (400 MHz, CDCl3 d) d : 9.79 (s, 1H), 8.43 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.87 (dd, J = 8.1, 1.6 Hz, 1H), 7.48 (d, J =2.3 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.41(dd, J = 8.1, 4.7 Hz, 1H), 6.82(d, J = 33.9 Hz, 1H), 4.15 (s, 3H), 2.28 (s, 3H) ppm.

[0320]

[0321] Synthesis Example 18

[0322] At room temperature, intermediate Ia-17-2 (840.6 mg, 1.4 mmol) was added to a 50 mL flask containing 10 mL of methanol, followed by monomethylamine hydrochloride (202.5 mmol, 3 mmol) and triethylamine (0.5 mL). The reaction was allowed to proceed for 5 h. The reaction was confirmed to be complete by TLC. The organic phase was purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give a white solid (756.6 mg, 90% yield) of the target compound from Example 18.

[0323] 1 H NMR (400 MHz, CDCl3 d) d : 9.65 (s, 1H), 8.47 (dd, J = 4.7, 1.6 Hz, 1H), 7.98 (d, J= 2.3 Hz, 1H), 7.87 (dd, J = 8.1, 1.6 Hz, 1H), 7.48 (d, J =2.3 Hz, 1H), 7.43 (d, J = 2.4 Hz, 1H), 7.42(dd, J = 8.1, 4.7 Hz, 1H), 6.80(d, J = 33.9 Hz, 1H), 6.20 (q, J = 4.9 Hz, 1H), 4.15 (s, 3H), 2.28 (s, 3H)ppm.

[0324] Example 19: Synthesis ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)acrylamide)-5-chloro-3-methylbenzamide (Compound 1 in Table 5)

[0325]

[0326]

[0327] Step 1: Synthesis of intermediate Ib-2, 2-amino-5-chloro-3-methylbenzyl alcohol

[0328] Under ice bath conditions, anhydrous tetrahydrofuran (80 mL) was added to a 250 mL single-necked flask containing intermediate Ib-1 (3.712 g, 20 mmol), and the flask was purged with argon gas. Under ice bath stirring conditions, lithium aluminum tetrahydrofuran powder (total 910.8 mg, 24 mmol) was added to the reaction flask in three batches, with each addition 10 min apart, and the flask was purged with argon gas after each addition. After the addition was completed, the reaction was carried out under ice bath conditions for 1 h, and the reaction was confirmed to be complete by TLC.

[0329] Under ice bath conditions, ice water (0.91 mL), NaOH aqueous solution (1 M, 0.91 mL), and ice water (2.73 mL) were added dropwise in sequence while stirring rapidly to quench the reaction; an appropriate amount of ethyl acetate was added for dilution (100 mL); the reaction solution was quickly allowed to stand and filtered, and the filtrate (yellow) was collected. The filtrate was washed with saturated brine (50 mL × 3), and the organic phase was dried with anhydrous sodium sulfate. The organic phase was then purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 2:1) to give intermediate Ib-2 as a white solid (1.592 mg, yield 46%).

[0330] 1 H NMR (400 MHz, CDCl3) δ 7.01 (d,J = 2.1 Hz, 1H), 6.92 (d, J = 2.3Hz, 1H), 4.61 (s, 2H), 2.15 (s, 3H).

[0331] Step 2: Synthesis of intermediate Ib-3,2-amino-5-chloro-3-methylbenzaldehyde

[0332] Under ice bath conditions, dichloromethane (60 mL) and slowly activated manganese dioxide (MnO2) (2.087 g, 24 mmol) were added to a 250 mL single-necked flask containing intermediate Ib-2 (1.373 g, 8 mmol). The reaction was then transferred to room temperature and allowed to proceed for 2 h. The reaction was confirmed to be complete by TLC.

[0333] The reaction solution was washed with saturated saline solution (50 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the organic phase was purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 3:1) to give intermediate Ib-3 as a yellow solid (1.204 g, yield 89%).

[0334] 1 H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.12(d, J = 1.6 Hz, 1H), 2.08 (s, 3H) ppm.

[0335] Step 3: Synthesis of intermediate Ib-5 3-bromo-N-(4-chloro-2-formyl-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide

[0336] Dichloromethane (32 mL) was added to a 100 mL single-necked flask containing intermediate Ib-4 (2.420 g, 8 mmol) at room temperature. Oxaloyl chloride (0.9 mL, 10 mmol) and DMF (55.2 μL, 0.8 mmol) were added sequentially with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 min. The reaction was confirmed to be complete by TLC. The solvent was evaporated to obtain the acyl chloride corresponding to Ib-4, which was then stored dry for a short period.

[0337] Under ice bath conditions, anhydrous acetonitrile (20 mL) and DIEA (2.73 mL, 21 mmol) were added sequentially to a 100 mL single-necked flask containing intermediate Ib-3 (1.187 g, 7 mmol). The acyl chloride corresponding to Ib-4 prepared in the previous step was dissolved in 10 mL of anhydrous acetonitrile and slowly added dropwise to the reaction flask under ice bath stirring. After the addition was complete, the temperature was raised to 50°C and the reaction was carried out for 5 h. The reaction was confirmed to be complete by TLC.

[0338] The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL), the organic phase was rotary evaporated, and the organic phase was washed with saturated ammonium chloride aqueous solution (40 mL × 3) in ethyl acetate (40 mL). The organic phase was dried with anhydrous sodium sulfate, and the organic phase was purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 3:1) to give intermediate Ib-5 as a white solid (1.935 g, yield 61%).

[0339] 1 H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 9.92 (s, 1H), 8.47 (dd, J =4.7, 1.6 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 7.47 (d, J = 2.2 Hz, 1H), 7.39 (dd, J = 8.0, 4.7 Hz, 1H), 7.09 (s, 1H), 2.22(s, 3H) ppm.

[0340] Step 4: Synthesize intermediate Ib-6 ( E Ethyl acrylate 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1Hpyrazole-5-carboxamido)-5-chloro-3-ethylphenyl)

[0341] At room temperature, dichloromethane (12 mL) and ethoxyformylmethylenetriphenylphosphine (1.672 g, 4.8 mmol) were added to a 100 mL single-necked flask containing intermediate Ib-5 (1.816 g, 4 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. The reaction was confirmed to be complete by TLC.

[0342] Rotary evaporation of the organic phase followed by column chromatography (n-heptane:ethyl acetate = 3:1) yielded intermediate Ib-6 as a white solid (1.887 g, 90% yield). E : Z >99:1).

[0343] 1 H NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 4.7, 1.4 Hz, 1H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H), 7.71 (s, 1H), 7.69 (d, J = 15.9 Hz, 1H), 7.44 (d, J = 2.0Hz, 1H), 7.36 (dd, J = 8.0, 4.7 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 6.97 (s,1H), 6.37 (d, J = 15.9 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 2.21 (s, 3H), 1.31(t, J = 7.1 Hz, 3H) ppm.

[0344] Step 5: Synthesize intermediate Ib-7 ( E )-3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1Hpyrazol-5-carboxamido)-5-chloro-3-ethylphenyl)acrylic acid

[0345] Under ice bath conditions, ethanol (15 mL) and NaOH aqueous solution (1 M, 15 mL) were added sequentially to a 100 mL single-necked flask containing intermediate Ib-6 (1.887 g, 3.60 mmol). After the addition was completed, the reaction was carried out at room temperature for 4 h. The reaction was confirmed to be complete by TLC.

[0346] The reaction solution was concentrated by rotary evaporation, and dilute hydrochloric acid (2M, 9 mL) was slowly added under ice bath stirring. A white solid precipitated out. The reaction solution was filtered, washed with water (10 mL × 3), and the filter cake was recovered and dried to obtain a white solid of intermediate Ib-7 (1.511 mg, yield 85%).

[0347] 1 H NMR (400 MHz, CDCl3) δ 8.52 (dd, J = 4.7, 1.4 Hz, 1H), 7.94 (dd, J = 8.0, 1.4 Hz, 1H), 7.80 (s, 1H), 7.74 (d, J= 15.9 Hz, 1H), 7.68 (dd, J =8.0, 4.7 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.19(s, 1H), 6.70 (d, J = 15.9 Hz, 1H), 2.21 (s, 3H) ppm.

[0348] Step 6: Synthesis Example 19 ( E 2-(3-amino-3-oxopropyl-1-en-1-yl)-4-chloro-6-methylphenyl-3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide

[0349] Anhydrous acetonitrile (3 mL) was added to a 50 mL single-necked flask containing intermediate Ib-7 (496.1 mg, 1 mmol). Oxaloyl chloride (0.12 mL, 1.3 mmol) and DMF (6.9 μL, 0.1 mmol) were added sequentially with stirring. After the addition was complete, the reaction was allowed to proceed at room temperature for 1 h. The reaction was confirmed to be complete by TLC. The solvent was evaporated to obtain the acyl chloride corresponding to Ib-7, which was then stored dry for a short period.

[0350] The acyl chloride corresponding to Ib-4 prepared in the previous step was dissolved in 2 mL of anhydrous acetonitrile. Under ice bath and stirring, the acetonitrile solution of the acyl chloride was slowly added dropwise to a 50 mL single-necked flask containing ammonia water (0.3 mL) and anhydrous acetonitrile (3 mL). After the addition was completed, the reaction was continued at 0°C for 0.5 h. A large amount of white solid precipitated at the bottom of the reaction solution. The reaction was completed by TLC detection.

[0351] The reaction was terminated by adding saturated ammonium chloride aqueous solution (2 mL), the reaction solution was filtered, the filter cake was washed with a small amount of acetonitrile (1 mL × 3) and water (5 mL × 3), the filter cake was recovered and dried to obtain a white solid of the target compound in Example 19 (382.3 mg, yield 77%).

[0352] 1 H NMR (400 MHz, DMSO) δ 10.42 (s, 1H), 8.52 (dd, J = 4.6, 1.5 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.60 (dd, J = 8.0, 4.7 Hz, 1H), 7.50 (d,J = 1.8 Hz, 1H), 7.45 (d, J = 15.7 Hz, 1H), 7.41 (s, 1H), 7.40 (d, J = 1.9Hz, 1H), 6.60 (d, J = 15.7 Hz, 1H), 5.53 (s, 2H), 2.15 (s, 3H) ppm.

[0353] Example 20: Synthesis of (E)-3-bromo-N-(4-chloro-2-(3-(isopropylamino)-3-oxopropyl-1-en-1-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 4 in Table 5)

[0354]

[0355] Referring to step 6 of Example 19, replace the ammonia with isopropylamine;

[0356] The other steps are similar to those in Example 19, yielding a white solid of the target compound of Example 20.

[0357] 1 H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 8.52 (dd, J = 4.6, 1.5 Hz, 1H), 8.16 (dd, J = 8.0, 1.5 Hz, 1H), 7.97 (d, J = 7.5 Hz, 1H), 7.60 (dd, J =8.0, 4.7 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.45 (d, J = 15.7 Hz, 1H), 7.41(s, 1H), 7.40 (d, J = 1.9 Hz, 1H), 6.60 (d, J = 15.7 Hz, 1H), 3.93 (dq, J =13.4, 6.5 Hz, 1H), 2.15 (s, 3H), 1.10 (d, J = 6.5 Hz, 6H) ppm.

[0358] Example 21: Synthesis ( E)-3-bromo-N-(4-chloro-2-(3-(isopropylamino)-2-methyl-3-oxopropyl-1-en-1-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 14 in Table 5)

[0359]

[0360] Synthetic intermediate Ib-6-Me ( E ethyl 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3-methylphenyl)-2-methacrylate

[0361] At room temperature, dichloromethane (12 mL) and ethoxyformyl ethylidene triphenylphosphine (1.672 g, 4.8 mmol) were added to a 100 mL single-necked flask containing intermediate Ib-5 (1.816 g, 4 mmol). After the addition was complete, the reaction was allowed to proceed at room temperature for 2 h. The reaction was confirmed to be complete by TLC.

[0362] Rotary evaporation of the organic phase followed by column chromatography (n-heptane:ethyl acetate = 3:1) yielded the intermediate Ib-6-Me as a white solid (1.956 g, 91% yield). E : Z >99:1).

[0363] 1 H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 4.7, 1.6 Hz, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 7.54 (s, 1H), 7.49 (s, 1H), 7.37 (dd, J = 8.0, 4.7 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.91 (s, 1H), 4.24(q, J = 7.1 Hz, 2H), 2.21 (s, 3H), 1.93 (d, J = 1.3 Hz, 3H), 1.31 (t, J = 7.1Hz, 3H) ppm.

[0364]

[0365] Referring to step 5 of Example 19, Ib-6 is replaced with intermediate Ib-6-Me;

[0366] Referring to step 6 of Example 19, replace the ammonia with isopropylamine;

[0367] The remaining steps are similar to those in Example 19, yielding a white solid of the target compound of Example 21.

[0368] 1 H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 8.50 (dd, J = 4.7, 1.6 Hz, 1H), 8.16 (dd, J = 8.0, 1.6 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.61 (dd, J =8.0, 4.7 Hz, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.07(d, J = 2.0 Hz, 1H), 3.98 (dq, J = 13.0, 6.5 Hz, 1H), 2.14 (s, 3H), 1.85 (s,3H), 1.11 (d, J = 6.5 Hz, 6H) ppm.

[0369] Example 22: Synthesis ( E )-3-bromo-N-(4-chloro-2-(3-(isopropylamino)-2-ethyl-3-oxopropyl-1-en-1-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 24 in Table 5)

[0370]

[0371] Synthetic intermediate Ib-6-Et ( E 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3-methylphenyl)-2-ethyl acrylate

[0372] Under argon protection, NaH (115.2 mg, 4.8 mmol) and triethyl 2-phosphonobutyrate (1.110 g, 4.4 mmol) were added to a 100 mL three-necked flask containing anhydrous THF (20 mL). The mixture was stirred at room temperature for 0.5 h, and then Ib-5 (1.816 g, 4 mmol) was added. The reaction was carried out at room temperature for 8 h under argon protection. The reaction was confirmed to be complete by TLC.

[0373] The reaction was quenched with dilute hydrochloric acid aqueous solution, the solvent was removed by rotary evaporation, and the solution was redissolved in ethyl acetate (30 mL). The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), and the organic phase was dried with anhydrous sodium sulfate. The organic phase was then purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 3:1) to give the intermediate Ib-6-Et as a white solid (1.804 g, yield 82%, E:Z > 99:1).

[0374] 1 H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 4.7, 1.6 Hz, 1H), 7.86 (dd, J = 8.0, 1.6 Hz, 1H), 7.58 (s, 1H), 7.43 (s, 1H), 7.37 (dd, J = 8.0, 4.7 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.91 (s, 1H), 4.25(q, J = 7.1 Hz, 2H), 2.34 (q, J = 7.1 Hz, 2H), 2.20 (s, 3H), 1.31 (t, J = 7.1Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H) ppm.

[0375]

[0376] Referring to step 5 of Example 19, Ib-6 is replaced with intermediate Ib-6-Et;

[0377] Referring to step 6 of Example 19, replace the ammonia with isopropylamine;

[0378] The remaining steps are similar to those in Example 19, yielding a white solid of the target compound of Example 22.

[0379] 1 H NMR (400 MHz, CDCl3) δ 9.34 (s, 1H), 8.40 (dd, J = 4.7, 1.3 Hz, 1H), 7.83 (dd, J = 8.0, 1.3 Hz, 1H), 7.35 (dd, J = 8.0, 4.7 Hz, 1H), 7.25 (s,1H), 7.17 (d, J = 1.4 Hz, 1H), 6.97 (d, J = 1.4 Hz, 1H), 6.80 (s, 1H), 6.01(d, J = 7.7 Hz, 1H), 3.95 (dq, J = 13.3, 6.6 Hz, 1H), 2.21 (s, 3H), 2.19 (q, J = 7.4 Hz, 2H), 1.08 (d, J = 6.5 Hz, 6H), 0.97 (t, J = 7.4 Hz, 3H) ppm.

[0380] Example 23: Synthesis ( Z )-3-bromo-N-(4-chloro-2-(3-(((1-cyclopropylethyl)amino)-2-fluoro-3-oxopropyl-1-en-1-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 39 in Table 5)

[0381]

[0382] Following the synthesis steps in Example 19, intermediate Ib-2-5 was obtained.

[0383] Synthetic intermediate Ib-6-F ( Z )(Z)-3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3-methylphenyl)-2-fluoroacrylate

[0384] At room temperature, anhydrous TEA (1.04 mL, 8 mmol) was added to a 100 mL three-necked flask containing triethyl 2-fluoro-2-phosphorylacetate (1.066 g, 4.4 mmol). The flask was purged with argon. Anhydrous THF (20 mL) and anhydrous magnesium bromide (810.1 mg, 4.4 mmol) were added. After stirring at room temperature for 1 min, intermediate Ib-2-5 (1.982 g, 4 mmol) was added. The reaction was carried out at room temperature for 2 h under argon protection. The reaction was confirmed to be complete by TLC.

[0385] The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, and the organic phase was purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 3:1) to give intermediate Ib-2-6-F. Z A white solid (2.064 g, yield 88%), E:Z < 1:99.

[0386] 1 H NMR (400 MHz, CDCl3) δ 8.44 (dd, J = 4.7, 1.6 Hz, 1H), 7.85 (dd, J = 8.0, 1.6 Hz, 1H), 7.84 (s, 1H), 7.63 (d, J = 2.0 Hz, 1H), 7.36 (dd, J =8.0, 4.7 Hz, 1H), 7.22 (d, J = 1.9 Hz, 1H), 6.92 (s, 1H), 6.91 (d, J = 33.6Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.16 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H)ppm.

[0387]

[0388] Referring to step 5 of Example 19, intermediate Ib-2-6-F ( Z Replace Ib-6;

[0389] Referring to step 6 of Example 19, the ammonia was replaced with 1-cyclopropylethylamine hydrochloride;

[0390] The remaining steps are similar to those in Example 19, yielding a white solid of the target compound of Example 23.

[0391] 1 H NMR (400 MHz, DMSO) δ 10.28 (s, 1H), 8.42 (d, J = 8.4 Hz, 1H), 8.32 (dd, J = 4.6, 1.6 Hz, 1H), 7.95 (dd, J = 8.0, 1.6 Hz, 1H), 7.42 (d, J =2.0 Hz, 1H), 7.40 (dd, J = 8.0, 4.6 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.21(s, 1H), 6.68 (d, J = 36.7 Hz, 1H), 3.10 (qd, J = 14.7, 7.3 Hz, 1H), 1.98 (s,3H), 1.01 (d, J = 6.7 Hz, 3H), 0.86 – 0.76 (m, 1H), 0.26 (m, 1H), 0.23 – 0.15(m, 1H), 0.09 – -0.04 (m, 2H) ppm.

[0392] Example 24: Synthesis ( E )-2-(3-(3-bromo-1-(3-chloro-2-pyridyl)-1H-pyrazol-5-yl)-2-fluoroacrylamide)-5-chloro-3-methyl-N-methylbenzamide (Compound 180 in Table 5)

[0393]

[0394] Following the synthesis steps in Example 19, intermediate Ib-3-5 was obtained.

[0395] Synthetic intermediate Ib-6-F ( E ()( E 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-3,5-dichlorophenyl)-2-fluoroacrylate ethyl ester

[0396] Under argon protection and at -78°C, 3.03 mL of 1.6 M butyllithium (4.8 mmol) in THF was added to a 100 mL three-necked flask containing triethyl 2-fluoro-2-phosphorylacetate (1.162 g, 4.8 mmol) and anhydrous THF (10 mL). A solution of intermediate Ib-3-5 in anhydrous THF (10 mL) was then added to the reaction mixture, and the reaction was carried out at -78°C for 30 min. The reaction was confirmed to be complete by TLC.

[0397] The reaction was quenched with dilute hydrochloric acid aqueous solution, the solvent was removed by rotary evaporation, and the solution was redissolved in ethyl acetate (20 mL). The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), and the organic phase was dried with anhydrous sodium sulfate. The organic phase was then purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 3:1) to give intermediate Ib-3-6-F. E A white solid (1.053 g, yield 64%, E:Z = 73:27).

[0398] 1 H NMR (400 MHz, CDCl3) δ 8.43 (dd, J = 4.7, 1.5 Hz, 1H), 8.16 (s,1H), 7.85 (dd, J = 8.1, 1.5 Hz, 1H), 7.80 (dd, J = 8.1, 4.7 Hz, 1H), 7.72 (d, J = 1.9 Hz, 1H), 7.15 (d, J = 1.9 Hz, 1H), 6.83 (s, 1H), 6.72 (d, J = 19.5Hz, 1H), 4.22 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H) ppm.

[0399]

[0400] Referring to step 5 of Example 19, intermediate Ib-2-6-F ( E Replace Ib-6;

[0401] Referring to step 6 of Example 19, cyclopropylamine was used to replace the ammonia.

[0402] The remaining steps are similar to those in Example 19, yielding a white solid of the target compound of Example 24.

[0403] 1 H NMR (400 MHz, DMSO) δ 8.79 (d, J = 4.2 Hz, 1H), 8.53 (dd, J = 4.7, 1.5 Hz, 1H), 8.17 (dd, J = 8.1, 1.5 Hz, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 8.1, 4.7 Hz, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.11 (s, 1H), 6.84 (d, J =19.8 Hz, 1H), 2.85 – 2.74 (m, 1H), 0.75 – 0.67 (m, 2H), 0.64 – 0.53 (m, 2H)ppm.

[0404] Example 25: Synthesis ( Z )-3-bromo-N-(4-chloro-2-(2-chloro-3-(isopropylamino)-3-oxopropyl-1-en-1-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 54 in Table 5)

[0405]

[0406] Synthetic intermediate Ib-6-Cl ( Z Ethyl 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3-methylphenyl)-2-chloroacrylate

[0407] Dichloromethane (20 mL) was added to a 100 mL three-necked flask containing ethoxyformylmethylenetriphenylphosphine (1.672 g, 4.8 mmol) at -20°C. The flask was then purged with argon. NCS (640.9 mg, 4.8 mmol) was added at -20°C, and the mixture was kept at -20°C for 1 h. The temperature was then raised to room temperature. At room temperature, intermediate Ib-5 (1.816 g, 4 mmol) and K2CO3 (1.382 g, 10 mmol) were added, and the mixture was reacted at room temperature for 10 h. The reaction was confirmed to be complete by TLC.

[0408] The reaction solution was washed with saturated brine (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the organic phase was rotary evaporated and purified by column chromatography (n-heptane: ethyl acetate = 3:1) to give the intermediate Ib-6-Cl as a white solid (1.580 g, yield 71%, E:Z < 1:99).

[0409] 1 H NMR (400 MHz, CDCl3) δ 8.46 (dd, J = 4.6, 1.3 Hz, 1H), 7.87 (dd, J = 8.0, 1.3 Hz, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.60 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.0, 4.6 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 6.94 (s, 1H), 4.32(q, J = 7.1 Hz, 2H), 2.23 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H) ppm.

[0410]

[0411] Referring to step 5 of Example 19, Ib-6 is replaced with intermediate Ib-6-Cl;

[0412] Referring to step 6 of Example 19, replace the ammonia with isopropylamine;

[0413] The remaining steps are similar to those in Example 19, yielding a white solid of the target compound of Example 25.

[0414] 1 H NMR (400 MHz, DMSO) δ 10.41 (s, 1H), 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 8.18 (d, J =8.0 Hz, 1H), 8.16 (dd, J =8.1, 1.6 Hz, 1H), 7.69 (s, 1H),7.65 (d, J = 1.9 Hz, 1H), 7.61 (dd, J = 8.1, 4.7 Hz, 1H), 7.46 (d, J= 1.9Hz, 1H), 7.35 (s, 1H), 4.01 (dq, J = 13.2, 6.6 Hz, 1H), 2.17 (s, 3H), 1.14(d, J = 6.6 Hz, 6H) ppm.

[0415] Example 26: Synthesis ( Z )-3-bromo-N-(4-chloro-2-(2-bromo-3-(isopropylamino)-3-oxopropyl-1-en-1-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 64 in Table 5)

[0416]

[0417] Synthetic intermediate Ia-4-Br ( Z ethyl 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-chloro-3-methylphenyl)-2-bromoacrylate

[0418] Referring to the synthesis method of Example 25, NBS was used to replace NCS to obtain the intermediate Ib-6-Br;

[0419] 1 H NMR (400 MHz, CDCl3) δ 8.45 (dd, J = 4.7, 1.3 Hz, 1H), 8.06 (s,1H), 7.87 (dd, J = 8.1, 1.3 Hz, 1H), 7.66 (s, 1H), 7.64 (d, J = 2.1 Hz, 1H), 7.38 (dd, J = 8.0, 4.7 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 6.93 (s, 1H), 4.31(t, J = 7.1 Hz, 2H), 2.24 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H) ppm.

[0420]

[0421] Referring to step 5 of Example 19, Ib-6 is replaced with intermediate Ib-6-Br;

[0422] Referring to step 6 of Example 19, replace the ammonia with isopropylamine;

[0423] The remaining steps are similar to those in Example 19, yielding a white solid of the target compound of Example 26.

[0424] 1 H NMR (400 MHz, DMSO) δ 10.37 (s, 1H), 8.51 (dd, J = 4.7, 1.5 Hz, 1H), 8.17 (dd, J = 8.1, 1.5 Hz, 1H), 8.07 (d, J = 7.9 Hz, 1H), 7.75 (s, 1H), 7.62 (dd, J = 8.1, 4.7 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 2.2Hz, 1H), 7.34 (s, 1H), 3.96 (dq, J = 13.3, 6.6 Hz, 1H), 2.17 (s, 3H), 1.13(d, J = 6.6 Hz, 6H) ppm.

[0425] Example 27: Synthesis ( E )-3-bromo-N-(4-chloro-2-(2-cyano-3-(isopropylamino)-3-oxopropyl-1-en-1-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 74 in Table 5)

[0426]

[0427] Piperidine (340.6 mg, 4 mmol) was added to a 100 mL single-necked flask containing intermediate Ib-5 (1.816 g, 4 mmol) and 2-cyano-N-isopropylacetamide (605.57 mg, 4.8 mmol). The reaction was allowed to proceed for 4 h at room temperature, and the reaction was confirmed to be complete by TLC.

[0428] The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the organic phase was purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 3:1) to give a white solid of Example 26 (1.783 mg, yield 79%, E:Z > 99:1).

[0429]

[0430] 1 H NMR (400 MHz, CDCl3) δ 15.85 (s, 1H), 10.68 (d, J = 7.4 Hz, 1H), 9.22 (s, 1H), 8.53 (dd, J = 4.7, 1.5 Hz, 1H), 7.94 (dd, J = 8.0, 1.5 Hz, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.54 (d, J = 1.4 Hz, 1H), 7.45 (dd, J = 8.0, 4.7Hz, 1H), 7.01 (s, 1H), 4.36 (dq, J = 13.2, 6.6 Hz, 1H), 2.46 (s, 3H), 1.41(d, J = 6.6 Hz, 6H) ppm.

[0431] Example 28: Synthesis ( Z )-3-bromo-N-(4-chloro-2-methyl-6-(3,3,3-trifluoro-2-(isopropylcarbamoyl)prop-1-en-1-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 84 in Table 5)

[0432]

[0433] Under argon protection at room temperature, CuI (38.1 mg, 0.2 mmol) was added to a 50 mL three-necked flask containing compound 64 (602.1 mg, 1 mmol), anhydrous DMF (4 mL), and HMPA (0.5 mL). The mixture was heated to 75°C, and while stirring, an anhydrous DMF solution (1 mL) of methyl fluorosulfonyl difluoroacetate (384.2 mg, 2 mmol) was slowly added via syringe. The addition process lasted for 2 h. The reaction was carried out at 75°C for 14 h under argon protection, and the reaction was confirmed to be complete by TLC.

[0434] The reaction was quenched with a saturated ammonium chloride aqueous solution (2 mL), diluted with dichloromethane (15 mL), and the organic phase was washed with saturated brine (20 mL × 5). The organic phase was dried over anhydrous sodium sulfate, and purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give a white solid (320.8 mg, yield 53%) as described in Example 27.

[0435]

[0436] 1 H NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 4.6, 1.5 Hz, 1H), 7.94 (s,1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.54 (s, 1H), 7.39 (dd, J = 8.0, 4.7 Hz,1H), 7.10 (s, 1H), 6.99 (s, 1H), 6.01 (d, J = 7.6 Hz, 1H), 4.11 (td, J =13.5, 6.6 Hz, 1H), 2.23 (s, 3H), 1.17 (d, J = 6.6 Hz, 6H) ppm.

[0437] Example 29: Synthesis ( Z )-3-bromo-N-(2-bromo-4-chloro-6-(2-fluoro-3-(piperidin-1-yl)-3-thioprop-1-en-1-yl)phenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 199 in Table 5)

[0438]

[0439]

[0440] Step 1: Synthesize intermediate Ib-29-1

[0441] At room temperature, anhydrous TEA (1.3 mL, 10 mmol) was added to a 100 mL three-necked flask containing triethyl 2-fluoro-2-phosphorylacetate (1.332 g, 5.5 mmol). The flask was purged with argon gas, and anhydrous THF (20 mL) and anhydrous magnesium bromide (1.013 mg, 5.5 mmol) were added. After stirring at room temperature for 1 min, intermediate Ib-3 (1.172 g, 5 mmol) was added. The reaction was carried out at room temperature for 2 h under argon protection. The reaction was confirmed to be complete by TLC.

[0442] The reaction solution was washed with saturated ammonium chloride aqueous solution (30 mL × 3), the organic phase was dried with anhydrous sodium sulfate, the organic phase was rotary evaporated and purified by column chromatography (n-heptane: ethyl acetate = 3:1) to give intermediate Ib-28-1 as a yellow solid (1.458 g, yield 90%, E:Z < 1:99).

[0443] 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 2.3 Hz, 1H), 7.31 (d, J = 2.2Hz, 1H), 6.92 (d, J = 33.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.83 (s, 2H), 1.39 (t, J = 7.1 Hz, 3H) ppm.

[0444] Step 2: Synthesize intermediate Ib-29-2

[0445] Under ice bath conditions, ethanol (10 mL) and NaOH aqueous solution (1 M, 10 mL) were added sequentially to a 100 mL single-necked flask containing intermediate Ib-29-1 (1.452 g, 4.5 mmol). After the addition was completed, the reaction was carried out at room temperature for 4 h. The reaction was confirmed to be complete by TLC.

[0446] The reaction solution was concentrated by rotary evaporation. Under ice bath stirring, dilute hydrochloric acid (2M, 5 mL) was slowly added to adjust the pH to neutral, and ethyl acetate was added to dilute (30 mL). The solution was washed with water (20 mL × 3), and the organic phase was dried with anhydrous sodium sulfate. The organic phase was removed by rotary evaporation to obtain crude intermediate Ib-29-2.

[0447] Step 3: Synthesize intermediate Ib-28-3

[0448] At -10°C, dichloromethane (20 mL), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (1 M, 5.4 mmol), and 1-hydroxybenzotriazole (Hobt) were added sequentially to a 100 mL single-necked flask containing intermediate Ib-29-2 (1.325 g, 4.5 mmol). After the addition was complete, the reaction was carried out at -10°C for 1 h. The Ib-29-2 spot disappeared as detected by TLC. Then, DIEA (1.82 mL, 14 mmol) and piperidine (510.9 mg, 6 mmol) were added, and the temperature was raised to room temperature for 2 h. The reaction was completed as detected by TLC.

[0449] The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL), the organic phase was rotary evaporated, and the organic phase was redissolved in ethyl acetate (30 mL) and washed with saturated ammonium chloride aqueous solution (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, and the organic phase was rotary evaporated and purified by column chromatography (n-heptane: ethyl acetate = 2:1) to give a yellow solid of intermediate Ib-29-3 (1.395 g, yield 86%).

[0450] 1 H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 2.3 Hz, 1H), 7.34 (d, J = 2.3Hz, 1H), 6.90 (d, J = 33.3 Hz, 1H), 3.97 (s, 2H), 3.76 – 3.74 (m, 2H), 3.55 –3.52 (m, 2H), 1.82 – 1.78 (m, 2H), 1.72 – 1.67 (m, 2H) ppm.

[0451] Step 4: Synthesize intermediate Ib-29-4

[0452] At room temperature, Lawson's reagent (889.8 mg, 2.2 mmol) was added to a 100 mL single-necked flask containing Ib-29-3 (1.266 g, 3.5 mmol) and toluene (20 mL). The flask was purged with argon gas and heated to 80°C for 6 h. The reaction was confirmed to be complete by TLC.

[0453] The solvent was removed by rotary evaporation, and the organic phase was redissolved in dichloromethane (30 mL). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, and purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 3:1) to give intermediate Ib-28-4 as a yellow solid (959.7 mg, yield 73%).

[0454] 1 H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 2.3 Hz, 1H), 7.21 (d, J = 2.3Hz, 1H), 7.01 (d, J = 33.8 Hz, 1H), 3.98 (s, 2H), 3.46 – 3.44 (m, 2H), 3.17 –3.15 (m, 2H), 1.72 – 1.69 (m, 2H), 1.67 – 1.64 (m, 2H) ppm.

[0455] Step 5: Synthesis Example 29

[0456] Under ice bath conditions, anhydrous acetonitrile (10 mL) and DIEA (1.04 mL, 8 mmol) were added sequentially to a 100 mL single-necked flask containing intermediate Ib-29-4 (944.3 mg, 2.5 mmol). The acyl chloride corresponding to Ib-4 (3 mmol) prepared in the previous step was dissolved in 5 mL of anhydrous acetonitrile and slowly added dropwise to the reaction flask under ice bath stirring. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 5 h. The reaction was confirmed to be complete by TLC.

[0457] The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL), the organic phase was rotary evaporated, and the organic phase was washed with ethyl acetate (30 mL) saturated ammonium chloride aqueous solution (30 mL × 3). The organic phase was dried with anhydrous sodium sulfate, and the organic phase was rotary evaporated and purified by column chromatography (n-heptane: ethyl acetate = 2:1) to obtain the white solid of Example 29 (689.9 g, yield 42%).

[0458] 1 H NMR (400 MHz, DMSO) δ 10.73 (s, 1H), 8.53 (dd, J = 4.7, 1.5 Hz, 1H), 8.17 (dd, J = 8.1, 1.5 Hz, 1H), 7.94 (d, J = 2.3 Hz, 1H), 7.75 (d, J =2.3 Hz, 1H), 7.61 (dd, J = 8.1, 4.7 Hz, 1H), 7.42 (s, 1H), 6.82 (d, J = 35.8Hz, 1H), 3.46 – 3.44 (m, 2H), 3.17 – 3.15 (m, 2H), 1.72 – 1.69 (m, 2H), 1.67 – 1.64 (m, 2H) ppm.

[0459] Example 30: Synthesis ( Z )-3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-thioamino)-5-cyano-3-methylphenyl)-N-(tert-butyl)-2-fluoroacrylamide (Compound 216 in Table 5)

[0460]

[0461] Referring to the synthesis method of Example 22, intermediate Ib-1 was replaced with 2-amino-5-cyano-3-methylbenzoic acid to synthesize intermediate Ib-30-6. Z Ethyl 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-5-cyano-3-methylphenyl)-2-fluoroacrylate

[0462] Synthetic intermediate Ib-29-7 ( Z Ethyl 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-thioamino)-5-cyano-3-methylphenyl)-2-fluoroacrylate

[0463] At room temperature, Lawson's reagent (485.4 mg, 1.2 mmol) was added to a 100 mL single-necked flask containing intermediate Ib-30-6 (1.066 g, 2 mmol) and toluene (10 mL). The flask was purged with argon gas and heated to 110°C for 3 h. The reaction was confirmed to be complete by TLC.

[0464] The solvent was removed by rotary evaporation, and the organic phase was redissolved in dichloromethane (15 mL). The organic phase was washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, and purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ib-29-7 as a white solid (829.6 mg, yield 76%).

[0465] 1 H NMR (400MHz, CDCl3) δ 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 7.94 (dd, J =8.1, 1.6 Hz, 1H), 7.85 (s, 1H), 7.71 (d, J = 2.0 Hz, 1H), 7.65 (d, J = 2.1Hz, 1H), 7.45 (dd, J = 8.1, 4.7 Hz, 1H), 7.12 (s, 1H), 7.03 (d, J = 33.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.22 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H) ppm.

[0466]

[0467] Referring to step 6 of Example 22, 1-cyclopropylethylamine hydrochloride is replaced with tert-butylamine;

[0468] The other steps are similar to those in Example 22, yielding a white solid of the target compound of Example 30.

[0469] 1 H NMR (400MHz, DMSO- d 6) δ 10.73 (s, 1H), 8.45 (dd, J = 4.7, 1.6 Hz, 1H), 8.16 (dd, J = 8.1, 1.6 Hz, 1H), 7.85 (s, 1H), 7.67 (d, J = 2.1 Hz, 1H), 7.63 (dd, J = 8.1, 4.7 Hz, 1H), 7.43 (d, J = 2.2 Hz, 1H), 7.41 (s, 1H), 7.03(d, J = 35.6 Hz, 1H), 2.22 (s, 3H), 1.36 (s, 9H) ppm.

[0470] Example 31: Synthesis ( Z )-3-bromo-N-(4-bromo-2-(3-(ethylamino)-1-fluoro-3-oxoprop-1-en-1-yl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 166 in Table 5)

[0471]

[0472] Step 1: Synthesize intermediate Ib-31-2

[0473] Under ice bath conditions, dichloromethane (15 mL) and DIEA (2.08 mL, 16 mmol) were added sequentially to a 100 mL single-necked flask containing intermediate Ib-31-1 (1.725 g, 5 mmol). The acyl chloride corresponding to Ib-4 (6 mmol) prepared in the previous step was dissolved in 10 mL of dichloromethane and slowly added dropwise to the reaction flask under ice bath stirring. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 2 h. The reaction was confirmed to be complete by TLC.

[0474] The reaction was quenched by adding saturated ammonium chloride aqueous solution (10 mL), the organic phase was rotary evaporated, and the organic phase was washed with saturated ammonium chloride aqueous solution (30 mL × 3) in ethyl acetate (40 mL). The organic phase was dried over anhydrous sodium sulfate, and the organic phase was purified by rotary evaporation and column chromatography (n-heptane: ethyl acetate = 3:1) to give intermediate Ib-30-2 as a white solid (2.447 g, yield 82%).

[0475] 1 H NMR (400 MHz, DMSO- d 6) δ 8.51 (dd, J = 4.8, 1.6 Hz, 1H), 8.20 (dd, J = 8.0, 1.6 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.81 (s, 1H), 7.61 (dd, J = 8.0, 4.8 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 6.96 (s, 1H), 2.18 (s, 3H) ppm.

[0476] Step 2: Synthesize intermediate Ib-31-3

[0477] At room temperature, anhydrous DME (20 mL) was added to a 100 mL three-necked flask containing ethyl propynate (470.93 mg, 4.8 mmol) to replace the argon gas in the flask. Then, intermediate Ib-30-2 (2.386 g, 4 mmol), CuI (7.62 mg, 0.04 mmol), (PPh3)2PdCl2 (56.15 mg, 0.08 mmol), and K2CO3 (1.106 g, 8 mmol) were added sequentially. After the addition was completed, the mixture was heated to 80°C and reacted for 8 h. The reaction was confirmed to be complete by TLC.

[0478] The reaction was quenched by adding 2 mL of saturated ammonium chloride aqueous solution, the solvent was removed by rotary evaporation, the mixture was diluted with 40 mL of ethyl acetate, and the organic phase was washed with 30 mL × 3 saturated ammonium chloride aqueous solution. The mixture was dried over anhydrous sodium sulfate, and the organic phase was purified by rotary evaporation and column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ib-30-3 as a white solid (1.389 g, yield 62%).

[0479] 1 H NMR (400 MHz, DMSO- d 6) δ 8.52 (dd, J= 4.7, 1.6 Hz, 1H), 8.17 (dd, J = 8.0, 1.6 Hz, 1H), 7.87 (d, J = 2.3 Hz, 1H), 7.78 (s, 1H), 7.61 (dd, J = 8.0, 4.7 Hz, 1H), 7.55 (d, J = 2.3 Hz, 1H), 7.02 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H),2.18 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H) ppm.

[0480] Step 3: Synthesize intermediate Ib-31-4

[0481] At room temperature, anhydrous acetonitrile (16 mL), water (0.25 mL), and AgF (634.4 mg, 5 mmol) were added to a 100 mL single-necked flask containing intermediate Ib-31-3 (1.133 g, 2 mmol). After the addition was completed, the mixture was heated to 80°C and reacted for 12 h. The reaction was confirmed to be complete by TLC.

[0482] The reaction mixture was removed by rotary evaporation, diluted with dichloromethane (30 mL), dried over anhydrous sodium sulfate, and purified by rotary evaporation of the organic phase followed by column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ib-30-4 as a white solid (885.8 mg, yield 75%, E:Z < 1:99).

[0483] 1 H NMR (400 MHz, DMSO- d 6) δ 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.18 (dd, J = 8.0, 1.6 Hz, 1H), 7.83 (s, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.61 (dd, J = 8.0, 4.7 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 7.07 (s, 1H), 6.68 (d, J = 36.7 Hz, 1H), 4.31 (q, J= 7.1 Hz, 2H), 2.18 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H) ppm.

[0484]

[0485] Referring to steps 5 and 6 of Example 18, Ia-4 was replaced with Ib-30-4 and ammonia was replaced with ethylamine hydrochloride to obtain the white solid of the target compound of Example 31.

[0486] 1 H NMR (400 MHz, DMSO- d 6) δ 11.07 (s, 1H), 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 8.09 (dd, J = 8.1, 1.6 Hz, 1H), 7.65 (s, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.47 (dd, J = 8.1, 4.7 Hz, 1H), 7.37 (d, J = 2.3 Hz, 1H), 6.98 (s, 1H), 6.87(d, J = 36.6 Hz, 1H), 3.67 (q, J = 6.6 Hz, 2H), 2.18 (s, 3H), 1.19 (t, J =6.6 Hz, 3H) ppm.

[0487] Example 32: Synthesis ( E )-3-bromo-1-(3-chloropyridin-2-yl)-N-(2,4-dichloro-6-(3-(ethylamino)1-fluoro-3-oxoprop-1-en-1-yl)phenyl)-1H-pyrazole-5-carboxamide (Compound 182 in Table 5)

[0488]

[0489] Referring to the synthesis method of Example 31, intermediate Ib-32-1 was replaced with 2,4-dichloro-6-iodoaniline to obtain intermediate Ib-32-3.

[0490] Synthetic intermediate Ib-31-4 ( E 3-(2-(3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamido)-3,5-dichlorophenyl)-3-fluoroacrylate ethyl ester

[0491] At room temperature, anhydrous DMF (15 mL) was added to a 100 mL three-necked flask containing ethyl 2,2-difluoro-2-bromoacetate (608.9 mg, 3 mmol) and activated zinc powder (202.7 mg, 3.1 mmol). The argon gas in the flask was then replaced. Intermediate Ib-32-3 (1.085 g, 2 mmol), CuI (76.2 mg, 0.4 mmol), and Pd(PPh3)4 (115.6 mg, 0.1 mmol) were added sequentially. After the addition was complete, the mixture was heated to 70°C and reacted for 2 h. The reaction was confirmed to be complete by TLC.

[0492] The reaction was quenched by adding 2 mL of saturated ammonium chloride aqueous solution, the solvent was removed by rotary evaporation, the organic phase was diluted with 30 mL of ethyl acetate, washed with 30 mL × 5 saturated ammonium chloride aqueous solution, dried over anhydrous sodium sulfate, and purified by rotary evaporation of the organic phase and column chromatography (n-heptane:ethyl acetate = 2:1) to give intermediate Ib-32-4 as a white solid (372.24 mg, yield 37%, E:Z = 89:11).

[0493] 1 H NMR (400 MHz, DMSO- d 6) δ 8.50 (dd, J = 4.7, 1.6 Hz, 1H), 8.15 (dd, J = 8.1, 1.6 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.67 (d, J = 2.3Hz, 1H), 7.49 (dd, J = 8.1, 4.7 Hz, 1H), 7.21 (s, 1H), 6.97 (d, J = 21.2 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H) ppm.

[0494]

[0495] Referring to steps 5 and 6 of Example 18, Ia-4 was replaced with Ib-31-4, and ammonia was replaced with ethylamine hydrochloride to obtain the white solid of the target compound of Example 32.

[0496] 1 H NMR (400 MHz, DMSO-d 6) δ 10.59 (s, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.13 (dd, J = 8.1, 1.6 Hz, 1H), 7.93 (s, 1H), 7.65 (d, J = 2.3 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.51 (dd, J = 8.1, 4.7 Hz, 1H), 7.17 (s, 1H), 7.00(d, J = 21.2 Hz, 1H), 3.86 (q, J = 6.2 Hz, 2H), 1.14 (t, J = 6.2 Hz, 3H) ppm.

[0497] Example 33: Synthesis ( Z )-N-(2-(3-(benzylamino)-2-fluoro-3-oxopropyl-1-en-1-yl)-4-bromo-6-methylphenyl)-3-bromo-1-(2,4-dichlorophenyl)-1H-pyrazole-5-carboxamide (Compound 170 in Table 5)

[0498]

[0499] Referring to step 3 of Example 22, Ib-4 was replaced with 3-bromo-1-(2,4-dichlorophenyl)-1H-pyrazole-5-carboxylic acid;

[0500] Referring to step 6 of Example 22, 1-cyclopropylethylamine hydrochloride is replaced with benzylamine;

[0501] The other steps are similar to those in Example 22, yielding a white solid of the target compound in Example 33.

[0502] 1 H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 8.47(t, J =4.6 Hz, 1H), 7.89(d, J =1.0 Hz, 1H), 7.83 (d, J =6.0 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H). 8.56 –7.53 (m, 2H), 7.31 – 7.27 (m, 2H), 7.26 – 7.22 (m, 3H), 7.02 (s, 1H), 6.82(d, J = 35.7 Hz, 1H), 4.45 (d, J = 4.6 Hz, 2H), 2.24 (s, 3H) ppm.

[0503] Example 34: Synthesis ( Z )-4-bromo-N-(6-bromo-3-chloro-2-(2-fluoro-3-(methylamino)-3-oxopropyl-1-en-1-yl)phenyl)-3-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 201 in Table 5)

[0504]

[0505] Referring to step 1 of Example 22, 2-amino-3-methyl-5-chlorobenzoic acid was replaced with 2-amino-3-bromo-5-chlorobenzoic acid.

[0506] Referring to step 3 of Example 22, Ib-4 was replaced with 3-chloro-1-(3-chloro-2-pyridyl)-1H-pyrazole-5-carboxylic acid;

[0507] Referring to step 6 of Example 22, 1-cyclopropylethylamine hydrochloride is replaced with monomethylamine hydrochloride;

[0508] The other steps were similar to those in Example 22, resulting in a white solid of the target compound in Example 34.

[0509] 1 H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.62 (q, J = 4.8 Hz, 1H), 8.51 (dd, J = 4.7, 1.6 Hz, 1H), 7.96 (dd, J = 8.1, 1.6 Hz, 1H), 7.58 (d, J =6.0 Hz, 1H), 7.40 (dd, J = 8.0, 4.6 Hz, 1H), 7.46 (d, J = 6.0 Hz, 1H), 6.76(d, J = 35.9 Hz, 1H), 2.87 (d, J= 4.8 Hz, 3H) ppm.

[0510] Example 35: Synthesis ( Z )-3-bromo-N-(4-chloro-2-(2-fluoro-2-(isoxazol-3-yl)vinyl)-6-methylphenyl)-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxamide (Compound 15 in Table 2)

[0511]

[0512] Referring to intermediate Ib-2-6-F(Z) of Example 22, triethyl 2-fluoro-2-phosphorylacetate was replaced with diethyl (fluoro(isoxazol-3-yl)methyl)phosphonate;

[0513] The other steps are similar to those in Example 22, yielding a white solid of the target compound from the example.

[0514] 1 H NMR (400 MHz, DMSO) δ 10.48 (s, 1H), 8.63 (q, J = 4.6 Hz, 1H), 8.52 (dd, J = 4.7, 1.6 Hz, 1H), 8.17 (dd, J = 8.1, 1.6 Hz, 1H), 8.03 (q, J =6.0 Hz, 1H), 7.60 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.18 (q, J = 6.0 Hz, 1H), 6.87 (dd, J = 36.9, 2.3 Hz, 1H), 2.73 (d, J =4.6 Hz, 3H), 2.17 (s, 3H) ppm.

[0515] Example 36: Synthesis ( Z )-N-(4-chloro-2-(2-fluoro-3-(methylamino)-3-oxopropyl-1-en-1-yl)-6-methylphenyl)-1-(2,6-dichloro-4-nitrophenyl)-4-(trifluoromethyl)-1H-pyrrole-2-carboxamide (Compound 2 in Table 2)

[0516]

[0517] Referring to step 3 of Example 22, Ib-4 was replaced with 1-(2,6-dichloro-4-nitrophenyl)-4-(trifluoromethyl)-1H-pyrrole-2-carboxylic acid;

[0518] The other steps are similar to those in Example 22, yielding a white solid of the target compound from the example.

[0519] 1 H NMR (400 MHz, DMSO) δ 10.45 (s, 1H), 8.59 (q, J = 4.6 Hz, 1H), 8.23 ​​(s, 2H), 7.60 (s, 1H), 7.45 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 2.8 Hz, 1H), 6.87 (d, J = 37.0, 1Hz, 1H), 2.76 (d, J = 4.6Hz, 3H), 2.15 (s, 3H).

[0520] Example 37: Insecticidal activity test of the compound of the present invention:

[0521] Experiment A: Cotton bollworm

[0522] Take a set of 260 ml cups, and place one cotton seedling in each cup. Prepare solutions of each experimental compound to the required concentration (solution volume ratio: DMSO / distilled water = 1 / 49). Using three cups as a group, evenly spray each experimental solution onto the plant (spray pressure: 10 psi, equivalent to 0.7 kg / cm²; spray volume: 0.5 mL; spray distance: 15-20 cm), spraying only one solution per group. After the leaves have naturally dried in the shade, place 10 third-instar larvae of the cotton bollworm in each cup. Insert a damp gauze into each cup to prevent drying, cover each cup, and place it at 27°C and 50% relative humidity for 72 hours, then collect data. The mortality rate of the test insects at a compound concentration of 500 ppm is shown in Tables 3 to 7.

[0523] Experiment B: Asian Corn Borer

[0524] Take a set of 260 ml cups, and place one corn seedling in each cup. Group the cups into sets of three, and spray each set with only one pesticide solution as described in Experiment A. After the leaves have air-dried naturally, place 10 third-instar larvae of the Asian corn borer into each cup. Insert a damp gauze into each cup to prevent drying, cover the cups, and place them at 27°C and 50% relative humidity for 72 hours. Data are then collected. The mortality rate of the test insects at a compound concentration of 500 ppm is shown in Tables 3 to 7.

[0525] Experiment C: Rice leaf roller

[0526] Take a set of 260 ml cups, and place one rice seedling in each cup. Group the cups into sets of three, and spray each set with only one pesticide solution as described in Experiment A. After the leaves have naturally dried in the shade, place 10 adult rice leaf rollers in each cup. Insert a damp gauze into each cup to prevent drying, cover the cups, and place them at 27°C and 50% relative humidity for 72 hours. Then collect the data. The mortality rate of the test insects at a compound concentration of 500 ppm is shown in Tables 3 to 7.

[0527] Experiment D: Diamondback moth

[0528] Take a set of 6cm diameter petri dishes, cover the bottom with a layer of filter paper, and add an appropriate amount of tap water to maintain humidity. Place cabbage leaves cut into 3cm diameter discs in each dish. Use three dishes as a group, and spray each group with only one pesticide solution as described in Experiment A. After the leaves have air-dried naturally, place 10 third-instar larvae of the diamondback moth in each dish. Cover the petri dishes and place them at 27℃ and 50% relative humidity for 72 hours, then collect data. The mortality rate of the test insects at a compound concentration of 500ppm is shown in Tables 3 to 7.

[0529] Experiment E: Armyworm

[0530] Take a set of 260 ml cups, and place several 2 cm wide corn seedling leaves in each cup. Group the cups into sets of three, and spray each set with only one pesticide solution as described in Experiment A. After the leaves have air-dried naturally, place 10 third-instar larvae of the Oriental armyworm in each cup. Insert a damp gauze into each cup to prevent drying, cover the cups, and place them at 27°C and 50% relative humidity for 72 hours. Data are then collected. The mortality rate of the test insects at a compound concentration of 500 ppm is shown in Tables 3 to 7.

[0531] The results showed that, compared with existing insecticide compounds with similar structures, the compounds of the present invention had better insecticidal effects, and the vast majority of the compounds caused high levels of toxicity in the tested pests at a concentration of 500 ppm.

[0532] Table 1. Structure and insecticidal activity test results of compounds (No. 1–No. 32)

[0533] (The numbers next to the C atoms in the structural formulas represent the identification numbers, and the numbers before the substituents in the table correspond to their positions in the structure.)

[0534]

[0535] Table 2. Structure and insecticidal activity test results of compounds (No. 1–No. 32)

[0536] (The numbers next to the C atoms in the structural formulas represent the identification numbers, and the numbers before the substituents in the table correspond to their positions in the structure.)

[0537]

[0538] Table 3. Structure and insecticidal activity test results of compounds (No. 1–No. 30)

[0539] (The numbers next to the C atoms in the structural formulas represent the identification numbers, and the numbers before the substituents in the table correspond to their positions in the structure.)

[0540]

[0541] Table 4. Structure and insecticidal activity test results of compounds (No. 1–No. 230)

[0542] (The numbers next to the C atoms in the structural formulas represent the identification numbers, and the numbers before the substituents in the table correspond to their positions in the structure.)

[0543]

[0544] Table 5. Structure and insecticidal activity test results of compounds (No. 1–No. 230)

[0545] (The numbers next to the C atoms in the structural formulas represent the identification numbers, and the numbers before the substituents in the table correspond to their positions in the structure.)

[0546]

[0547] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

[0548] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A compound having the structure shown in formulas Ii and Ij, or a pesticide-acceptable salt thereof: R 3 Selected from the following groups: hydrogen, halogen, nitro, carboxyl, cyano, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy groups, C 1-4 Alkylthio, C 2-4 Haloalkenyl, C 3-6 Trialkylsilyl; R 8 Independently selected from the group consisting of: hydrogen, halogen, hydroxyl, mercapto, nitro, carboxyl, cyano, substituted or unsubstituted C. 1-8 Alkyl, substituted or unsubstituted C 1-8 Halogenated alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Halogenated alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 1-8 Haloalkylthio, substituted or unsubstituted C 1-8 Alkylamine group, substituted or unsubstituted C 1-8 Dialkylamine group, substituted or unsubstituted C 1-8 Halogenated alkylamine group, substituted or unsubstituted C 1-8 Halogenated dialkylamine, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 Haloalkenyl, substituted or unsubstituted C 2-8 Alkenyl group, substituted or unsubstituted C 2-8 Alkyne, substituted or unsubstituted C 5-7 Cycloalkenyl, substituted or unsubstituted C 1-8 Alkyl thionyl, substituted or unsubstituted C 1-8 thionylalkyl, substituted or unsubstituted C 1-8 alkylsulfonyl, substituted or unsubstituted C 1-8 sulfonylalkyl, substituted or unsubstituted C 2-8 Alkyl carbonyl, substituted or unsubstituted C 2-8 Carbonyl alkyl, substituted or unsubstituted C 2-8 alkoxycarbonyl, substituted or unsubstituted C 2-8 Carbonylalkoxy, substituted or unsubstituted C 2-8 Alkylaminocarbonyl, substituted or unsubstituted C 2-8 Carbonyl alkylamine, substituted or unsubstituted C 2-8 Alkylamine thiocarbonyl, substituted or unsubstituted C 2-8 Thiocarbonyl alkylamine, substituted or unsubstituted C 3-6 Cycloalkoxy, substituted or unsubstituted C 3-6 Cycloalkylamino, substituted or unsubstituted C 1-4 Alkyl C 3-6 Cycloalkylamino, substituted or unsubstituted C 3-6 Trialkylsilyl, substituted or unsubstituted C 2-6 Phosphate group, substituted or unsubstituted C 2-6 Boron ester group, substituted or unsubstituted 5-7 membered non-aromatic heterocyclic group, substituted or unsubstituted benzyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted azo aryl group, substituted or unsubstituted phenoxy group, substituted or unsubstituted 5- or 6-membered heteroaromatic ring or aromatic ring, substituted or unsubstituted 8, 9 or 10-membered fused heterobicyclic system; R 9 Independently selected from: hydrogen, hydroxyl, mercapto, carboxyl, cyano, substituted or unsubstituted C 1-8 Alkyl, substituted or unsubstituted C 1-8 Halogenated alkyl, substituted or unsubstituted C 1-8 Alkoxy, substituted or unsubstituted C 1-8 Halogenated alkoxy, substituted or unsubstituted C 1-8 alkylthio, substituted or unsubstituted C 1-8 Haloalkylthio, substituted or unsubstituted C 1-8 Alkylamine group, substituted or unsubstituted C 1-8 Dialkylamine group, substituted or unsubstituted C 1-8 Halogenated alkylamine group, substituted or unsubstituted C 1-8 Halogenated dialkylamine, substituted or unsubstituted C 3-8 cycloalkyl, substituted or unsubstituted C 2-8 alkenyl, substituted or unsubstituted C 2-8 Alkenyl group, substituted or unsubstituted C 2-8 Alkyne group, substituted or unsubstituted C 5-7 Cycloalkenyl, substituted or unsubstituted C 1-8 Alkyl thionyl, substituted or unsubstituted C 1-8 thionylalkyl, substituted or unsubstituted C 1-8 alkylsulfonyl, substituted or unsubstituted C 1-8 sulfonylalkyl, substituted or unsubstituted C 2-8 Alkyl carbonyl, substituted or unsubstituted C 2-8 Carbonyl alkyl, substituted or unsubstituted C 2-8 alkoxycarbonyl, substituted or unsubstituted C 2-8 Carbonylalkoxy, substituted or unsubstituted C 2-8 Alkylamine carbonyl, substituted or unsubstituted C 2-8 Carbonyl alkylamine, substituted or unsubstituted C 2-8 Alkylamine thiocarbonyl, substituted or unsubstituted C 2-8 Thiocarbonyl alkylamine, substituted or unsubstituted C 3-6 Cycloalkoxy, substituted or unsubstituted C 3-6 Cycloalkylamino, substituted or unsubstituted C 1-4 Alkyl C 3-6 Cycloalkylamino, substituted or unsubstituted C 3-6 Trialkylsilyl, substituted or unsubstituted C 2-6 Phosphate group, substituted or unsubstituted C 2-6 Boron ester group, substituted or unsubstituted 5-7 membered non-aromatic heterocyclic group, substituted or unsubstituted benzyl group, substituted or unsubstituted benzoyl group, substituted or unsubstituted azo aryl group, substituted or unsubstituted phenoxy group, substituted or unsubstituted 5- or 6-membered heteroaromatic ring or aromatic ring, substituted or unsubstituted 8-, 9- or 10-membered fused heterobicyclic system; R 10 R 11 R 12 R 13 Independently selected from: hydrogen, halogen, methyl, cyano, trifluoromethyl, difluoromethyl; p is an integer between 0 and 4.

2. The compound of claim 1, or a pesticidally acceptable salt thereof, wherein The halogen is F, Cl, Br or I; The substituted or unsubstituted 5- or 6-membered aromatic ring is a substituted or unsubstituted phenyl group.

3. The compound of claim 1, or a pesticidally acceptable salt thereof, wherein The compounds are selected from the group consisting of: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 4. A pesticide composition comprising (1) 0.001-99.99 wt% of the compound of any one of claims 1-3, or a pesticide-acceptable salt thereof, by weight of the total pesticide composition; and (2) a pesticide-acceptable carrier or excipient.

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