WO2013059984A1 - Derivative of methacryloyl-benzimidazol-one (thione) and use thereof as anti-microbial drug - Google Patents

Abstract

Disclosed are a new kind of derivative of methacryloyl-benzimidazol-one (thione), a preparation method for the compound, and the use of the compound as an anti-microbial drug. The compound has the structure as shown in the following general formula (I) in which R and Y have the meaning described in the description.

Description

 Methacryloylbenzimidazole (thio)ketone derivatives and their use as antibacterials

 The present invention relates to a novel class of methacryloylbenzimidazole (thio)ketone derivatives, a process for the preparation of the compounds, and the use of the compounds as antibacterial agents; in particular, the use of the compounds as antibacterial and antifungal agents In particular, the bacterium is a human or animal-infected bacterium, which is a causative, animal-infected fungus, or a phytopathogenic fungus, and the present invention belongs to the fields of medical technology and agricultural technology.

Background technique

,15-27)。 除此之外， 苯并咪 唑酮衍生物也具有明显的药理活性， 作为临床用药普遍应用， 如第二代抗组胺药物奥 沙米特就属于苯并咪唑酮衍生物（Iwamoto K.， et al. Arzneimittel-forschung-drug Research. 2001 ,51 :971-976.)c 最近欧洲专利公布了一个新型的磷酸二酯酶抑制剂， 在 临床上对多种心血管疾病具有很好的疗效，其有效成分就是苯并咪唑酮衍生物，其中 位引入取代吡啶衍生物， N₃位则引入烷基、 芳基、 杂环以及芳杂环等多种取代基 (European patent. EP 1 958 947 Al)。英国科学家发现苯并咪唑酮在 N₃引入苯氧丙基哌 啶后得到的一系列衍生物是新型阿片受体（NOP )激动剂， 由于基于传统阿片受体的 药物如吗啡等具有较大的副作用， 因此该受体自 1994年被发现后即引起了药物学家 的极大兴趣， 而这类苯并咪唑酮衍生物则表现出了开发成新型止痛药物的极大潜力 (Ronald Palin et al.Bioorganic & Medicinal Chemistry. 2007, 15: 1828-1847.)=意大利药 物学家在苯并咪唑酮的 引入取代芳基以后发现其表现出了较好的抗艾滋活性， 其 主要作用机理是抑制非核苷逆转录酶的活性 (Anna-Maria Monforte et al. Bioorganic & Me^dra/ O^w/Wr; . 2008,16: 7429— 7435·)。 Benzimidazolone is an oxidized derivative of a 2-carbon atom on the imidazole ring and has a very wide range of uses as an intermediate in the dye industry (Jolanta S. et al.

, 15-27). In addition, benzimidazolone derivatives also have significant pharmacological activities and are commonly used as clinical drugs. For example, the second-generation antihistamine drug oxazide is a benzimidazolone derivative (Iwamoto K., et Al. Arzneimittel-forschung-drug Research. 2001 , 51 :971-976.)c Recently, a new type of phosphodiesterase inhibitor has been published in European patents, which has a good clinical effect on various cardiovascular diseases. The active ingredient is a benzimidazolone derivative in which a substituted pyridine derivative is introduced, and a substituent such as an alkyl group, an aryl group, a heterocyclic ring or an aromatic heterocyclic ring is introduced at the N ₃ position (European patent. EP 1 958 947 Al). . British scientists have discovered that a series of derivatives of benzimidazolone after the introduction of phenoxypropyl piperidine in N ₃ are novel opioid receptor (NOP) agonists, due to the large opioid receptor-based drugs such as morphine. Side effects, so the receptor has been of great interest to pharmacologists since its discovery in 1994, and such benzimidazolone derivatives have shown great potential for the development of new analgesics (Ronald Palin et al) .Bioorganic & Medicinal Chemistry. 2007, 15: 1828-1847.)=Italian pharmacologists have shown that they exhibit better anti-AIDS activity after the introduction of benzimidazolone to replace the aryl group. The main mechanism of action is inhibition of non-nuclear The activity of the glucoside reverse transcriptase (Anna-Maria Monforte et al. Bioorganic &Me^dra/O^w/Wr; . 2008, 16: 7429-7435).

However, it is worth noting that there are few reports on the antibacterial activity of benzimidazolone derivatives. Applicants found in the screening of antibacterial active compounds, after the introduction of methacryloyl group at the N ₃ position of benzimidazolone, the result

1

Replacement page (Article 26) The derivatives exhibit extremely high antibacterial activity. This discovery provides an antibacterial compound with a novel molecular skeleton that is expected to be developed into a new class of antibacterial drugs. At the same time, there have been few reports on the antifungal activity of benzimidazolone derivatives, and the applicant has found that the compounds of the present application exhibit good antibacterial activity against some medical or agricultural fungi in the screening of antibacterial active compounds.

 The present invention discloses methacryloylbenzimidazole (thio)ketone derivatives, processes for their preparation and their use as antibacterial agents.

Summary of the invention

 The object of the present invention is to provide a methacryloylbenzimidazole (thio)ketone derivative having an antibacterial action, a process for the preparation thereof and use thereof as an antibacterial agent; in particular, the use of the compound as an antibacterial and antifungal drug .

 The methacryloylbenzimidazole (thio)ketone derivative provided by the present invention has a structure represented by the following formula (I),

 In the formula (I), R stands for:

Hydrogen; D ~ C ₈ alkyl; and optionally substituted, or cyano, halogen, phenyl, Q~C ₄ group or embankment embankment Q ~ C ₄ - alkylthio group, C ₃ ~C ₈ alkenyl Or a C ₃ ～C ₈ alkynyl group; or a c ₃ ～ c ₈ alkenyl group or a c ₃ ～ c ₈ alkyne optionally substituted by a cyano group, a halogen, a C ₄ alkoxy group or a d—C ₄ alkylthio group a phenyl group or a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of: halogen, ~C ₈ fluorenyl, C ₃ -C ₈ cycloalkyl, hydroxy, decyloxy, ~C ₄ Halogenated fluorenyl, ~C ₄ haloalkoxy, Ci~C ₄ halosulfonyl, ~C4 haloalkylsulfonyl, carboxy, nitro, cyano, phenyl, phenoxy, benzoyl;

 Y stands for:

Hydrogen; or 1 to 4 substituents selected from the group consisting of: halogen, nitro, 〜3⁄4 fluorenyl, C ₃ ～C ₈ cyclodecyl, haloalkyl;

 Wherein, when Y represents hydrogen, R is not isopropenyl;

 Or Y stands for:

2

Replacement page (Article 26) Wherein, on behalf of: hydroxy, Q~C ₈ embankment group, a C ₃ ~C ₈ alkylene group or a C ₃ ~C ₈ alkynyl group, an amino group, or substituted with 1 or 2 ~C ₈ alkyl with amine ;

 Or Y stands for:

One 0 (S Guang Z ₂

Wherein, Z ₂ represents: a hydrogen, ~C ₄ alkyl with, C ₃ ~C ₈ alkenyl or C ₃ ~C ₈ alkynyl group, Q~C ₄ haloalkyl group Huan, ~¾ fatty acyl groups, halogenated aliphatic acyl group ~ , carbamoyl, N-methylaminoformyl, N-ethylaminoformyl, hydrazine, hydrazine-dimethylaminoformyl, hydrazine, hydrazine-diethylaminoformyl, phenyl, Benzoyl, phenylacetyl, phenylsulfonyl or phenyl, benzoyl or benzene optionally substituted by 1 to oe3n substituents selected from the group consisting of

 Z

Sulfonyl group: halogen, fluorenyl group, C ₃ -C ₈ cyclodecyl group, hydroxy group, decyloxy group, Q~C ₄ halogenated fluorenyl group, ~haloalkoxy group, Ci~C ₄ halogenated sulfonyl group, ^ ~. _4- halodecylsulfonyl, carboxy, nitro, cyano;

 Or Y stands for:

Wherein, 3⁄4 represents hydrogen, ^~3⁄4 fluorenyl, c ₃ ～c ₈ cyclodecyl, c ₃ ～c ₈ alkenyl, c ₃ ～c ₈ alkynyl,

^ ~ ^ Alkyl with halo, ~C ₈ acyl group, or a 5- or 6-membered heterocyclic group having 1 ~ 3 hetero atoms selected from nitrogen, oxygen and sulfur, a phenyl, benzoyl, phenylacetyl a phenylsulfonyl group or a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of benzoyl or benzenesulfonyl: halogen, ～C ₈ fluorenyl, C ₃ ～C ₈ cycloalkyl, hydroxy ~ 垸oxy, ~C ₄ halodecyl, ^ C ^ halodecyloxy, CA haloalkylthio, ~C ₄ haloalkylsulfonyl, carboxy, nitro, cyano; Z ₄ represents hydrogen, ~ C ₈ alkyl, C ₃ ~C ₈ alkyl with cycloalkyl, C ₃ ~ C ₈ ¾ chain group, C ₃ ~C ₈ alkynyl group, Ci~C4 alkyl with halo, or Z ₃ and Z ₄ are attached to them The nitrogen atoms together form a 5- to 7-membered heterocyclic group, and the heterocyclic group may contain, in addition to a nitrogen atom, one or two or more hetero atoms selected from nitrogen and oxygen.

Particularly, a methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I) having the following definition is preferably:

3

Replacement page (Article 26) Wherein R represents: hydrogen, ethyl, n-propyl, isopropyl, propenyl, isopropenyl, 2-cyanoethyl, benzyl, 2-fluoroethyl, 2-chloroethyl, 2-bromo Ethyl, 2-methoxyethyl, 2-methoxypropyl, 2-methoxyisopropyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-ethoxyisopropyl, phenyl, Or by one selected from the following! ~ 3 substituents optionally substituted phenyl: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy, propoxy , isopropoxy, 2-chloroethyl, 2-chloropropyl, 2-chloroethoxy, 2-chloropropoxy, carboxy, nitro, cyano;

 Y represents: hydrogen, or 1 to 4 substituents selected from the group consisting of: fluorine, chlorine, bromine, nitro, methyl, ethyl, n-propyl, isopropyl, 2-chloroethyl, 2-chloropropane Base, 2-chlorobutyl, 2-bromoethyl, 2-bromopropyl, 2-bromobutyl; wherein, when Y represents hydrogen, R is not isopropenyl;

 Or Y stands for -

Wherein Zi represents: hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, amino, N-methylamino, N-ethylamino, hydrazine, fluorene-di Methylamino, hydrazine, hydrazine-diethylamino; or Υ represents:

One 0 (S Guangyu ₂

Wherein Ζ ₂ represents: hydrogen, methyl, ethyl, propyl, isopropyl, 2-chloromethyl, 2-chloroethyl, 2-chloropropyl, formyl, acetyl, phenyl, benzoyl An acyl group, a phenylsulfonyl group, or a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of benzoyl, phenylacetyl or benzenesulfonyl: fluorine, chlorine, bromine, methyl, ethyl, propyl Isopropyl, isopropyl, 2-chloroethyl, 2-chloropropyl, cyclopropene, hydroxy, methoxy, ethoxy, 2-chloroethyl, 2-chloropropyl, 2-chlorobutyl, 2-Bromoethyl, 2-bromopropyl, 2-bromobutyl, chloromethoxy, 2-chloroethoxy, 2-chloropropoxy, bromomethoxy, 2-bromoethoxy, 2 - bromopropyloxy, carboxy, nitro, cyano;

 Or, Υ represents -

— \

Wherein Ζ ₃ represents hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropenyl, propenyl, isopropenyl, propynyl, 2-chloroethyl, 2-chloropropyl, 2 -Chlorobutyl, 2-bromoethyl, 2-bromopropyl, 2-bromobutyl, formyl, acetyl, n-propionyl, isopropionyl, phenyl, benzoyl, phenylacetyl, benzenesulfonate Acyl group or selected from the following

4

Replacement page (Article 26) ~ 3 substituents of optionally substituted phenyl, benzoyl or phenylsulfonyl group: halo, _{~C 8} alkyl, C ₃ ~ C ₈ cycloalkyl group embankment, hydroxy, ^ ~. 4 alkoxy, Ci~C ₄ halodecyl, ~3⁄4 halodecyloxy, ~halosulfonylthio, ~C ₄ halosulfonylsulfonyl, carboxy, nitro, cyano; Z ₄ represents Hydrogen, methyl, ethyl, n-propyl, isopropyl, propenyl, isopropenyl, propynyl, 2-chloroethyl, 2-chloropropyl, 2-chlorobutyl, 2-bromoethyl , 2-bromopropyl, 2-bromobutyl, or _3⁄4 and ∑4 together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic group.

Particularly, a methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I) having the following definition is more preferably:

 Wherein R represents: hydrogen, propenyl, isopropenyl, benzyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-methoxyisopropyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-ethoxyisopropyl;

 Y stands for:

 O

I I

-cz ₁

 Wherein, represents: hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, amino, N-methylamino, N-ethylamino, hydrazine, hydrazine-dimethylamine Base, hydrazine, hydrazine-diethylamino group;

 Or Υ represents:

One 0 (S Guangyu ₂

Wherein Ζ ₂ represents: hydrogen, formyl, acetyl, benzoyl, benzenesulfonyl, or benzoyl optionally substituted by 1 to 3 substituents selected from the group consisting of phenylacetyl or phenylsulfonyl: Fluorine, chlorine, bromine, hydroxyl, methoxy, ethoxy, nitro, cyano;

 Or, Υ stands for:

Wherein ζ ₃ represents hydrogen, formyl, acetyl-, n-, propionyl, isopropionyl, benzoyl, phenylacetyl, phenylsulfonyl; ζ ₄ represents hydrogen, methyl, ethyl, n-propyl, Isopropyl, propenyl, isopropenyl, propynyl, 2-chloroethyl, 2-chloropropyl, 2-chlorobutyl, 2-bromoethyl, 2-bromopropyl, 2-bromobutyl , or _3⁄4 and ∑ ₄ with them

5

Replacement page (Article 26) The nitrogen atoms to be bonded together form a 5- to 7-membered heterocyclic group. Particularly, a methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I) having the following definition is more preferably:

 Wherein R represents: hydrogen, propenyl, isopropenyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-methoxy Isopropyl;

Y stands for:

 Wherein, represents: hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy. The compound of the present invention further includes a pharmaceutically acceptable salt of a methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I). The compounds of the formula (I) of the present application can be chemically synthesized according to the following synthetic route:

 Synthetic route one:

In the methacryloylbenzimidazole (thio) ketone derivative represented by the formula (I), Y is: hydrogen, or 1 to 4 substituents selected from the group consisting of: a compound, a C^Cs, a C ₃ ~ C ₈ ring 垸, ^ ~. When a 4 13⁄4 alkyl group is used, and other groups are as defined in the above formula (I), the methacryloylbenzene represented by the formula (I) to be protected by the present invention can be produced by a synthetic route as shown in the following scheme. Imidazole (thio) ketone derivatives:

 6

Replacement page (Article 26) The synthetic route starts with a halogen (or a fluorenyl group or a halogenated fluorenyl group) instead of an o-nitroaniline. First, a halogenated hydrocarbon is used as a hydrocarbylating agent, and various hydrocarbon groups or substituted hydrocarbon groups are introduced on the amino nitrogen, and then Reduction of the nitro group in the iron powder/hydrochloric acid system to obtain a substituted o-phenylenediamine derivative, followed by refluxing with urea or thiourea in xylene to obtain a benzimidazole (thio) ketone derivative, and finally with methacryloyl chloride The acylation reaction is carried out to obtain the target compound.

 This method is a general synthetic route, and for a specific compound, a target compound can be obtained by a simple procedure using a more convenient intermediate.

 Examples of the methacryloylbenzimidazolone derivatives of the present invention prepared according to the reaction scheme are shown in Table 1.

 Table 1

 Compound number Y R Compound number Y R

 IA-01 Hydrogen Hydrogen Ia-01 Hydrogen Hydrogen

IA-02 Hydrogen Ethyl Ia-02 Hydrogen Ethyl

IA-03 Hydrogen Isopropyl Ia-03 Hydrogen Isopropyl

IA-04 Hydrogen n-Butyl Ia-04 Hydrogen n-Butyl

IA-05 Hydrocyclopropane Group Ia-05 Hydrogen Cyclopropenyl

IA-06 Hydrogen 2-methoxybutyl Ia-06 Hydrogen 2-methoxybutyl

1A-07 Hydrogen 2-Chlorobutyl Ia-07 Hydrogen 2-Chlorobutyl

IA-08 Hydrogen 2-cyanobutyl Ia-08 Ammonia 2-Cyanobutyl

IA-09 Hydroxybenzyl Ia-09 Hydroxybenzyl

IA-10 hydrogen vinyl la- 10 hydrogen vinyl

IA-11 hydrogen n-propenyl group Ia-11 hydrogen n-propenyl group

IA-12 hydrogen 3-chlorobutenyl alkenyl la-12 hydrogen 3-chlorobut-1-enyl

IA-13 Hydrogen-1--1-ynyl la- 13 Hydrogen Prop-1-ynyl

IA-14 hydrogen 3-chlorobut-1-ynyl Ia-14 hydrogen 3-chlorobutane alkynyl

IA-15 hydrogen base la- 15 hydrogen phenyl

IA-16 hydrogen 2-methylphenyl Ia-16 hydrogen 2-methylphenyl

IA-17 hydrogen 3-methylphenyl la- 17 hydrogen 3-methylphenyl

1A-18 hydrogen 4-methylphenyl la- 18 hydrogen 4-methylphenyl

IA-19 hydrogen 2-chlorophenyl la- 19 hydrogen 2-chlorophenyl

IA-20 hydrogen 3-chlorophenyl Ia-20 hydrogen 3-chlorophenyl

IA-21 hydrogen 4-chlorophenyl Ia-21 hydrogen 4-chlorophenyl

IA-22 hydrogen 2-nitrophenyl la-22 hydrogen 2-nitrophenyl

Replacement page (Article 26) IA-23 hydrogen 3-nitrophenyl Ia-23 hydrogen 3-nitrophenyl

IA-24 hydrogen 4-nitrophenyl Ia-24 hydrogen 4-nitrophenyl

IA-25 Hydrogen ² -Hydroxymethylene Ia-25 Hydrogen 2-Hydroxyphenyl

IA-26 Hydrogen 3-Hydroxyphenyl Ia-26 Hydrogen 3-Hydroxyphenyl

IA-27 hydrogen 4-hydroxyphenyl Ia-27 hydrogen 4-light phenyl

IA-28 hydrogen 2-carboxyphenyl Ia-28 hydrogen 2-carboxyphenyl

IA-29 hydrogen 3-carboxyphenyl Ia-29 hydrogen 3-carboxyphenyl

IA-30 Hydrogen 4-carboxyphenyl Ia-30 Hydrogen 4-carboxyphenyl

IA-31 Hydrogen 2-Cyclohexaneylphenyl Ia-31 Hydrogen 2-Cyclohexaneylphenyl

IA-32 Hydrogen 3-Cyclohexylphenyl Ia-32 Hydrogen 3-Cyclohexylphenyl

IA-33 Hydrogen 4-Cyclohexaneylphenyl Ia-33 Hydrogen 4-Cyclohexylphenyl

IA-34 Hydrogen 2-methoxyphenyl Ia-34 Hydrogen 2-methoxyphenyl

IA-35 Hydrogen 3-methoxyphenyl Ia-35 Hydrogen 3-methoxyphenyl

IA-36 Hydrogen 4-methoxyphenyl Ia-36 Hydrogen 4-methoxyphenyl

IA-37 hydrogen 2-(2-chloroethyl)phenyl Ia-37 hydrogen 2-(2-chloroethyl)phenyl

IA-38 hydrogen 3-(2-chloroethyl)phenyl Ia-38 hydrogen 3-(2-chloroethyl)phenyl

IA-39 Hydrogen 4-(2-Chloroethyl)phenyl Ia-39 Hydrogen 4-(2-Chloroethyl)phenyl

IA-40 methyl hydrogen la-40 methyl hydrogen

 IA-41 methylethyl Ia-41 methyl ethyl

IA-42 methyl isopropyl Ia-42 methyl isopropyl

IA-43 methyl n-butyl Ia-43 methyl n-butyl

IA-44 methylcyclopropane Ia-44 methylcyclopropenyl

IA-45 methyl 2-methoxybutyl la-45 methyl 2-methoxybutyl

IA-46 methyl 2-chlorobutyl Ia-46 methyl 2-chlorobutyl

IA-47 methyl 2-cyanobutyl Ia-47 methyl 2-cyanobutyl

1A-48 methylbenzyl Ia-48 methylbenzyl

IA-49 methyl vinyl Ia-49 methyl vinyl

IA-50 methyl isopropenyl group Ia-50 methyl isopropenyl

IA-51 methyl 3-chlorobut-1-enyl Ia-51 methyl 3-chlorobutenyl

IA-52 methyl prop-1-ynyl Ia-52 methyl prop-1-ynyl

IA-53 methyl 3-chlorobut-1-ynyl Ia-53 methyl 3-chlorobut-1-ynyl

IA-54 methyl phenyl Ia-54 methyl

IA-55 methyl 2-methylphenyl Ia-55 methyl 2-methylphenyl

IA-56 methyl 3-methylphenyl Ia-56 methyl 3-methylphenyl

IA-57 methyl 4-methylphenyl Ia-57 methyl 4-methylphenyl

IA-58 methyl 2-chlorophenyl Ia-58 methyl 2-chlorophenyl

IA-59 methyl 3-chlorophenyl Ia-59 methyl 3-chlorophenyl

IA-60 methyl 4-chlorophenyl la-60 methyl 4-chlorophenyl

IA-61 methyl 2-nitrophenyl Ia-61 methyl 2-nitrophenyl

IA-62 methyl 3-nitrophenyl Ia-62 methyl 3-nitrophenyl

8

Replacement page (Article 26) IA-63 methyl 4-nitrophenyl Ia-63 methyl 4-nitrophenyl

IA-64 methyl 2-hydroxyphenyl Ia-64 methyl 2-hydroxyphenyl

IA-65 methyl 3-hydroxyphenyl Ia-65 methyl 3-hydroxyphenyl

IA-66 methyl 4-hydroxyphenyl Ia-66 methyl 4-hydroxyphenyl

IA-67 methyl 2-carboxyphenyl Ia-67 methyl 2-carboxyphenyl

IA-68 methyl 3-carboxyphenyl Ia-68 methyl 3-carboxyphenyl

IA-69 methyl 4-carboxyphenyl Ia-69 methyl 4-carboxyphenyl

IA-70 methyl 2-cyclohexanephenyl Ia-70 methyl 2-cyclohexyl phenyl

IA-71 methyl 3-cyclohexanephenyl Ia-71 methyl 3-cyclohexylphenyl

IA-72 methyl 4-cyclohexanephenyl Ia-72 methyl 4-cyclohexylphenyl

IA-73 methyl 2-methoxyphenyl Ia-73 methyl 2-methoxyphenyl

IA-74 methyl 3-methoxyphenyl Ia-74 methyl 3-methoxyphenyl

IA-75 methyl 4-methoxyphenyl Ia-75 methyl 4-methoxyphenyl

IA-76 methyl 2-(2-chloroethyl)phenyl Ia-76 methyl 2-(2-chloroethyl)phenyl

IA-77 methyl 3-(2-chloroethyl)phenyl Ia-77 methyl 3-(2-chloroethyl)phenyl

IA-78 methyl 4-(2-chloroethyl)phenyl Ia-78 methyl 4-(2-chloroethyl)phenyl

IA-79 Chlorine Hydrogen Ia-79 Chlorine Hydrogen

IA-80 Chloroethyl Ia-80 Chloroethyl

IA-81 Chloropropyl Ia-81 Chloropropyl

IA-82 wind n-butyl Ia-82 n-butyl

IA-83 chlorocyclopropenyl Ia-83 chloro 'cyclopropenyl

IA-84 Chloro 2-methoxybutyl Ia-84 Chloro 2-methoxybutyl

IA-85 Wind 2-Chlorobutyl Ia-85 Chloro 2-Chlorobutyl

IA-86 Chloro 2-cyanobutyl Ia-86 Chloro 2-cyanobutyl

IA-87 Chlorobenzyl Ia-87 Chlorobenzyl

IA-88 chloroethylene Ia-88 chlorovinyl

IA-89 isopropenyl group Ia-89 chloroisopropenyl

IA-90 wind 3-chlorobut-1-enyl Ia-90 chloro 3-chlorobutanthyl

IA-91 chloroprop-1-ynyl Ia-91 chloroprop-1-ynyl

IA-92 Chlor 3-chlorobutyl-1-ynyl Ia-92 Chloro 3-chlorobut-1-ynyl

IA-93 gas phenyl Ia-93 chlorine base

IA-94 Chloro 2-methylphenyl Ia-94 Chloro 2-methylphenyl

IA-95 wind 3-methylphenyl Ia-95 chloro 3-methylphenyl

IA-96 chloro 4-methylphenyl Ia-96 chloro 4-methylphenyl

IA-97 Chloro 2-Chlorophenyl Ia-97 Chloro 2-Chlorophenyl

IA-98 Chloro-3-chlorophenyl Ia-98 Chloro-3-chlorophenyl

IA-99 chloro 4-chlorophenyl Ia-99 atmosphere 4-chlorophenyl

IA-100 Chlorine 2-Nitrophenyl Ia-100 Chloro 2-Nitrophenyl

IA-101 Chlor 3-nitrophenyl Ia-101 Chlor 3-nitrophenyl

IA-102 chloro 4-nitrophenyl la- 102 chloro 4-nitrophenyl

9

Replacement page (Article 26) IA-103 chloro 2-light phenyl la- 103 chloro 2-hydroxyphenyl

IA-104 wind 3-hydroxyphenyl la- 104 chloro 3-hydroxyphenyl

IA-105 4-hydroxyphenyl la- 105 chloro 4-hydroxyphenyl

IA-106 Chloro 2-Carboxyphenyl Ia-106 Chloro 2-Carboxyphenyl

IA-107 Chloro 3-carboxyphenyl la- 107 Chlor 3-carboxyphenyl

IA-108 chloro 4-carboxyphenyl la- 108 chloro 4-carboxyphenyl

IA-109 2-cyclohexaneylphenyl la- 109 Chloro 2-cyclohexylphenyl

IA-110 Chloro 3-cyclohexylphenyl Ia-110 Chloro 3-cyclohexylphenyl

IA-111 Chloro 4-cyclohexylphenyl Ia-111 Chloro 4-cyclohexanephenyl

IA-112 Chloro 2-methoxyphenyl Ia-112 Chloro 2-methoxyphenyl

IA-113 Chlor 3-methoxyphenyl Ia-113 Chlor 3-methoxyphenyl

IA-114 chloro 4-methoxyphenyl Ia-114 chloro 4-methoxyphenyl

IA-115 Chloro 2-(2-chloroethyl)phenyl Ia-115 Chloro 2-(2-chloroethyl)phenyl

IA-116 Chlor 3-(2-chloroethyl)phenyl Ia-116 Chlor 3-(2-chloroethyl)phenyl

IA-117 chloro 4-(2-chloroethyl)phenyl Ia-117 chloro 4-(2-chloroethyl)phenyl

IA-118 2-chloroethyl hydrogen Ia-118 2-chloroethyl hydrogen

IA-119 2-chloroethyl ethyl Ia-119 2-chloroethyl ethyl

IA-120 2-chloroethyl isopropyl la- 120 2-chloroethyl isopropyl

IA-121 2-chloroethyl n-butyl Ia-121 2-chloroethyl n-butyl

IA-122 2-chloroethylcyclopropenyl la- 122 2-chloroethyl cyclopropane

1A-123 2-chloroethyl 2-methoxybutyl la- 123 2-chloroethyl 2-methoxybutyl

IA-124 2-chloroethyl 2-chlorobutyl la- 124 2-chloroethyl 2-chlorobutyl

IA-125 2-chloroethyl 2-cyanobutyl la- 125 2-chloroethyl 2-cyanobutyl

IA-126 2-chloroethyl benzyl Ia-126 2-chloroethyl benzyl

IA-127 2-chloroethyl vinyl Ia-127 2-chloroethyl vinyl

IA-128 2-chloroethyl isopropenyl la- 128 2-chloroethyl isopropenyl

IA-129 2-chloroethyl 3-chlorobut-1-enyl la- 129 2-chloroethyl 3-chlorobut-1-enyl

IA-130 2-chloroethyl propyl-1-ynyl Ia-130 2-chloroethyl propyl-1-ynyl

IA-131 2-chloroethyl 3-chlorobut-1-ynyl Ia-131 2-chloroethyl 3-chlorobut-1-ynyl

IA-132 2-chloroethyl This volume la- 132 2-chloroethyl phenyl

IA-133 2-chloroethyl 2-methylphenyl Ia-133 2-chloroethyl 2-methylphenyl

IA-134 2-chloroethyl 3-methylphenyl la- 134 2-chloroethyl 3-methylphenyl

IA-135 2-chloroethyl 4-methylphenyl Ia-135 2-chloroethyl 4-methylphenyl

IA-136 2-chloroethyl 2-chlorophenyl Ia-136 2-chloroethyl 2-chlorophenyl

IA-137 2-chloroethyl 3-chlorophenyl Ia-137 2-chloroethyl 3-chlorophenyl

IA-138 2-chloroethyl 4-chlorophenyl Ia-138 2-chloroethyl 4-chlorophenyl

IA-139 2-chloroethyl 2-nitrophenyl Ia-139 '2-chloroethyl 2-nitrophenyl

IA-140 2-chloroethyl 3-nitrophenyl la- 140 2-chloroethyl 3-nitrophenyl

IA-141 2-chloroethyl 4-nitrophenyl la-141 2-chloroethyl 4-nitrophenyl

IA-142 2-chloroethyl 2-hydroxyphenyl la- 142 2-chloroethyl 2-light phenyl

10

Replacement page (Article 26) IA-143 2-chloroethyl 3-hydroxyphenyl la- 143 2-chloroethyl 3-hydroxyphenyl

IA-144 2-chloroethyl 4-hydroxyphenyl Ia-144 2-chloroethyl 4-hydroxyphenyl

IA-145 2-chloroethyl 2-carboxyphenyl Ia-145 2-chloroethyl 2-carboxyphenyl

IA-146 2-chloroethyl 3-carboxyphenyl Ia-146 2-chloroethyl 3-carboxyphenyl

IA-147 2-chloroethyl 4-carboxyphenyl la- 147 2-chloroethyl 4-carboxyphenyl

IA-148 2-chloroethyl 2-cyclohexylphenyl Ia-148 '2-chloroethyl 2-cyclohexanephenyl

IA-149 2-chloroethyl 3-cyclohexyl phenyl la- 149 2-chloroethyl 3-cyclohexanephenyl

IA-150 2-chloroethyl 4-cyclohexyl phenyl group Ia-150 2-chloroethyl 4-cyclohexanephenyl

IA-151 2-chloroethyl 2-methoxyphenyl Ia-151 2-chloroethyl 2-methoxyphenyl

IA-152 2-chloroethyl 3-methoxyphenyl Ia-152 2-chloroethyl 3-methoxyphenyl

IA-153 2-chloroethyl 4-methoxyphenyl la- 153 2-chloroethyl 4-methoxyphenyl

IA-154 2-chloroethyl 2-(2-chloroethyl)phenyl Ia-154 2-chloroethyl 2-(2-chloroethyl)phenyl

IA-155 2-chloroethyl 3-(2-chloroethyl)phenyl la- 155 2-chloroethyl 3-(2-chloroethyl)phenyl

IA-156 2-chloroethyl 4-(2-chloroethyl)phenyl la- 156 2-chloroethyl 4-(2-chloroethyl)phenyl

IA-157 Nitrohydrogen Ia-157 Nitrohydrogen

IA-158 nitroethyl Ia-158 nitroethyl

IA-159 nitroisopropyl la- 159 nitroisopropyl .

IA-160 nitro-n-butyl Ia-160 nitro-n-butyl

IA-161 nitrocyclopropane group Ia-161 nitrocyclopropenyl

1A-162 Nitro 2-methoxybutyl Ia-162 Nitro 2-methoxybutyl

IA-163 nitro 2-chlorobutyl la- 163 nitro 2-chlorobutyl

IA-164 Nitro 2-cyanobutyl Ia-164 Nitro 2-Actylbutyl

IA-165 nitrobenzyl la- 165 nitrobenzyl

IA-166 nitro vinyl la- 166 nitro vinyl

IA-167 Nitroisopropenyl Ia-167 Nitroisopropenyl

IA-168 nitro 3-chlorobut-1-enyl la- 168 nitro 3-chlorobut-1-enyl

IA-169 nitroprop-alkynyl group Ia-169 nitropropan-1-ynyl

IA-170 nitro 3-chlorobut-1-ynyl la- 170 nitro 3-chlorobut-1-ynyl

IA-171 nitro base Ia-171 nitrophenyl

IA-172 nitro 2-methylphenyl la- 172 nitro 2-methylphenyl

IA-173 Nitro 3-methylphenyl Ia-173 Nitro 3-methylphenyl

IA-174 nitro 4-methylphenyl la- 174 nitro 4-methylphenyl

IA-175 nitro 2-chlorophenyl la- 175 nitro 2-chlorophenyl

1A-176 Nitro 3-chlorophenyl Ia-176 Nitro 3-chlorophenyl

IA-177 nitro 4-chlorophenyl la- 177 nitro 4-chlorophenyl

1A-178 nitro 2-nitrophenyl Ia-178 nitro 2-nitrophenyl

IA-179 Nitro 3-nitrophenyl la- 179 Nitro 3-nitrophenyl

IA-180 nitro 4-nitro stupid Ia-180 nitro 4-nitrophenyl

IA-181 nitro 2-hydroxyphenyl Ia-181 nitro 2-hydroxyphenyl

IA-182 nitro 3-light phenyl la- 182 nitro 3-hydroxyphenyl

11

Replacement page (Article 26) IA-183 nitro 4-hydroxyphenyl la- 183 nitro 4-hydroxyphenyl

IA-184 nitro 2-carboxyphenyl la- 184 nitro 2-carboxyphenyl

IA-185 Nitro 3-carboxyphenyl la- 185 Mercapto 3-carboxyphenyl

IA-186 nitro 4-carboxyphenyl la- 186 nitro 4-carboxyphenyl

IA-187 nitro 2-cyclohexaneylphenyl la- 187 nitro 2-cyclohexyl phenyl

IA-188 nitro 3-cyclohexaneylphenyl la- 188 nitro 3-cyclohexanephenyl

IA-189 nitro 4-cyclohexaneylphenyl la- 189 nitro 4-cyclohexyl phenyl

IA-190 Nitro '2-methoxyphenyl Ia-190 Nitro 2-methoxyphenyl

IA-191 Nitro 3-methoxyphenyl Ia-191 Nitro 3-methoxyphenyl

IA-192 nitro 4-methoxyphenyl la- 192 nitro 4-methoxyphenyl

IA-193 nitro 2-(2-chloroethyl)phenyl la- 193 nitro 2-(2-chloroethyl)phenyl

IA-194 nitro 3-(2-chloroethyl)phenyl la- 194 nitro 3-(2-chloroethyl)phenyl

IA-195 ethyl) phenyl

Compound number Y R Compound number Y R

 IB-01 Hydrogen methyl Ib-01 Hydrogen methyl

IB-02 ft Ethyl Ib-02 Hydrogen Ethyl

IB-03 Hydrogen Isopropyl Ib-03 Hydrogen Isopropyl

IB-04 hydrogen n-butyl Ib-04 hydrogen n-butyl

1B-05 Hydrogen Cyclopropyl Ib-05 Hydrogen 'Cyclopropyl fluorenyl

IB-06 Hydrogen 2-methoxybutyl Ib-06 Hydrogen 2-methoxybutyl

IB-07 Hydrogen 2-Chlorobutyl Ib-07 Hydrogen 2-Chlorobutyl

IB-08 2-cyanobutyl Ib-08 Hydrogen 2-cyanobutyl

IB-09 Hydroxybenzyl Ib-09 Hydroxybenzyl

IB-10 'vinyl Ib-10 hydrogen vinyl

IB- 11 hydrogen n-propenyl lb- 11 hydrogen n-propenyl

IB-12 Hydrogen 3-chlorobut-1-enyl 1b Hydrogen 3-chlorobut-1-enyl

IB-13 prop-1-ynyl lb- 13 hydropropan-1-ynyl

IB-14 hydrogen 3-chlorobut-1-ynyl lb-14 hydrogen 3-chlorobut-1-ynyl

IB-15 hydrogen phenyl lb- 15 hydrogen

IB-16 hydrogen 2-methylphenyl lb- 16 hydrogen 2-methylphenyl

IB-17 hydrogen 3-methylphenyl lb- 17 hydrogen 3-methylphenyl

IB-18 Hydrogen 4-methylphenyl lb- 18 Hydrogen 4-methylphenyl

IB- 19 . Hydrogen 2-chlorophenyl Ib-19 Hydrogen 2-chlorophenyl

IB-20 3-chlorophenyl Ib-20 Hydrogen 3-chlorophenyl

12

Replacement page (Article 26) IB-21 hydrogen 4-chlorophenyl Ib-21 hydrogen 4-chlorophenyl

IB-22 hydrogen 2-nitrophenyl Ib-22 2-nitrophenyl

IB-23 hydrogen 3-nitrophenyl ib-23 hydrogen 3-nitrophenyl

IB-24 Oxygen 4-Nitrophenyl Ib-24 Gas 4-Nitrophenyl

IB-25 hydrogen 2-light phenyl lb-25 hydrogen 2-hydroxyphenyl

IB-26 Hydrogen 3-Hydroxyphenyl Ib-26 Hydrogen 3-Hydroxyphenyl

IB-27 hydrogen 4-hydroxyphenyl Ib-27 4-light phenyl

1B-28 Hydrogen 2-carboxyphenyl Ib-28 2-carboxyphenyl

IB-29 Hydrogen 3-carboxyphenyl lb-29 Hydrogen 3-carboxyphenyl

IB-30 Hydrogen 4-carboxyphenyl Ib-30 Hydrogen 4-carboxyphenyl

IB-31 Hydrogen 2-Cyclohexaneylphenyl Ib-31 Hydrogen 2-Cyclohexylphenyl

IB-32 Hydrogen 3-Cyclohexaneylphenyl lb-32 Hydrogen 3-Cyclohexaneylphenyl

IB-33 Hydrogen 4-Cyclohexylphenyl Ib-33 Hydrogen 4-Cyclohexylphenyl

IB-34 Hydrogen 2-methoxyphenyl Ib-34 Hydrogen 2-methoxyphenyl

IB-35 Hydrogen 3-methoxyphenyl lb-35 Hydrogen 3-methoxyphenyl

IB-36 Hydrogen 4-methoxyphenyl Ib-36 Hydrogen 4-methoxyphenyl ffi-37 Hydrogen 2-(2-chloroethyl)phenyl Ib-37 Hydrogen 2-(2-chloroethyl) Phenyl

IB-38 hydrogen 3-(2-chloroethyl)phenyl . ib-38 hydrogen 3-(2-chloroethyl)phenyl

IB-39 Hydrogen 4-(2-Chloroethyl)phenyl Ib-39 Hydrogen 4-(2-Chloroethyl)phenyl

IB-40 methyl hydrogen lb-40 methyl hydrogen

IB-41 methyl ethyl Ib-41 methyl ethyl

IB-42 methyl isopropyl Ib-42 methyl isopropyl

IB-43 methyl n-pentyl Ib-43 methyl n-pentyl

IB-44 methylcyclopropenyl Ib-44 methylcyclopropyl

IB-45 methyl 2-methoxybutyl Ib-45 methyl 2-methoxybutyl

IB-46 methyl 2-chlorobutyl Ib-46 methyl 2-chlorobutyl

IB -47 methyl 2-cyanobutyl Ib-47 methyl 2-cyanobutyl

IB-48 methyl benzyl Ib-48 methyl benzyl

1B-49 methyl vinyl lb-49 methyl vinyl

IB-50 methyl isopropenyl Ib-50 methyl isopropenyl

IB-51 methyl 3-chlorobut-1-enyl Ib-51 methyl 3-chlorobutyl-]-strip

IB-52 methyl prop-1-ynyl Ib-52 methyl prop-1-ynyl

IB-53 methyl 3-chlorobut-1-ynyl Ib-53 methyl 3-chlorobut-1-ynyl

IB-54 methyl phenyl Ib-54 methyl phenyl

IB-55 methyl 2-methylphenyl Ib-55 methyl 2-methylphenyl

IB-56 methyl 3-methylphenyl Ib-56 methyl 3-methylphenyl

IB-57 methyl 4-methylphenyl Ib-57 methyl 4-methylphenyl

IB-58 methyl 2-chlorophenyl Ib-58 methyl 2-chlorophenyl

IB-59 methyl 3-chlorophenyl Ib-59 methyl 3-chlorophenyl

IB-60 methyl 4-chlorophenyl Ib-60 methyl 4-chlorophenyl

13

Replacement page (Article 26) IB-61 methyl 2-nitrophenyl Ib-61 methyl 2-pictylphenyl

IB-62 methyl 3-nitrophenyl Ib-62 methyl 3-nitrophenyl

IB-63 methyl 4-nitrophenyl Ib-63 methyl 4-nitrophenyl

IB-64 methyl 2-hydroxyphenyl lb-64 methyl 2-hydroxyphenyl

IB-65 methyl 3-hydroxyphenyl Ib-65 methyl 3-hydroxyphenyl

1B-66 methyl 4-hydroxyphenyl Ib-66 methyl 4-phenylphenyl

IB-67 methyl 2-carboxyphenyl Ib-67 methyl 2-carboxyphenyl

IB-68 methyl 3-carboxyphenyl Ib-68 methyl 3-carboxyphenyl

IB-69 methyl 4'-carboxyphenyl Ib-69 methyl 4-carboxyphenyl

IB-70 methyl 2-cyclohexylphenyl Ib-70 methyl 2-cyclohexanephenyl

1B-71 methyl 3-cyclohexanephenyl phenyl Ib-71 methyl 3-cyclohexanephenyl

IB-72 methyl 4-cyclohexanephenyl Ib-72 methyl 4-cyclohexylphenyl

IB-73 methyl 2-methoxyphenyl Ib-73 methyl 2-methoxyphenyl

IB-74 methyl 3-methoxyphenyl Ib-74 methyl 3-methoxyphenyl

IB-75 methyl 4-methoxyphenyl Ib-75 methyl 4-methoxyphenyl

IB-76 methyl 2-(2-chloroethyl)phenyl Ib-76 methyl 2 2-chloroethyl)phenyl

IB-77 methyl 3-(2-chloroethyl)phenyl Ib-77 methyl 3-(2-chloroethyl)phenyl

IB-78 methyl 4-(2-chloroethyl)phenyl Ib-78 methyl 4-(2-chloroethyl)phenyl

IB-79 Chlorine Hydrogen Ib-79 Chlorine Hydrogen

IB-80 gas ethyl Ib-80 chloroethyl

IB-81 chloroisopropyl Ib-81 nitrogen isopropyl

IB-82 Chloro-n-butyl Ib-82 Nitrogen n-Butyl

IB-83 chlorocyclopropane group Ib-83 chlorocyclopropane group

IB-84 Chloro 2-methoxybutyl Ib-84 Chloro 2-methoxybutyl

IB- 85 2-chlorobutyl Ib-85 chloro 2-chlorobutyl ffi-86 chloro 2-cyanobutyl Ib-86 chloro 2-cyanobutyl

IB-87 chlorobenzyl Ib-87 nitrogen benzyl

IB-88 Chlorine Vinyl lb-88 Chlorovinyl

1B-89 Chloroisopropenyl Ib-89 Chloroisopropenyl

IB-90 3-chlorobut-1-enyl Ib-90 nitrogen 3-chlorobutene-1-recording

1B-91 Chloropropanyl alkynyl group Ib-91 Chloropropane small alkynyl group

IB-92 Chlor 3-chlorobutyl-1-ynyl Ib-92 Chloro 3-chlorobut 4-ynyl

IB-93 chlorophenyl Ib-93 gas phenyl

IB-94 2-methylphenyl lb-94 gas 2-methylphenyl

IB-95 gas 3-methylphenyl Ib-95 chloro 3-methylphenyl

IB-96 chloro 4-methylphenyl Ib-96 gas 4-methylphenyl

IB-97 Chloro 2-Chlorophenyl lb-97 Chloro 2-Chlorophenyl

IB-98 3-chlorophenyl Ib-98 chloro-3-chlorophenyl

IB-99 chloro 4-chlorophenyl lb-99 gas 4-chlorophenyl

IB-100 Chlorine 2-Nitrophenyl lb- 100 Nitrogen 2-Nitrophenyl

14

Replacement page (Article 26) IB-101 Chloro 3-nitrophenyl Ib-101 Chloro 3-nitrophenyl

IB- 102 Chlorine 4-Nitrophenyl lb- 102 Wind 4-Nitrophenyl

IB- 103 2-hydroxyphenyl ib-103 2-hydroxyphenyl

IB- 104 Chlor 3-hydroxyphenyl Ib-104 Chloro 3-light phenyl

IB-105 chloro 4-hydroxyphenyl lb- 105 wind 4-light phenyl

IB-106 Chloro 2-carboxyphenyl lb- 106 Chloro 2-carboxyphenyl

IB- 107 Chlor 3-carboxyphenyl lb- 107 Chlor 3-carboxyphenyl

IB- 108 chloro 4-carboxyphenyl Ib-108 chloro 4-carboxyphenyl

IB-109 Chloro 2-cyclohexanephenyl lb- 109 Chloro 2-cyclohexanephenyl

ΙΒ-Π0 chloro 3-cyclohexaneylphenyl Ib-110 chloro 3-cyclohexanephenyl

IB-I l l chloro 4-cyclohexaneylphenyl Ib-111 chloro 4-cyclohexanephenyl

IB-112 chloro 2-methoxyphenyl Ib-112 chloro 2-methoxyphenyl .

IB-113 Chlor 3-methoxyphenyl Ib-113 Gas 3-methoxyphenyl

IB- 114 chloro 4-methoxyphenyl lb-114 chloro 4-methoxyphenyl

ΙΒ-Π 5 Chloro 2-(2-chloroethyl)phenyl Ib-115 Chloro 2-(2-chloroethyl)phenyl

1B-116 : L 3-(2-chloroethyl)phenyl Ib-116 chloro 3-(2-chloroethyl)phenyl

IB-117 'Chloro 4- (2-chloroethyl)phenyl Ib-1 17 chloro 4-(2-chloroethyl)phenyl

IB-118 2-chloroethyl hydrogen Ib-118 2-chloroethyl hydrogen

IB-119 2-chloroethyl ethyl Ib-11 2-chloroethyl ethyl

IB-120 2-chloroethyl isopropyl lb- 120 2-chloroethyl isopropyl

IB-121 2-chloroethyl n-butyl Ib-121 2-chloroethyl n-butyl

IB-122 2-chloroethyl cyclopropane lb- 122 2-chloroethyl cyclopropane

IB- 123 2-chloroethyl 2-methoxybutyl lb- 123 2-chloroethyl 2-methoxybutyl

IB- 124 2-chloroethyl 2-chlorobutyl Ib-124 2-chloroethyl 2-chlorobutyl

IB-125 2-chloroethyl 2-cyanobutyl lb- 125 2-chloroethyl 2-cyanobutyl

IB- 126 2-chloroethylbenzyl lb- 126 2 ^_ pro-ethyl ^ 3⁄4 benzyl

IB- 127 2-chloroethyl vinyl Ib-127 2-chloroethyl vinyl

IB-128 2-chloroethyl Isopropenyl Ib-128 2-chloroethyl Isopropenyl

IB-129 2-chloroethyl 3-chloroprene-1-chidyl lb-129 2-chloroethyl 3-chlorobut-1-enyl

IB-130 2-chloroethyl propyl -1 -alkynyl lb- 130 2-chloroethyl propyl -1 -alkynyl

IB-131 2-chloroethyl 3-chlorobut-1-ynyl Ib-133 2-chloroethyl 3-chlorobutyl-I-alkynyl

IB-132 2-chloroethyl phenyl lb- 132 2-chloroethyl phenyl

IB-133 2-chloroethyl 2-methylphenyl lb-133 2-chloroethyl 2-methylphenyl

IB- 134 2-chloroethyl 3-methylphenyl Ib-134 2-chloroethyl 3-methylphenyl

IB-135 2-chloroethyl 4-methylphenyl lb- 135 2-chloroethyl 4-methylphenyl

IB-136 2-chloroethyl 2-chlorophenyl lb- 136 2-chloroethyl 2-chlorophenyl

IB-137 2-chloroethyl 3-chlorophenyl Ib-137 2-chloroethyl 3-chlorophenyl

IB-138 2-chloroethyl 4-chlorophenyl Ib-138 2-chloroethyl 4-chlorophenyl

IB-139 2-chloroethyl 2-nitrophenyl lb-139 2-chloro i-yl 2-nitrophenyl

IB-140 2-chloroethyl 3-nitrophenyl lb- 140 2-chloroethyl 3-nitrophenyl

15

Replacement page (Article 26) 1B-141 2-chloroethyl 4-nitrophenyl Ib-141 2-chloroethyl 4-nitrophenyl

IB-142 2-chloroethyl 2-hydroxyphenyl lb- 142 2-chloroethyl 2-hydroxyphenyl

IB- 143 2-Chloroethyl 3-diabase phenyl Ib-143 2-chloroethyl 3-hydroxyphenyl

IB- 144 2-chloroethyl 4-hydroxyphenyl Ib-144 2-chloroethyl 4-hydroxyphenyl

IB-145 2-gas ethyl 2-carboxyphenyl lb- 145 2-chloroethyl 2-carboxyphenyl

IB-146 2-chloroethyl 3-carboxyphenyl lb- 146 2-chloroethyl 3-carboxyphenyl

IB- 147 2-Chloroethyl 4-carboxyphenyl lb- 147 2-chloroethyl 4-carboxyphenyl

IB-148 2-chloroethyl 2-cyclohexaneylphenyl Ib-148 2-chloroethyl 2-cyclohexanephenyl

IB- 149 2-Ethylethyl 3-Cyclohexaneylphenyl lb-149 2-Chloroethyl 3-cyclohexylphenyl

IB- 150 2-chloroethyl 4-cyclohexanephenyl phenyl Ib-150 2-chloroethyl 4-cyclohexanephenyl

IB-151 2-chloroethyl 2-methoxyphenyl Ib'151 2-chloroethyl 2-methoxyphenyl

IB- 152 2-Chloroethyl 3-methoxyphenyl lb- 152 2-chloroethyl 3-methoxyphenyl

IB- 153 2-Chloroethyl 4-methoxyphenyl Ib-153 2-chloroethyl 4-methoxyphenyl

IB-154 2-chloroethyl 2-(2-chloroethyl)phenyl Ib-154 2-chloroethyl 2-(2-chloroethyl)phenyl

IB- 155 2-Chloroethyl 3-(2-chloroethyl)phenyl Ib-155 2-chloroethyl 3-(2-chloroethyl)phenyl

1B-156 2-chloroethyl 4-(2-chloroethyl)phenyl lb- 156 2-chloroethyl 4-(2-chloroethyl)phenyl

1B-157 Nitrohydrogen lb- 157 Nitrohydrogen

IB-158 nitroethyl lb- 158 nitroethyl

IB- 159 nitroisopropyl Ib-159 nitroisopropyl

IB-160 nitro-n-butyl lb-160 nitro-n-butyl iB-161 nitrocyclopropane group Ib-161 nitrocyclopropane group

IB- 162 nitro 2-methoxybutyl lb- 162 nitro 2-methoxybutyl

IB-163 Nitro 2-chlorobutyl lb- 163 Nitro 2-chlorobutyl

IB-164 nitro 2-cyanobutyl Ib-164 nitro 2-cyanobutyl

IB-165 nitrobenzyl lb- 165 nitrobenzyl

IB-166 Nitro Vinyl lb- 166 Nitro Vinyl

IB- 167 nitroisopropenyl lb- 167 nitroisopropenyl

IB- 168 nitro 3-chlorobut-1-enyl Ib-168 nitro 3-chlorobut-1-enyl

IB-169 Nitropropan-1-ynyl Ib-169 Nitro-propyl-] - Block

ΙΒ-Π0 nitro 3-chlorobut-1-ynyl lb- 170 nitro 3-chlorobutandinyl

1B-171 Nitrophenyl Ib-171 Nitrophenyl

B-172 Nitro 2-methylphenyl lb- 172 Nitro 2-methylphenyl

IB- 173 nitro 3-methylphenyl lb- 173 nitro 3-methylphenyl

IB-174 nitro 4-methylphenyl lb-174 nitro 4-methylphenyl

IB-175 nitro 2-chlorophenyl lb- 175 nitro 2-chlorophenyl

IB-176 Nitro 3-chlorophenyl lb- 176 Nitro 3-chlorophenyl

IB- 177 nitro 4-chlorophenyl lb- 177 nitro 4-chlorophenyl

IB- 178 nitro 2-nitrophenyl lb- 178 nitro 2-latyl phenyl

IB- 179 nitro 3-nitrophenyl Ib-179 nitro 3-nitrophenyl

1B-180 nitro 4-nitrophenyl lb- 180 nitro 4-nitrophenyl

16

Replacement page (Article 26) IB-181 nitro 2-hydroxyphenyl Ib-181 nitro 2-hydroxyphenyl

IB-182 Nitro 3-hydroxyphenyl Ib-182 Nitro 3-hydroxyphenyl

IB-183 nitro 4-pyridyl Ib-183 nitro 4-hydroxyphenyl

IB-184 nitro 2-carboxyphenyl lb- 184 nitro 2-carboxyphenyl

IB-185 Nitro 3-carboxyphenyl lb- 185 Nitro 3-carboxyphenyl

IB- 186 nitro 4-carboxyphenyl lb- 186 nitro 4-carboxyphenyl

ΓΒ-187 nitro 2-cyclohexanephenyl Ib-187 nitro 2-cyclohexyl phenyl

IB-188 nitro 3-cyclohexanephenyl Ib-188 nitro 3-cyclohexyl phenyl

IB-189 Nitro 4-cyclohexylphenyl lb- 189 Nitro 4-cyclohexanephenyl

IB-190 Nitro 2-methoxyphenyl Ib-190 Nitro 2-methoxyphenyl

IB-191 Nitro 3-methoxyphenyl Ib-191 Nitro 3-methoxyphenyl

IB-192 nitro 4-methoxyphenyl lb- 192 nitro 4-methoxyphenyl

IB-193 Nitro 2-(2-chloroethyl)phenyl lb- 193 Nitro 2-(2-chloroethyl)phenyl

IB- 194 nitro 3-0 chloroethyl) phenyl lb- 194 nitro 3-(2-chloroethyl) phenyl

IB-195 ethyl) phenyl

Compound number Y R Compound number Y R

 IC-01 Hydrogen Methyl Ic-01 Hydrogen Methyl

IC-02 Hydrogen Ethyl Ic-02 Hydrogen Ethyl

IC-03 Hydrogen Isopropyl Ic-03 Hydrogen Isopropyl

IC-04 hydrogen n-butyl Ic-04 hydrogen n-butyl

IC-05 Hydrocyclopropane Group Ic-05 Hydrogen Cyclopropenyl

IC-06 Hydrogen 2-methoxybutyl Ic-06 Hydrogen 2-methoxybutyl

IC-07 Hydrogen 2-Chlorobutyl Ic-07 Hydrogen 2-Chlorobutyl

IC-08 Hydrogen 2-cyanobutyl Ic-08 Hydrogen 2-cyanobutyl

IC-09 hydrogen. Benzyl Ic-09 hydrogen benzyl

IC-10 Hydrogen Vinyl Ic-10 Hydrogen Vinyl

IC-11 hydrogen n-propenyl group Ic-11 hydrogen n-propenyl group

IC-12 Hydrogen 3-Chlorobut-1-enyl Ic-12 3-chlorobut-1-enyl

IC-13 Hydrogen-1-Acynyl Ic-13 Hydrogen Prop-1-ynyl

IC-14 3-chlorobut-1-ynyl Ic-14 hydrogen 3-chlorobut-1-ynyl

IC-15 Hydrogen phenyl Ic-15 Hydrogen This St base

IC-16 Hydrogen 2-Methylphenyl Ic-16 Hydrogen 2-Methylphenyl

IC-17 hydrogen 3-methylphenyl Ic-17 hydrogen 3-methylphenyl

IC-18 Hydrogen 4-methylphenyl Ic-18 Hydrogen 4-methylphenyl

17

Replacement page (Article 26) IC-19 hydrogen 2-chlorophenyl Ic-19 hydrogen 2-chlorophenyl

IC-20 Hydrogen 3-Chlorophenyl Ic-20 Hydrochlorophenyl

IC-21 Hydrogen 4-chlorobenzene, yl. Ic-21 Hydrogen 4-chlorophenyl

IC-22 Hydrogen 2-Nitrophenyl Ic-22 Hydrogen 2-Nitrophenyl

IC-23 Hydrogen 3-Nitrophenyl Ic-23 Hydrogen 3-Nitrophenyl

IC-24 Hydrogen 4-Nitrophenyl Ic-24 Hydrogen 4-Nitrophenyl

1C-25 hydrogen 2-hydroxyphenyl Ic-25 hydrogen 2-hydroxyphenyl

IC-26 Hydrogen 3-Light phenyl Ic-26 Hydrogen . 3-Hydroxyphenyl

IC-27 Hydrogen 4-Hydroxyphenyl Ic-27 Hydrogen 4-Hydroxyphenyl

IC-28 2-carboxyphenyl Ic-28 hydrogen 2-carboxyphenyl

IC-29 3-carboxyphenyl Ic-29 Hydrogen 3-carboxyphenyl

IC-30 Hydrogen 4-carboxyphenyl Ic-30 Hydrogen 4-carboxyphenyl

IC-31 Hydrogen 2-Cyclohexaneylphenyl Ic-31 Hydrogen 2-Cyclohexylphenyl

IC-32 Argon 3-Cyclohexaneylphenyl Ic-32 Hydrogen 3-Cyclohexaneylphenyl

IC-33 4-Cyclohexaneylphenyl Ic-33 Hydrogen 4-Cyclohexaneylphenyl

IC-34 Hydrogen 2-methoxyphenyl Ic-34 Hydrogen 2-methoxyphenyl

IC-35 Hydrogen 3-methoxyphenyl Ic-35 Hydrogen ₃ -methoxyphenyl

1C-36 Hydrogen 4-methoxyphenyl Ic-36 Hydrogen 4-methoxyphenyl

IC-37 Hydrogen 2-(2-Chloroethyl)phenyl Ic-37 Hydrogen 2-(2-Chloroethyl)phenyl

IC-38 hydrogen 3-(2-chloroethyl)phenyl lc-38 hydrogen 3-(2-chloroethyl)phenyl

IC-39 Hydrogen 4-(2-Chloroethyl)phenyl Ic-39 Hydrogen 4-(2-Chloroethyl)phenyl

IC-40 methyl hydrogen Ic-40 methyl hydrogen

IC-41 methyl ethyl Ic-41 methyl ethyl

IC-42 methyl isopropyl lc-42 methyl isopropyl

IC-43 methyl n-butyl Ic-43 methyl n-butyl

IC-44 methylcyclopropane Ic-44 methylcyclopropenyl

IC-45 methyl 2-methoxybutyl Ic-45 methyl 2-methoxybutyl

IC-46 methyl 2-chlorobutyl lc-46 methyl 2-chlorobutyl

IC-47 methyl 2-cyanobutyl Ic-47 methyl 2-cyanobutyl

IC-48 methylbenzyl Ic-48 methyl benzyl

1C-49 methyl vinyl Ic-49 methyl vinyl

IC-50 methyl isopropenyl group Ic-50 methyl isopropenyl

IC-51 methyl 3-gas butyl-1-yl Ic-51 methyl 3-chlorobut-1-enyl

IC-52 methyl propan 4-alkynyl Ic-52 methyl propyl -1 -alkynyl

IC-53 methyl 3-chlorobutandinyl Ic-53 methyl 3-chlorobut-1-ynyl

1C-54 methylphenyl Ic-54 methyl group

IC-55 methyl 2-methylphenyl Ic-55 methyl 2-methylphenyl

IC-56 methyl 3-methylphenyl Ic-56 methyl 3-methylphenyl

IC-57 methyl 4-methylphenyl Ic-57 methyl 4-methylphenyl

IC-58 methyl 2-chlorophenyl Ic-58 methyl 2-chlorophenyl

 18

Replacement page (Article 26) IC-59 methyl 3-chlorophenyl Ic-59 methyl 3-chlorophenyl

IC-60 methyl 4-chlorophenyl Ic-60 methyl 4-chlorophenyl

IC-61 methyl 2-nitrophenyl Ic-61 methyl 2-nitrophenyl

IC-62 methyl 3-nitrophenyl Ic-62 methyl 3-nitrophenyl

IC-63 methyl 4-nitrophenyl Ic-63 methyl 4-nitrophenyl

IC-64 methyl 2-hydroxyphenyl Ic-64 methyl 2-hydroxybenzene 3⁄4

IC-65 methyl 3-hydroxyphenyl Ic-65 methyl 3-hydroxyphenyl

IC-66 methyl 4-hydroxyphenyl Ic-66 methyl 4-hydroxyphenyl

IC-67 methyl 2-carboxyphenyl Ic-67 methyl 2-carboxyphenyl

IC-68 methyl 3-carboxyphenyl Ic-68 methyl 3-carboxyphenyl

IC-69 methyl 4-carboxyphenyl Ic-69 methyl 4-carboxyphenyl

IC-70 methyl 2-cyclohexylphenyl Ic-70 methyl 2-cyclohexyl phenyl

IC-71 methyl 3-cyclohexanephenyl phenyl Ic-71 methyl 3-cyclohexanephenyl

IC-72 methyl 4-cyclohexanephenyl Ic-72 methyl 4-cyclohexanephenyl

IC-73 methyl 2-methoxyphenyl Ic-73 methyl 2-methoxyphenyl

IC-74 methyl 3-methoxyphenyl lc-74 methyl 3-methoxyphenyl

IC-75 methyl 4-methoxyphenyl Ic-75 methyl 4-methoxyphenyl

IC-76 methyl 2-(2-chloroethyl)phenyl Ic-76 methyl 2-(2-chloroethyl)phenyl

IC-77 methyl 3-(2-chloroethyl)phenyl Ic-77 methyl 3-(2-chloroethyl)phenyl

IC-78 methyl 4-(2-chloroethyl)phenyl Ic-78 methyl 4-(2-chloroethyl)phenyl

IC-79 Chlorine Hydrogen Ic-79 Chlorine Hydrogen

IC-80 Chloroethyl Ic-80 Chloroethyl

IC-81 Chloropropyl Ic-81 Chloropropyl

IC-82 Chloro-n-butyl Ic-82 Chloro-n-butyl

IC-83 Chloropropylidene Ic-83 Chlorocyclopropane

IC-84 2-methoxybutyl Ic-84 chloro 2-methoxybutyl

IC-85 Chloro 2-Chlorobutyl Ic-85 Chloro 2-Chlorobutyl

IC-86 Chloro 2-cyanobutyl Ic-86 Chloro 2-cyanobutyl

IC-87 Benzyl Ic-87 Chlorobenzyl

IC-88 Chlorine Vinyl Ic-88 Chlorine Vinyl

IC-89 Chloroisopropenyl Ic-89 Chloroisopropenyl

IC-90 Chloro 3-chlorobutene-1-decyl Ic-90 Chloro 3-chlorobut-1-enyl

IC-91 Chloropropan-1-ynyl Ic-91 Chloroprop-1-ynyl

IC-92 Chloro 3-chlorobutane alkynyl Ic-92 Chloro 3-chlorobut-1-ynyl

IC-93 Chlorophenyl Ic-93 Chlorophenyl

IC-94 Chloro 2-methylphenyl Ic-94 Chloro 2-methylphenyl

IC-95 Chloro 3-methylphenyl Ic-95 Chloride 3-methylphenyl

IC-96 chloro 4-methylphenyl Ic-96 chloro 4-methylphenyl

IC-97 Chloro 2-Chlorophenyl Ic-97 Chloro 2-Chlorophenyl

IC-98 Chloro-3-chlorophenyl Ic-98 Chloro-3-chlorophenyl

19

Replacement page (Article 26) IC-99 wind 4-chlorophenyl Ic-99 chloro 4-chlorophenyl

IC-100 Chlorine 2-Nitrophenyl Ic-100 Chloro 2-Nitrophenyl

IC-101 Chlorine 3-Nitrophenyl Ic-101 Chlor 3-nitrophenyl

IC-102 Chlorine 4-Nitrophenyl Ic-102 Chloro 4-nitrophenyl

IC-103 Chloro 2-hydroxyphenyl Ic-103 Chloro 2-hydroxyphenyl

IC-104 chloro-3-ylphenyl Ic-104 chloro 3-light phenyl

IC-105 4-hydroxyphenyl Ic-105 chloro 4-light phenyl

IC-106 Chloro 2-carboxyphenyl Ic-106 Chloro 2-Carboxyphenyl

IC-107 Chlorine 3-carboxyphenyl Ic-107 Chlor-3-carboxyphenyl

IC-108 Chloro 4-carboxyphenyl Ic-108 Chloro 4-carboxyphenyl

IC- 09 Chloro 2-cyclohexanephenyl Ic-109 Chloro 2-cyclohexylphenyl

IC-110 chloro 3-cyclohexanephenyl phenyl Ic-110 chloro 3-cyclohexyl phenyl

IC-111 Chloro 4-cyclohexanephenyl Ic-111 Chloro 4-cyclohexylphenyl

IC-112 Chloro 2-methoxyphenyl Ic-112 Chloro 2-methoxyphenyl

IC-113 Chlor 3-methoxyphenyl Ic-113 Chlor 3-methoxyphenyl

IC-114 Chloro 4-methoxyphenyl Ic-114 . Chloro 4-methoxyphenyl

IC-115 Chloro 2-(2-chloroethyl)phenyl Ic-115 Chloro 2-(2-chloroethyl)phenyl

IC-116 Phoenix 3-(2-chloroethyl)phenyl Ic-116 Chlor 3-(2-chloroethyl)phenyl

IC-117 Chloro 4-(2-chloroethyl)phenyl Ic-117 Chloro 4-(2-chloroethyl)phenyl

IC-118 2-chloroethyl hydrogen Ic-118 2-chloroethyl hydrogen

IC-119 2-chloroethyl ethyl Ic-119 2-chloroethyl ethyl

IC-120 2-chloroethyl Isopropyl Ic-120 2-chloroethyl Isopropyl

IC-121 2-chloroethyl n-butyl Ic-121 2-chloroethyl n-butyl

IC-122 2-Chloroethyl Cyclopropenyl Ic-122 2-Chloroethyl Cyclopropyl fluorenyl

IC-123 2-chloroethyl 2-methoxybutyl Ic-123 2-chloroethyl 2-methoxybutyl

IC-124 2-chloroethyl 2-chlorobutyl Ic-124 2-chloroethyl 2-chlorobutyl

IC-125 2-chloroethyl 2-cyanobutyl Ic-125 2-chloroethyl 2-cyanobutyl

IC-126 2-chloroethyl benzyl Ic-126 2-chloroethyl benzyl

IC-127 2-chloroethyl vinyl Ic-127 2-chloroethyl vinyl

IC-128 2-chloroethyl Isopropenyl Ic-128 2-chloroethyl Isopropenyl

IC-129 2-Chloroethyl 3-chlorobutenyl alkenyl Ic-129 2-chloroethyl 3-chlorobut-1-enyl

IC-130 2-chloroethyl propyl-1-ynyl Ic-130 2-chloroethyl propyl-1-ynyl

IC-131 2-Chloroethyl 3-chlorobutyrynyl Ic-131 2-chloroethyl 3-chlorobut-1-ynyl

IC-132 2-chloroethyl phenyl Ic-132 2-chloroethyl phenyl

IC-133 2-chloroethyl 2-methylphenyl Ic-133 2-chloroethyl 2-methylphenyl

IC-134 2-chloroethyl 3-methylphenyl Ic-134 2-chloroethyl 3-methylphenyl

IC-135 2-chloroethyl 4-methylphenyl Ic-135 2-chloroethyl 4-methylphenyl

IC-136 2-chloroethyl 2-chlorophenyl Ic-136 2-chloroethyl 2-chlorophenyl

IC-137 2-chloroethyl 3-chlorophenyl Ic-137 2-chloroethyl 3-chlorophenyl

IC-138 2-chloroethyl 4-chlorophenyl Ic-138 2-chloroethyl 4-chlorophenyl

20

Replacement page (Article 26) 1C-139 2-chloroethyl 2-nitrophenyl Ic-139 2-chloroethyl 2-nitrophenyl

IC-140 2-chloroethyl 3-nitrophenyl Ic-140 2-chloroethyl 3-nitrophenyl

IC-141 2-chloroethyl 4-nitroindenyl. Ic-141 2-chloroethyl 4-nitrophenyl

IC-142 2-chloroethyl 2-hydroxyl group Ic-1 2 2-chloroethyl 2-hydroxyphenyl

IC-143 2-chloroethyl 3-hydroxyphenyl Ic-143 2-chloroethyl 3-hydroxyphenyl

IC-144 2-chloroethyl 4-hydroxyphenyl Ic-144 2-chloroethyl 4-hydroxyphenyl

IC-145 2-chloroethyl 2-carboxyphenyl Ic-145 2-chloroethyl 2-carboxyphenyl

IC-146 2-chloroethyl 3-carboxyphenyl Ic-146 2-chloroethyl 3-carboxyphenyl

IC-147 2-Chloroethyl 4-carboxyphenyl lc-1 7 2-chloroethyl 4-carboxyphenyl

IC-148 2-chloroethyl 2-cyclohexylphenyl phenyl Ic-148 2-chloroethyl 2-cyclohexanephenyl

IC-149 2-chloroethyl 3-cyclohexaneylphenyl Ic-149 2-chloroethyl 3-cyclohexylphenyl

IC-150 2-chloroethyl 4-cyclohexaneylphenyl Ic-150 2-chloroethyl 4-cyclohexanephenyl

IC-151 2-chloroethyl 2-methoxyphenyl Ic-151 2-chloroethyl 2-methoxyphenyl

IC-152 2-chloroethyl 3-methoxyphenyl Ic-152 2-chloroethyl 3-methoxyphenyl

IC-153 2-chloroethyl 4-methoxyphenyl Ic- 53 2-chloroethyl 4-methoxyphenyl 54 2-chloroethyl 2-(2-chloroethyl)phenyl Ic-154 2-chloroethyl 2-(2-chloroethyl)phenyl

IC-155 2-chloroethyl 3-(2-chloroethyl)phenyl Ic-155 2-chloroethyl 3-(2-chloroethyl)phenyl

IC-156 2-Chloroethyl 4-(2-chloroethyl)phenyl Ic-156 2-chloroethyl 4-(2-chloroethyl)phenyl

IC-157 Nitrohydrogen Ic-157 Nitrohydrogen

IC-158 nitroethyl lc-158 nitroethyl

IC- 59 Nitroisopropyl Ic-159 Nitroisopropyl

1C-160 nitro-n-butyl Ic-160 nitro-n-butyl

IC-161 nitrocyclopropane group Ic-161 nitrocyclopropenyl

IC-162 Nitro 2-methoxybutyl Ic-162 Nitro 2-methoxybutyl

IC-163 Nitro 2-Chlorobutyl Ic-163 Nitro 2-Chlorobutyl

IC-164 Nitro 2-cyanobutyl Ic-164 Nitro 2-cyanobutyl

IC-165 Nitrobenzylidene Ic-165 Nitrobenzylidene

IC-166 Nitro Vinyl Ic-166 Nitro Vinyl

IC-167 Nitroisopropenyl Ic-167 Nitroisopropenyl

IC-168 nitro 3-chlorobut-1-enyl Ic-168 nitro 3-chlorobut-1-enyl

IC-169 nitropropandinyl group Ic-169 nitropropane small alkynyl group

IC-170 Nitro 3-Chloro T-1-block Ic-170 Nitro 3-chlorobut-1-ynyl

IC-171 nitrophenyl Ic-171 nitro base

IC-172 nitro 2-methylphenyl Ic-172 nitro 2-methylphenyl

IC-173 Nitro 3-methylphenyl Ic-173 Nitro 3-methylphenyl

IC-174 Nitro 4-methylphenyl Ic-174 Nitro 4-methylphenyl

IC-175 Nitro 2-Chlorophenyl Ic-175 Nitro 2-Chlorophenyl

IC-176 Nitro 3-chlorophenyl Ic-176 Nitro 3-chlorophenyl

IC-177 Nitro 4-chlorophenyl Ic-177 Nitro 4-chlorophenyl

IC-178 Nitro 2-Nitrophenyl Ic-178 Nitro 2-Nitrophenyl

twenty one

Replacement page (Article 26) IC-179 Nitro 3-nitrophenyl lc-179 Nitro 3-nitrophenyl

IC-180 nitro 4-nitrophenyl Ic-180 nitro 4-nitrophenyl

IC-181 nitro 2-hydroxyphenyl Ic-181 nitro 2-hydroxyphenyl

IC-182 Nitro 3-hydroxyphenyl Ic-182 Nitro 3-hydroxyphenyl

IC-183 nitro 4-hydroxyphenyl Ic-183 decyl 4-hydroxyphenyl

IC-184 Nitro 2-carboxyphenyl Ic-184 Nitro 2-carboxyphenyl

IC-185 Nitro 3-carboxyphenyl Ic-185 Nitro 3-carboxyphenyl

IC-186 Nitro 4-carboxyphenyl Ic-186 Nitro 4-carboxyphenyl

IC-187 Nitro 2-cyclohexylphenyl Ic-187 Nitro 2-cyclohexylphenyl

IC-188 nitro 3-cyclohexaneylphenyl Ic-188 nitro 3-cyclohexanephenyl

IC-189 nitro 4-cyclohexanephenyl Ic-189 nitro 4-cyclohexanephenyl

IC-190 Nitro 2-methoxyphenyl Ic-190 Nitro 2-methoxyphenyl

IC-191 Nitro 3-methoxyphenyl Ic-191 Nitro 3-methoxyphenyl

IC-192 nitro 4-methoxyphenyl Ic-192 nitro 4-methoxyphenyl

IC-193 Nitro 2-(2-chloroethyl)phenyl Ic-193 Nitro 2-(2-chloroethyl)phenyl

IC-194 Nitro 3-(2-chloroethyl)phenyl Ic-194 Nitro 3-(2-chloroethyl)phenyl

IC-195 ethyl) phenyl

Compound number Y R Compound number Y R

 ID-01 Hydrogen methyl Id-01 Hydrogen methyl

ID-02 Hydrogen . Ethyl Id-02 Hydrogen Ethyl

ID-03 Hydrogen Isopropyl Id-03 Hydrogen 'Isopropyl

ID-04 n-butyl Id-04 hydrogen n-butyl

ID-05 Hydrogen Cyclopropenyl Id-05 Hydrogen Cyclopropenyl

ID-06 Hydrogen 2-methoxybutyl Id-06 Hydrogen 2-methoxybutyl

ID-07 Hydrogen 2-Chlorobutyl Id-07 Hydrogen 2-Chlorobutyl

ID-08 Hydrogen 2-cyanobutyl Id-08 Hydrogen 2-cyanobutyl

ID-09 Hydroxybenzyl ld-09 Benzyl

ID-10 Hydrogen Vinyl Id- 10 Vinyl

ID- 11 hydrogen n-propenyl Id- 11 n-propenyl

ID-12 hydrogen 3-chlorobut-1-enyl Id- 12 ft 3-chlorobutenyl

ID-13 Hydrogen-1-Acynyl Id- 13 Hydrogen Prop-1-ynyl

ID-14 Hydrogen 3-chlorobut-1-ynyl Id-14 Oxygen 3-chlorobut-1-ynyl

ID- 15 hydrogen . phenyl Id- 15 hydrogen phenyl

ID-16 Hydrogen 2-Methylphenyl Id- 16 Hydrogen 2-Methylphenyl

twenty two

Replacement page (Article 26) ID-17 Hydrogen 3-methylphenyl Id- 17 Hydrogen 3-methylphenyl

ID-18 hydrogen 4-methylphenyl Id- 18 hydrogen 4-methylphenyl

ID-19 2-chlorophenyl 14-19 hydrogen 2-chlorophenyl

ID-20 Hydrogen 3-Chlorophenyl Id-20 Hydrogen 3-Chlorophenyl

1D-21 hydrogen ' . 4-chlorophenyl Id-21 hydrogen 4-chlorophenyl

ID-22 Hydrogen 2-Nitrophenyl Id-22 Hydrogen 2-Nitrophenyl

ID-23 hydrogen 3-nitrophenyl Id-23 hydrogen 3-nitrophenyl

ID-24 Hydrogen 4-Nitrophenyl Id-24 Hydrogen 4-Nitrophenyl

ID-25 Hydrogen 2-Hydroxyphenyl Id-25 Hydrogen 2-Light phenyl

ID-26 . Hydrogen 3-light phenyl Id-26 hydrogen 3-hydroxyphenyl

ID-27 Hydrogen 4-Hydroxyphenyl Id-27 Hydrogen 4-Hydroxyphenyl

ID-28 hydrogen 2-carboxyphenyl Id-28 hydrogen 2-carboxyphenyl

ID-29 Hydrogen 3-carboxyphenyl Id-29 Hydrogen 3-carboxyphenyl

ID-30 Hydrogen 4-carboxyphenyl Id-30 Hydrogen 4-carboxyphenyl

ID-31 Hydrogen 2-Cyclohexylphenyl Id-31 Hydrogen 2-Cyclohexaneylphenyl

ID-32 Hydrogen 3-Cyclohexaneylphenyl Id-32 Hydrogen 3-Cyclohexylphenyl

ID-33 Hydrogen 4-Cyclohexaneylphenyl Id-33 Hydrogen 4-Cyclohexylphenyl

ID-34 Hydrogen 2-methoxyphenyl Id-34 Hydrogen 2-methoxyphenyl

ID-35 Hydrogen 3-methoxyphenyl Id-35 Hydrogen 3-methoxyphenyl

ID-36 Hydrogen 4-methoxyphenyl Id-36 Hydrogen 4-methoxyphenyl

ID-37 Hydrogen 2-(2-Chloroethyl)phenyl Id-37 Hydrogen 2-(2-Chloroethyl)phenyl

ID-38 Hydrogen 3-(2-Chloroethyl)phenyl Id-38 Hydrogen 3-(2-Chloroethyl)phenyl

ID-39 Hydrogen 4-(2-Chloroethyl)phenyl Id-39 Hydrogen 4-(2-Chloroethyl)phenyl

ID-40 methyl hydrogen Id-40 methyl hydrogen

ID-41 methylethyl Id-41 methyl ethyl

ID-42 methyl isopropyl Id-42 methyl isopropyl

ID-43 methyl n-butyl Id-43 methyl n-butyl

ID-44 methylcyclopropenyl Id-44 methylcyclopropenyl

ID-45 methyl 2-methoxybutyl ld-45 methyl 2-methoxybutyl

ID-46 methyl 2-chlorobutyl Id-46 methyl 2-chlorobutyl

ID-47 methyl 2-cyanobutyl Id-47 methyl 2-cyanobutyl

ID-48 methylbenzyl Id-48 methylbenzyl

ID-49 methyl vinyl Id-49 methyl B; 13⁄4 base

ID-50 methyl isopropenyl Id-50 methyl isopropenyl

ID-51 methyl 3-chlorobut-1-enyl Id-51 methyl 3-chlorobutenyl

ID-52 methyl prop-1-ynyl Id-52 methyl prop-1-ynyl

ID-53 methyl 3-chlorobut-1-ynyl Id-53 methyl 3-chlorobut-1-ynyl

ID-54 methyl δ Id-54 methyl phenyl

ID-55 methyl 2-methylphenyl Id-55 methyl 2-methylphenyl

ID-56 methyl 3-methylphenyl Id-56 methyl 3-methylphenyl

twenty three

Replacement page (Article 26) ID-57 methyl 4-methylphenyl Id-57 methyl 4-methylphenyl

ID-58 methyl 2-chlorophenyl Id-58 methyl 2-chlorophenyl

ID-S9 methyl 3-chlorobenzene.yl. Id-59 methyl 3-chlorophenyl

ID-60 methyl 4-chlorophenyl Id-60 methyl 3⁄4 4-chlorophenyl

ID-61 methyl 2-nitrophenyl Id-61 methyl 2-nitrophenyl

ID-62 methyl 3-nitrophenyl Id-62 methyl 3-nitrophenyl

ID-63 methyl 4-nitrophenyl Id-63 methyl 4-nitrophenyl

ID-64 methyl 2-hydroxyphenyl Id-64 methyl 2-hydroxyphenyl

ID-65 methyl 3-hydroxyphenyl Id-65 methyl 3-hydroxyphenyl

ID-66 methyl 4-hydroxyphenyl Id-66 methyl 4-hydroxyphenyl

ID-67 methyl 2-carboxyphenyl Id-67 methyl 2-carboxyphenyl

ID-68 'Methyl 3-carboxyphenyl Id-68 methyl 3-phenylphenyl

ID-69 methyl 4-carboxyphenyl Id-69 methyl 4-carboxyphenyl

ID-70 methyl 2-cyclohexanephenyl Id-70 methyl 2-cyclohexyl phenyl

ID-71 methyl 3-cyclohexanephenyl phenyl Id-71 methyl 3-cyclohexanephenyl

ID-72 methyl 4-cyclohexylphenyl Id-72 methyl 4-cyclohexyl phenyl

ID-73 methyl 2-methoxyphenyl Id-73 methyl 2-methoxyphenyl

ID-74 methyl 3-methoxyphenyl Id-74 methyl 3-methoxyphenyl

ID-75 methyl 4-methoxyphenyl Id-75 methyl 4-methoxyphenyl

ID-76 methyl 2-(2-chloroethyl)phenyl Id-76 methyl 2-(2-chloroethyl)phenyl

ID-77 methyl 3-(2-chloroethyl)phenyl Id-77 methyl 3-(2-chloroethyl)phenyl

ID-78 methyl 4-(2-chloroethyl)phenyl Id-78 methyl 4-(2chloroethyl)phenyl

ID-79 Chlorine Oxygen Id-79 Chlorine Oxygen

ID-80 Chloroethyl Id-80 Chloroethyl

ID-81 Chloropropyl Id-81 Chloropropyl

ID-82 n-butyl Id-82 n-butyl

ID-83 Chlorocyclopropane Id-83 Chlorocyclopropane

ID-84 Chloro 2-methoxybutyl Id-84 Chloro 2-methoxybutyl

ID-85 Chloro 2-chlorobutyl Id-85 Chloro 2-chlorobutyl

ID-86 Chloro 2-cyanobutyl Id-86 Chloro 2-cyanobutyl

ID-87 Chlorobenzyl Id-87 Chlorobenzyl

ID-88 Vinyl Id-88 Chlorine Vinyl

ID-89 Chloroisopropenyl Id-89 Chloroisopropenyl

ID-90 Chloro 3-chlorobutene-1-alkenyl ld-90 Chloro-3-chlorobutenyl

ID-91 prop-1-ynyl Id-91 chloroprop-1-ynyl

ID-92 Chlor 3-chlorobutyl-1-ynyl Id-92 Chloro 3-chlorobutane alkynyl

ID-93 Wind Phenyl Id-93 Chlorophenyl

ID-94 Chloro 2-methylphenyl Id-94 Chloro 2-methylphenyl

ID-95 Chloro 3-methylphenyl Id-95 Chloride 3-methylphenyl

ID-96 chloro 4-methylphenyl Id-96 chloro 4-methylphenyl

twenty four

Replacement page (Article 26) ID-97 paper 2-chlorophenyl Id-97 chloro 2-chlorophenyl

ID-98 Chloro-3-chlorophenyl Id-98 Phoenix 3-chlorophenyl

ID-99 Chloro 4-chlorophenyl ld-99 Chloro 4-chlorophenyl

ID-100 Chlorine 2-Nitrophenyl Id- 100 Chloro 2-Nitrophenyl

ID-101 Chlor 3-nitrophenyl Id-101 wind 3-nitrophenyl

ID- 102 Chloro 4-nitrophenyl Id- 102 Chloro 4-nitrophenyl

ID-103 2-hydroxyphenyl Id- 103 chloro 2-light phenyl

ID- 104 Chlor 3-hydroxyphenyl Id- 104 Chlor 3-hydroxyphenyl

ID-105 Chloro-4-light phenyl Id- 105 chloro 4-hydroxyphenyl

ID- 106 Chloro 2-carboxyphenyl Id- 106 Chloro 2-carboxyphenyl

ID-107 3-carboxyphenyl Id- 107 chloro 3-carboxyphenyl

ID- 108 Chloro 4-carboxyphenyl Id- 108 Chloro 4-carboxyphenyl

ID- 109 Chloro 2-cyclohexylphenyl Id-109 Chloro 2-cyclohexylphenyl

ID-110 Chlor 3-cyclohexylphenyl Id-110 Chlor 3-cyclohexanephenyl

ID-Ill chloro 4-cyclohexaneylphenyl Id-I l l chloro 4-cyclohexanephenyl

ID-112 Chloro 2-methoxyphenyl Id- 112 Chloro 2-methoxyphenyl

ID-113 Chlor 3-methoxyphenyl Id-113 Chlor 3-methoxyphenyl

ID- 114 chloro 4-methoxyphenyl ld-114 chloro 4-methoxyphenyl

ID-115 2-(2-Chloroethyl)phenyl Id-115 2-(2-chloroethyl)phenyl

ID-116 Chlor 3-(2-chloroethyl)phenyl Id-116 Chlor 3-(2-chloroethyl)phenyl

ID-117 Chloro 4-(2-chloroethyl)phenyl Id-117 Chloro 4-(2-chloroethyl)phenyl

ID-118 2-chloroethyl hydrogen Id-118 2-chloroethyl hydrogen

ID-119 2-chloroethyl ethyl Id-119 2-chloroethyl ethyl

ID-120 2-chloroethyl Isopropyl Id- 120 2-chloroethyl-isopropyl

ID-121 2-chloroethyl n-butyl Id-121 2-chloroethyl n-butyl

ID-122 2-Chloroethyl Cyclopropylidene Id- 122 2-Chloroethylcyclopropane

ID- 123 2-Chloroethyl 2-methoxybutyl Id-123 2-chloroethyl 2-methoxybutyl

ID- 124 2-Chloroethyl 2-chlorobutyl Id-124 2-chloroethyl 2-chlorobutyl

ID-125 2-Chloroethyl 2-cyanobutyl Id- 125 2-chloroethyl 2-cyanobutyl

ID- 126 2-Chloroethyl benzyl Id- 126 2-chloroethyl benzyl

ID- 127 2-chloroethyl vinyl Id- 127 2-chloroethyl vinyl

ID- 128 2-chloroethyl Isopropenyl Id-128 2-chloroethyl Isopropenyl

ID- 129 2-Chloroethyl 3-chlorobut-1-enyl Id- 129 2-chloroethyl 3-chlorobutene-1-diyl

ID-130 2-chloroethyl propyl-1-ynyl Id-130 2-chloroethyl propyl-1-ynyl

ID-131 2-Chloroethyl 3-chlorobut-1-ynyl Id-131 2-chloroethyl 3-chlorobut-1-ynyl

ID- 132 2-chloroethyl group Id- 132 2-chloroethyl phenyl

ID- 133 2-Chloroethyl 2-methylphenyl Id-133 2-chloroethyl 2-methylphenyl

ID- 134 2-Chloroethyl 3-methylphenyl Id-134 2-chloroethyl 3-methylphenyl

ID- 135 2-Chloroethyl 4-methylphenyl Id-135 2-chloroethyl 4-methylphenyl

ID-136 2-chloroethyl 2-chlorophenyl Id- 136 2-chloroethyl 2-chlorophenyl

25

Replacement page (Article 26) ID-137 2-Chloroethyl 3-chlorophenyl Id-137 2-chloroethyl 3-chlorophenyl

ID-138 2-Chloroethyl 4-chlorophenyl Id-138 2-chloroethyl 4-chlorophenyl

ID-139 2-chloroethyl 2-nitrophenyl Id- 139 2-chloroethyl 2-nitrophenyl

ID-140 2-Chloroethyl 3-nitrophenyl Id- 140 2-chloroethyl 3-nitrophenyl

ID-141 2-chloroethyl 4-nitrophenyl Id-141 2-chloroethyl 4-nitrophenyl

ID- 142 2-Chloroethyl 2-light phenyl Id- 142 2-chloroethyl 2-hydroxyphenyl

ID- 143 2-Chloroethyl 3-hydroxyphenyl Id- 143 2-chloroethyl 3-hydroxyphenyl

ID- 144 2-Chloroethyl 4-hydroxyphenyl Id- 144 2-chloroethyl 4-hydroxyphenyl

ID- 145 2-Chloroethyl 2-carboxyphenyl Id- 145 2-chloroethyl 2-carboxyphenyl

ID- 146 2-chloroethyl. 3-carboxyphenyl Id- 146 2-chloroethyl 3-carboxyphenyl

ID- 147 2-Chloroethyl 4-carboxyphenyl Id- 147 2-chloroethyl 4-carboxyphenyl

ID- 148 2-Chloroethyl 2-cyclohexylphenyl Id- 148 2-chloroethyl 2-cyclohexanephenyl

ID- 149 2-Chloroethyl 3-cyclohexanephenyl Id- 149 2-chloroethyl 3-cyclohexanephenyl

ID- 150 2-Chloroethyl 4-cyclohexylphenylphenyl Id-] 50 2-chloroethyl 4-cyclohexanephenyl

ID-151 2-Chloroethyl 2-methoxyphenyl Id-151 2-chloroethyl 2-methoxyphenyl

ID- 152 2-Chloroethyl 3-methoxyphenyl Id- 152 2-chloroethyl 3-methoxyphenyl

ID- 153 2-Chloroethyl 4-methoxyphenyl Id- 153 2-chloroethyl 4-methoxyphenyl

ID- 154 2-Chloroethyl 2-(2-chloroethyl)phenyl Id-154 2-chloroethyl 2-(2-chloroethyl)phenyl

ID-155 2-Chloroethyl 3-(2-chloroethyl)phenyl ld-155 2-Chloroethyl 3-(2-chloroethyl)phenyl

ID-156 2-Chloroethyl 4-(2-chloroethyl)phenyl Id-156 2-chloroethyl chloroethyl)phenyl

ID-157 Nitrohydrogen Id-157 Nitrohydrogen

ID-158 Nitroethyl Id- 158 Nitroethyl

ID- 159 Nitroisopropyl Id-159 Nitroisopropyl

ID-160 nitro-n-butyl Id-160 nitro-n-butyl

ID-161 Nitrocyclopropanyl Id-161 Nitrocyclopropenyl

ID- 162 Nitro 2-methoxybutyl Id- 162 Nitro 2-methoxybutyl

ID- 163 Nitro 2-chlorobutyl Id- 163 Nitro 2-chlorobutyl

ID-164 Nitro 2-cyanobutyl Id-164 Nitro 2-cyanobutyl

ID-165 nitrobenzyl Id- 165 nitrobenzyl

1D-166 nitro vinyl ' Id- 166 nitro vinyl

ID-167 Nitroisopropenyl Id- 167 Nitroisopropenyl

ID- 168 nitro 3-chlorobut-1-enyl Id- 168 nitro 3-chlorobut-1-enyl

ID- 169 nitroprop-1-ynyl Id-169 nitroprop-1-ynyl

ID-170 Nitro 3-chlorobutan-1-ynyl Id- 170 Nitro 3-chlorobutan-]-alkynyl

ID-171 Nitrophenyl Id-171 Nitrophenyl

ID- 172 Nitro 2-methylphenyl Id-172 Nitro 2-methylphenyl

ID-173 Nitro 3-methylphenyl Id- 173 Nitro 3-methylphenyl

ID- 174 nitro 4-methylphenyl Id-174 nitro 4-methylphenyl

ID- 175 nitro 2-chlorophenyl Id- 175 nitro 2-chlorophenyl

ID- 176 Nitro 3-chlorophenyl Id- 176 Nitro 3-chlorophenyl

26

Replacement page (Article 26) ID- 177 Nitro 4-chlorophenyl Id- 177 Nitro 4-chlorophenyl

ID- 178 nitro 2-nitrophenyl Id- 178 nitro 2-nitrophenyl

ED- 179 Nitro 3-nitrophenyl Id- 179 Nitro 3-nitrophenyl

ID- 180 nitro 4-nitrophenyl Id- 180 nitro 4-nitrophenyl

ID-181 Nitro 2-hydroxyphenyl Id-181 Nitro 2-hydroxyphenyl

ID-182 Nitro 3- 3⁄4ylphenyl Id- 182 Nitro 3-hydroxyphenyl

ID-183 Nitro 4-light phenyl Id-183 Nitro 4-hydroxyphenyl

ID-184 Nitro 2-carboxyphenyl Id- 184 Nitro 2-carboxyphenyl

ID- 185 nitro 3-carboxyphenyl Id- 185 nitro 3-carboxyphenyl

ID-186 nitro 4-carboxyphenyl Id- 186 nitro 4-carboxyphenyl

ID- 187 nitro 2-cyclohexylphenyl Id- 187 nitro 2-cyclohexanephenyl

ID-188 Nitro 3-cyclohexanephenyl Id-188 Nitro 3-Cyclohexanephenyl

ID- 189 nitro 4-cyclohexanephenyl Id-189 nitro 4-cyclohexyl phenyl

ID- 190 nitro 2-methoxyphenyl Id- 190 nitro 2-methoxyphenyl

ID-191 Nitro 3-methoxyphenyl Id-191 Nitro 3-methoxyphenyl

ID- 92 nitro 4-methoxyphenyl Id- 192 nitro 4-methoxyphenyl

ID- 193 Nitro 2-(2-chloroethyl)phenyl Id- 193 Nitro 2-(2-chloroethyl)phenyl

ID- 194 Nitro 3-(2-chloroethyl)phenyl Id-194 Nitro 3-(2-chloroethyl)phenyl

ID-195 Nitro 4-(2-chloroethyl)phenyl Id-195 Nitro 4-(2-chloroethyl)phenyl Synthetic Route 2:

 In the methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I), Y represents:

— c-z

Wherein: hydroxy, ^~ decyloxy, c ₃ ～c ₈ alkenyloxy or c ₃ ～ c ₈ alkynyloxy, amino, or an amine substituted by 1 or 2 〜3⁄4 fluorenyl, and other groups When the group is as defined in the above formula (I), the methacryl benzimidazole (thio)one derivative represented by the formula (I) to be protected by the present invention can be produced by a synthetic route as shown in the following scheme:

27

Replacement page (Article 26)

 The synthesis route uses a carboxy-substituted o-nitroaniline as a starting material, firstly introducing a halogenated hydrocarbon as a hydrocarbylating agent, introducing various hydrocarbyl groups or substituted hydrocarbyl groups on the amino nitrogen, and then reducing the nitro group in an iron powder/hydrochloric acid system. And refluxing with urea or thiourea in xylene to obtain a benzimidazolone derivative, and then acylation with methacryloyl chloride, and finally the carboxyl group on the benzene ring is esterified with an alcohol to form an ester, or with ammonia ( The amine is reacted to form an amide to obtain the target compound.

 The method is a general synthetic route, and for a specific compound, a target compound can be obtained by a simple procedure using a more convenient intermediate. Examples of methacryl benzimidazole (thio) ketone derivatives of the present invention prepared according to the reaction scheme are shown in the table.

2.

 Table 2

 Compound Number 3⁄4 R Compound Number R

IIA-01 Hydroxyl Hydrogen IIa-01

 IIA-02 Hydroxy Isopropyl IIa-02 Isopropyl

IIA-03 Hydroxy 2-methoxybutyl IIa-03 2-methoxybutyl

IIA-04, hydroxy 2-chlorobutyl lla-04 2-chlorobutyl

IIA-05 Hydroxy 2-cyanobutyl IIa-05 2-cyanobutyl

IIA-06 Hydroxybenzylmethyl IIa-06 Benzyl

IIA-07 Hydroxy Isobutyl IIa-07 Isobutyl

28

Replacement page (Article 26) 11A-08 hydroxy-n-pentyl IIa-08 hydroxy-n-pentyl

IIA-09 Hydroxy Vinyl IIa-09 Hydroxy Vinyl

IIA-10 hydroxy n-propenyl IIa-10 hydroxy n-propenyl

ILA.-11 Hydroxyisopropenyl Ha-11 Hydroxyisopropenyl

IIA-12 hydroxy phenyl Ha- 12 hydroxy phenyl

1IA-13 hydroxy 2-propenylphenyl Ha- 13 hydroxy 2-methylphenyl

IIA-14 hydroxy 3-nitrophenyl IIa-14 hydroxy 3-nitrophenyl

ΠΑ-15 hydroxy 4-carboxyphenyl IIa-15 hydroxy 4-carboxyphenyl

IIA-16 ethoxy hydrogen IIa-16 ethoxy hydrogen

IIA-17 Ethoxy Isopropyl IIa-17 Ethoxy Isopropyl

I1A-18 Ethoxy 2-methoxybutyl IIa-18 Ethoxy • 2-Methoxybutyl

IIA-19 Ethoxy 2-chlorobutyl IIa-19 Ethoxy 2-chlorobutyl

IIA-20 Ethoxy 2-cyanobutyl IIa-20 Ethoxy 2-cyanobutyl

IIA-21 Ethoxybenzylmethyl IIa-21 Ethoxybenzyl

IIA-22 Ethoxy Isobutyl Ha-22 Ethoxy Isobutyl

11A-23 ethoxy n-pentyl IJa-23 ethoxy n-pentyl

IIA-24 Ethoxyvinyl IIa-24 Ethoxy Vinyl

IIA-25 ethoxy n-propenyl IIa-25 ethoxy n-propenyl

IIA-26 Ethoxy Isopropenyl Ha-26 Ethoxy Isopropenyl

IIA-27 Ethoxyphenyl lla-27 Ethoxyphenyl

IIA-28 Ethoxy 2-methylphenyl IIa-28 Ethoxy 2-methylphenyl

IIA-29 Ethoxy 3-nitrophenyl IIa-29 Ethoxy 3-nitrophenyl

1IA-30 Ethoxy 4-carboxyphenyl IIa-30 Ethoxy 4-carboxyphenyl

IIA-31 N-ethylamino hydrogen Ha-31 N-ethylamine 3⁄4

IIA-32 N-ethylamino isopropyl IIa-32 N-ethylamino isopropyl

IIA-33 N-ethylamino 2-methoxybutyl IIa-33 N-ethylamino 2-methoxybutyl

IIA-34 N-ethylamino 2-chlorobutyl IIa-34 , N-ethylamino 2-chlorobutyl

IIA-35 N-ethylamino 2-cyanobutyl IIa-35 ethylamino 2-cyanobutyl

IIA-36 N-ethylamino benzyl Ila-36 N-ethylamino benzyl

ΠΑ-37 N-ethylaminoisobutyl IIa-37 N-ethylaminoisobutyl

I1A-38 N-ethylamino-n-pentyl IIa-38 N, ethylamino-n-pentyl

IIA-39 N-ethylamino vinyl IIa-39 ethylamino vinyl

IIA-40 N-ethylamino n-propenyl group IIa-40 ethylamino group n-propenyl

IIA-41 N-ethylaminoisopropenyl IIa-41 N-ethylaminoisopropenyl

1IA-42 N-ethylamine group IIa-42 N-ethylamine group

1IA-43 N-ethylamino 2-methylphenyl IIa-43 N-ethylamino 2-methylphenyl

IIA-44 N-ethylamino 3-nitrophenyl IIa-44 N-ethylamino 3-nitrophenyl

IIA-45 N-ethylamino 4-carboxyphenyl IIa-45 N-ethylamino 4-carboxyphenyl

29

Replacement page (Article 26)

Compound number R Compound number z, R

IIB-01 Hydroxyl Hydrogen IIb-01 Hydroxyl

 IIB-02 hydroxyisopropyl Ib-02 hydroxyisopropyl

IIB-03 Hydroxy 2-methoxybutyl IIb-03 Hydroxy 2-methoxybutyl

IIB-04 Hydroxy 2-Chlorobutyl IIb-04 Hydroxy 2-Chlorobutyl

IIB-05 Hydroxy 2-cyanobutyl IIb-05 Hydroxy 2-cyanobutyl

IIB-06 Hydroxybenzylidene IIb-06 Hydroxybenzylidene

IIB-07 Hydroxyisobutyl IIb-07 Hydroxyisobutyl

IIB-08 hydroxy n-pentyl IIb-08 hydroxy n-pentyl

IIB-09 Hydroxy Vinyl IIb-09 Hydroxy Vinyl

IIB-10 hydroxy n-propenyl lib- 10 hydroxy n-propenyl

IIB-11 hydroxy isopropenyl llb-ll hydroxy isopropenyl

I1B- 2 hydroxyphenyl lib- 12 hydroxy phenyl

IIB-13 hydroxy 2-methylphenyl lib- 13 hydroxy 2-methylphenyl

IIB-14 hydroxy 3-nitrophenyl lib- 14 hydroxy 3-nitrophenyl

IIB-15 hydroxy 4-carboxyphenyl lib- 15 hydroxy 4-carboxyphenyl

IIB-16 ethoxy hydrogen IIb-16 ethoxy hydrogen

IIB-17 ethoxy isopropyl lib- 17 ethoxy isopropyl

IIB-18 Ethoxy 2-methoxybutyl lib- 18 Ethoxy 2-methoxybutyl

IIB-19 Ethoxy 2-chlorobutyl lib- 19 Ethoxy 2-chlorobutyl

IIB-20 Ethoxy 2-cyanobutyl IIb-20 Ethoxy 2-cyanobutyl

IIB-21 ethoxybenzyl benzyl IIb-21 ethoxy benzyl

1IB-22 ethoxylated isobutyl IIb-22 ethoxylated isobutyl

IIB-23 ethoxy n-pentyl IIb-23 ethoxy n-pentyl

ΠΒ-24 ethoxy vinyl IIb-24 ethoxy vinyl

ΠΒ-25 ethoxy n-propenyl IIb-25 ethoxy n-propenyl

IIB-26 Ethoxy Isopropenyl Ilb-26 Ethoxy Isopropenyl

IIB-27 Ethoxyphenyl IIb-27 Ethoxyphenyl

IIB-28 Ethoxy 2-methylphenyl IIb-28 Ethoxy 2-methylphenyl

IIB-29 Ethoxy 3-nitrophenyl IIb-29 Ethoxy 3-nitrophenyl

IIB-30 Ethoxy 4-carboxyphenyl IIb-30 Ethoxy 4-carboxyphenyl

IIB-31 N-ethylamino. llb-31 N-ethylamino,

11B-32 N-ethylamino isopropyl IIb-32 N-ethylamino isopropyl

IIB-33 N-ethylamino 2-methoxybutyl IIb-33 N-ethylamino 2-methoxybutyl

IIB-34 N-ethylamino 2-chlorobutyl IIb-34 N-ethylamino 2-chlorobutyl

30

Replacement page (Article 26) IIB-35 N-ethylamino 2-cyanobutyl IIb-35 N-ethylamino 2-cyanobutyl

IIB-36 N-ethylamino benzyl Ib-36 N-ethylamino benzyl

IIB-37 N-ethylaminoiso T-based IIb-37 N-ethylaminoisobutyl

IIB-38 N-ethylamine n-pentyl Ilb-38 N-ethylamine n-pentyl

ΠΒ-39 N-ethylamino vinyl Hb-39 N-ethylamino vinyl

IIB-40 N-ethylamine

 Hydroxylhydroxyl hydroxyl. n-propenyl IIb-40 N-ethylamino n-propenyl

IIB-41 N-ethylaminoisopropenyl IIb-41 N-ethylaminoisopropenyl

ΠΒ-42 N-ethylamino phenyl IIb-42 N-ethylamino phenyl

IIB-43 N-ethylamino 2-methylphenyl IIb-43 N-ethylamino 2-methylphenyl

I1B-44 N-ethylamino 3-nitrophenyl IIb-44 N-ethylamino 3-nitrophenyl

IIB-45 phenyl

Compound Number Compound Number R

IIC- 1 hydroxyhydrogen llc-01 Hydrogen IIC-02 Hydroxyisopropyl IIc-02 Isopropyl IIC-03 Hydroxy 2-methoxybutyl IIc-03 2-methoxybutyl IIC-04 Hydroxy 2-chloro Butyl IIc-04 hydroxy hydroxyhydroxyl hydroxy hydroxy hydroxy hydroxy hydroxy hydroxy 2-chlorobutyl IIC-05 IIc-05 base yl base.

 Hydroxy 2-cyanobutyl 2-cyanobutyl IIC-06 Hydroxybenzyl IIc-06 Benzyl IIC-07 Hydroxyisobutyl IIc-07 Isobutyl IIC-08 Hydroxy-n-pentyl IIc-08 Pentyl IIC-09-ethyl fluorenyl IIc-09 vinyl IIC-10 yl-n-propenyl He- 0 n-propenyl IIC-11 isopropyl isopropanyl Ilc- oxime isopropenyl 11C-12 phenyl lie- 12 benzene Group IIC-13, 2-methylphenyl lie- 13 2-methylphenyl IIC-14, 3-nitrophenyl IIc-14, 3-nitrophenyl IIC-15, 4-carboxyphenyl IIc- 15 4-carboxyphenyl

IIC-16 Ethoxyhydrogen IIc-16 Ethoxyhydrogen 11C-17 Ethoxyisopropyl lie- 17 Ethoxyisopropyl IIC-18 Ethoxy 2-methoxybutyl lie- 18 Ethylene 2-methoxybutyl IIC-19 ethoxy 2-chlorobutyl lie- 19 ethoxy 2-chlorobutyl IIC-20 ethoxy 2-cyanobutyl Ik-20 ethoxy 2- Cyanobutyl IIC-21 ethoxybenzyl Uc-21 ethoxybenzyl IIC-22 Ethoxyisobutyl IIc-22 Ethoxyisobutyl IIC-23 Ethoxy n-pentyl IIc -23 ethoxy-n-pentyl

31

Replacement page (Article 26) 1IC-24 Ethoxyvinyl IIc-24 Ethoxy Vinyl

IIC-25 ethoxy n-propenyl IIc-25 ethoxy n-propenyl

IIC-26 Ethoxyisopropenyl IIc-26 Ethoxyisopropenyl

IIC-27 Ethoxyphenyl IIc-27 Ethoxyphenyl

IIC-28 Ethoxy 2-methylphenyl Ilc-28 Ethoxy 2-methylphenyl

IIC-29 3-nitrophenyl IIc-29 ethoxy 3-nitrophenyl

IIC-30 4-carboxyphenyl IIc-30 ethoxy 4-carboxyphenyl

IIC-31 N-ethylamino hydrogen IIc-31 N-ethylamino hydrogen

IIC-32 N-ethylamino isopropyl IIc-32 N-ethylamino isopropyl

IIC-33 N-ethylamino 2-methoxybutyl IIc-33 N-ethylamino 2-methoxybutyl

I1C-34 N-ethylamino 2-chlorobutyl IIc-34 N-ethylamino 2-chlorobutyl

IIC-35 N-ethylamino 2-alkyl butyl IIc-35 N-ethylamino 2-cyanobutyl

IIC-36 N-ethylamino benzyl methyl IIc-36 N-ethylamino benzyl

IIC-37 N-ethylamino isobutyl IIc-37 N-ethylamino isobutyl

IIC-38 N-ethylamine n-pentyl IIc-38 ethylamine n-pentyl

IIC-39 N-ethylamino vinyl IIc-39 N-ethylamino vinyl

IIC-40 N-ethylamino group n-propyl group IIc-40 N-ethylamino group n-propenyl group

IIC-41 . N-Ethylamino Isopropenyl IIc-41 N-Ethylamino Isopropenyl

IIC-42 N-ethylamino group Benyl IIc-42 N-ethylamino group

IIC-43 N-ethylamino 2-methylphenyl Hc-43 N-ethylamine 棊 2-methylphenyl

 Compound number R Compound number R

IID-01 Hydrogen IId-01 Hydroxyhydrogen IID-02 Isopropyl IId-02 Hydroxyisopropyl IID-03 2-Methoxybutyl IId-03 Hydroxy 2-methoxybutyl IID-04 2-Chloridine Base IId-04 Hydroxy 2-chlorobutyl IID-05 2-cyanobutyl IId-05 Hydroxy 2-alkylbutyl IID-06 Benzyl IId-06 Hydroxybenzyl IID-07 Isobutyl IId- 07 Hydroxyisobutyl IID-08 n-pentyl IId-08 hydroxy-n-pentyl IID-09 vinyl IId-09 hydroxyvinyl IID-10 n-propenyl IId-10 hydroxy-n-propenyl IID-11 isopropenyl-lid- 11 hydroxyisopropenyl

32

Replacement page (Article 26) IID-12 hydroxyphenyl 2 hydroxyphenyl

IK)- 13 hydroxy 2-methylphenyl lid- 13 hydroxy 2-methylphenyl

IID-14 hydroxy 3-nitrophenyl IId-14 hydroxy 3-nitrophenyl

IID-15 hydroxy 4-carboxyphenyl lid- 15 hydroxy 4-carboxyphenyl

IID-16 ethoxy hydrogen IId-16 ethoxy hydrogen

IID-17 ethoxy isopropyl lid- 17 ethoxy isopropyl

IID-18 Ethoxy 2-methoxybutyl IId-18 Ethoxy 2-methoxybutyl

IID-19 Ethoxy 2-Chlorobutyl Ild-19 Ethoxy 2-Chlorobutyl

IID-20 Ethoxy 2-cyanobutyl IId-20 Ethoxy 2-cyanobutyl

IID-21 ethoxybenzylmethyl IId-21 ethoxybenzyl

IID-22 ethoxylated isobutyl IId-22 ethoxylated isobutyl

1ID-23 ethoxy n-pentyl IId-23 ethoxy n-pentyl

IID-24 Ethoxy Vinyl IId-24 Ethoxy Vinyl

IID-25 ethoxy n-propenyl IId-25 ethoxy n-propenyl

IID-20 Ethoxy Isopropenyl Ild-26 Ethoxy Isopropenyl

IID-27 Ethoxyphenyl IId-27 Ethoxy 3⁄4

IID-28 Ethoxy 2-methylphenyl IId-28 Ethoxy 2-methylphenyl

IID-29 Ethoxy 3-nitrophenyl IId-29 Ethoxy 3-nitrophenyl

IID-30 Ethoxy 4-carboxyphenyl Ild-30 Ethoxy 4-carboxyphenyl

IID-31 N-ethylamino hydrogen IId-31 N-ethylamine

 IID-32 N-ethylamino isopropyl IId-32 N-ethylamino isopropyl

IID-33 N-ethylamino 2-methoxybutyl IId-33 N-ethylamino 2-methoxybutyl

IID-34 N-ethylamino 2-chlorobutyl IId-34 N-ethylamino 2-chlorobutyl

IID-35 N-ethylamino 2-cyanobutyl IId-35 N-ethylamino 2-cyanobutyl

IID-36 N-ethylamino benzyl Id-36 N-ethylamino benzyl

IID-37 N-ethylaminoisobutyl IId-37 N-ethylaminoisobutyl

IID-38 N-ethylamino-n-pentyl IId-38 N-ethylamino-n-pentyl

IID-39 N-ethylamino vinyl IId-39 N-ethylamino vinyl

IID-40 N-ethylamino n-propenyl IId-40 N-ethylamino n-propenyl

IID-41 N-ethylaminoisopropenyl IId-41 N-ethylaminoisopropenyl

IID-42 N-ethylamino group IId-42 N-ethylamino phenyl

11D-43 N-ethylamino 2-methylphenyl IId-43 N-ethylamino 2-methylphenyl

IID-44 N-ethylamino 3-nitrophenyl Hd-44 N-ethylamino 3-nitrophenyl

1ID-45 N-ethylamino 4-carboxyphenyl IId-45 N-ethylamino 4-carboxyphenyl Synthetic route III:

 When in the methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I), Y represents -

— o(s wide z ₂

33

Replacement page (Article 26) Wherein Z ₂ represents: hydrogen, ~ alkyl, C _{3 -} C ₈ chain dilute or C _{3 -} C ₈ alkynyl, ~. Embankment ₄ haloalkyl group, ~C ₈ fatty acyl group, C ^ haloalkyl aliphatic acyl group, a carbamoyl group, N- methyl-carbamoyl, N- ethyl-carbamoyl, Ν, Ν- dimethylamino Formyl, hydrazine, hydrazine-diethylaminoformyl, phenyl, benzoyl, phenylacetyl, phenylsulfonyl or phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of phenyl or a phenylsulfonyl group: halo, ~C ₈ alkyl, C ₃ ~C ₈ alkyl with cycloalkyl, hydroxyl, ~. ₄垸oxy, ~. 4 halogenated thiol, ~. 4 halodecyloxy, ~C ₄ halosulfonylthio, ~ halosulfonylsulfonyl, carboxy, nitro, cyano, and other groups as defined by the above formula (I), may be as follows The synthetic route shown in the figure prepares the methacryloylbenzimidazole (thio)ketone derivative of the formula (I) to be protected by the present application:

 The synthesis route uses nitroamino-substituted phenol as a starting material, wherein the substitution positions of the nitro group and the amino group are indefinite, but the two must be ortho-position. First, a halogenated hydrocarbon is used as a hydrocarbylating agent, and various hydrocarbon groups are introduced on the amino nitrogen. Or substituted hydrocarbyl group, followed by hydroxyacetylation protection, nitro reduction, cyclization to obtain benzimidazolone derivatives, acylation with methacryloyl chloride, deprotection of hydroxyl groups, and finally hydrocarbylation by halogenated hydrocarbons The target compound is obtained by introducing a hydrocarbon group or introducing an acyl group by esterification reaction with an acid chloride.

 This method is a general synthetic route, and for a specific compound, a target compound can be obtained by a simple procedure using a more convenient intermediate.

34

Replacement page (Article 26) Examples of methacryloylbenzimidazole (thio)ketone derivatives of the present invention prepared according to the reaction scheme are shown in Table o.

 table 3

Compound

 R R

 Number number

 IIIA-01 Hydrogen Hydrogen IIIa-01 Hydrogen Hydrogen

IIIA-02 Hydrogen Isopropyl IIIa-02 Hydrogen Isopropyl

IIIA-03 Hydrogen 2-methoxybutyl IIIa-03 Hydrogen 2-methoxybutyl

IIIA-04 Hydrogen 2-Chlorobutyl IIIa-04 Hydrogen 2-Chlorobutyl

IIIA-05 Hydrogen 2-cyanobutyl IIIa-05 Hydrogen 2-cyanobutyl -06 Hydrogen Benzyl IIIa-06 Hydrogen Benzyl

IIIA-07 Hydrogen Isobutyl IIIa-07 Hydrogen Isobutyl

IIIA-08 hydrogen n-pentyl IIIa-08 hydrogen n-pentyl

IIIA-09 Hydrogen Vinyl HIa-09 Hydrogen Vinyl

IIIA-10 hydrogen n-propenyl Ilia-10 hydrogen n-propenyl

IIIA-11 Hydrogen isopropenyl Ilia-11 Oxy isopropenyl

IIIA-12 hydrogen base IIIa-12 hydrogen phenyl

IIIA-13 hydrogen 2-methylphenyl IIIa-13 hydrogen 2-methylphenyl

IIIA-14 hydrogen 3-nitrophenyl Ilia- 14 hydrogen 3-nitrophenyl

1IIA-15 Hydrogen 4-carboxyphenyl Ilia- 15 Hydrogen 4-carboxyphenyl

IIIA-16 acetyl hydrogen Ilia- 16 acetyl hydrogen

IIIA-17 acetyl isopropyl Ilia- 17 acetyl isopropyl

IIIA-18 acetyl 2-methoxybutyl IIIa-18 acetyl 2-methoxybutyl

IIIA-19 acetyl 2-chlorobutyl llla-19 acetyl 2-chlorobutyl

IIIA-20 Acetyl 2-cyanobutyl IIIa-20 Acetyl 2-cyanobutyl Epoxy-21 Acetylbenzylmethyl IIIa-21 Acetylbenzyl

IIIA-22 acetyl isobutyl IIIa-22 acetyl isobutyl

IIIA-23 acetyl n-pentyl IIIa-23 acetyl n-pentyl

IIIA-24 acetyl vinyl llIa-24 acetyl ^ alkenyl

IIIA-25 acetyl n-propenyl IIIa-25 acetyl n-propenyl

IIIA-26 Acetyl Isopropenyl IIIa-26 Acetyl Isopropenyl

IIIA-27 acetyl phenyl IIIa-27 acetyl phenyl

ΠΙΑ-28 acetyl 2-methylphenyl IIIa-28 acetyl 2-methylphenyl

ΠΙΑ-29 acetyl 3-nitrophenyl IIIa-29 acetyl 3-nitrophenyl

35

Replacement page (Article 26) Earn -30 acetyl 4-carboxyphenyl IIIa-30 acetyl 4-carboxyphenyl

ΙΠΑ-31 ethyl hydrogen IIIa-31 ethyl hydrogen

ΠΙΑ-32 ethyl isopropyl IIIa-32 ethyl isopropyl

ΙΙΙΑ-33 ethyl 2-methoxybutyl IIIa-33 ethyl 2-methoxybutyl

■-34 ethyl 2-chlorobutyl IIIa-34 ethyl 2-chlorobutyl

ΙΙΙΑ-35 ethyl 2-cyanobutyl IIIa-35 ethyl 2-cyanobutyl

ΠΙΑ-36 ethyl benzyl methyl IIIa-36 ethyl benzyl

ΙΙΙΑ-37 ethyl isobutyl IIIa-37 ethyl isobutyl

ΙΙΙΑ-38 ethyl n-pentyl IIIa-38 ethyl n-pentyl

11IA-39 ethyl vinyl IIIa-39 ethyl vinyl

ΙΙΙΑ-40 ethyl n-propenyl IIIa-40 ethyl n-propenyl

ΙΙΙΑ-41 ethyl isopropenyl Illa-41 ethyl isopropenyl

ΙΙΙΑ-42 ethyl phenyl IIIa-42 ethyl phenyl

1IIA-43 ethyl 2-methylphenyl IIIa-43 ethyl 2-methylphenyl

I1IA-44 ethyl 3-nitrophenyl IIIa-44 ethyl 3-nitrophenyl

ΙΙΙΑ-45 ethyl 4-carboxyphenyl IIIa-45 ethyl 4-carboxyphenyl

ΙΙΙΑ-46 Ν-methylcarbamoyl hydrogen IIIa-46 N-methylcarbamoyl hydrogen

ΙΙΙΑ-47 Ν-methylamino.formyl isopropyl IIIa-47 N-methylcarbamoyl isopropyl

ΙΙΙΑ-48 Ν-methylcarbamoyl 2-methoxybutyl IIIa-48 N-methylcarbamoyl 2-methoxybutyl

II1A-49 Ν-Methylcarbamoyl 2-chlorobutyl IIIa-49 N-methylcarbamoyl 2-chlorobutyl

ΙΙΙΑ-50 Ν-methylcarbamoyl 2-cyanobutyl IIIa-50 N-methylcarbamoyl 2-cyanobutyl

ΙΙΙΑ-51 Ν-methylcarbamoyl benzylmethyl IIIa-51 N-methylcarbamoyl benzyl

ΙΙΙΑ-52 Ν-methylcarbamoyl isobutyl IIIa-52 N-methylcarbamoyl isobutyl

ΠΙΑ-53 Ν-methylcarbamoyl n-pentyl IIIa-53 N-methylcarbamoyl n-pentyl

1IIA-54 Ν-methylcarbamoyl vinyl IIIa-54 N-methylcarbamoyl vinyl

ΙΙΙΑ-55 Ν-methylcarbamoyl n-propenyl IIIa-55 N-methylcarbamoyl n-propenyl

1IIA-56 Ν-methylcarbamoyl isopropenyl IIIa-56 N-methylcarbamoyl isopropylidene

ΙΙΙΑ-57 Ν-methylcarbamoyl phenyl IIIa-57 N-methylcarbamoyl phenyl

1IIA-58 Ν-methylcarbamoyl 2-methylphenyl IIIa-58 N-methylcarbamoyl 2-methylphenyl

ΙΙΙΑ-59 Ν-methylcarbamoyl 3-nitrophenyl IIIa-59 N-methylcarbamoyl 3-nitrophenyl

ΙΙΙΑ-60 phenyl

Compound compound

 Zi R Zi R number number

 IIIB-01 Hydrogen IIIb-01

IIIB-02 isopropyl IIIb-02 isopropyl

36

Replacement page (Article 26) II1B-03 Hydrogen 2-methoxybutyl IIIb-03 Hydrogen 2-methoxybutyl

IIIB-04 Hydrogen 2-Chlorobutyl HIb-04 Hydrogen 2-Chlorobutyl

IIIB-05 Hydrogen 2-cyanobutyl HIb-05 Hydrogen 2-cyanobutyl

IIIB-06 a Benzyl IIIb-06 Hydrogen Benzyl

IIIB-07 Hydrogen Isobutyl lllb-07 Hydrogen Isobutyl

I11B-08 hydrogen n-pentyl IIIb-08 . hydrogen n-pentyl

IIIB-09 Hydrogen Vinyl IIIb-09 Hydrogen Vinyl

IIIB-10 hydrogen n-propenyl IIIb-10 hydrogen n-propenyl

IIIB-11 Hydrogen isopropenyl IIIb-11 Hydrogen isopropenyl

IIIB-12 Hydrogen phenyl IIlb-12 Hydrogen phenyl

1IIB-13 hydrogen • 2-methylphenyl IIIb-13 hydrogen 2-methylphenyl

MB- 14 hydrogen 3-nitrophenyl IIIb-14 hydrogen 3-nitrophenyl

IIIB-15 Hydrogen 4-carboxyphenyl Illb- 15 Hydrogen 4-carboxyphenyl

IIIB-16 acetyl hydrogen IIIb-16 acetyl hydrogen

IIIB-17 acetyl isopropyl IIlb-17 acetyl isopropyl

I11B-18 acetyl 2-methoxybutyl IIIb-18 acetyl 2-methoxybutyl

IIIB-19 acetyl 2-chlorobutyl IIIb-19 acetyl 2-chlorobutyl

IIIB-20 Acetyl 2-cyanobutyl IIIb-20 Acetyl 2-cyanobutyl

IIIB-21 acetyl benzyl methyl IIIb-21 acetyl benzyl

IIIB-22 acetyl isobutyl lllb-22 acetyl isobutyl

II1B-23 acetyl n-pentyl IIIb-23 acetyl n-pentyl

IIIB-24 acetyl group III IIIb-24 acetyl group vinyl

ΙΠΒ-25 acetyl n-propenyl lIIb-25 acetyl n-propenyl

IIIB-26 Acetyl Isopropenyl lHb-26 Acetyl Isopropenyl

IIB-27 acetyl phenyl -27 acetyl phenyl

1I1B-28 acetyl 2-methylphenyl IIIb-28 acetyl 2-methylphenyl

ΙΠΒ-29 acetyl 3-nitrophenyl IIIb-29 acetyl 3-nitrophenyl

IIIB-30 acetyl 4-carboxyphenyl IIIb-30 acetyl 4-carboxyphenyl

ΙΠΒ-31 ethyl hydrogen IIIb-31 ethyl chloride

ΙΙΪΒ-32 ethyl isopropyl lIIb-32 ethyl isopropyl

I11B-33 Ethyl 2-methoxybutyl IIIb-33 . Ethyl 2-methoxybutyl

IIIB-34 Ethyl 2-Chlorobutyl IIIb-34 Ethyl 2-Chlorobutyl

IIIB-35 Ethyl 2-cyanobutyl IIlb-35 Ethyl 2-cyanobutyl

IIIB-36 ethyl benzyl methyl lIIb-36 ethyl benzyl

II1B-37 Ethyl isobutyl IIIb-37 Ethyl isobutyl

111B-38 ethyl n-pentyl IIIb-38 ethyl n-pentyl

ΠΙΒ-39 ethyl vinyl -39 ethyl vinyl

IIIB-40 ethyl n-propenyl IHb-40 ethyl n-propenyl

IIIB-41 Ethyl isopropenyl IIIb-41 Ethyl isopropenyl

ΙΠΒ-42 ethyl benzene some IIIb-42 ethyl phenyl

37

Replacement page (Article 26) IIIB-43 Ethyl 2-methylphenyl IIIb-43 Ethyl 2-methylphenyl

IIIB-44 ethyl 3-nitrophenyl IIIb-44 ethyl 3-nitrophenyl

IIIB-45 ethyl 4-carboxyphenyl IIIb-45 ethyl 4-carboxyphenyl

IIIB-46 N-methylcarbamoyl hydrogen Hlb-46 N-methylcarbamoyl hydrogen

IHB-47 N-methylcarbamoyl isopropyl IIIb-47 N-methylcarbamoyl isopropyl

ΠΙΒ-48 N-methylcarbamoyl 2-methoxybutyl IIIb-48 N-methylcarbamoyl 2-methoxybutyl

IIIB-49 N-methylcarbamoyl 2-chlorobutyl IIIb-49 N-methylcarbamoyl 2-chlorobutyl

IIIB-50 N-methylcarbamoyl 2-cyanobutyl IIIb-50 N-methylcarbamoyl 2-cyanobutyl

IIIB-51 N-methylcarbamoyl benzyl 3-b-51 N-methylcarbamoyl benzyl

IIIB-52 N-methylcarbamoyl isobutyl IIIb-52 N-methylcarbamoyl isobutyl

IIIB-53 N-methylcarbamoyl n-pentyl IIlb-53 N-methylcarbamoyl n-pentyl

IIIB-54 N-methylcarbamoyl vinyl IIlb-54 N-methylcarbamoyl vinyl

ΠΙΒ-55 N-methylcarbamoyl n-propenyl Illb-55 N-methylcarbamoyl n-propenyl

ΠΙΒ-56 N-methylcarbamoyl isopropenyl IIIb-56 N-methylcarbamoyl isopropenyl

IIIB-57 N-methylcarbamoylphenyl IIIb-57 N-methylcarbamoylphenyl

IIIB-58 N-methylcarbamoyl 2-methylphenyl llIb-58 N-methylcarbamoyl 2-methylphenyl

ΠΙΒ-59 N-methylcarbamoyl 3-nitrophenyl IIIb-59 N-methylcarbamoyl 3-nitrophenyl

 Compound

 2, R Ζι R number number

 IIIC-01 Hydrogen Hydrogen IlIc-01 Hydrogen Hydrogen

IIIC-02 Hydrogen Isopropyl IIIc-02 Hydrogen Isopropyl

IIIC-03 Hydrogen 2-methoxybutyl IIIc-03 Hydrogen 2-methoxybutyl

IIIC-04 Hydrogen 2-Chlorobutyl IIIc-04 Hydrogen 2-Chlorobutyl

IIIC-05 Hydrogen 2-cyanobutyl IIIc-05 Hydrogen 2-Protonylbutyl

IIIC-06 Hydrogen Benzyl IIIc-06 Hydrogen Benzyl

IIIC-07 Hydrogen Isobutyl IIIc-07 Hydrogen Isobutyl

IIIC-08 hydrogen n-pentyl IIIc-08 hydrogen n-pentyl

IHC-09 Hydrogen Vinyl HIc-09 Hydrogen Vinyl

IIIC-10 n-propenyl Ulc-10 hydrogen n-propenyl

IIIC-11 Hydrogen isopropenyl HIc-11 Hydrogen isopropenyl

IIIC-12 hydrogen phenyl IIIc-12 hydrogen phenyl

IIIC-13 hydrogen 2-methylphenyl IIIc-13 hydrogen 2-methylphenyl

IIIC-14 hydrogen 3-nitrophenyl IIIc-14 hydrogen 3-nitrophenyl

II1C-15 Hydrogen 4-carboxyphenyl IIIc-15 4-carboxyphenyl

38

Replacement page (Article 26) IIIC-16 acetyl hydrogen IIIc-16 acetyl hydrogen

IIIC-17 acetyl isopropyl IIIc-17 acetyl isopropyl

IIIC-18 acetyl 2-methyl'oxybutyl IIIc-18 acetyl 2-methoxybutyl a

IIIC-19 acetyl 2-chlorobutyl IlIc-19 acetyl 2-chlorobutyl

1IIC-20 acetyl 2-cyanobutyl IIIc-20 acetyl 2-cyanobutyl

IIIC-21 acetyl benzylmethyl IIIc-21 acetyl benzyl

IIIC-22 acetyl isobutyl IIIc-22 acetyl isobutyl

IIIC-23 acetyl n-pentyl IIIc-23 acetyl n-pentyl

IIIC-24 acetyl vinyl IIIc-24 acetyl vinyl

IIIC-25 acetyl n-propenyl IIIc-25 acetyl n-propenyl

IIIC-26 Acetyl Isopropenyl IIIc-26 Acetyl Isopropenyl

IIIC-27 acetyl phenyl IIIc-27 acetyl phenyl

IIIC-28 acetyl 2-methylphenyl IIIc-28 acetyl 2-methylphenyl

IIIC-29 acetyl 3-nitrophenyl IIIc-29 acetyl 3-nitrophenyl

IIIC-30 acetyl 4-carboxyphenyl IIIc-30 acetyl 4-carboxyphenyl

IIIC-31 Ethyl IIIc-31 Ethyl Hydrogen

IIIC-32 ethyl isopropyl IIIc-32 ethyl isopropyl

IIIC-33 Ethyl 2-methoxybutyl IIIc-33 Ethyl 2-methoxybutyl

IIIC-34 Ethyl 2-Chlorobutyl IIIc-34 Ethyl 2-Chlorobutyl

1IIC-35 Ethyl 2-cyanobutyl IIIc-35 Ethyl 2-cyanobutyl

IIIC-36 ethyl benzyl 3-c-36 ethyl benzyl

IIIC-37 ethyl isobutyl IIIc-37 ethyl isobutyl

IIIC-38 ethyl n-pentyl IIIc-38 ethyl n-pentyl

HIC-39 Ethyl Vinyl IIIc-39 Ethyl Vinyl

IIIC-40 ethyl n-propenyl IIIc-40 ethyl n-propenyl

IIIC-41 Ethyl isopropenyl IIIc-41 Ethyl isopropenyl

IIIC-42 ethyl phenyl IIIc-42 ethyl phenyl

IIIC-43 ethyl 2-methylphenyl IIIc-43 ethyl 2-methylphenyl

IIIC-44 ethyl 3-nitrophenyl IIIc-44 ethyl 3-nitrophenyl

111C-45 ethyl 4-carboxyphenyl IIIc-45 ethyl 4-carboxyphenyl

IIIC-46 N-methylcarbamoyl hydrogen IIIc-46 N-methylcarbamoyl hydrogen

IIIC-47 N-methylcarbamoyl isopropyl mc-47 N-methylcarbamoyl isopropyl

IIIC-48 N-methylcarbamoyl 2-methoxybutyl IIIc-48 N-methylcarbamoyl 2-methoxybutyl

IIIC-49 N-methylcarbamoyl 2-chlorobutyl IIIc-49 N-methylcarbamoyl 2-chlorobutyl

I1IC-50 N-methylcarbamoyl 2-cyanobutyl IIIc-50 N-methylcarbamoyl 2-cyanobutyl

IIIC-51 N-methylcarbamoyl benzyl 3-c-51 N-methylcarbamoyl benzyl

IIIC-52 N-methylcarbamoyl isobutyl IIIc-52 N-methylcarbamoyl isobutyl

IIIC-53 N-methylcarbamoyl n-pentyl IIIc-53 N-methylcarbamoyl n-pentyl

IIIC-54 N-methylcarbamoyl vinyl IIIc-54 N-methylcarbamoyl vinyl

IIIC-55 N-methylcarbamoyl n-propenyl IIIc-55 N-methylcarbamoyl n-propenyl

39

Replacement page (Article 26) IIIC-56 N-methylcarbamoylisopropenyl IIIc-56 N-methylcarbamoylisopropenyl

IIIC-57 N-methylcarbamoylphenyl IIIc-57 N-methylcarbamoylphenyl

IIIC-58 N-methylcarbamoyl 2-methylphenyl IIIc-58 N-methylcarbamoyl 2-methylphenyl

IHC-59 N-methylcarbamoyl 3-nitrophenyl IIIc-59 N-methylcarbamoyl 3-nitrophenyl

IIIC-60 base phenyl

Compound

 R R

 Number number

 IIID-01 . Hydrogen Hydrogen IIId-01 Hydrogen Hydrogen

IIID-02 Hydrogen Isopropyl IIId-02 Hydrogen Isopropyl

IIID-03 Hydrogen 2-methoxybutyl IIId-03 Hydrogen 2-methoxybutyl

IIID-04 Hydrogen 2-Chlorobutyl IIId-04 Hydrogen 2-Chlorobutyl

IIID-05 Hydrogen 2-cyanobutyl IIId-05 Hydrogen 2-cyanobutyl

IIID-06 Hydrogen Benzyl IIId-06 Oxygen Benzyl

IIID-07 Hydrogen . Isobutyl IIId-07 Hydrogen Isobutyl

IIID-08 hydrogen n-pentyl IIld-08 hydrogen n-pentyl

IIID-09 Hydrogen Vinyl IIId-09 Hydrogen Vinyl

IIID-10 hydrogen n-propenyl. IIId-10 hydrogen n-propenyl

IIID-11 Hydrogen isopropenyl IIId-11 Hydrogen isopropenyl

IIID-12 ft phenyl IIId-12 hydrogen phenyl

IIID-13 hydrogen 2-methylphenyl IIId-13 hydrogen 2-methylphenyl

IIID-14 hydrogen 3-nitrophenyl IIId-14 hydrogen 3-nitrophenyl

IIID-15 hydrogen 4-carboxyphenyl IIId-15 free 4-carboxyphenyl

IIID-16 acetyl hydrogen IIId-10 acetyl hydrogen

IIID-17 acetyl isopropyl IIId-17 acetyl isopropyl

1IID-18 acetyl 2-methoxybutyl 1IW-18 acetyl 2-methoxybutyl

II1D-19 acetyl 2-chlorobutyl IIId-19 acetyl 2-chlorobutyl

1IID-20 acetyl 2-cyanobutyl IIId-20 acetyl 2-cyanobutyl

IIID-21 Acetylbenzylidene Illd-21 Acetylbenzylidene

IIID-22 acetyl isobutyl IIId-22 acetyl isobutyl

IIID-23 acetyl n-pentyl IIId-23 acetyl n-pentyl

IIID-24 acetyl vinyl IIId-24 acetyl vinyl

IIID-25 acetyl n-propenyl IIId-25 acetyl n-propenyl

IIID-26 Acetyl Isopropenyl IIId-26 Acetyl Isopropenyl

IIID-27 acetyl phenyl IIId-27 acetyl it

 Base

IIID-28 acetyl 2-methylphenyl IIId-28 acetyl 2-methylphenyl

40

Replacement page (Article 26) IIID-29 acetyl 3-nitrophenyl iIId-29 acetyl 3-nitrophenyl

II1D-30 acetyl 4-carboxyphenyl IIId-30 acetyl 4-carboxyphenyl

II1D-31 Ethyl Hydrogen IIId-31 Ethyl Ammonia

II1D-32 Ethyl Isopropyl IIId-32 Ethyl Isopropyl

II1D-33 Ethyl 2-methoxybutyl IIId-33 Ethyl 2-methoxybutyl

1IID-34 ethyl 2-chlorobutyl IIId-34 ethyl 2-chlorobutyl

II1D-35 Ethyl 2-cyanobutyl IIId-35 Ethyl 2-cyanobutyl

II1D-36 ethyl benzyl methyl IIId-36 ethyl benzyl

IIID-37 ethyl isobutyl IIId-37 ethyl isobutyl

II1D-38 ethyl n-pentyl IIId-38 ethyl positive! 3⁄4 base

II1D-39 ethyl vinyl IIId-39 ethyl vinyl

IIID-40 ethyl n-propenyl IIId-40 ethyl n-propenyl

IIID-41 Ethyl isopropenyl IIId-41 Ethyl isopropenyl

II1D-42 Ethyl Phenyl IIId-42 Ethyl Phenyl

II1D-43 Ethyl 2-methylphenyl IIId-43 Ethyl 2-methylphenyl

1IID-44 ethyl 3-nitrophenyl IIId-44 ethyl 3-nitrophenyl

IIID-45 ethyl 4-carboxyphenyl IIId-45 ethyl 4-carboxyphenyl

II1D-46 N-methylcarbamoyl hydrogen IIId-46 N-methylcarbamoyl hydrogen

IIID-47 N-methylcarbamoyl isopropyl HId-47 N-methylcarbamoyl isopropyl

IIID-48 N-methylcarbamoyl 2-methoxybutyl IIId-48 N-methylcarbamoyl 2-methoxybutyl

IIID-49 N-methylcarbamoyl 2-chlorobutyl IIId-49 N-methylcarbamoyl 2-chlorobutyl

IIID-50 N-methylcarbamoyl 2-cyanobutyl IIId-50 N-methylcarbamoyl 2-cyanobutyl

IIID-51 N-methylcarbamoylbenzylmethyl IIId-51 N-methylcarbamoylbenzylidene

IIID-52 N-methylcarbamoyl isobutyl IIId-52 N-methylcarbamoyl isobutyl

II1D-53 N-methylcarbamoyl n-pentyl IIId-53 N-methylcarbamoyl n-pentyl

IIID-54 N-methylcarbamoylvinyl IIId-54 N-methylcarbamoylvinylexpansion-55 N-methylcarbamoyl. n-propenyl lIId-55 N-methylcarbamoyl n-propene base

IIID-56 N-methylcarbamoyl isopropenyl IIId-56 N-methylcarbamoyl isopropenyl

IIID-57 N-methylcarbamoyl phenyl IlId-57 N-methylcarbamoyl phenyl

I11D-58 N-methylcarbamoyl 2-methylphenyl IIId-58 N-methylcarbamoyl 2-methylphenyl

I11D-59 N-methylcarbamoyl 3-nitrophenyl IIId-59 N-methylcarbamoyl 3-pictylphenyl

IIID-60 N-methylcarbamoyl 4-carboxyphenyl IIId-60 N-methylcarbamoyl 4-carboxyphenyl Synthesis route IV.

When in the methacryl benzimidazole (thio) ketone derivative represented by the formula (I), Y represents -

Wherein ¾ represents hydrogen, Ci~C ₈ alkyl, c ₃ ~c ₈ cycloalkyl group embankment, c ₃ ~c ₈ alkenyl, c ₃ ~c ₈ alkynyl group,

41

Replacement page (Article 26) ~ Halogenated fluorenyl, ~ acyl, or 5- or 6-membered heterocyclic group with 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, phenyl, benzoyl, phenylacetyl, benzenesulfonate An acyl group or a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of benzoyl or phenylsulfonyl: halogen, ～C ₈ fluorenyl, C ₃ ～C ₈ cycloalkyl, hydroxy, 〜C ₄ embankment group, ~C ₄ haloalkyl group embankment, ~C ₄ haloalkoxy, C, ~C ₄ haloalkyl group embankment, embankment ^ ~ ^ haloalkyl sulfonyl group, a carboxyl group, a nitro group, a cyano group; Z ₄ represents hydrogen, ~C ₈ alkyl, C ₃ ~C ₈ alkyl with cycloalkyl, C ₃ ~ ¾ alkenyl, C ₃ ~C ₈ alkynyl group, Cr ^ t halo 'group embankment, or _3, and Z ₄ and The nitrogen atoms to which they are bonded together form a 5- to 7-membered heterocyclic group, and the heterocyclic group may contain, in addition to a nitrogen atom, one or two or more hetero atoms selected from nitrogen and oxygen, and the other groups are as defined above ( When I) is defined, the methacryloylbenzimidazole (thio)one derivative represented by the formula (I) to be protected by the present invention can be prepared by a synthetic route as shown in the following scheme:

 The synthesis route is based on dinitro-substituted aniline, wherein one nitro group and amino group are ortho-position, firstly, a halogenated hydrocarbon is used as a hydrocarbylating agent, and various hydrocarbyl groups or substituted hydrocarbyl groups are introduced on the amino nitrogen, and then the powder is used. Selective reduction of the amino- ortho-nitro group, followed by cyclization, acylation, and nitro reduction to obtain a benzimidazolone derivative having an amino group on the benzene ring, and finally introducing a hydrocarbon group by a hydrocarbylation reaction of the halogenated hydrocarbon. Alternatively, an acyl group is introduced by an esterification reaction with an acid chloride to obtain a target compound.

 This method is a general synthetic route, and for a specific compound, a target compound can be obtained by a simple procedure using a more convenient intermediate.

 Examples of the methacryloylbenzimidazole (thio)ketone derivatives of the present invention prepared according to the reaction scheme are shown in the table.

4.

42

Replacement page (Article 26)

Compound number z ₄ R Compound number _3⁄4 z ₄ R

IVA-01 Hydrogen Hydrogen IVa-01 Hydrogen Hydrogen

IVA-02 methyl hydrogen hydrogen IVa-02 methyl hydrogen hydrogen

IVA-03 ethyl hydrogen hydrogen IVa-03 ethyl hydrogen hydrogen

IVA-04 n-propyl hydrogen hydrogen IVa-04 n-propyl hydrogen hydrogen

IVA-05 isopropyl hydrogen IVa-05 isopropyl hydrogen hydrogen

IVA-06 n-butylhydrogen hydrogen IVa-06 n-butyl hydrogen

IVA-07 isobutyl hydrogen . hydrogen lVa-07 isobutyl hydrogen hydrogen

IVA-08 Cyclopropyl hydrazine Hydrogen Hydrogen IVa-08 Cyclopropyl hydrazine Hydrogen

IVA-09 Propylene Hydrogen IVa-09 Propylene Hydrogen

 IVA-10 isopropenyl hydrogen hydrogen IVa- 10 isopropenyl hydrogen hydrogen

IVA-11 propynyl hydrogen hydrogen IVa- 11 propynyl hydrogen hydrogen

IVA- 12 chloroethyl hydrogen hydrogen IVa- 12 wind ethyl

 IVA-13 bromoethyl hydrogen hydrogen IVa- 13 bromoethyl hydrogen hydrogen

IVA-14 Formyl Hydrogen IVa-14 Hydroformyl Hydrogen

IVA-15 acetyl hydrogen hydrogen IVa- 15 acetyl hydrogen hydrogen

IVA-16 benzoyl hydrogen hydride IVa- 16 benzoyl

 IVA-17 imidazole-1-yl-hydrogen IVa- 17 imidazole-1-yl-hydrogen

IVA- 18 Hydrogen Hydrogen Isopropanyl IVa-18 Hydrogen Hydrogen Isopropenyl

IVA-19 methylmethyl isopropenyl IVa- 19 methylmethyl isopropenyl

IVA-20 ethyl methyl isopropenyl IVa-20 ethyl ethyl isopropenyl

IVA-21 n-propyl ethyl isopropenyl IVa-21 n-propyl n-propyl isopropenyl

IVA-22 Isopropyl N-propyl Isopropenyl IVa-22 Isopropyl Isopropenyl

IVA-23 n-butyl Isopropyl isopropenyl IVa-23 n-butyl n-butyl isopropenyl

IVA-24 isobutyl n-butyl isopropenyl IVa-24 isobutyl isobutyl isopropenyl

IVA-25 Cyclopropenyl Isobutyl Isopropenyl IVa-25 Cyclopropenyl Cyclopropyl Isopropenyl

IVA-26 Propenyl Cyclopropenyl Isopropenyl IVa-26 Propenyl Propenyl Isopropenyl

IVA-27 isopropenyl propyl 'alkenyl isopropenyl IVa-27 isopropenyl isopropenyl isopropenyl

IVA-28 propynyl isopropenyl isopropenyl IVa-28 propynyl propynyl isopropenyl

IVA-29 chaotic ethyl propynyl isopropenyl IVa-29 chloroethyl chloroethyl isopropenyl

IVA-30 Bromoethyl Chloroethyl Isopropenyl IVa-30 Bromoethyl Bromoethyl Isopropenyl

IVA-31 formyl ethyl isopropenyl IVa-31 formyl ethyl isopropenyl

IVA-32 Acetyl Ethyl isopropenyl IVa-32 Acetyl Ethyl isopropenyl

IVA-33 benzoyl ethyl isopropenyl IVa-33 benzoyl ethyl isopropenyl

1VA-34 imidazole small group isopropenyl group IVa-34 imidazole-1-yl-isopropenyl

IVA-35 Hydrogen Hydrogen Benzyl IVa-35 Hydrogen Hydrogen Benzyl

IVA-36 methylmethylbenzylmethyl IVa-36 methylmethylbenzylidene

43

Replacement page (Article 26)

Gas hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen

 Compound 3⁄4 R Compound Number

 IVB-01 Hydrogen Hydrogen IVb-01 Hydrogen

 IVB-02 methyl hydrogen IVb-02 methyl

 Hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen.

 IVB-03 Ethyl Hydrogen IVb-03 Ethyl

 IVB-04 n-propyl hydrogen IVb-04 n-propyl

 IVB-05 isopropyl hydrogen IVb-05 isopropyl

 Hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen

IVB-06 n-butyl hydrogen IVb-06 n-butyl

 IVB-07 isobutyl hydrogen IVb-07 isobutyl

 IVB-08 cyclopropane hydrogen hydrogen IVb-08 cyclopropenyl

 IVB-09 Propylene Hydrogen IVb-09 Propylene

 IVB-10 isopropenyl hydrogen IVb-10 isopropenyl

 1VB-11 hydrogen IVb- 11 propynyl

 IVB-12 hydrogen IVb-12 chloroethyl

 IVB-13 Hydrogen IVb- 13 Bromoethyl

 IVB-14 IVb- 14 Formyl

 IVB-15 IVb- 15 Acetyl

 IVB-16 benzoyl IVb-16 benzoyl

 IVB-17 Miwa-1-yl Hydrogen IVb-17 Imidazole-1-yl

 IVB-18 Hydrogen isopropenyl IVb-18 Hydrogen isopropenyl

IVB-19 methyl isopropenyl IVb-19 methyl isopropenyl

IVB-20 Ethyl isopropenyl IVb-20 Ethyl isopropenyl

IVB-21 n-propyl isopropenyl IVb-21 n-propyl isopropenyl

IVB-22 Isopropyl Isopropenyl IVb-22 Isopropylisopropenyl

IVB-23 n-butyl isopropenyl IVb-23 n-butyl isopropenyl

44

Replacement page (Article 26) IVB-24 isobutyl IVb-24 isobutyl

 IVB-25 cyclopropane group IVb-25 cyclopropane group

 IVB-26 Propylene Group IVb-26 Propylene Group

 IVB-27 Isopropenyl IVb-27 Isopropenyl

 IVB-28 propynyl IVb-28 propynyl

 IVB-29 Chloroethyl IVb-29 Chloroethyl

 IVB-30 Bromoethyl IVb-30 Bromoethyl

 IVB-31 formyl IVb-31 formyl

 IVB-32 Acetyl IVb-32 Acetyl

 IVB-33 benzoyl 55 m 3333 0 B H^ CP ni 990 P H sβrl1tJl1 IVb-33 benzoyl

 IVB-34 base group yl base group

 Imidazole-1-yl IVb-34 imidazole-1-yl

 IVB-35 Hydrogen IVb-35 Hydrogen

 Heterogeneous heterosexual difference

 IVB-36 methyl benzene benzene benzene benzene benzene benzene IVb-36 methyl

 Hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H, H

 IVB-37 ethyl hydroxy remaining olefin residual olefin; base group yl group yl group IVb-37 ethyl group

 Base group yl group

 IVB-38 n-propyl IVb-38 n-propyl

 1VB-39 isopropyl IVb-39 isopropyl

 IVB-40 n-butyl IVb-40 n-butyl

 IVB-41 Isobutyl IVb-41 Isobutyl

 IVB-42 cyclopropane group IVb-42 cyclopropane group

 IVB-43 Propylene Group IVb-43 Propylene Group

 IVB-44 isopropenyl IVb-44 isopropenyl

 IVB-45 propynyl IVb-45 propynyl

 IVB-46 Chloroethyl IVb-40 Chloroethyl

 IVB-47 Bromoethyl IVb-47 Bromoethyl

 IVB-48 formyl IVb-48 formyl

 Base group base group

 IVB-49 Acetyl IVb-49 Acetyl

Heterogeneous iso-isoisomeric iso-benzene benzene benzene benzene benzene benzene benzene hydride hydrogen hydride hydrogen hydrogen hydride hydrogen hydrogen hydride Rn Rn R πρ base group base group Base group base group base group

 Compound Number Compound Number

 IVC-01 Hydrogen IVc-01 'Hydrogen

 IVC-02 methyl IVc-02 methyl

 IVC-03 Ethyl IVc-03 Ethyl

 IVC-04 n-propyl IVc-04 n-propyl

 IVC-05 isopropyl IVc-05 isopropyl

 IVC-06 n-butyl IVc-06 n-butyl

 IVC-07 isobutyl IVc-07 isobutyl

 IVC-08 Cyclopropyl fluorenyl IVc-08 Cyclopropyl fluorenyl

 IVC-09 Propylene Group IVc-09 Propylene Group

 IVC-10 isopropenyl IVc-10 isopropenyl

45

Replacement page (Article 26) 1VC-11 propynyl hydrogen IVc-11 propynyl hydrogen

IVC-12 chloroethyl hydrogen IVc-12 chloroethyl hydrogen

IVC-13 bromoethyl hydrogen IVc-13 bromoethyl hydrogen

IVC-14 Formyl Hydrogen IVc-14 Formyl Hydrogen

IVC-15 acetyl hydrogen IVc-15 acetyl hydrogen

IVC-16 benzoyl hydrogen lVc-16 benzoyl hydrogen

IVC-17 imidazole-1-ylhydrogen lVc-17 imidazole-1-ylhydrogen

IVC-18 Hydrogen isopropenyl IVc-18 Hydrogen isopropenyl

IVC-19 methyl isopropenyl IVc-19 methyl isopropenyl

IVC-20 Ethyl group ^ duck duck ί ^ 3⁄4 _ Hydrogen Hydrogen Hydrogen Hydrogen Hydroxide Hydrogen Hydrogen Hydrogen Hydroxide Hydrogen Hydroxide 3⁄4 Isopropenyl IVc-20 Ethyl Isopropenyl

IVC-21 n-propyl isopropenyl IVc-21 n-propyl isopropenyl

IVC-22 Isopropyl Isopropenyl IVc-22 Isopropylisopropenyl

IVC-23 n-butyl isopropenyl IVc-23 n-butyl isopropenyl

IVC-24 isobutyl isopropenyl IVc-24 isobutyl isopropenyl

IVC-25 Cyclopropenyl Isopropenyl IVc-25 Cyclopropyl Isopropenyl

IVC-26 Propenyl Isopropenyl IVc-26 Propenyl Isopropenyl

IVC-27 isopropenyl isopropenyl IVc-27 isopropenyl isopropenyl

IVC-28 propynyl isopropenyl IVc-28 propynyl isopropenyl

IVC-29 Chloroethyl Isopropenyl IVc-29 Chloroethyl Isopropenyl

IVC-30 Bromoethyl Isopropenyl IVc-30 Bromoethyl Isopropenyl

IVC-31 formyl isopropenyl lVc-31 formyl isopropenyl

IVC-32 Acetyl Isopropenyl IVc-32 Acetyl Isopropenyl

IVC-33 benzoyl isopropenyl IVc-33 benzoyl isopropenyl

IVC-34 imidazole-1-ylisopropenyl IVc-34 imidazole-1-ylisopropenyl

IVC-35 Hydrogen Benzyl IVc-35 Hydrogen 3 m - 3 - 1 3 - 1 m - 1 Hydrogen" Hydrogen Hydrogen Hydrogen Hydrogen Hydrogen Hydrogen Hydrogen Hydrogen Hydrogen Hydrogen Hydrogen Hydrochloride Hydrogen Hydrochloride

IVC-36 methylbenzylmethyl IVc-36 methylolyl benzyl

IVC-37 ethyl benzyl methyl IVc-37 ethyl benzyl

IVC-38 n-propyl benzyl IVc-38 n-propyl benzyl

IVC-39 isopropyl benzyl IVc-39 isopropyl benzyl

IVC-40 n-butyl benzyl IVc-40 n-butyl benzyl

IVC-41 isobutyl benzyl IVc-41 isobutyl benzyl

IVC-42 cyclopropane benzyl methyl IVc-42 cyclopropenyl benzyl

IVC-43 Propylene Benzyl IVc-43 Propylene Benzyl

IVC-44 isopropenyl benzyl methyl IVc-44 isopropenyl benzyl

IVC-45 propynyl benzyl IVc-45 propynyl benzyl

IVC-46 Chloroethyl Benzyl IVc-46 Chloroethyl Benzomethyl

IVC-47 Bromoethyl Benzyl IVc-47 Bromoethyl Benzyl

IVC-48 formyl benzyl IVc-48 formyl benzyl

IVC-49 Acetylbenzylmethyl IVc-49 Acetylbenzyl

IVC-50 benzoyl benzyl methyl IVc-50 benzoyl benzyl

IVC-51 imidazole-1-ylbenzylmethyl IVc-51 imidazole small benzyl

46

Replacement page (Article 26) benzene

 M3⁄4 Hydrogen Compound No. Compound No. R IVD-01 IVd-01

 Hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen

 IVD-02 methyl IVd-02

 IVD-03 IVd-03

 IVD-04 n-propyl IVd-04

 IVD-05 Isopropyl IVd-05

 Hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen

 IVD-06 n-butyl IVd-06

 IVD-07 isobutyl IVd-07

 IVD-08 Cyclopropyl thiol IVd-08

 IVD-09 IVd-09 Propylene

 IVD-10 Isopropenyl IVd-10 Isopropylene

 IVD-11 propynyl IVd-11 propynyl

 IVD-12 IVd-12 Chloroethyl

 IVD-13 bromoethyl IVd-1 iso-orthogonal bromide

 IVD-14 Formyl IVd-14 Ethyl Hydrogen 3⁄4 Propionylbutyryl Acyl Ethyl

 IVD-15 IVd-15 base group base group

 IVD-16 base IVd-10 benzoyl hydride hydrogen hydride hydrogen hydride hydrogen hydrogen hydride

Hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen, hydrogen

47

Replacement page (Article 26) IVD-41 Isobutyl IVd-41 Isobutyl

 IVD-42 Cyclopropenyl IVd-42 cyclopropane

 IVD-43 Propylene IVd-43 Propylene

 IVD-44 isopropenyl IVd-44 isopropenyl

 IVD-45 lVd-45

 IVD-46 Chlorobromide IV IV-46

 Cool acetylene

 1VD-47 base group IVd-47

 IVD-48 IVd-48

 IVD-49 IVd-49

 IVD-50 Benzoyl Methylmethylmethylmethylmethyl IVd-50 Benzoyl

 IVD-51 Imidazolyl-1-ylyl yl. IVd-51 Imidazolyl benzophenone

 The compound of the present invention further comprises a methacryl benzimidazolyl (thio) keto yl yl group represented by the formula (I).

A pharmaceutically acceptable salt of a derivative.

 When the Y represents a carboxyl group in the methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I), the sodium salt, potassium salt or ammonium salt thereof can be produced by the following industrially general methods. The methacryloylbenzimidazole (thio)ketone carboxylic acid derivative is formulated into an appropriate concentration of ethyl acetate solution, and then an appropriate concentration of sodium hydrogencarbonate (propyl bromide)

The potassium hydrogen or ammonium hydrogencarbonate solution is extracted, and after phase separation, the aqueous phase is mixed with n-butyrylacetylacetyl ethyl alcohol in an appropriate ratio on the base group.

The sodium salt, potassium salt or hinge salt of the methacryloyl benzimidazole (thio) ketone carboxylic acid derivative is obtained by steam distillation.

 When in the methacryl benzimidazole (thio) ketone derivative of the formula (I), it is methylmethylmethylmethylmethyl, and Y represents an amino group or a yl group.

In the case of an amine group, an inorganic acid salt such as a hydrochloride or a sulfate or an organic acid salt such as a formate or an acetate can be produced by the following industrially common methods. Formulating a methacryloylbenzimidazole (thio)ketone carboxylic acid derivative into an appropriate concentration of benzene benzophenone

Ttt tt HHH 5 H ttlt tf H 5t-I ¹¹ <" ¹ -I" acid ethyl ester solution, and then extract with a suitable concentration of hydrochloric acid (sulfuric acid, formic acid or acetic acid) solution, after phase separation, base group The base group is further mixed with n-butanol in an appropriate ratio, and a hydrochloric acid such as a hydrochloride or a sulfate of a methacryl benzimidazole (thio)ketonecarboxylic acid derivative is obtained under reduced pressure distillation. An organic acid salt such as a salt or a formate or acetate.

 The present invention provides a methacryloylbenzimidazole (thio)ketone derivative against Staphylococcus aureus

{Staphyloccocus aureus)^. Streptococcus agalactiae Bacillus subtilis, Bacillus cereus (BacU!us cereus and other Gram-positive bacteria and Escherichia coli

C Escherichia coli ^^fM Pseudomonas aenig! iosci ), Yahe! j. Salmonella (<3⁄4/«3⁄4o"e//. arizonae) and other Gram-negative bacteria have high antibacterial activity. The results of the activity assay showed that the minimum inhibitory concentration of all the compounds in Tables 1, 2, 3 and 4 against Bacillus cereus ranged from 0.10 μ _δ · ηιυ ¹ to 12.5 g-ml / ¹ , wherein preferably, the compound IB-35, IC-01, ID-01, Ia-20, Ib-40, Ib-79, Id-10, Id-157, IIA-20, IIA-31, IIB-05, IIB-45, IIC- 20, IIC-35, IID-18 and IVd-51 are waxy

48

g^I/¹之间， 其中优 选地，化合物 IB-20, IB-35, IC-01, ID-01, ID-35, Ib-18, Ib-40, Id-20, IIA-20, IIA-31, IIb-16, IIc-20, IId-41 , IIIB-26和 IIId-46对金黄色葡萄球菌和耐甲氧西林的金黄色葡 萄球菌（MRSA) 的最小抑制浓度（MIC值）均不大于 0.19 g/mL， 而对照药剂氨苄 青霉素钠盐对金黄色葡萄球菌的最小抑制浓度为 ^ZS gTni;¹， 对 MRSA的最小抑制 浓度为 >100 μ^ηιΐ;¹, 所有供试化合物对敏感金黄色葡萄球菌和 MRSA的活性完全 一致， 说明该类化合物与 β-内酰胺类抗生素之间不存在交互抗性。 MRSA作为遍及 全球的重要病原菌之一， 己对大多数 β-内酰胺类抗生素产生了耐药性，而其对本申请 提供的化合物则仍然表现敏感，这一特点使其非常适合于治疗耐药性细菌感染引起的 疾病。； Replacement page (Article 26) The minimum inhibitory concentration (MIC value) of Bacillus was not more than 0.19 g/mL, while the minimum inhibitory concentration of the control drug ampicillin sodium salt was 3.13 μ -ιηΓ ¹ for the test bacteria; Tables 1, 2, 3 and 4 The minimum inhibitory concentration of all compounds against Bacillus subtilis ranges between 0.10 μηηη / ^12.5 g'mL - ', preferably, compound IA-50, IA-157, IB-20, IB-35, IC Minimum inhibitory concentration (MIC) of Bacillus subtilis -01, IIC-41, IID-26, IIa-35, IIb-05, IIc-12, IId-41, IIIA-56, IVC-51 and IVd-51 None of them is greater than 0.19 g/mL, and the minimum inhibitory concentration of the control agent ampicillin sodium salt on the test bacteria is 25.0 μ _§ · ηι ¹ ; the minimum inhibition of Escherichia coli by all the compounds in Tables 1, 2, 3 and 4. concentration range between ^{_{0.10 μ β · ηιΓ 1 ~ 12.5}} g'ml / 1, wherein preferably, compound IA-50, IA-157, IB-40, Ic-167, Id-10, Id-89, IIB- 16. The minimum inhibitory concentration (MIC value) of IId-05, IId-12 and IVb-01 for Escherichia coli is not more than 0.19 g/mL, and the minimum inhibitory concentration of the control agent ampicillin sodium salt for the test bacteria is\ 2.5μ _& · ταν ^1; 1, 2, and 3 in all 4 compounds minimum inhibitory concentration of Pseudomonas aeruginosa in the range of ^{0.19 g-ml; 1 ~ SO.O} g'mi; between ^1, wherein preferably, the compound ID-01, ID- 167, Ia-20, Ib-40, Ic-01, Ic-79, IIA-20, IIb-31, IIC-31 and Ivd-51 have minimum inhibitory concentrations (MIC values) for Pseudomonas aeruginosa not more than 0.39 g /mL, and the control agent ampicillin sodium salt has a minimum inhibitory concentration of 25.0 μ _Ε · πιί - ¹ for the test bacteria; all compounds in Tables 1, 2, 3 and 4 are against Staphylococcus aureus and methicillin-resistant The minimum inhibitory concentration of Staphylococcus aureus (MRSA) is in the range of 0.10

Between g^I/ ¹ , preferably, compounds IB-20, IB-35, IC-01, ID-01, ID-35, Ib-18, Ib-40, Id-20, IIA-20, IIA -31, IIb-16, IIc-20, IId-41, IIIB-26 and IIId-46 have no minimum inhibitory concentration (MIC) for Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA) More than 0.19 g/mL, and the minimum inhibitory concentration of ampicillin sodium salt against Staphylococcus aureus is ^ZS gTni; ¹ , the minimum inhibitory concentration of MRSA is >100 μ^ηιΐ; ¹ , all tested compounds are sensitive The activity of S. aureus and MRSA was completely consistent, indicating that there was no cross-resistance between the compound and the β-lactam antibiotic. As one of the most important pathogens throughout the world, MRSA has developed resistance to most β-lactam antibiotics, and it is still sensitive to the compounds provided by this application, which makes it very suitable for the treatment of drug resistance. A disease caused by a bacterial infection. ;

 The methacryl benzimidazole (thio) ketone derivatives provided by the present invention can be processed into powder injections, tablets, capsules or other suitable dosage forms for the treatment and/or prevention of human (animal) diseases caused by bacterial infections. .

 The present invention provides a methacryloylbenzimidazole (thio)ketone derivative against Trichophyton rubrum chophyton rubrum Monili albican-, Microsporum canis and Malasse

49

; 表 1， 2, 3 和 4 中的所有化合物对白念珠菌 (Monilia albican) 的最小抑制浓度范围均在 S^ gTnL^nS gTnL—¹之间， 其中优选 地， 化合物 Ic-79, IIB-05, IIc-12, IIIa-11, IIIb-41, IVB-45和 IVd-19对白念珠菌的 最小抑制浓度为 3.9μ£·Γηΐ 表 1, 2, 3和 4中的所有化合物对犬小孢子菌 ( mw wm canis) 的最小抑制浓度范围均在 S gTOL^US gTOL— ¹之间， 其中优选地， 化合物 IIIA-01和 IllC-Oi X才犬小孢子菌的最小抑制浓度为 ^μ^ηιΐ;¹; 表 1， 2, 3和 4中的所 有化合物对糠秕马拉色菌 Malassezia furfur ) 的最小抑制浓度范围均在 3.9ig-mV^l~\25\ig-mL-¹之间， 其中优选地， 化合物 Wa-18 Si IVc-34对糠秕马拉色菌 的最小抑制浓度为 S^ g^L—¹- 本发明提供的甲基丙烯酰基苯并咪唑 （硫）酮衍生物可以加工成软膏剂、 乳剂、 粉剂或其它适宜剂型用于治疗和 /或预防由真菌感染所致的人 （畜）皮肤病。 Replacement page (Article 26) Most fungi of the genus Malassezia also exhibit a certain degree of bacteriostatic activity. The in vitro antifungal activity of some of the compounds was tested by in-vehicle drug method (drug dilution method), and the results showed that all the compounds in Tables 1, 2, 3 and 4 were against Trichophyton rub m. the minimum inhibitory concentrations are in the range of _3.9μ β · ϊ ηΐ; between ¹ ~ ^125μ · ^{ιηΙ 1,} wherein preferably, the compound IVD-30, IIID-16 ΙΑ-89, and the minimum inhibitory concentration of Trichophyton rubrum

The minimum inhibitory concentration range for all compounds in Tables 1, 2, 3 and 4 against Monilia albican is between S^gTnL^nS gTnL- ¹ , preferably, compounds Ic-79, IIB-05 , IIc-12, IIIa-11, IIIb-41, IVB-45 and IVd-19 have a minimum inhibitory concentration against Candida albicans of 3.9μ£·Γηΐ All compounds in Tables 1, 2, 3 and 4 against Microsporum canis The minimum inhibitory concentration range of (mw wm canis) is between S gTOL^US gTOL- ¹ , wherein preferably, the minimum inhibitory concentration of compound IIIA-01 and IllC-Oi X Microsporum canis is ^μ^ηιΐ; ¹ ; the minimum inhibitory concentration range of all the compounds in Tables 1, 2, 3 and 4 against Malassezia furfur) is between 3.9 ig-mV ^l ~\25\ig-mL- ¹ , wherein preferably The minimum inhibitory concentration of the compound Wa-18 Si IVc-34 against Malassezia furfur is S^g^L- ¹ - the methacryloyl benzimidazole (thio)one derivative provided by the invention can be processed into an ointment , Emulsions, powders or other suitable dosage forms for the treatment and/or prevention of human (animal) skin diseases caused by fungal infections.

 The invention provides a methacryloylbenzimidazole (thio)ketone derivative for phytopathogenic fungi, such as Botrytis cinerea, cucumber downy mildew {Pseudoperonospora cubensis, wheat powdery mildew (Erysiphe graminis'), apple anthrax The pathogen (G7omere〃" cingulata), Fw iw oxysporium and Phytophtho infestcms have significant antibacterial activity.

The results of inhibition of spore germination activity showed that the concentrations of the compounds in Tables 1, 2, 3 and 4 against the cinerea of Botrytis cinerea were in the range of 9.2 g/mL to _{87.2 μ§} /πΛ, wherein preferably, the compound ID-18 The inhibitory concentrations of IId-12 and IIIB-11 were 9.5 g/mL, 9.2 g/mL and 9.7 g/mL, respectively; the inhibition of cucumber downy mildew (P cubensis) by the compounds in Tables 1, 2, 3 and 4. The medium concentration range is from 7.8 g/mL to 98.5 g/mL, wherein preferably, the inhibitory concentrations of the compounds IIIB-11, Ib-40 and IVc-17 are 7.8 g/mL, 10.4 g/mL and 10.5 g/mL, respectively. The concentrations of the compounds in Tables 1, 2, 3 and 4 for inhibition of wheat graminis (E graminis) ranged from 9.2 g/mL to 88.6 gmL, wherein preferably, the concentrations of the inhibitors of the compounds ID-35 and Ib-40 were respectively 9.2 g/mL and 9.7 g/mL; the concentrations of the compounds in Tables 1, 2, 3 and 4 against apple anthracnose G cingulata) ranged from 10.4 g/mL to 98.5 g/mL, preferably, compound IID The inhibitory concentrations of -18 and ΠΙΒ-ll were both 10.4 g/mL; the compounds in Table 1, 2, 3 and 4 were cotton

50

Replacement page (Article 26) The inhibitory concentration of Fusarium oxysporum f. (F w; 3⁄4tW'w) ranges from 8.7 g/mL to 87.8 g/niL, wherein preferably, the inhibitory concentrations of compounds IA-40 and IIIA-01 are 8.7 g/mL, respectively. 10.4 g/mL; the concentrations of the compounds in Tables 1, 2, 3 and 4 for inhibition of Phytophthora infestans infestam range from 9.7 g/mL to 9 g. 5 g/mL, preferably, compounds IIc-12 and IVc- The inhibitory concentrations of 17 were 9.7 g/mL and 10.4 g AnL, respectively. The control agent carbendazim did not show significant inhibition of spore germination at the test concentration.

表 1， 2， 3和 4 中化合物对苹果炭疽病菌（G i^gwtoa)的抑制中浓度范围为 18.^g/mL~107.5 g/mL， 其中优选地， 化合物 IIb-05和 IId-12的抑制中浓度分别为 18.(^g/mL和 18.5 g/mL， 对照药剂多菌灵的抑制中浓度为 6.8 g/mL; 表 1， 2， 3和 4中化合物对棉花枯萎病菌 ( oxysporium 的抑制中浓度范围为 9.8 g/mL〜98.5 g/mL, 其中优选地， 化合物 IIA-01和 IId-12的抑制中浓度分别为 9.8 gmL和 10.6 gmL， 对照药剂多菌灵的抑 制中浓度为 1 5 g/mL_; 表 1, 2, 3和 4中化合物对马铃薯晚疫病菌 P infestam 的 抑制中浓度范围为 11.8pg/mL~97.8 g/mL， 其中优选地， 化合物 IB-20和 IA-40对马 铃薯晚疫病菌 P infest 的抑制中浓度分别为 11.8 gmL和 16.8 gmL， 对照药剂 多菌灵的抑制中浓度为 0.9 g/mL。 The results of inhibition of mycelial growth activity showed that the concentrations of the compounds in Tables 1, 2, 3 and 4 against B. cinere were in the range of 22.5 g/mL to 85.7 g/mL, preferably, the compound ΠΑ The inhibitory concentrations of -01 and nC-01 were 22.9 g/mL and 22.5 gmL, respectively, and the inhibitory concentration of the control drug carbendazim was 18.7 g/mL; the compounds in Tables 1, 2, 3 and 4 against cucumber downy mildew (The concentration of inhibition of P cubemis ranges from 20.6 g/mL to 98.5 g/mL, wherein preferably, the inhibitory concentrations of compounds IVB-34 and IC-40 are 20.6 g/mL and 22.9 g/mL, respectively. The concentration of bacteriostatic inhibition was 15.6 g/mL _; the inhibitory concentrations of the compounds in Tables 1, 2, 3 and 4 against wheat graminis (£ graminis) ranged from 17.6 g/mL to n0.5 g/mL, with preference The inhibitory concentrations of compounds IA-40 and IId-12 were 17.6 g/mL and 18.5 g/mL, respectively, and the concentration of the control agent carbendazim was

The concentrations of the compounds in Tables 1, 2, 3 and 4 for inhibition of apple anthracnose (G i^gwtoa) range from 18. g/mL to 107.5 g/mL, preferably, compounds IIb-05 and IId-12 The inhibitory concentrations were 18. (^g/mL and 18.5 g/mL, and the control agent carbendazim was inhibited at a concentration of 6.8 g/mL; Table 1, 2, 3 and 4 compounds against Fusarium oxysporum (oxysporium) The concentration in the inhibition range is 9.8 g/mL to 98.5 g/mL, wherein preferably, the inhibitory concentrations of the compounds IIA-01 and IId-12 are 9.8 gmL and 10.6 gmL, respectively, and the concentration of the control agent carbendazim is 1 5 g/mL _{; the} concentrations of the compounds in Tables 1, 2, 3 and 4 against the Phytophthora infestans P infestam range from 11.8 pg/mL to 97.8 g/mL, preferably, compounds IB-20 and IA- The inhibitory concentrations of 40 pairs of Phytophthora infestans P infest were 11.8 gmL and 16.8 gmL, respectively, and the inhibitory concentration of the control agent carbendazim was 0.9 g/mL.

 The susceptible strains and the carbendazim-resistant Fusarium g匪ineumm were used as test pathogens, respectively, and the virulence of the inhibitory mycelium growth of the compound IIIA-56 and carbendazim provided by the present invention against the two pathogenic bacteria were determined. . The inhibitory concentrations of carbendazim against the susceptible and resistant strains of Fusarium graminearum were 0.67 g/mL and 8.12 g/mL, respectively, ie the resistance fold was 12.1 times, while IIIA-56 was against two strains of Fusarium graminearum. The inhibitory concentrations were 9.83 g/mL and 8.75 g/mL, respectively, and there was no significant difference between them, indicating that there was no cross-resistance between the test agent and carbendazim. The field efficacy test structure for controlling tomato gray mold showed that 50% ΙΙΙΑ-56 can

51

Replacement page (Article 26) The 1200-fold dilution of the wet powder and the 1200-fold dilution of the 40% pyrimethanil suspension are equivalent, and can effectively control the damage of the gray mold of tomato.

 The virulence of the compound provided by the invention for inhibiting the growth of phytopathogenic fungi mycelium is lower than that of the control agent carbendazim, but carbendazim does not exhibit significant inhibition of spore germination at the test concentration, while the test compound is for spores. Germination has a significant inhibitory effect. It can be seen that the mode of action is more diverse. It is worth noting that due to the frequent use of carbendazim for many years, phytopathogenic fungi have generally developed strong resistance to this fungicide, and the compounds provided by the present invention have completely different molecular structures and have antibacterial activity. In the measurement, no cross-resistance with the benzimidazole fungicide was exhibited.

 The methacryl benzimidazole (thio) ketone derivatives provided by the present invention can be processed into emulsifiable concentrates, aqueous emulsions, microemulsions, wettable powders, water-dispersible granules, suspensions, or other suitable dosage forms for treatment and/or treatment. Prevent plant diseases caused by fungal infections.

The present invention provides a novel class of antibacterial compounds having a molecular skeleton different from any known antibacterial compound, which is structurally characterized in that a methacryloyl group is introduced at the N ₃ position of the benzimidazolone molecular skeleton. One of the advantages of the present invention is that the compound provided by the present invention has a strong inhibitory effect on various bacteria and fungi which can cause human (animal) infection, and is a broad-spectrum antibacterial compound, and is relatively used in clinical use. - There is no cross-resistance between lactam antibiotics, which has broad application prospects. The compound provided by the invention also has antibacterial activity against phytopathogenic fungi, and at the same time has the effects of inhibiting spore germination and inhibiting mycelial growth, and there is no cross-resistance between the benzimidazole fungicides widely used on the market. Another advantage of the present invention is that it provides a compound having a simple synthetic route, a desired raw material that is inexpensive and readily available, and a product having a lower production cost.

detailed description

 The invention is understood by the following specific examples of preparation and biological examples, without limiting the scope of the invention.

 The following Preparation Examples 1 to 18 further illustrate the preparation of the compound of the formula (I) and the preparation of the present invention, but are not limited thereto.

 Example 1

 Synthesis of 3-methacryloylbenzimidazole-2 (3H)-one (Compound No.: IA-01)

52

Replacement page (Article 26)

I 1 -11 IA-01 In a 50 mL pear-shaped flask, add intermediate I-1 1.08g (10 mmol), urea 0.72g (12 mmol), xylene 10 mL, heated to reflux for 4 h, cooled to room temperature, and added with acetic acid The ester/water (volume ratio 2/1) 30 mL was stirred for 10 min, then transferred to a sep. funnel and the mixture was partitioned. The aqueous phase was extracted with ethyl acetate (10 mL). Intermediate l-II 1.86 g, yield 92.1%; dry intermediate 1-II 1.62 g (8 mmol), 10 mL anhydrous pyridine in lOOmL pear-shaped flask, add methyl methacrylate under ice bath The acid chloride was 1.04 g (10 mmol, dissolved in 5 mL of dichloromethane). After the addition, the mixture was slowly warmed to room temperature, stirring was continued for 15 min, and the temperature was raised to 60 ° C to continue the reaction for 5 h. 60 mL of ethyl acetate/water (volume ratio 2/1) mixed solution was added to the reaction flask, stirred for 10 min, transferred to a separating funnel and allowed to stand for separation, and the aqueous phase was extracted once more with ethyl acetate. The organic phase was combined and washed with 10 mL of 1N hydrochloric acid, deionized water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by silica gel column chromatography Ether/ethyl acetate = 6/1) gave the title compound IA-01 1.08 g, yield 66.7%. Compound IA-01: colorless powder, m.p. 159.1-161.0. Mass spectrometry (electrospray, negative ion mode) m/z 201 (MH)"c 1H NMR (CDC1 ₃ , 500MHz, δ, ppm): 2.15 (s, 3H, CH ₃ ), 5.60 (s, IH, C=CH ₂ ), 5.62 (s, IH, C=CH ₂ ), 7.05 (d, J=8.0Hz, IH), 7.16 (m, 2H), 7.90 (d, J=8.0 Hz, IH), 8.84 (s, 1H , NH). ¹³ C NMR (CDC1 ₃ , 125 MHz, δ, ppm): 18.8, 109.4, 114.9, 122.2, 122.7, 124.6, 127.7, 128.2, 140.4, 152.6, 170.1.

 Synthesis of 3-methacryloyl-LfiT-benzimidazole-2(3)-thione (Compound No.: Ia-01)

53

Replacement page (Article 26) The title compound Ia-01 was obtained in the same manner as in Example 1 except that the urea was changed to thiourea. Compound Ia-01 _: light yellow powder, m.p. 163.5-165.2 °C. Mass spectrometry (electrospray, negative ion mode) m/z 217 (Μ-Η) Ό 1H NMR (CDC1 ₃ , 500ΜΗζ, δ, ppm): 2.16 (s, 3H, CH ₃ ), 5.60 (s, IH, C=CH ₂ ), 5.63 (s, IH, C=CH ₂ ), 6.85 (t, J=8.0 Hz, IH), 6.98 (t, J-8.0 Hz, IH), 7.15 (d, J=8.0 Hz, 1H) 7.66 (d, J=8.0 Hz, IH), 5.82 (s, IH, NH). ¹³ C NMR (CDC1 ₃ , 125MHz, δ, ppm): 19.6, 109.5, 111.6, 114.7, 122.8, 124.9, 125.7, 131.7 , 140.4, 165.9, 172.3.

 Example 3

 Synthesis of 3-methacryloyl-5-methyl-1-pentyl-IH-benzimidazole-2-one (Compound No.: IB-43)

 3-IV IB-43 Weigh 1.52g (10 mmol) 4-methyl-2-nitroaniline (3-D, 3.36g (60 mmol) potassium hydroxide, 10mL dimethylformamide (DMF) in lOOmL In a pear-shaped flask, stir at room temperature for 30 min, add 2.38 g (12 tnmol) of iodopentane, and continue stirring at room temperature for 15 h. Add ethyl acetate / 7j (volume ratio 2/1) 50 mL, stir for 10 min, transfer to a separatory funnel The layers were allowed to stand, and the aqueous phase was extracted with 10 mL of ethyl acetate. The organic phase was combined, dried over anhydrous sodium sulfate, and then evaporated to dryness to afford Intermediate 3-II 2.05 g, yield 92.3%; (20 mmol), concentrated hydrochloric acid 3 mL and deionized water 50 mL added lOOmL pear shape

54

Replacement page (Article 26) The flask was heated to reflux for 15 min, cooled to 85 ° C, and the intermediate 3-Π 1.78 g (8 mmol) was slowly added. After the addition was completed, the mixture was heated to reflux, cooled to room temperature, filtered, filtered, and filtrate evaporated. The intermediate 3-indole 1.45 g, yield 94.4%; the intermediate 3-ΠΙ U5g (6 mmol), urea 0.54 g (9 mmol), xylene 10 mL, heated under reflux for 4 h, cooled to 50 mL. Add 30 mL of ethyl acetate/water (volume ratio 2/1) at room temperature, stir for 10 min, transfer to a separatory funnel and let stand. The aqueous phase is extracted once more with 10 mL of ethyl acetate. After drying, the organic layer was concentrated under reduced pressure to give Intermediate 3-IV L 18 g (yield: 90.1%). The dry intermediate 3-IV 1.09 g (5 mmol), 2 mL triethylamine, 20 mL anhydrous dichloromethane In a 50 mL pear-shaped flask, 0.63 g of methacryloyl chloride (6 mmol, dissolved in 5 mL of dichloromethane) was added dropwise to the ice bath. After the addition, the mixture was slowly warmed to room temperature and stirring was continued for 5 hours. 15 mL of saturated sodium bicarbonate solution was added to the reaction flask, stirred for 10 min, transferred to a separating funnel and allowed to stand for separation, and the aqueous phase was extracted once with dichloromethane. The organic phase was combined, and washed with 10 mL portions of deionized water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography. =6/1), the title compound IB-43 1.21 g, yield 84.6%. Compound IB-43, colorless needle crystal, melting point 230.1 to 231.6 °C. Mass spectrometry (electrospray, positive ion mode) m/z

287 (M+H) ⁺ . 1H NMR (CDC1 ₃ , 500MHz, δ, ppm): 0.89 (t, J = 8.0Hz, 3H, CH ₃ ), 1.33~1.42 (m, 4H, 2 X C3⁄4), 1.52 (m, 2H, CH ₂ ) , 2.19(s, CH ₃ ), 2.42(s, C3⁄4), 4.11(t, J=8.0Hz, 2H, CH ₂ ), 5.47(s, IH, C=CH ₂ ), 5.61(s, IH, C =CH ₂ ), 6.85(d, J=8.0Hz, IH), 7.68(d, J=8.0Hz, IH), 8.0 l(s, IH). ¹³ C NMR (CDC1 ₃ , 125MHz, δ, ppm) : 13.5, 19.8, 21.9, 22.7, 26.8, 29.6, 45.7, 108.7, 115.4, 122.3, 124.5, 129.8, 132.1, 134.6, 137.1, 150.9, 174.1. Example 4

 Synthesis of 3-methacryloyl-5-methyl-1-pentyl-IH-benzimidazole-2 (3H thio-ketone (Compound No.: Ib-43)

55

称取化合物 4-1 (即实施例 3中的 3-IV， 0.218g, lmmol), 劳森试剂（Lawesson's Reagent, 0.404g, lmmol) 于干净干燥的 25mL圆底烧瓶中， 加入甲苯 10mL， 安装 上冷凝管以及干燥管， 加热回流反应， TLC跟踪监测至原料点消失， 加入 15 mL饱 和碳酸钠溶液淬灭反应， 分液， 乙酸乙酯萃取无机相 （15mLX 3 )， 合并有机相， 有 机相依次用饱和碳酸钠溶液（10mLX 2)， 水 UOmLX 2)和饱和氯化钠（10mL)洗 涤， 无水硫酸钠干燥， 柱层析 （V石油醚 /V乙酸乙酯 =5: 1 ) 后得产物 4-ΠΙ 2.13g， 产率 91.1%。 Replacement page (Article 26)

Compound 4-1 (ie 3-IV, 0.218 g, lmmol in Example 3), Lawesson's Reagent (0.404 g, 1 mmol) was weighed into a clean dry 25 mL round bottom flask, 10 mL of toluene was added and installed. The upper condensing tube and the drying tube are heated and refluxed, and the TLC is traced and monitored until the disappearance of the starting point. The reaction is quenched by adding 15 mL of saturated sodium carbonate solution, and the organic phase is extracted by ethyl acetate (15 mL×3), and the organic phase is combined. The mixture was washed with saturated sodium carbonate solution (10 mL×2), EtOAc (EtOAc) (EtOAc) (EtOAc) The product 4-ΠΙ 2.13 g, yield 91.1%.

The title compound was obtained in the same manner as in Example 3 except that the intermediate 3-IV was changed to 4-11. Compound Ib-43: Light yellow needle crystal, melting point 234.0~235.8 Ό. Mass spectrometry (electrospray, positive ion mode) m/z 303 (M+H)+. 1H NMR (CDC1 ₃ , 500MHz, δ, ppm): 0.89 (t, J = 8.0Hz, 3H, CH ₃ ), 1.31~1.39 (m, 4H, 2 X CH ₂ ), 1.46 (m, 2H, CH ₂ ), 2.16(s, CH ₃ ), 2.42(s, CH ₃ ), 4.45(t, J=8.0Hz, 2H, CH ₂ ), 5.47(s, IH, C=C3⁄4), 5.61 (s, IH, C=CH ₂ ), 6.45 (d, J=8.0Hz, IH), 6.72 (d, J=8.0Hz, 1H), 7.63(s, IH). ¹³ C NMR (CDC1 ₃ , 125MHz, δ, ppm) : 13.5, 19.8, 21.9, 22.7, 27.3, 29.9, 49.7, 108.7, 115.4, 122.3, 124.5, 131.5, 132.1, 134.2, 136.5, 170.4, 172.9. Example 5

 3-methacryloyl-5-chloroisoisopropenyl-IH-benzimidazole-2 (3/-ketone (Compound No.: IB-89) and 3-methacryloyl-6-chloroisoisopropenyl Synthesis of -Lff-benzimidazole-2 H-ketone (Compound Number: IC-89)

56

Replacement page (Article 26)

 5-llb IC-89

In a 50 mL three-necked reaction flask equipped with a water separator, intermediate 5-1 1.42 g (10 mmol) and 10 mL of xylene were added, and the mixture was stirred under reflux with heating, and then 1.56 g (12 mmol) of ethyl acetoacetate was slowly added dropwise. 5 mL of the xylene mixture was added, and after completion of the dropwise addition, azeotropic dehydration was carried out under reflux to the appearance of anhydrous beads, and stirring was continued for further 2 hours. After completion of the reaction, cooling, precipitation of crystals, filtration, drying, and column chromatography (V petroleum ether / V ethyl acetate = 3:1) gave intermediate 5-IIa 1.28 g, 5-IIb 0.46 g _; In the same manner, the intermediates 5-IIa and 5-IIb were reacted with methacryloyl chloride in anhydrous pyridine to obtain the title compounds IB-89 and IC-89, respectively, yields 76.5% and 73.8, respectively. %. Compound IB-89: pale yellow crystal, m.p. 125.7 - 126.9. Mass spectrometry (electrospray, negative ion mode) m/z

275 (Μ-Η)· ₀ 1H MR (CDC1 ₃ , 500ΜΗζ, δ, ppm): 2.17(s, 3Η, CH ₃ ), 2.2 l(s, 3H, CH ₃ ), 5.25(s, IH, C= CH ₂ ), 5.47(s, IH, C=CH ₂ ), 5.41(s, IH, C=CH ₂ ), 5.61(s, IH, C=CH ₂ ), 7.25(d J=8.0Hz, IH) , 7.83 (d, J = 8.0 Hz, IH), 8.15 (s, IH). ¹³ C NMR (CDC1 ₃ , 125 MHz, δ, ppm): 19.8, 20.1, 108.7, 117.9, 122.0, 124.3, 125.6, 124.7, 128.9, 131.2, 140.5, 148.9, 154.8, 170.2. Compound IC-89: pale yellow crystal, melting point 117.5~119.2 Ό. Mass spectrometry (electrospray, negative ion mode) m/z 275 (MH) -. 1H NMR (CDC1 ₃ , 500ΜΗζ, δ, ppm): 2.16(s, 3H, CH ₃ ), 2.2 l(s, 3H, CH ₃ ), 5.18(s, 1H, C=CH ₂ ) ₅ 5.35(s, IH, C=CH ₂ ), 5.41(s, IH, C=CH ₂ ), 5.61(s, IH, C=C3⁄4), 7.19(d J=8.0Hz, 1H), 7.25(d, J=8.0Hz , IH), 8.0 l(s, IH). ¹³ C NMR (CDC1 ₃ , 125MHz, δ, ppm): 19.7, 20.1, 108.2, 118.3, 123.5, 124.1, 124.6, 128.7, 130.7, 132.9, 140.7, 149.1, 154.2,

57

Replacement page (Article 26) Example 6

 Ethyl-3-methacryloyl-2-oxo-isopropenyl-2,3-dihydro-benzimidazole-4-carboxylate (Compound No.: IIA-26) and Ethyl-3-A Synthesis of acryloyl-2-oxoisopropenyl-2,3-dihydrobenzimidazole-7-carboxylate (Compound No.: IID-26)

称取 2,3-二氨基苯甲酸 1.52g (6-I)(10 mmol)， 乙醇 4.6g (100 mmol), 甲苯 30 mL 置于 lOO mL梨形瓶中， 再加入浓硫酸 3 mL加热回流 3h， 冷至室温后， 加入饱和碳 酸氢钠中和反应液， 转移至分液漏斗后， 用乙酸乙酯萃取（20mLX 3)， 合并有机相， 无水硫酸钠干燥后， 减压浓缩， 得中间体 6- II 1. 72g, 收率 95. 6%; 在装有分水器的 50 mL三口反应瓶中， 加入中间体 6-Π 1.44g (8 mmol)和 lOmL 二甲苯， 加热搅拌回流后， 缓慢滴加乙酰乙酸乙酯 1.3g(10 mmol)和 5mL二甲苯混合 液， 滴完后， 搅拌回流共沸脱水至无水珠出现为止， 再继续搅拌回流 2h。 反应毕， 冷却， 析出结晶， 过滤、 干燥， 得中间体 6-IIIa 0.79g， 6-IIIb 0.86g_; 再按照实施例 1中同样的方法， 分别用中间体 6-IIIa和 6-IIIb与甲基丙烯酰氯在 无水吡啶中反应，即可制得标题化合物 IIA-26和 IID-26,产率分别为 79.8%和 86.5%。。 化合物 ΠΑ-26: 无色针状晶体，熔点 132.2~134.5°C。质谱 (电喷雾，正离子模式) m/z 315 (M+H) ⁺o 1H NMR (CDC1₃, 500ΜΗζ, δ, ppm): 1.21(t, J=8.0,3H, CH₃), 2.17(s, 3H， CH₃), 2.21(s, 3H, CH₃), 4.52(2H, d, J=8.0, CH₂)， 5.21(s, IH, C=CH₂), 5.44(s, IH,

Weigh 1.52g (6-I) (10 mmol) of 2,3-diaminobenzoic acid, 4.6g (100 mmol) of ethanol, 30 mL of toluene, place it in a 100 mL pear-shaped flask, and add 3 mL of concentrated sulfuric acid to heat and reflux. After the reaction mixture was cooled to room temperature, the mixture was evaporated, evaporated, evaporated, evaporated, evaporated Intermediate 6-II 1. 72 g, yield 95.6%; In a 50 mL three-neck reaction flask equipped with a water separator, the intermediate 6-Π 1.44 g (8 mmol) and 10 mL of xylene were added and stirred under reflux with heating. Thereafter, a mixture of 1.3 g (10 mmol) of ethyl acetoacetate and 5 mL of xylene was slowly added dropwise, and after completion of the dropwise addition, azeotropic dehydration was carried out with stirring and reflux until the appearance of anhydrous beads, and stirring was continued for further 2 hours. After completion of the reaction, the mixture was cooled, crystallized, filtered and dried to give Intermediate 6-IIIa 0.79 g, 6-IIIb 0.86 g _; and in the same manner as in Example 1, using intermediates 6-IIIa and 6-IIIb respectively. The title compound IIA-26 and IID-26 were obtained by reacting acryloyl chloride in anhydrous pyridine in yields of 79.8% and 86.5%, respectively. . Compound ΠΑ-26: colorless needle crystal, melting point 132.2~134.5 °C. Mass spectrometry (electrospray, positive ion mode) m/z 315 (M+H) ⁺ o 1H NMR (CDC1 ₃ , 500 ΜΗζ, δ, ppm): 1.21 (t, J = 8.0, 3H, CH ₃ ), 2.17 (s , 3H, CH ₃ ), 2.21(s, 3H, CH ₃ ), 4.52(2H, d, J=8.0, CH ₂ ), 5.21(s, IH, C=CH ₂ ), 5.44(s, IH,

58

Replacement page (Article 26) C=CH ₂ ), 5.4 l(s, IH, C=CH ₂ ), 5.61 (s, IH, C-CH ₂ ), 7.25(m,]H), 7.65(d, J=8.0Hz,]H ), 8.12 (d, J = 8.0 Hz, IH). ^I3 C NMR (CDC1 ₃ , 125 MHz, δ, ppm): 14.3, 19.9, 20.0, 58.6, 108.7, 115.8, 117.9, 121.5, 123.3, 126.6, 127, 8, 128.9, 131.2, 148.9, 154.8, 168.9, 170.2. Compound IID-26: colorless needle crystal, melting point 136.0~137.6O. Mass spectrometry (electrospray, positive ion mode) m/z 315 (M+H) ⁺ . _{1H NMR (CDC1 3, 500ΜΗζ,} δ, ppm): 1.18 (t, J = 8.0,3H, CH 3), 2.15 (s, 3H, CH 3), 2.2 l (s, 3H, CH 3), 4.42 ( 2H, d, J=8.0, CH ₂ ), 5.2 l(s, IH, C=CH ₂ ), 5.44(s, IH, C=CH ₂ ), 5.41(s, IH, C=CH ₂ ), 5.61 (s, IH, C-CH ₂ ), 7.20(m, IH), 7.58(d, J=8.0Hz, IH), 8.02(d, J=8.0Hz, IH). ¹³ C NMR (CDC1 ₃ , 125MHz , δ, ppm): 14.1, 19.7, 20.5, 58.6, 108.7, 115.8, 117.9, 122.3, 123.8, 126.0, 128.7, 129.2, 131.6, 148.9, 154.6, 168.6, 170.7.

Example 7

 Synthesis of diethyl-3-methylacryloyl-2-one-2,3-dihydro-1 benzimidazole-5-carboxamide (JIB-41)

 IIB-1

59

Replacement page (Article 26) Starting from 3-nitro-4-aminobenzoic acid, the N-alkylation reaction was carried out according to the method of Example 3 to obtain Intermediate 7-11, and the carboxyl group was subjected to the method of Example 6. Esterification gave intermediate 7-11, and the intermediate -VI was obtained by the nitro reduction, cyclization and acylation in three steps as in Example 3. Weigh the intermediate 7-VI 0.364g (10 mmol) in a lOOmL pear-shaped bottle and add 1N sodium hydroxide solution.

20 mL, stirred at room temperature for 1 h, and the reaction was stopped after thin layer chromatography to confirm the disappearance of the starting point. The pH was adjusted to 4 to 5 with 1N hydrochloric acid solution, and ethyl acetate was extracted three times, 30 mL each time, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate 7-VII 2.60 g, yield 94.9%; Dry intermediate 7-VII 1.37 g (5 mmol), ethylamine 0.23 g (5 mmol), 1,3-dicyclohexylcarbodiimide (DCC) 1.24 g (6 mmol) and catalytic amount 2- The methylazopyridine (DMAP) was placed in a 50 mL pear-shaped flask, 20 mL of anhydrous dichloromethane was added, and the mixture was stirred at room temperature for 5 liters. After the reaction was stopped, the solid was removed by filtration, and the residue was washed twice with ethyl acetate (5 mL). The organic phase was combined, and 10 mL of deionized water and saturated sodium chloride solution were successively washed and washed, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent petroleum ether) /ethyl acetate = 5/1) gave the title compound IIB-4H.16 g, yield 76.8%.

 Compound ΠΒ-41 : pale yellow crystal, melting point 135.0~136.5'C. Mass spectrometry (electrospray, positive ion mode) m/z

302 (M+H) ⁺ o 1H NM (CDC1 ₃ , 500MHz, 6, ppm) : 0.98 (t, J=7.0Hz, 3H, CH ₃ ) , 1.21(t, J=7.5, 3H, C3⁄4), 2.19 (s, 3H, CH ₃ ), 3.28 (q, J=7.0 Hz, 2H, CH ₂ ), 4.75 (q, J=7.5, 2H, CH ₂ ), 5.4 l(s, IH, C=CH ₂ ) , 5.61(s, IH, C-CH ₂ ), 7.48(d, J-8.0Hz, IH), 7.96(d, J=8-0Hz, IH), 8.10(s, ΙΗ, ΝΗ), 8.20(s , IH). ¹³ C MR (CDC1 ₃ , 125MHz, δ, ppm): 13.1, 14.8, 19.9, 34.8, 41.2, 117.3, 118.9, 121.6, 125.3, 127.8, 130.7, 137.2, 141.9, 15S.8, 167.5, 170.5.

 Example 8

 Ethyl 3-methacryloyl-2-thione-2,3-dihydro-1 benzimidazole-5carboxylate (Compound No.: IIb-16) and ethyl-3-methacryloyl- Synthesis of 2-thione-2,3-dihydro-1 benzimidazole-6carboxylate (Compound No.: IIc-16)

60

Replacement page (Article 26)

8-IVa llc-16 Starting from 3,4-diaminobenzoic acid (8-1), the carboxyl group was subjected to ethyl esterification according to the method of Example 6 to give Intermediate 8-11. The title compound lib-16 and lie-16 were prepared by the procedure of Example 1 except that the urea was replaced with thiourea. The total yield of the reaction was 42.9%, and the ratio of 8-IVa and 8-IVb was 1:1. Compound IIb-16: pale yellow crystal, m.p. 187.9. (89.5 ° C. Mass Spectrum (electrospray, positive ion mode) m/z 291 (M+H) ⁺ 1H NMR (CDC1 ₃ , 500 ΜΗζ, δ, ppm): 1.21(t, J=8.0, 3H, CH ₃ ), 2.19(s, 3H, CH ₃ ), 4.26(q, J=8.0Hz, 2H, CH ₂ ), 5.28(s, IH, NH), 5.41( s, IH, C=CH ₂ ), 5.61(s, IH, C=CH ₂ ), 6.85(d, J=8.0Hz, IH), 7.32(d, J=8.0Hz, IH), 8.06(s, IH). ¹³ C NMR (CDC1 ₃ , 125 MHz, δ, ppm): 14.8, 20.2, 62.3, 117.6, 119.2, 125.6, 126.5, 126.8, 129.5, 133.2, 141.6, 165.8, 167.6, 171.9. Compound IIc-16: Light yellow crystal, melting point 195.2~197.0 ° C. Mass spectrum (electrospray, positive ion mode) m/z 291 (M+H) + 1H NMR (CDC1 ₃ , 500 ΜΗζ, δ, ppm ): 1.20 (t, J= 8.0, 3H, CH ₃ ), 2.19(s, 3H, CH ₃ ), 4.2 l(q, J=8.0Hz ₅ 2H, CH ₂ ), 5.12(s, IH, NH), 5.40(s, IH, C =CH ₂ ), 5.60(s, 1H, C=CH ₂ ), 6.56(d, J=8.0Hz, IH), 7.18(d, J=8.0Hz, IH), 7.86(s, IH). ¹³ C NMR (CDC1 ₃ , 125 MHz, δ, ppm): 14.9, 20.2, 63.6, 117.2, 119.8, 126.6, 127.8, 128.3, 129.9, 132.5, 140.9, 166.4, 167.8, 171.5. Example 9

 3-methacryloyl-2-oxo-2,3-dihydro-l^benzimidazole-5-carboxylic acid (Compound No.: ΠΒ- 01) Synthesis of sodium salt

61

Replacement page (Article 26) Sodium bicarbonate

NaOOC

 I old sodium salt weighed compound IIB-01 2.46g (10 mmol) dissolved in 20 mL of ethyl acetate, extracted with saturated sodium bicarbonate solution at room temperature, until the aqueous phase pH 7.0, after phase separation, The aqueous phase is about 30 mL, and 60 mL of n-butanol is added to the aqueous phase. After stirring, the mixture is filtered uniformly. The filtrate is further subjected to azeotropic distillation and crystallization at 0.2 atm. After filtration, washing with absolute ethanol and drying to obtain ΠΒ-01 sodium. The salt was 2.18 g, and the yield was 81.3%.

IIB-01 sodium salt: colorless needle crystal, melting point 243.5~245.2 °C. Mass spectrometry (electrospray, negative ion mode) m/z 245 (M-Na)-, Elemental analysis: C, 53.68%; H, 3.41%; N, 10.65%; Theory: C, 53.74%; H, 3.38% ; , 10.44%. 1H NMR (D ₂ 0, 500MHz, 8, ppm): 2.21(s, 3H, CH ₃ ), 5.52(s, IH, C=CH ₂ ), 5.68(s, IH, C=C3⁄4), 5.82(s , IH, NH), 7.82 (d, J = 8.0 Hz, IH), 8.03 (d, J = 8.0 Hz, IH), 8.35 (s, IH). ¹³ C NMR (D ₂ 0, 125 MHz, δ, ppm ): 19.3, 118.5, 123.1, 124.5, 130.6, 131.2, 132.8, 134.6, 142.8, 150.8, 170.6, 172.5.

Example 10

 3-methacryloyl-2-oxo-isopropenyl-2,3-dihydro-1benzimidazol-4-yl acetate (Compound No.: ΠΙΑ-26) and 3-methacryloyl-1 Synthesis of -Isopropenylbenzimidazolone-7-acetate (Compound No.: IIID-26)

 IIID-26

Replacement page (Article 26) Weigh 2,3-diaminophenol (10-1) 1.24g (10 mmol), acetic acid 60g (100 mmol), toluene 30 mL in a 100 mL pear-shaped flask, and add 3 mL of concentrated sulfuric acid to reflux for 3 h. After cooling to room temperature, the reaction mixture was combined with EtOAc EtOAc EtOAc (EtOAc m. 10-II 1.54g, yield 92.8%; In a 50 mL mouthwashing reaction flask equipped with a water separator, the intermediate 10-11 1.33g (8 mmol) and 10 mL of xylene were added, and the mixture was stirred under reflux with heating. A mixture of 1.3 g (10 mmol) of ethyl acetoacetate and 5 mL of xylene was slowly added dropwise. After the completion of the dropwise addition, the mixture was stirred and refluxed to azeotropically dehydrated to the appearance of anhydrous beads, and stirring was continued for further 2 hours. After completion of the reaction, the mixture was cooled, crystallized, filtered, and dried to give Intermediate 10-IIIa 0.65 g, 10-IIIa 0.57 g, and dry intermediate 10-3a 0.23 g (1 mmol), 2 mL triethylamine, 20 mL of anhydrous dichloromethane was placed in a 50 mL pear-shaped flask. 0.13 g of methacryloyl chloride (1.2 mmol, dissolved in 5 mL of dichloromethane) was added dropwise in an ice bath. After the addition, slowly warm to room temperature and continue. Stir for 5 h. 15 mL of saturated sodium bicarbonate solution was added to the reaction flask, stirred for 10 min, transferred to a separating funnel and allowed to stand for separation, and the aqueous phase was extracted once with dichloromethane. The organic phase was combined, washed with 10 mL portions of EtOAc (EtOAc) EtOAc. = 6/1 ) gave Compound ΠΙΑ-26 0.26 g, yield 86.0%. The title compound IIID-260.23 g (yield: 75.0%), Compound ΙΠΑ-26: colorless needle crystals, melting point 113.2~ 115.0 ° C. Mass spectrometry (electrospray, positive ion mode) m/z 301 (M+H) ⁺ . 1H NMR (CDC1 ₃ , 500MHz, 5, ppm): 2.17(s, 3H, CH ₃ ), 2.2 l(s, 3H, CH ₃ ), 2.35(s, 3H, CH ₃ ), 5.21(s, 1H, C=CH ₂ ), 5.44(s, IH, C=CH ₂ ), 5.41 (s, IH, C=CH ₂ ), 5.61(s, IH, C=CH ₂ ), 7.16(m, IH), 7.68 (d, J = 8.0 Hz, IH), 7.82 (d, J = 8.0 Hz, IH). ¹³ C NMR (CDC1 ₃ , 125 MHz, δ, ppm): 19.9, 20.0, 21.6, 108.5, 109.0, 110.6, 112.8 , 122.5, 124.6, 126.8, 141.5, 145.2, 149.7, 154.8, 168.0, 170.6. Compound IIID-26: colorless needle crystal, melting point 108.0~110. (TC. mass spectrometry (electrospray, positive ion mode) m/z 301 (M+H) ⁺ 1H NMR (CDC1 ₃ , 500 ΜΗζ, δ, ppm): 2.14 (s, 3H, CH ₃ ), 2.21 (s, 3H, CH ₃ ), 2.37 (s, 3H, CH ₃ ) , 5.20(s, IH, C=CH ₂ ), 5.42(s, 1H, C=CH ₂ ), 5.46(s, 1H, C=CH ₂ ), 5.65(s, 1H, C=CH ₂ ), 7.25 (m, IH), 7.72 (d, J = 8.0 Hz, IH), 7.88 (d, J = 8.0 Hz, IH). ¹³ C NMR (CDCI3, 125 MHz, S, ppm): 19.7, 20.6, 21.7, 108.9 , 109.1, 110.6, 112.2, 123.8, 124.0,

63

Replacement page (Article 26) 126.5, 142.7, 146.8, 148.2, 154.3, 168.1, 170.5. Example 11

Synthesis of 3-methacryloyl-2-oxo-1-isopropenyl-2,3-dihydro-Lff-benzimidazole-4-iV-methylcarbamate (Compound No.: ΙΠΑ-56)

 11-1 1 1 -11 IIIA-56

Using the final product of Example 10 as the starting material 11-1, weigh 11-13.0 g (10 mmol) in a 100 mL pear-shaped flask, add 20 mL of 1N sodium hydroxide solution, stir at room temperature for 1 h, and test the raw materials by thin layer chromatography. Stop the reaction after the point disappears. The pH was adjusted to 4~5 with 1N hydrochloric acid solution, and extracted with ethyl acetate three times, 30 mL each time, and the organic phase was combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate ll-II 2.4 g, yield 93.8%; To a 100 mL three-necked flask, 0.29 g (5 mmol) of methyl isocyanate and 5 mL of dichloromethane were added, and the mixture was stirred at room temperature. The intermediate 11-11 2.06g (8 mmol), triethylamine 0.2mL and 10 mL of dichloromethane were added to the constant pressure dropping funnel. After mixing, the mixture was slowly added dropwise to the above methyl isocyanate solution. Stirring was continued for 5 h at room temperature. 60 mL of ethyl acetate/7K (volume ratio 2/1) mixed solution was added to the reaction flask, stirred for 10 min, transferred to a separating funnel and allowed to stand for separation, and the aqueous phase was extracted once more with ethyl acetate. The organic phase was combined, washed with 10 mL portions of 1N hydrochloric acid, EtOAc (EtOAc), EtOAc. Ethyl acetate = 3/1) gave title compound IIIA-56 1.48 g, yield 93.7%. Compound ΠΙΑ-56: colorless needle crystal, melting point 165.0-166.8 Ό. Mass spectrometry (electrospray, positive ion mode) m/z 316 (M+H) ⁺ . 1H NMR (CDC1 ₃ , 500ΜΗζ, δ, ppm): 2.17(s, 3H, C3⁄4), 2.2 l(s, 3H, CH ₃ ), 2.65(s, 3H, CH ₃ ), 5.21(s, IH, C =CH ₂ ), 5.44(s, IH, C=CH ₂ ), 5.41(s, IH, C=CH ₂ ), 5.61(s, 1H, C=CH ₂ ), 7.18(m, 1H), 7.65( d, J=8.0Hz, IH), 7.80(d, J=8.0Hz, 1H), 8.10 (s, IH,

64

Replacement page (Article 26) H) . ¹³ C NMR (CDCI 3, 125 MHz, 5, ppm): 19.9, 20.0, 28.2, 108.5, 109.0, 111.6, 112.7: 123.5, 124.9, 126.8, 141.9, 145.8, 149.1, 154.8, 157.3, 170.6. 12

 5-ethoxy-3-methylpropenylbenzimidazole-2 (3H)-one (Compound No.: IIIB-31) and 6-ethoxy-3-methylpropenylbenzimidazole-2 2^) -ketone (Compound No.: IIIC-31) Synthesis

Urea/dimethyl reflux

 12-1 12-11 12-111

除起始原料改为 3，4-二硝基苯酚、 烷基化试剂改为碘乙垸， 其余垸基化、 硝基还 原、 环化等操作步骤与实施例 3完全相同， 可以制得中间体 12-IV。 再采用与实施例 1 完全相同的方法对 12-IV 进行甲基丙烯酰化， 即可制得标题化合物 ΙΠΒ-31 和 IIIC-31 , 反应总收率 68.2%， ΙΠΒ-31与 IIIC-31比例为 2:1。 化合物 IIIB-31 :无色针状晶体，熔点 218 〜 219.5°C。质谱 (电喷雾，负离子模式)， m/z 245 (Μ-Η)Ό 1H NMR (CDC1₃, 500ΜΗζ, δ, ppm): 1.28(t, J=7.0Hz， 3H, CH₃), 2.16 (s， 3H, CH₃), 4.08(q, J=7.0Hz, 2H, CH₂), 5.41 (s， 1H, C=CH₂), 5.63 (s， 1H, C=CH₂), 6.78 (d, J=8.0Hz, 1H), 7.38(s, 1H), 7.72 (d, J=8.0 Hz, 1H), 8.81 (s， 1H， NH). ¹³C NMR (CDC1_3; 125MHz, δ, ppm): 13.9, 19.1, 63.8, 106.7, 109.5, 114.9, 122.2, 122.7, 127.7, 128.2, 142.5,

化合物 IIIC-31 :无色针状晶体，熔点 220.0~221.8°C。质谱 (电喷雾，负离子模式)， m/z 245 (M-H)-。 1H NMR (CDC1₃, 500MHz, δ， ppm): 1.25(t, J=7.0Hz, 3H， CH₃)， 2.16 (s, 3H, CH₃), 3.97(q, J=7.0Hz, 2H， CH₂)， 5.45 (s， 1H, C=CH₂), 5.68 (s, 1H, C=CH₂), 6.85 (d, J=8.0Hz, 1H), 7.49(s, 1H), 7.96 (d, J=8.0 Hz, 1H), 8.07 (s, 1H, NH). ¹³C NMR (CDC1₃,

The operation steps are the same as in the third embodiment except that the starting material is changed to 3,4-dinitrophenol, the alkylating reagent is changed to iodonium, and the other steps are the same as in the third embodiment. Body 12-IV. Further, methacrylation of 12-IV was carried out in exactly the same manner as in Example 1, whereby the title compounds ΙΠΒ-31 and IIIC-31 were obtained, and the total reaction yield was 68.2%, and the ratio of ΙΠΒ-31 to IIIC-31 was obtained. It is 2:1. Compound IIIB-31: colorless needle crystal, m.p. 218 - 219.5 °C. Mass spectrometry (electrospray, negative ion mode), m/z 245 (Μ-Η) Ό 1H NMR (CDC1 ₃ , 500 ΜΗζ, δ, ppm): 1.28 (t, J = 7.0 Hz, 3H, CH ₃ ), 2.16 (s , 3H, CH ₃ ), 4.08 (q, J=7.0Hz, 2H, CH ₂ ), 5.41 (s, 1H, C=CH ₂ ), 5.63 (s, 1H, C=CH ₂ ), 6.78 (d, J = 8.0 Hz, 1H), 7.38 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 8.81 (s, 1H, NH). ¹³ C NMR (CDC1 _3; 125MHz, δ, ppm): 13.9, 19.1, 63.8, 106.7, 109.5, 114.9, 122.2, 122.7, 127.7, 128.2, 142.5,

Compound IIIC-31: colorless needle crystal, melting point 220.0 to 221.8 °C. Mass spectrometry (electrospray, negative ion mode), m/z 245 (MH)-. 1H NMR (CDC1 ₃ , 500MHz, δ, ppm): 1.25 (t, J = 7.0Hz, 3H, CH ₃ ), 2.16 (s, 3H, CH ₃ ), 3.97 (q, J=7.0Hz, 2H, CH ₂ ), 5.45 (s, 1H, C=CH ₂ ), 5.68 (s, 1H, C=CH ₂ ), 6.85 (d, J=8.0Hz, 1H), 7.49(s, 1H), 7.96 (d, J=8.0 Hz, 1H), 8.07 (s, 1H, NH). ¹³ C NMR (CDC1 ₃ ,

65

Replacement page (Article 26) 125 MHz, δ, ppm): 13.7, 18.6, 62.8, 107.9, 109.1, 115.3, 123.5, 124.2, 127.4, 128.9, 142.6, 150.2, 170.1.

 Example 13

 N-(3-methacrylic acid-2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)acetic acid amine (Compound No.: IVB-15) and N-(3-methacrylic acid- Synthesis of 2-oxo-2,3-dihydrobenzimidazol-6-yl)acetic acid amine (Compound No.: IVC-15)

0 ₂

 13-lllb

Η ₂ Ν

 Iron powder / hydrochloric acid 13-IVa acetic acid / triphosgene / dichloromethane / triethylamine IVB-15

除将邻苯二胺改为 2-氨基 -4-硝基苯胺外， 其余试剂与操作条件与实施例 1完全 相同， 制备得到中间体 13-IIIa和 13-Iffl>， 再参照实施例 12中的方法进行硝基还原， 即制得中间体 13-IVa和 13-IVb， 以上三步反应总收率 65.8%， 13-IVa组分和 13-IVb 组分比例为 3: 2。 取中间体 13-IVa 0.73g(3 mmol)和乙酸 0. 42g(4 mmoL)置于 50mL干燥的梨形瓶 Mm '

Except that the o-phenylenediamine was changed to 2-amino-4-nitroaniline, the other reagents and operating conditions were exactly the same as in Example 1, and intermediates 13-IIIa and 13-Iffl> were prepared, and then referring to Example 12 The nitro reduction was carried out to obtain intermediates 13-IVa and 13-IVb. The total yield of the above three steps was 65.8%, and the ratio of the 13-IVa component to the 13-IVb component was 3:2. Take intermediate 13-IVa 0.73g (3 mmol) and acetic acid 0. 42g (4 mmoL) in 50mL dry pear-shaped bottle

66

Replacement page (Article 26) Into, 20 mL of the dried dichloromethane was added, stirred until completely dissolved, and 0.2 mL of triethylamine was added. The phosgene U9g (0.004 moL) was weighed and dissolved in 10 mL of dry dichloromethane, and slowly added dropwise to the reaction flask under ice bath. After the completion of the dropwise addition, the reaction system was returned to room temperature, and stirring was continued for 5 to 8 hours. After the reaction was completed, 20 mL of a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction system, and the mixture was shaken well and allowed to stand for phase separation. The organic phase was washed with water, dried and reduced by magnesium chloride. The mixture was decomposed, and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 4/1) to give the title compound IVB-15 0.72 g, yield 84.7%. The title compound IVC-15 0.72 g, yield 87.6%, Compound IVB-1S: White powder, melting point 117.6-U9.4O was obtained by the same procedure as above. Mass spectrometry (electrospray, positive ion mode), m/z 286 (M+H)+. 1H NMR (CDC1 ₃ , 500MHz, δ, ppm): 1.28 (t, J=7.0Hz, 3H, CH ₃ ), 2.16 (s, 3H, CH ₃ ), 4.08 (q, J=7.0Hz, 2H, CH ₂ ), 5,60 (s, IH, C=CH ₂ ), 5.63 (s, IH, C=CH ₂ ), 6.78 (d, J=8.0Hz, IH), 7.38(s, IH), 7.72 ( d, J = 8.0 Hz, IH), 8.81 (s, IH, NH). ¹³ C NMR (CDC1 _{3 >} 125 MHz, δ, ppm): 13.9, 19.1, 63.8, 106.7, 109.5, 114.9, 122.2, 122.7, 127.7 , 128.2, 142.5, 150.6, 170.6. Compound IVC-15: White powder, m.p. 120.1 to 121.8 °C. Mass spectrometry (electrospray, positive ion mode), m/z 286 (M+H) ⁺ . 1H NMR (CDC1 ₃ , 500 g, δ, ppm): 1.28 (t, J = 7.0 Hz, 3H, CH ₃ ), 2.15 (s, 3H, CH ₃ ), 4.15 (q, J = 7.0 Hz, 2H , CH ₂ ), 5.62 (s, IH, C=CH ₂ ), 5.61 (s, IH, C=CH ₂ ), 6.72 (d, J=8.0Hz, IH), 7.35(s, IH), 7.66 ( d, J-8.0 Hz, IH), 8.41 (s, IH, NH). ¹³ C NMR (CDC1 _3> 125 MHz, δ, ppm): 13.5, 19.4, 63.8, 106.9, 109.8, 113.8, 122.7, 123.5, 127.5 , 128.8, 143.2, 150.4, 170.2. Example 14

5-Ethylamino-3-methacryloyl-1-isopropenyl-IH-benzimidazole-2(3H)-one (Compound No.: IVB-20) and 4-ethylamino-3-methyl Synthesis of Acryloyl-1-Isopropenylbenzimidazole-2(3H)-one (Compound Number: IVC-20)

67

Replacement page (Article 26)

The intermediates were completely identical to those of Example 5 except that the starting material was changed to 2-amino-4-nitroaniline, and intermediates 14-KIa and 14-IIIb were obtained. The nitro reduction and N-grafting reaction were carried out in the same manner as in Example 12 to obtain the title 'Compounds IVB-20 and IVC-20, the total reaction yield was 42.6%, and the ratio of IVB-20 and IVC-20 was obtained. For 3: 2. Compound WB-20: colorless needle crystal, melting point 124.8~126.5Ό. Mass spectrometry (electrospray, positive ion mode), m/z 286 (M+H) ⁺ . 1H NMR (CDa ₃ , 500 ΜΗζ, δ, ppm): 1.26 (t, J = 7.0 Hz, 3H, CH ₃ ), 2.17 (s, 3H, CH ₃ ), 2.2 l (s, 3H, C3⁄4), 3.58 ( q, J=7.0Hz, 2H, C3⁄4), 5.2](s, IH, C=CH ₂ ), 5.42(s, IH, C=CH ₂ ), 5.41(s, IH, C=CH ₂ ), 5.61 (s, IH, C=CH ₂ ), 6.01 (s, IH, NH), 6.38 (d, J=8.0Hz, IH), 6.85(s, IH), 7.52 (d, J=8.0 Hz, IH) ¹³ C NMR (CDC1 ₃ , 125MHz, 5, ppm): 15.9, 19.1, 20.3, 38.4, 108.5, 109.4, 110.8, 113.0, 123.4, 125.6, 126.2, 141.0, 146.4, 148.2, 154.9, 170.2.

68

Replacement page (Article 26) Compound IVC-20: colorless needle crystal, m.p. 127.0 to 128.8 °C. Mass spectrometry (electrospray, positive ion mode), m/z 286 (M+H) ⁺ . ^ NMR iCDC, 500MHz, δ, ppm): 1.25(t, J=7.0Hz, 3H, CH ₃ ), 2.17(s, 3H, C3⁄4), 2.20(s, 3H, CH ₃ ), 3.32(q, J =7.0Hz, 2H, C3⁄4), 5.19(s, IH, C=C3⁄4), 5.40(s, IH, C=CH ₂ ), 5.44(s, IH, C=CH ₂ ), 5.65(s, IH, C=CH ₂ ), 6.25 (s, IH, NH), 6.43 (d, J=8.0Hz, IH), 6.92(s, IH), 7.27 (d, J=8.0 Hz, IH). ¹³ C NMR ( CDC1 ₃ , 125 MHz, 6, ppm): 15.8, 18.9, 20.4, 38.7, 108.6, 109.6, 110.8, 113.5, 122.5, 125.8, 128.0, 141.5, 146.0, 148.9, 154.7, 170.6. Preparation Example 15

Synthesis of 5-(lH-imidazolidinyl)-3-methylacryloyl small isopropenyl-IH-benzimidazole-2 (3//)-one (Compound No.: IVB-34)

 15-1 IVB-34

First, 3-methacryloyl-5-chloro-1-isopropenyl-1H-benzimidazole-2 (3H)-one (15-1) was obtained by the method of Preparation Example 5. The title compound IVB-34 was obtained by the procedure of the synthesis of 14-V in Example 14 except that iodoethyl hydrazine was changed to 15-1. The total reaction yield was 56.9%. Compound IVB-34: Colorless needle crystal, melting point 158.1~159.7Ό. Mass spectrometry (electrospray, positive ion mode), m/z 309 (M+H) ⁺ . 1H NMR (CDC1 ₃ , 500MHz, δ, ppm): 2.17(s, 3H, CH ₃ ), 2.20(s, 3H, CH ₃ ), 5.2 l(s, IH, C=CH ₂ ), 5.43(s, 1H, C=CH ₂ ), 5.4 l(s, IH, C=CH ₂ ), 5.6 l(s, IH, C=CH ₂ ), 6.85 (s, IH), 7.15 (s, IH), 7.18 ( d, J = 7.0 Hz, IH), 7.42 (d, J = 7.0 Hz, IH), 7.36 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, IH). ¹³ C NMR ( CDC1 ₃ , 125MHz, δ, ppm): 19.1, 20.4, 105.7, 108.5, 109.6, 114.6, 119.5, 123.6, 126.7, 128.3, 130.6, 134.6, 135.8, 142.1, 149.6, 155.8, 170.6. Preparation Example 16 3-methylacryloyl-2-oxo-1-isopropenyl-23-dihydro-I-benzimidazole-4~carboxylate

69

Replacement page (Article 26) (ΙΠΑ-26) Preparation of tablets as active ingredients 50 g of IIIA-26 and 100 g of sucrose were weighed, mixed well, and then excipients (such as sodium carboxymethylcellulose, microcrystalline cellulose, crospovidone) were added. Etc.), 1000 tablets of the specification 50 mg/tablet can be prepared according to the conventional tablet manufacturing method. Preparation Example 17 Preparation of 3-methoxyacryloyl group using a powder injection of 3-methacryloyl-2-oxo-2,3-dihydro-1^ "benzimidazole-5carboxylic acid sodium salt as an active ingredient" 2-oxo-2,3-dihydro-IT^benzimidazole-5carboxylic acid sodium salt 2g, hydroxypropyl-β-cyclodextrin 23g, add 500mL of water for injection to make a paste, then add 75g of mannitol to dissolve Adjust pH 6 with 1 mol/L hydrochloric acid, add the needle with activated carbon, stir at room temperature, filter for decarburization, and finely filter. The filtrate is packed in 2 mL each, and the quick freezing method is used to reduce the temperature by 10 ° C every minute until the solution is cooled. After heating to -40 ° C for 4 h, and then heating to - 20 ° C, sublimation drying, the product was taken out and sealed to obtain 3-methoxyacryloyl-2-oxo-2,3- Dihydro-I benzimidazole 5-carboxylic acid sodium salt powder injection. Preparation Example 18 Ethyl-3-methacryloyl-2-oxo-1-isopropenyl-2,3-dihydrobenzimidazole- Preparation of 4-carboxylate (IIA-26) as an active ingredient ointment 0.75 g of carbomer was adjusted to pH 6.5-7.5 with 10% sodium hydroxide solution, and stirred to make it swell evenly; l.Og is dissolved in 10g of ethanol, then add 20g Mix the oil, mix the mixture with the carbomer solution uniformly, add 3.0g of azone, 2.0g of Tween 80, add deionized water to the total amount of 100g, grind until the emulsion is even, then obtain 1.0% B 3-Benzene acyl-2-oxo-1-isopropenyl-2,3-dihydrobenzimidazole-4-carboxylate cream. Preparation Example 19 3-methacryloyl-2 -oxy-1-isopropenyl-2,3-dihydro-benzoimidazole-4-7V-methylcarbamate

70

Replacement page (Article 26) (ΠΙΑ-56) Preparation of wettable powder as active ingredient 40 kg of ΙΠΑ-56 original drug, 6 kg of sodium decyl sulphate, 8 kg of sodium lignin sulfonate and 46 kg of attapulgite over 450 mesh were added to the mixing device. Then, the uniformly mixed material is slowly and uniformly added to the jet mill through the feeder for pulverization, and the pulverized material is sent to the mixer and mixed again to obtain a 3-methacryloyl-2 content of 40%. - Oxo-1-isopropenyl-2,3-dihydro-1H-benzimidazole-4-N-methylcarbamate wettable powder. Preparation Example 20 Suspension with 3-methacryloyl-2-oxoisopropenyl-2,3-dihydrobenzimidazole-4-N-methylcarbamate (IIIA-56) as an active ingredient Preparation of the agent 称-56 original drug 40kg, sodium dodecyl naphthalene sulfonate 2kg, sodium dodecyl benzene sulfonate 8kg, gum arabic 2kg, sodium benzoate 1.5kg, antifreeze glycerol 5k _g , Defoamer silicone lkg, add deionized water to 100kg. After mixing and homogenizing in a sand mill for 3 h, 40% 3-methacryloyl-2-oxo-1-isopropenyl-2,3-dihydrobenzimidazole-4-N-methylamino was obtained. Formate. Biological embodiment

 The biological activities of the compounds of the general formula (I) of the present application were determined by the following Biological Examples 1 to 6: Example 1 Determination of the antibacterial activity of the compound on a part of the tested bacteria

The minimum inhibitory concentration of the representative compound of the formula (I) of the present application is determined by the microdilution method developed by NCCLS. The specific steps are as follows: 4 to 5 samples of the same type of bacteria are picked from the culture plate by the inoculating loop. , in Mueller-Hinton broth, 35 Ό cultured to mild turbidity (about 3~5h), transferred to 0.9% physiological saline, adjusted to a turbidity of 0.5 (make the absorbance at 650nm wavelength 0.020) At this time, it is equivalent to 1.5 X 10 ⁸ CFU/mL), and then diluted 200 times with Mueller-Hinton broth, and the inoculum amount is equivalent to 7.5 X 10 ⁵ CFU/mL. The diluted inoculum was transferred to a 96-well plate at a volume of 190 L per well. 2 mg of the test agent was dissolved in 1 mL of dimethyl sulfoxide (DMSO), and then diluted to a series of concentration gradients with deionized water, and then added to the inoculum of the 96-well plate, so that the final concentration gradient of the solution was respectively For 100, 50, 25,

71

Replacement page (Article 26) 12.50, 6.25, 3.13, 1.56, 0.78μ _β ·ιηΐ Each plate was provided with a blank control without drug addition and a positive control with sodium ampicillin. Each treatment was repeated three times in the experiment. The treated 96-well plates were placed in an incubator, cultured at 35 ° C for 24 h, and the light transmittance was measured at 650 nm, and the MIC values of the different agents against the test bacteria were recorded. The light transmittance is greater than 85% as a criterion for inhibiting growth, and MIC is the lowest concentration for inhibiting growth. The results are shown in Table 5.

 Table 5 shows the antibacterial activity of some compounds on six kinds of bacteria

Minimum inhibitory concentration ( g · ml / ¹ )

 Test compound

 B.C B.S S.A MESA E.C PA

IA-01 3.13 1.56 3.13 3.13 1.56 1.56

IA-40 0.78 0.78 1.56 1.56 0.78 0.78

IA-50 0.39 0.19 0.39 0.39 0.19 0.78

IA-89 0.78 0.39 0.39 0.39 0.39 1.56

IA-118 12.5 12.5 6.25 6.25 3.13 50.0

IA-128 0.78 0.78 1.56 1.56 0.78 0.78

IA-157 0.39 0.19 0.39 0.39 0.19 0.78

IA-167 0.78 0.39 0.39 0.39 0.39 1.56

IB-01 12.5 12.5 6.25 6.25 3.13 50.0

IB-20 0.39 0.19 0.19 0.19 0.39 25.0

IB-35 0.19 0.19 0.19 0.19 0.39 25.0

IB-40 0.78 0.78 0.39 0.39 0.19 50.0

IB-79 0.78 0.39 0.39 0.39 0.39 50.0

IC-01 0.10 0.10 0.10 0.10 0.39 12.5

IC-20 0.39 0.78 0.78 0.78 0.39 12.5

IC-40 0.78 0.78 1.56 1.56 6.25 50.0

IC-60 0.78 1.56 1.56 1.56 0.78 50.0

IC-89 0.39 0.39 1.56 1.56 6.25 12.5

IC-157 1.25 0.39 1.56 1.56 6.25 0.78

ID-01 0.19 0.38 0.19 0.19 0.78 0.39

1D-35 0.78 0.39 0.10 0.10 12.5 12.5

ID-40 12.5 1,56 1.56 1.56 12.5 50.0

1D-50 0.39 1.56 0.39 0.39 0.78 50.0

ID-157 0.78 0.39 0.39 0.39 1.56 12.5

ID- 167 1.56 0.39 0.78 0.78 0.78 0.39

Ia-01 3.13 1.56 1.56 1.56 12.5 50.0

Ia-20 0.19 0.39 0.19 0.19 1.56 0.19

Ia-40 1.56 0.78 1.56 1.56 1.56 12.5

Ia-60 0.39 0.39 0.39 0.39 0.78 1.56

Ia-89 0.39 0.39 0.39 0.39 0.78 0.78 la- 167 1.56 1.56 1.56 1.56 6.25 12.5 lb- 18 0.78 0.39 0.19 0.19 12.5 50.0

Ib-40 0.19 0.39 0.19 0.19 0.78 0.39

Ib-79 0.19 3.13 1.56 1.56 3.13 6.25

Ib-118 0.78 1.56 1.56 1.56 0.39 0.78

72

Replacement page (Article 26) Ib-157 0.39 0.39 0.78 0.78 0.78 12.5

Ic-0] 0.78 0.39 0.39 0.39 1.56 0.39

Ic-35 1.56 1.56 1.56 1.56 3.13 6.25

Ic-79 0.39 0.39 0.78 0.78 1.56 0.39

Ic-89 1.56 0.39 0.78 0.78 12.5 12.5

Ic-167 0.78 0.78 1.56 1.56 0.19 1.56

Id-10 0.19 6.25 3.13 3.13 0.19 1.56

Id-20 0.39 1.56 0.19 0.19 0.78 0.78

Id-40 12.5 0.39 1.56 1.56 0.39 0.78

Id-89 0.78 0.78 0.39 0.39 0.10 6.25

Id- 157 0.19 6.25 0.39 0.39 0.78 12.5

IIA-01 0.39 0.39 1.56 1.56 0.78 0.78

IIA-10 12.5 0.39 0.78 0.78 1.56 3.13

IIA-20 0.19 0.39 0.19 0.19 0.39 0.39

IIA-31 0.19 0.78 0.19 0.19 0.39 50.0

IIA-45 0.78 3.13 1.56 1.56 0.78 6.25

IIB-05 0.19 0.78 039 0.39 0.39 0.78

IIB-16 0.39 0.39 0.78 0.78 0.10 6.25

IIB-26 12.5 0.78 6.25 6.25 0.78 6.25

IlB-35 0.78 12.5 1.56 1.56 0.78 0.78

IIB-45 0.19 0.78 0.39 0.39 1.56 12.5

IIC-01 0.39 0.39 0.78 0.78 0.39 12.5

IIC-12 12.5 0.78 6.25 6.25 0.39 0.78

IIC-20 0.19 12.5 0.39 0.39 0.38 1.56

IIC-35 0.19 0.39 0.39 0.39 0.39 0.78

IIC-41 0.78 0.19 0.39 0.39 1.56 12.5

IID-10 0.39 0.78 0.39 0.39 1.56 1.56

IID-18 0.10 0.78 0.39 0.39 0.39 1.56

IID-26 0.78 0.10 0.78 0.78 3.13 50.0

IID-41 0.78 0.39 1.56 1.56 】.56 50.0

IID-45 1.56 0.78 0.39 0.39 0.39 12.5 lla-01 0.39 0.78 0.39 0.39 0.39 12.5

IIa-10 0.39 0.39 0.39 0.39 1.56 0.78

IIa-20 0.39 1.25 0.78 0.78 0.39 12.5

IIa-35 0.39 0.19 1.56 1.56 0.39 50.0

IIa-45 1.56 0.78 0.78 0.78 0.78 50.0

IIb-05 】.56 0.10 0.78 0.78 6.25 12.5 lib- 16 0.39 0.39 0.10 0.10 1.56 6.25

IIb-26 0.39 0.78 0.78 0.78 0.39 50.0

Hb-31 1.56 0.78 0.78 0.78 0.78 0.19

IIb-41 0.39 0.39 6.25 6.25 6.25 12.5

IIc-01 0.78 1.25 0.78 0.78 0.39 1.56 lie- 12 0.39 0.19 0.39 0.39 0.39 0.78

IIc-20 0.39 0.78 0.19 0.19 0.39 12.5

IIc-35 1.56 12.5 1.56 1.56 0.78 50.0

73

Replacement page (Article 26) IIc-45 0.39 0.39 0.39 0.39 3.13 0.39 IId-05 0.39 0.78 0.78 0.78 0.10 6.25 IId-12 0.39 1.56 12.5 12.5 0.10 6.25 IId-31 1.56 3.13 0.39 0.39 0.78 12.5 IId-41 0.39 0.19 0.19 0.19 0.78 50.0 IId-45 0.39 1.56 0.78 0.78 1.56 12.5 IIIA-01 0.78 0.39 0.78 0.78 0.39 0.78 IIIA-11 6.25 0.39 1.56 1.56 0.78 1.56 IIIA-31 1.56 1.56 0.39 0.39 6.25 0.78 IIIA-46 0.39 0.78 0.39 0.39 0.39 12.5 IIIA-56 0.78 0.19 0.78 0.78 0.39 1.56 IIIB -11 6.25 6.25 0.39 0.39 0.39 50.0 IlIB-26 0.39 1.56 0.10 0.10 0.39 12.5 IIIB-41 0.39 0.39 0.78 0.78 0.39 0.78 ΙΠΒ-46 0.39 0.78 0.78 0.78 0.78 1.56 IIIB-56 0.78 6.25 1.56 1.56 1.56 12.5 IIIC-01 3.13 0.39 0.39 0.39 0.39 50.0 IIIC-11 0.78 0.39 0.39 0.39 0.39 1.56 IIIC-31 0.39 0.39 0.38 0.38 0.39 0.39 IIIC-41 0.78 0.78 0.39 0.39 0.78 6.25 IIIC-56 1.56 0.39 1.56 1.56 0.39 0.78 IIID-01 0.39 0.39 1.56 1.56 1.56 0.78 HID- 16 0.78 0.39 1.56 1.56 0.39 6.25 IIID-31 6.25 1.56 0.39 0.39 0.39 6.25 IIID-46 1.56 0.39 0.39 0.39 0.78 0.78 IIID-56 0.39 0.39 1.56 1.56 6.25 12.5 IIIa-01 0.78 0.7 8 0.39 0.39 1.56 1.56 Ilia- 11 6.25 6.25 0.78 0.78 0.39 50.0 IIIa-26 0.39 1.56 0.39 0.39 0.78 50.0 IIIa-41 0.39 0.39 0.39 0.39 6.25 1.56 IIIa-46 0.39 0.78 1.56 1.56 0.39 50.0 Illb- 11 0.39 6.25 0.39 0.39 0.39 0.78 IIIb-16 0.39 0.39 0.39 0.39 0.39 50.0 lllb-31 0.78 0.39 1.56 1.56 1.56 6.25 IIIb-41 1.56 0.39 0.39 0.39 0.39 0.78 IIIb-56 0.39 0.78 0.39 0.39 0.78 6.25 IIIc-01 0.39 3.13 3.13 3.13 0.39 6.25 IIIc-26 0.39 0.39 1.56 1.56 0.39 12.5 IIIc-46 0.78 0.39 1.56 1.56 1.56 IIIc-56 0.39 0.39 0.39 0.39 0.78 IIId-11 0.39 0.78 1.56 1.56 6.25 IIId-41 0.39 6.25 0.78 0.39 6.25 IIId-46 0.78 1.56 19 0.19 0.78 0.78 IIId-56 0.39 0.39 25 6.25 0.39 12.5 IVA-01 0.39 0.78 ' .56 0 " 1.56

 74

Replacement page (Article 26) 1VA-19 0.39 6.25 0.39 0.39 1.56 50.0

1VA-51 1.56 0.39 0.78 0.78 0.39 0.78

IVB-17 0.39 0.39 6.25 6.25 0.39 12.5

IVB-34 0.39 0.39 0.39 0.39 1.56 1.56

IVB-45 0.78 0.39 0.39 0.39 0.39 50.0

IVC-02 6.25 0.39 0.78 0.78 0.39 50.0

IVC-34 1.56 0.78 6.25 6.25 3.13 1.56

IVC-51 6.25 0.10 0.39 0.39 6.25 50.0

IVD-01 0.39 0.78 0.39 0.39 0.39 1.56

IVD-30 0.39 0.78 1.56 1.56 0.39 50.0

1VD-51 0.39 1.56 0.39 0.39 0.39 0.78

IVa-01 0.39 0.39 0.39 0.39 0.39 12.5 lVa-18 0.39 0.39 0.78 0.78 0.39 1.56 lVa-45 0.78 0.38 6.25 6.25 0.78 50.0

IVb-01 1.56 0.39 1.56 1.56 0.10 50.0

IVb-19 0.39 1.56 6.25 6.25 0.78 1.56

IVb-45 0.39 1.56 0.39 0.39 0.78 50.0

IVc-17 0.39 1.56 0.39 0.39 1.56 0.78 lVc-34 0.78 0.39 0.39 0.39 0.39 50.0

IVc-45 0.39 0.39 0.39 0.39 0.78 0.78

IVd-01 1.56 1.56 0.78 0.78 6.25 50.0

IVd- 19 0.39 0.39 0.78 0.78 1.56 6.25

IVd-51 0.19 0.10 0.39 0.39 0.78 0.19 Ampicillin sodium salt 3.13 25.0 6.25 >100.0 12.5 25.0 Note: Bacillus cereus ^id//z« cem«; BS: Bacillus subtilis β« '//ι« «/ / _; SA Staphyloccocus aureus; MRS A: Methicillin-resistant methicillin-resistant Staphylococcus aureus

而对照药剂氨苄青霉素钠盐对该供试菌的最小抑制浓度为 3.13 g-mL-¹; 本申请提供的通式 （I)化合物对枯草芽孢杆菌的最小抑制浓度范围为 0.10 g'mL -¹〜 12.5 g-mL ，其中活性最高的是 IC-01 , IID-26，IIb-05，IVC-51和 Ivd-51 , 其最小抑制浓度均为 0.10

而对照药剂氨苄青霉素钠盐对该供试菌的最小抑 制浓度为 Ζδ.Ο μ^ιηΐ;¹; 本申请提供的通式（I)化合物对金黄色葡萄球菌的最小抑制 浓度范围为 O.lO g'mL—LU.S g'mL'¹, 其中活性最高的是 IC-01， IIb-16和 ΠΙΒ-26， 其最小抑制浓度均为 0.10 μ_§·ηιΓ¹, 而对照药剂氨苄青霉素钠盐对该供试菌的最小抑 制浓度为 ό^δ μ η ΐ;¹; 本申请提供的通式（I)化合物对大肠杆菌的最小抑制浓度范 Staphylococcus aureus-, .C: Escherichia colh / : Pseudomonas aeruginosa As can be seen from Table 5, the minimum inhibitory concentration of the compound of formula (I) provided by the present application against Bacillus cereus ranges from 0.10 g' mL_ ^l ~12.5 μ^ιηυ ¹ , the highest activity is IC-01 and IID-18, the minimum inhibitory concentration is 0.10

The minimum inhibitory concentration of the control agent ampicillin sodium salt on the test bacteria is 3.13 g-mL- ¹ ; the minimum inhibitory concentration of the compound of the formula (I) provided by the present application against Bacillus subtilis is 0.10 g'mL ^-1 ~ 12.5 g-mL, the highest activity is IC-01, IID-26, IIb-05, IVC-51 and Ivd-51, the minimum inhibitory concentration is 0.10

The minimum inhibitory concentration of the control agent ampicillin sodium salt to the test bacteria is Ζδ.Ο μ^ιηΐ; ¹ ; The minimum inhibitory concentration of the compound of the formula (I) provided by the present application against Staphylococcus aureus is O.lO g'mL-LU.S g'mL' ¹ , the highest activity is IC-01, IIb-16 and ΠΙΒ-26, the minimum inhibitory concentration is 0.10 μ _§ · ηιΓ ¹ , and the control agent ampicillin sodium salt The minimum inhibitory concentration of the test bacteria is ό^δ μ η ΐ; ¹ ; the minimum inhibitory concentration of the compound of the general formula (I) provided herein for Escherichia coli

75

而对照药剂氨苄青霉素钠盐对该供试菌的最小抑制浓度 为 SS.O g-ml/ 此外， 本申请提供的通式（I)化合物对耐甲氧西林金黄色葡萄球菌 ( MRSA ) 也表现出强烈的抑菌活性， 其最小抑制浓度范围为 0.10 μ_§·ηιΙ ¹〜 12.5 Hg-mL-¹ , 而对照药剂氨苄青霉素钠盐对该供试菌的最小抑制浓度为> 100

所有供试化合物对敏感金黄色葡萄球菌和 MRSA的活性完全一致， 说明该类化合物 与 β-内酰胺类抗生素之间不存在交互抗性。 MRSA作为遍及全球的重要病原菌之一， 已对大多数 β-内酰胺类抗生素产生了耐药性，而其对本申请提供的化合物则仍然表现 敏感， 这一特点使其非常适合于治疗耐药性细菌感染引起的疾病。 Replacement page (Article 26) The circumference is O.lO g-mL'Lu.S g'mi ¹ , and the highest activity is IIB-16, IId-05, IId-12 and IVb-01, the minimum inhibitory concentration is 0.10 ^g mU ¹ , The minimum inhibitory concentration of the control agent ampicillin sodium salt for the test bacteria is ^μ^πιΙ ¹ ; the minimum inhibitory concentration of the compound of the formula (I) provided by the present application against Pseudomonas aeruginosa is O.lQ g'ml ^ OO g'mL' ¹ , the highest activity is Ia-20, IIb-31 and IVd-51, the minimum inhibitory concentration is 0.19

The minimum inhibitory concentration of the control agent ampicillin sodium salt on the test bacteria is SS.O g-ml/ In addition, the compound of the formula (I) provided by the present application also exhibits methicillin-resistant Staphylococcus aureus (MRSA). Strong inhibitory activity, the minimum inhibitory concentration range is 0.10 μ _§ · ηιΙ ¹ ~ 12.5 Hg-mL- ¹ , while the control agent ampicillin sodium salt has a minimum inhibitory concentration of > 100 for the test bacteria.

All test compounds were completely consistent with the activity of sensitive S. aureus and MRSA, indicating that there was no cross-resistance between the compounds and the β-lactam antibiotics. As one of the most important pathogens throughout the world, MRSA has developed resistance to most β-lactam antibiotics, and it is still sensitive to the compounds provided by this application, which makes it very suitable for the treatment of drug resistance. A disease caused by a bacterial infection.

 The compounds of the general formula (I) provided herein also exhibit strong antibacterial activity against Gram-negative bacteria such as Escherichia coli, and most of the compounds also exhibit strong antibacterial activity against Pseudomonas aeruginosa.

 Thus, the compound of the formula (I) provided by the present application has a broad antibacterial spectrum, and the antibacterial activity against Gram-positive bacteria is particularly prominent. Example 2 Determination of antifungal activity of compounds against skin fungi

The minimum inhibitory concentration of the compound of the formula (I) provided by the present invention is determined by an in-vehicle drug-based method (drug dilution method), and the specific steps are as follows: The activated test bacteria are picked from the culture plate by the inoculating loop, and the activated test bacteria are used. The concentration of the bacterial suspension was adjusted to 1.0 X 10 ⁶ CFU/mL with sterile physiological saline. 2 mg of the test agent was dissolved in 1 mL of dimethyl sulfoxide (DMSO), and then diluted to a series concentration gradient with deionized water, and placed in a refrigerator for storage. Prepare drug-free Sabouraud medium and olive oil medium (containing glucose, agar, peptone, yeast extract, glyceryl monostearate, Tween, olive oil, etc.), and add different when cooling to 40~50Ό The concentration of the solution is mixed and made into a bevel, and the final volume of each tube is 3 mL. 2 μί of the above prepared bacterial suspension was inoculated separately in different concentrations of Sabouraud's medium containing different drugs (Trichophyton rubrum, Microsporum canis and Candida albicans) and olive oil medium (M. marxian) in vitro. Trichophyton rubrum and M. canis were cultured at 28 °C for 10-15 days. The results were observed after cultured for 48 hours. The results were observed after cultured at 36~37'C for 7~10 days. In the above test, the culture medium was inoculated with the bacterial suspension but no drug was used as the positive control, and the drug-free medium (pure culture)

76

Replacement page (Article 26) Nutrient) as a negative control. The minimum concentration in the test tube without fungal growth is the minimum inhibitory concentration based on the unfiltered blank control tube. Each treatment was repeated 3 times, taking the middle value as a valid value. The test results are shown in Table 6. Table 6 Minimum inhibitory concentration of test compound on four dermatophytes

Minimum inhibitory concentration (μ ιηΐ ¹ )

 Test compound

 Trichophyton rubrum Candida albicans Candida albicans Malassezia

IA-01 7.8 15.6 15.6 7.8

IA-40 15.6 15.6 15.6 7.8

IA-50 7.8 7.8 15.6 15.6

IA-89 3.9 15.6 15.6 15.6

1B-01 31.3 31.3 15.6 15.6

IB-20 62.5 31.3 31.3 31.3

1B-35 62.5 62.5 62.5 31.3

IC-20 62.5 125 62.5 62.5

IC-40 125 125 125 125

IC-60 31.3 62.5 62.5 31.3

 31.3 62.5 62.5 31.3

ID-35 62.5 125 125 31.3

ID-40 125 62.5 31.3 31.3

Ia-01 125 62.5 31.3 62.5

Ia-20 62.5 125 62.5 125

Ia-167 15.6 31.3 31.3 125

Ib-18 15.6 31.3 31.3 62.5

Ib-40 31.3 62.5 62.5 62.5

Ib-79 7.8 7.8 7.8 15.6

Ic-01 15.6 15.6 15.6 7.8

Ic-35 31.3 7.8 15.6 15.6

Ic-79 31.3 3.9 15.6 31.3

Id-10 62.5 31.3 31.3 31.3

Id-20 125 62.5 31.3 62.5

Id-40 125 62.5 62.5 125

IIA-01 15.6 7.8 15.6 15.6

IIA-10 15.6 15.6 15.6 15.6

1IA-20 15.6 7.8 7.8 31.3

IIB-05 31.3 3.9 15.6 7.8

IIB-16 62.5 125 31.3 125

IIB-26 62.5 . 62.5 31.3 125

IIC-01 125 62.5 62.5 62.5

IIC- 12 62.5 62.5 125 62.5

IIC-20 62.5 125 125 125

IID-10 125 62.5 62.5 62.5

IID-18 31.3 62.5 62.5 125

IID-26 62.5 62.5 62.5 125

77

Replacement page (Article 26) .

 ST9 9'St 9"SI 10-ΙΛΙ

6'ε ε·ιε 9'Sl S'Z9

 Ε'ιε 9'Sl πε

 8X 9'St 9'Sl 6·ε οε-αΛΐ

9"St %'L "Si %-L ιο-αΜ ί'Ιί 8'Ζ. 9'Sl ΓΙ£ IS-DA1

9'Si ζ'Ζ9 8'£ £Ί£

 8'£ ε·ιε 6'ε

 9"Sl ε*ιε 8'B

 9"Sl 6I-VAI

9'Sl rie 9'Sl ΙΟ-ΥΛΙ

2'L πε ε·ιε 9'Z9 9^-ΡΙΙΙ

S'Z9 9·ςι £'U ί ΡΙΙΙ 9 £ 9'Sl ε·ιε ΙΙ-ΡΠΙ

8 £8' 9ε- ι ςτ9 9· SI ψζϊ ιο-3⁄4ιι ε'ίε ψζ\ 6·ε 9'ζΙ i^-qiii ε·ιε 9'ξΙ ϊε-qni ζΖΙ 9'Sl ς 9 9ΐ -qui

 Ε'ιε 8·ί ςχ9 ιο-ειιι ε'ιε £-\ί 8·ί Cl£ ιε-αιπ

9'Sl ψςι 9'Sl 6 ε 91-αιπ

9'Sl 9·ς\ 9'?l XL ιο-αιπ

9'Sl 9"Si 9'Sl ιε-οπι

 9·ςι S'L 8'£ ιι-απι ε'ΐε 6'ε 9'Sl Γ1£ 10-DIII

 9"St Π£9S-H1II

9'Sl 9Si 9"Sl 9'51 Π-9ΗΙ

9'SI 8' . 8'8'L π-νιιι

ε [ 9'Sl 9SI ιε-ριι ς'Ζ9 πε 9'Sl -ΡΙΙ ε'ΐε 9'£1 ειε 8'厶ΟΖ-3ΙΙ

SZl S'Z9 %-L ££ 10-311

ζ'Ζ9 SZX %'L ζ·Ζ9 9i-qn ξΖΙ S'Z9 ξ'Ζ9 Γΐ£ so-qn

ST9 £-\£ ε·ιε Π£ Qi- ςτ9 £·\£ ί'ΙΖ SZI 01 -«n

SZI ιο- CZ180/110ZN3/X3d 17866S0/C10Z OAV IVc-34 15.6 15.6 3.9 IVd-19 15.6 15.6 15.6 IVd-51 15.6 It can be seen from the results in Table 6 that the compounds of the general formula (I) have inhibitory effects on four skin-borne fungi, and the minimum inhibitory concentration range Both are between S g'mL^US g'ml/ ¹ , but there is a significant difference in activity between different compounds. Among the test compounds, IVD-30, IIID-16 and IA-89 had the highest activity against Trichophyton rubrum, and the minimum inhibitory concentration was 3.9μ^πι. Ic-79, IIB-05, IIc-12 in the test compound. IIIa-11, IIIb-41, IVB-45 and IVc 9 had the highest activity against Candida albicans, and the minimum inhibitory concentration ranged from S g.mL/ ¹ ; ΙΠΑ-01 and IIIC-01 to canine microspores in the test compounds The activity of the bacteria was the highest, and the minimum inhibitory concentration range was .9\ig-m - ^l x. The tested compounds had the highest activity against M. maltophilia, and the minimum concentration range was 3.9. μ · πιΐΛ

Example 3 Determination of spore germination activity of compounds against phytopathogenic fungi

 The in vitro antibacterial activity of some of the compounds provided by the present invention is determined by the method of inhibiting spore germination, and the specific procedures are as follows. The spores of the test pathogen were prepared into a spore suspension of appropriate concentration, and 80 to 100 spores per field of view under a 10 X 10 low 僙 mirror. Weigh 2 mg of the test drug dissolved in 1 mL of dimethyl sulfoxide (DMSP), dilute it to a series concentration gradient with deionized water, and mix it with the spore suspension, take a drop and add | έ concave slide, each treatment 3 Repeat. The germination of the control spores was examined by moisturizing at 25 6 for 6 h. When the germination rate of the control reached 85%, the germination rate of all treatments was checked. The germination of the spore bud tube length is greater than the short radius of the spore. Another carbendazim was used as a positive control, and no drug treatment was used as a blank control. The inhibition of spore germination rate is calculated as follows:

Xianyouyi,. Eight control spore germination rate - treatment spore germination rate _{1 ΛΛ} inhibition spore germination rate (%) = control spore germination rate ^{χ 10} ° The logarithm of the test drug mass concentration is the independent variable (x), the probability of inhibition rate For the dependent variable (y), the virulence regression equation of the test agent was determined by the least squares method, and the inhibitory concentration (EC ₅₍₎ ) was calculated. The EC _5Q values of the test compounds are shown in Table 7.

 Test compound inhibits spore germination activity of phytopathogenic fungi

^{3⁄4 ?}

Inhibition of medium concentration (EC ₅₀ , g/mL )

 Test compound

 B cinerea P cubensis E graminis G cing lata F oxysporiwn P infestans

IA-40 17.2 10.6 19.5 28.6 8.7 24.5

IA-50 43.5 28.4 72.0 60.4 58.3 72.6

79

Replacement page (Article 26) 1B-01 68.0 44.1 88.6 98.5 77.5 81.8

IB-20 】 6.4 18.5 11.8 20.6 16.7 32.0

IC-40 19.6 15.8 18.0 25.2 10.6 20.8

IC-60 48.8 31.0 67.8 65.8 54.7 78.6

BD-01 65.8 48.6 80.5 87.8 82.4 76.2

ID-35 12.9 23.7 9.2 18.0 19.8 28.1

Ia-01 55.6 43.2 78.4 65.6 55.8 60.5

Ia-20 40.3 18.5 22.7 39.8 41.6 23.5 lb- 18 11.3 25.6 35.0 44.7 22.0 15.7

Ib-40 12.5 10.4 9.7 11.8 25.9 17.5

Ic-01 25.9 45.8 44.8 68.9 11.5 27.3

Ic-35 45.5 44.2 12.3 11.2 54.0 62.3

Id-20 24.5 29.4 23.7 10.5 25.4 12.9

Id-40 25.2 16.4 43.2 28.7 65.6 55.7

IIA-01 65.8 19.6 18.5 44.4 87.8 40.5

IIA-10 87.2 48.4 25.6 18.0 18.8 11.7

IIB-05 18.1 65.2 10.4 15.9 65.7 12.2

IIB-16 65.9 .12.7 45.8 31.7 39.3 25.4

IIC-01 39.0 55.5 44.1 48.4 44.7 45.5

IIC-12 44.9 40.2 18.5 18.5 10.6 24.5

IID-10 21.4 10.6 15.8 25.6 28.4 28.0

11D-18 9.5 24.7 31.0 10.4 24.1 17.8

IIa-01 52.0 72.4 48.6 25.8 38.5 60.5

IIa-10 28.6 19.8 23.7 44.2 25.8 19.2

IIb-05 11.8 35.8 23.2 29.4 31.0 18.4 lib- 16 18.0 41.6 18.5 16.4 48.6 22.7

IIc-01 67.8 52.0 85.6 79.6 63.7 55.0

IIc-12 10.5 25.9 10.4 18.4 43.2 9.7

Ild-12 9.2 Π.5 25.8 1S.2 18.5 44.8

IId-31 7S.4 54.0 44.2 52.7 25.6 82.3

IIIA-01 22.7 25.4 29.4 18.5 10.4 23.7 lIlA-11 35.0 45.6 16.4 25.6 45.8 43.2

IIIB-11 9.7 7.8 10.6 10.4 10.6 18.5

IIIB-26 44.8 38.8 54.7 45.8 28.4 25.6

IHC-01 24.5 28.5 10.5 17.5 11.7 18.7

IIIC-11 72.6 60.4 48.3 43.4 18.2 58.4

IIID-01 81.8 98.5 44.1 68.0 67.8 77,5

HID- 16 32.0 20.6 18.5 16.4 20.7 16.7

IIIa-01 20.8 25.2 15.8 19.6 19.2 30.6

IIIb-41 78.4 65.2 31.7 48.5 78.1 54.0

IIIc-01 76.0 87.4 48.5 65.7 22.0 82.1

HIc-26 28.0 18.1 23.2 12.7 35.0 19.2 llld-l l 60.5 65.6 43.2 55.6 69.7 55.8

IIId-41 23.5 39.8 18.5 40.3 44.8 41.6

80

Replacement page (Article 26) IVA-01 15.7 14.7 25.6 11.3 12.3 22.0

IVA-19 17.5 11.8 10.4 12.5 23.7 25.9

IVB-34 27.3 68.9 45.8 25.9 43.2 41.5

IVB-45 32.3 41.2 44.2 45.5 58.5 54.0

IVC-34 12.9 10.5 29.4 18.5 25.6 25.4

IVC-51 24.0 31.4 19.4 20.4 17.4 21.5

IVD-01 12.4 19.5 26.4 18.5 25.8 24.0

IVD-30 19.8 22.0 20.6 20.6 24.2 25.4

IVa-01 35.8 28.6 34.7 25.2 29.4 35.6

IVa-18 41.6 11.8 10.5 65.2 16.4 27.8

IVb-01 52.0 48.7 68.3 87.7 79.0 38.5

IVb-19 25.9 67.8 44.1 38.1 58.4 28.5

IVc-17 11.5 10.5 18.5 15.6 15.2 10.4

IVc-34 54.0 59.2 75.8 39.8 52.7 98.5

IVd-19 25.4 28.4 31.7 14.7 18.5 20.6

IVd-51 45.6 22.7 48.5 11.8 25.6 25.2 Carbendazim One-one. One-one note: "One" means that no significant inhibition was observed. As can be seen from Table 7, the control agent carbendazim did not show significant inhibition of spore germination at the test concentration, but the test agents showed different degrees of bacteriostatic activity. The inhibitory concentration of the test compound against Botrytis cinerea was between 9.2 g/mL and 87. 2 g/mL, and the inhibitory concentrations of the compounds IID-18, IId-12 and ΙΠΒ-11 were 9.5 g, respectively. /mL, 9^g/mL and 9^g/mL; the concentration of the test compound against Cucumber downy mildew (cw^ra^) is between 7.8 g/mL and 98. 5 g/mL, of which compound The inhibitory concentrations of IIIB-11, Ib-40 and IVc-17 were 7.8 g/mL, 10.4 ng/mL and 10.5 _g /mL, respectively _{; the} concentration of test compounds against wheat powdery mildew (£gmminis) was 9.2 g. /mL~88. 6 g/mL, wherein the inhibitory concentrations of the compound ID-35 and Ib-40 were 9.2 g/mL and 9.7 g/mL, respectively; the test compound inhibited the apple anthracnose (G cingulata) The medium concentration ranged from 10.4 g/mL to 98. 5 g/mL, wherein the inhibitory concentrations of the compounds IID-18 and ΠΙΒ-11 were both 10.4 g/mL _; the test compound against Fusarium oxysporum f. The inhibitory concentration ranged from 8.7 g/mL to 88.7 g/mL, wherein the inhibitory concentrations of compounds IA-40 and IIIA-01 were 8.7 g/mL and 10.4 g/mL, respectively _; Phytophthora infestans (Pinfest painting, inhibition of medium thick Between 9.7 g / mL~98. 5 g / mL, wherein the inhibiting compound and IIc-12 IVc-17 in concentrations of 9.7 g / mL and 10.4 g / mL.

Example 4 Determination of the activity of compounds against phytopathogenic fungi inhibiting mycelial growth

81

Replacement page (Article 26) The in vitro antibacterial activity of some of the compounds provided by the present invention is determined by the inhibition mycel growth rate method, and the specific procedure is as follows. Weigh 2 mg of the test drug in 1 mL of dimethyl sulfoxide (DMSO), dilute it to a series of concentration gradients with deionized water, and mix 1 mL of the test solution with 9 mL of melted PDA medium. Heat into a sterile Petri dish to make a plate with a drug medium. After the medium was solidified, one test fungus cake (4 mm in diameter) was placed in the plane of each medium, and the hyphae side was attached to the surface of the medium, and the treatment was repeated three times. After culturing for 72 to 96 hours, the growth diameter of the test colony was measured by the cross method, and the inhibition rate was calculated by the following formula. The results are shown in Table 1.

^ , _n/ , control colony growth diameter - treated colony growth diameter _{1 ΛΛ}

Mycelial growth inhibition rate (% ₎ = control colony growth diameter ^{χ 10} ° The logarithm of the concentration of the test drug is the independent variable (χ), and the probability of the inhibition rate is the dependent variable (y), and the least squares method is used. The virulence regression equation of the test drug was calculated, and the concentration in the inhibition (EC ₅ o) was calculated. The EC _5Q values of the test compounds are shown in Table 8. Test compound inhibits mycelial growth activity against phytopathogenic fungi

Inhibition of medium concentration (EC ₅ o, Hg/mL)

 Test compound

 B cinerea P cubemis E ff-aminis G cingulata F oxysporium P infestam

IA-40 68.5 26.4 17.6 45.2 32.8 16.8

IA-50 75.5 42.8 36.4 47.0 46.8 22.1

IB-01 85.7 64.9 33.6 52.1 44.9 32.0

IB-20 57.〗 32.6 20.1 33.4 39.6 11.8

1C-40 70.3 22.9 20.5 48.0 28.9 22.5

IC-60 62.5 45.8 30.8 52.3 37.6 44.8

ID-01 79.8 56.5 28.8 55.4 38.6 40.2

ID-35 55.6 35.7 25.4 28.9 33.0 17.5

Ia-01 35.8 28.6 34.7 25.2 29.4 35.6 la-20 27.1 30.6 49.5 28.6 38.7 44.7

Ib-18 43.5 28.7 32.0 20.8 38.2 42.6

Ib-40 78.0 64.1 88.0 78.5 77.5 71.8 lc-01 40.4 54.5 45.7 57.1 26.0 22.0

Ic-35 55.6 58.8 48.7 24.2 20.6 40.8

Id-20 68.7 51.0 67.8 65.5 54.4 78.3

Id-40 65.4 58.6 70.5 77.8 92.4 56.8

IIA-01 22.9 28.7 】9.2 28.0 9.8 28.8

IIA-10 65.6 33.2 58.4 35.8 25.8 40.7

IIB-05 47.3 58.5 32.7 59.8 31.6 33.5

IIB-16 49.3 75.6 45.0 64.8 42.0 75.7

82

Replacement page (Article 26) IIC-01 22.5 30.7 19.8 21.5 25.5 37.5

I1C-12 25.9 45.8 44.8 68.9 61.5 27.3

IID-10 45,5 44.2 52.3 71.2 64.0 62.3

I1D-18 24.5 39.4 53.7 80.5 35.4 52.9

IIa-01 55.2 46.4 43.2 78.7 65.6 55.7

IIa-10 65.8 39.6 28.5 44.4 87.8 40.5

IIb-05 57.2 48.4 25.6 18.0 18.8 61.7

IIb-16 38.1 65.2 50.4 25.9 65.7 52.2

IIc-01 65.9 32.7 45.8 31.7 39.3 25.4 lie- 12 39.8 55.0 44.5 48.4 44.7 45.5

IId-12 44.9 40.2 18.5 18.5 10.6 24.5

Hd-3] 61.4 70.6 55.8 25.6 28.4 28.0

IIIA-01 69.5 84.7 61.0 80.4 54.1 97.8

IIIA-11 52.0 72.4 48.6 25.8 38.5 60.5

IIIB-11 28.6 79.8 23.7 44.2 25.8 49.2

IIIB-26 51.8 35.8 23.2 29.4 31.0 28.4

IIIC-01 38.0 41.6 28.5 26.4 48.6 42.7

IIIC-11 67.8 52.0 85.6 79.6 63.7 55.0

IIID-01 50.5 25.9 70.4 58.4 43.2 59.7

HID- 16 69.2 51.5 25.8 85.2 98.5 44.8

IIIa-01 78.4 54.0 44.2 52.7 25.6 82.3

IIIb-41 52.7 55.4 29.4 78.5 60.4 93.7

IIIc-01 35.0 45.6 46.4 25.6 45.8 43.2

IIIc-26 59.7 77.8 100.6 90.4 30.6 88.5

IIId-11 44.8 38.8 54.7 45.8 78.4 85.6

IIId-41 54.5 28.5 110.5 107.5 71.7 88.7

IVA-01 72.6 60.4 48.3 43.4 18.2 58.4

IVA-19 81.8 98.5 44.1 68.0 67.8 77.5

IVB-34 32.0 20.6 88.5 77.4 50.7 66.7

IVB-45 80.8 25.2 35.8 49.6 59.2 90.6

IVC-34 78.4 65.2 31.7 48.5 78.1 54.0

IVC-51 76.0 87.4 48.5 65.7 82.0 82.1

IVD-01 28.0 58.1 83.2 72.7 95.0 79.2

IVD-30 60.S 65.6 43.2 55.6 69.7 55.8

IVa-01 63.5 39.8 78.5 40.3 44.8 41.6

IVa-18 45.7 34.7 25.6 31.3 72.3 22.0

IVb-01 27.5 51.8 80.4 72.5 43.7 85.9

IVb-19 77.3 68.9 45.8 25.9 43.2 41.5

IVc-17 52.3 41.2 44.2 45.5 58.5 54.0

IVc-34 62.9 50.5 79.4 58.5 45.6 85.4

IVd-]9 34.0 71.4 89.4 50.4 47.4 91.5

IVd-51 52.4 49.5 56.4 78.5 75.8 94.0 Carbendazim 18.7 15.6 1.2 6.8 13.5 0.9

83

Replacement page (Article 26) As can be seen from Table 8, the test agents showed different degrees of antibacterial activity against the six test bacteria. The concentration of the test compound against Botrytis cinerea iB ci rea was between 22.5 g/mL and 85.7 g/mL, and the inhibitory concentrations of compounds IIA-01 and IIC-01 were 22.9 g/mL and 22.5 g, respectively. /mL, the inhibitory concentration of the control drug carbendazim was 18.7 g / mL; the concentration of the test compound against the cucumber downy mildew P cub sis was between 20.6 g / mL ~ 98.5 g / mL, of which compound IVB- The inhibitory concentrations of 34 and 1C-40 were 20.6 g/mL and 22.9 gmL, respectively, and the inhibitory concentration of the control drug carbendazim was 15.6 g/mL. The inhibitory concentration of the test compound against wheat powdery mildew £gmminis was 17.6 g. Between /mL~110.5 g/mL, the inhibitory concentrations of compounds IA-40 and IId-12 were 17.6 g/mL and 18.5 g/mL, respectively, and the concentration of the control drug carbendazim was 1.2 g/mL _. The concentration of the test compound against the apple anthracnose G cingu ta was between 18.0 g/mL and 107. ^glm, and the inhibitory concentrations of the compounds IIb-05 and IId-12 were 18. (g/mL and 18.5, respectively). g/mL, the inhibitory concentration of the control drug carbendazim was 6.8 g/mL _{; the} concentration of the test compound against Foxysporium was 9.2. Between g/mL and 98.5 g/mL, the inhibitory concentrations of compounds IIA-01 and Ild-12 were 9.8 g/mL and 10.6 g/mL, respectively, and the concentration of the control drug carbendazim was 13.5 g/mL. _The concentration of the test compound against P. falciparum P infest was between 11.8 g/mL and 97.8 g/mL, and the inhibitory concentrations of the compounds IB-20 and IA-40 were 11.8 g/mL, respectively. 16.8 g/mL, the inhibitory concentration of the control drug carbendazim was 0.9 g/mL.

 Example 5 Determination of the interaction resistance between a compound and a benzimidazole fungicide

 Using ΠΙΑ-56 as the test agent, sensitive strain and anti-polysaccharide strain of wheat genus iFile iwn gramineurum) as the test pathogen, the same inhibitory mycelial growth rate method as in Example 4 was used to determine the test agent and Whether carbendazim has cross-resistance. The specific results are shown in Table 9.

 Table 9 Antibacterial activity of test agents against two wheat scab

 ^ Inhibition of medium concentration (g/mL)

 Fusarium graminearum (sensitive strain) Fusarium graminearum (resistant strain) - IIIA-56 9^83 8?75

 Carbendazim ^67 8^ It can be seen from Table 9 that the inhibitory concentrations of carbendazim against the susceptible and resistant strains of Fusarium graminearum are 0.67 g/mL and 8.12 g/mL, respectively, ie the resistance multiple is 12.1 times, and the inhibitory concentrations of IIIA-56 against two strains of Fusarium graminearum were 9.83 g/mL and 8.75 g/mL, respectively. There was no significant difference between the two, indicating that there was no interaction between the test agent and carbendazim. Resistance.

84

Replacement page (Article 26) Example 6 50% IIIA-56 wettable powder for controlling field mold of tomato gray mold. Refer to "GB/T 17980.28-2000 pesticide field efficacy test guidelines (1) bactericide to control tomato gray mold disease", provide this hairpin The 50% ΠΙΑ-56 wettable powder (hereinafter referred to as "testing agent") was tested for the field efficacy of tomato gray mold.

The experiment was carried out in Zhangjiagang Village, Yangling District, Shaanxi Province. The soil type was sandy loam soil, medium fertility, and irrigated land. The test crop was tomato and the variety was Shanghai 908. The cultivation method is ridge planting, the plant spacing is 40emX 50cni, and the planting time is June 25, 2011. The first application was carried out during the initial stage of the gray stage of the tomato (July 20), and the second application was carried out during the expansion period (July 28). The test was set up with test reagents 800 times, 1000 times and 1200 times three concentrations, 40% pyrimethanil suspension 1200 times and clear water control 5 treatments, the area of the plot was 45m ² , 3 repetitions, random block arrangement, spray per plot The amount of liquid is 3.5Kg. The control effects were investigated 7 days after the first drug, 7 days after the second drug, and 14 days after the second drug. The results are shown in Table 10.

 Field test results of test chemicals against tomato gray mold

 Pre-medication 1st post-medication 7d 2nd post-medication 7d 2nd post-medicine 14d treatment

 Emotion Index Control Effect (%) Control Effect (%) Control Effect (%)

800 times 7.6 72.5 89.5 83.6 Test agent 1000 times 7.8 68.6 88.2 82.1

 1200 times 7.8 64.0 81.6 76.9

40% pyrimethanil suspension 1200 times 7.6 65.8 79.5 75.2

 The results of Table 10 of Qingshui Control 7.4 1-11 indicate that 50% ΠΙΑ-56 wettable powder 1200 times dilution and 40% pyrimethanil suspension 1200 times dilution have the same control effect, which can effectively control the damage of tomato gray mold . The methacryloylbenzimidazole (thio)ketone derivatives of the present invention and their use as antibacterial agents have been described by way of specific examples, and those skilled in the art can refer to the contents of the present invention to appropriately change the raw materials, process conditions and the like. Other suitable alternatives and modifications will be apparent to those skilled in the art, and are intended to be included within the scope of the present invention.

85

 Replacement page (Article 26)

Claims

A methacryloylbenzimidazole (thio)ketone compound having a structure represented by the following formula (I),

 In the formula (I), R stands for: Hydrogen; C C s ; ;; or optionally substituted by cyano, halogen, benzene ring, ~ ΰ ₄ alkoxy or d~C ₄ thiol-substituted alkyl, C ₃ ～ C ₈ alkenyl or C ₃ ~C ₈ alkynyl; or optionally substituted by cyano, halo, ~ C ₄ alkoxy or embankment embankment d ~ C ₄ alkylthio c ₃ ~c _{8-substituted} alkenyl or alkynyl group c ₃ ~c ₈ a phenyl group or a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of halogen, Ci~C ₈ fluorenyl group, C ₃ ～C ₈ cyclodecyl group, hydroxy group, ΰ ₄垸oxy group, halogenated alkane -C ₄ halodecyloxy, haloalkylthio, -C ₄ halosulfonylsulfonyl, carboxy, nitro, cyano, phenyl, phenoxy, benzoyl;  Y stands for: Hydrogen; or 1 to 4 substituents selected from the group consisting of: 素, nitro, ～C ₈ fluorenyl, C ₃ ～C ₈ cycloalkyl, halo fluorenyl;  Wherein, when Y represents hydrogen, R is not isopropenyl;  Or Y stands for: -C-Z! Wherein, represents: hydroxy, 〜 alkoxy, c ₃ ～ c ₈ alkenyloxy or c ₃ ～ c ₈ alkynyloxy, amino, or an amine substituted by 1 or 2 to C ₈ alkyl;  Or Y stands for: One o (s wide z ₂ Wherein Z ₂ represents: hydrogen, ~. 4 fluorenyl, C ₃ -C ₈ alkenyl or C ₃ -C ₈ alkynyl, ~ haloalkyl, Ci fatty acyl, Ci~C ₈ halo fatty acyl, carbamoyl, N-methylaminoformyl , N-ethylaminocarbonyl, hydrazine, hydrazine-dimethylamino decanoyl, hydrazine, hydrazine-diethylaminoformyl, phenyl, benzoyl, 86 Replacement page (Article 26) Phenylacetyl, phenylsulfonyl or phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of benzoyl or benzenesulfonyl: halogen, ～3⁄4 alkyl, C ₃ ～C ₈ cyclodecyl, Hydroxyl, ~. ₄ alkoxy, ~C ₄ haloalkyl, C C4 haloalkoxy, Q~C ₄ haloalkylthio, ~. _4- haloalkylsulfonyl, carboxy, nitro, cyano; Or Y stands for:

Wherein, Z ₃ represents hydrogen, hydrazino, C ₃ -C ₈ cyclodecyl, C ₃ -C ₈ alkenyl, ~. ₈ -alkynyl, ~haloindenyl, ~acyl, or 5- or 6-membered heterocyclic group having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, phenyl, benzoyl, benzene an acetyl group, phenylsulfonyl group or a 1 ~ 3 substituents selected from the group consisting of optionally substituted phenyl group, a benzoyl group or a phenylsulfonyl group: halo, Ci~C ₈ alkyl, - cycloalkyl, hydroxy, C ^Ct 垸oxy, ~C ₄ halogenated fluorenyl, ~. 4 haloalkoxy, C, ~C ₄ halosulfonylthio, ~ halosulfonylsulfonyl, carboxy, nitro, cyano; Z ₄ represents hydrogen, 〜C ₈ alkyl, C ₃ ～C _S naphthenic group, together form a C ₃ ~ ¾ alkenyl, C ₃ ~C ₈ alkynyl group, C ^ alkyl with haloalkyl, or ¾ Z ₄ and the nitrogen atom to which they are attached a 5 ~ 7 membered heterocyclic group, in addition to the nitrogen In addition to the atom, the heterocyclic group may contain one or two or more hetero atoms selected from nitrogen and oxygen;  Or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein, in the formula (I),  R represents: hydrogen, ethyl, n-propyl, isopropyl, propenyl, isopropenyl, 2-cyanoethyl, benzyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl , 2-methoxyethyl, 2-methoxypropyl, 2-methoxyisopropyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-ethoxyisopropyl, phenyl, or苯基 selected from the following: ~ 3 substituents optionally substituted phenyl: fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, hydroxy, methoxy, ethoxy , propoxy, isopropoxy, 2-chloroethyl, 2-chloropropyl, 2-chloroethoxy, 2-chloropropoxy, carboxy, nitro, cyanoguanidine  Y represents: hydrogen, or 1 to 4 substituents selected from the group consisting of: fluorine, chlorine, bromine, nitro, methyl, ethyl, n-propyl, isopropyl, 2-chloroethyl, 2-chloropropane Base, 2-chlorobutyl, 2-bromoethyl, 2-bromopropyl, 2-bromobutyl; wherein, when Y represents hydrogen, R is not isopropenyl;  Or Y stands for: 87 Replacement page (Article 26) O  I I  -c-z,  Wherein, represents: hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, amino, N-methylamino, N-ethylamino, hydrazine, hydrazine-dimethylamine Base, hydrazine, hydrazine-diethylamino group; Or Υ representative - one o (s vast ζ ₂ Wherein Ζ ₂ represents: hydrogen, methyl, ethyl, propyl, isopropyl, 2-chloromethyl, 2-chloroethyl, 2-chloropropyl, formyl, acetyl, phenyl, benzoyl An acyl group, a phenylsulfonyl group, or a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of benzoyl, phenylacetyl or benzenesulfonyl: fluorine, chlorine, bromine, methyl, ethyl, propyl Isopropyl, isopropyl, 2-chloroethyl, 2-chloropropyl, cyclopropene, hydroxy, methoxy, ethoxy, 2-chloroethyl, 2-chloropropyl, 2-chlorobutyl, 2-Bromoethyl, 2-bromopropyl, 2-bromobutyl, chloromethoxy, 2-chloroethoxy, 2-chloropropoxy, bromomethoxy, 2-bromoethoxy, 2 - bromopropyloxy, carboxy, nitro, cyano; Or, Υ stands for:

Wherein Ζ ₃ represents hydrogen, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, propenyl, isopropenyl, propynyl, 2-chloroethyl, 2-chloropropyl, 2- Chlorobutyl, 2-bromoethyl, 2-bromopropyl, 2-bromobutyl, formyl, acetyl, n-propionyl, isopropionyl, phenyl, benzoyl, phenylacetyl, phenylsulfonyl Or a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of benzoyl or phenylsulfonyl: halogen, ^~ fluorenyl, C ₃ -C ₈ cyclodecyl, hydroxy, decyloxy, Ci~C ₄ haloalkyl, ~^haloalkoxy, ~haloalkylthio, ~C ₄ fluorenylsulfonyl, carboxy, nitro, cyano; Z ₄ represents hydrogen, methyl, ethyl, n-propyl Isopropyl, propylene, isopropenyl, propynyl, 2-chloroethyl, 2-chloropropyl, 2-chlorobutyl, 2-bromoethyl, 2-bromopropyl, 2-bromo Butyl, or _3⁄4 and ∑4 together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocyclic group;  Or a pharmaceutically acceptable salt thereof.  The compound according to claim 1, wherein, in the formula (I),  R represents: hydrogen, propenyl, isopropenyl, benzyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-methoxyethyl, 2-methoxypropyl, 2- Methoxyisopropyl, 2-ethoxyethyl, 2-ethoxypropyl, 2-ethoxyisopropyl; 88 Replacement page (Article 26) Y stands for - ο II -cz ₁  Wherein, represents: hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, amino, N-methylamino, N-ethylamino, hydrazine, hydrazine-dimethylamino, hydrazine, hydrazine-diethylamino;  Or Υ represents: -0(S)-Z ₂ Wherein Z ₂ represents: hydrogen, formyl, acetyl, benzoyl, benzenesulfonyl, or a benzoyl group optionally substituted by 1 to 3 substituents selected from the group consisting of phenylacetyl or phenylsulfonyl: Fluorine, chlorine, bromine, hydroxyl, methoxy, ethoxy, nitro, cyano;  Or, Y stands for - ―, Wherein, represents hydrogen, formyl, acetyl, n-propionyl, isopropionyl, benzoyl, phenylacetyl, benzenesulfonyl; z ₄ represents hydrogen, methyl, ethyl, n-propyl, isopropyl, Propylene, isopropenyl, propynyl, 2-chloroethyl, 2-chloropropyl, 2-chlorobutyl, 2-bromoethyl, 2-bromopropyl, 2-bromobutyl, or 3⁄4 and Z ₄ together with the nitrogen atom to which they are attached form a 5 to 7 membered heterocyclic group;  Or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein, in the formula (I),  R represents: hydrogen, propenyl, isopropenyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 2-methoxyethyl, 2-methoxypropyl, 2-methoxyisopropyl Base  Y stands for:  0  II  -C-Z!  Wherein, represents: hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy; or a pharmaceutically acceptable salt thereof. A process for the preparation of a compound according to claim 1, characterized in that the compound of the formula (I) can be produced according to the following synthetic route: 89 Replacement page (Article 26) Synthetic Route 1: When in the methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I), Y is: hydrogen, or 1 to 4 substituents selected from the group consisting of: halogen, ~3⁄4 An alkyl group, a C ₃ -C ₈ cycloalkyl group, a ~C ₄ halogenated fluorenyl group, and other groups as defined in the general formula (I) of claim 1, the present invention can be prepared by the synthetic route shown in the following scheme A methacryloylbenzimidazole (thio)ketone derivative of the formula (I) to be protected:

 The synthesis route is based on a halogen or a fluorenyl group, or a halogenated fluorenyl-substituted o-nitroaniline. First, a halogenation is used as a hydrocarbylating agent, and various hydrocarbon groups or substituted hydrocarbon groups are introduced on the amino nitrogen, and then iron is used. The nitro group is reduced in a powder/hydrochloric acid system to obtain a substituted o-phenylenediamine derivative, which is then refluxed with urea or thiourea in xylene to obtain a benzimidazole (thio) ketone derivative, and finally with methacryloyl chloride. An acylation reaction to obtain a target compound;  Or Synthetic Route 2: In the methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I), Y represents: Representative wherein: hydroxy, ~C ₈ embankment group, a C ₃ ~C ₈ alkylene group or a C ₃ ~C ₈ alkynyl group, an amino group, or substituted with 1 or 2 substituents ^ ~ alkyl with an amine, and the other When the group is as defined in the above formula (I), the methacryl benzimidazole (thio)one derivative represented by the formula (I) to be protected by the present invention can be produced by a synthetic route as shown in the following scheme: 90 Replacement page (Article 26)

 The synthesis route uses a carboxy-substituted o-nitroaniline as a starting material, firstly introducing a halogenated hydrocarbon as a hydrocarbylating agent, introducing various hydrocarbyl groups or substituted hydrocarbyl groups on the amino nitrogen, and then reducing the nitro group in an iron powder/hydrochloric acid system. And refluxing with urea or thiourea in xylene to obtain a benzimidazolone derivative, and then acylation with methacryloyl chloride, and finally the carboxyl group on the benzene ring is esterified with an alcohol to form an ester, or with ammonia ( Amine) reacts to form an amide to obtain the target compound; Or Synthetic Route 3: When in the methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I), Y represents - one o (s wide z ₂ Wherein Z ₂ represents: a hydrogen, ~C ₄ alkyl, C ₃ ~C ₈ alkenyl or C ₃ ~C ₈ alkynyl group, Q~C ₄ alkyl with halo, Ci~C ₈ fatty acyl group, ~C ₈ halogen Fatty acyl group, carbamoyl group, N-methylaminoformyl group, N-ethylaminoformyl group, hydrazine, hydrazine-dimethylaminoformyl group, hydrazine, hydrazine-diethylaminoformyl group, Phenyl, benzoyl, phenylacetyl, phenylsulfonyl or phenyl optionally substituted by 1 to 3 substituents selected from the group consisting of benzoyl or benzenesulfonyl: halogen, 〜3⁄4 fluorenyl, C ₃ ~C ₈ cycloalkyl, hydroxy, ~ decyloxy, ~C ₄ halodecyl, ~C4 halodecyloxy, ^~. ₄ halosulfonylthio, ~ haloalkylsulfonyl, carboxy, nitro, cyano, and other groups as defined by the above formula (I), can be prepared by the following synthetic route as shown in the following figure Methacryloylbenzimidazole (thio)ketone derivative represented by the general formula (I) - 91 Replacement page (Article 26)

 The synthesis route uses nitroamino-substituted phenol as a starting material, wherein the substitution positions of the nitro group and the amino group are indefinite, but the two must be ortho-position. First, a halogenated hydrocarbon is used as a hydrocarbylating agent, and various hydrocarbon groups are introduced on the amino nitrogen. Or substituted hydrocarbyl group, followed by hydroxyacetylation protection, nitro reduction, cyclization to obtain benzimidazolone derivatives, acylation with methacryloyl chloride, deprotection of hydroxyl groups, and finally hydrocarbylation by hydrocarbon generation Introducing a hydrocarbon group, or introducing an acyl group by esterification reaction with an acid chloride, to obtain a target compound; Or Synthetic Route 4: In the methacryloylbenzimidazole (thio)ketone derivative represented by the formula (I), Y represents -

Wherein 3⁄4 represents hydrogen, ~C ₈ fluorenyl, C ₃ -C ₈ cyclodecyl, C ₃ -C ₈ alkenyl, C ₃ -C ₈ alkynyl, ^~3⁄4 halogenated fluorenyl, Ci~C ₈ An acyl group, or a 5- or 6-membered heterocyclic group having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur, phenyl, benzoyl, phenylacetyl, benzenesulfonyl or selected from the group consisting of 1 to 3 substituents optionally substituted phenyl, benzoyl or benzenesulfonyl: halogen, ~ fluorenyl, C ₃ -C ₈ cyclodecyl, hydroxy, Ci~C4 decyloxy, ~halofluorenyl , ~. ₄ halodecyloxy, ~ halogenated sulfonylthio,. ! ~ Haloalkylsulfonyl group, a carboxyl group, a nitro group, a cyano group; Ζ ₄ represents hydrogen, C] ~C ₈ embankment group, C ₃ ~ C ₈ cycloalkyl group embankment, C _{~. 3}  92 Replacement page (Article 26) C ₈ alkenyl, c ₃ ~ c ₈ alkynyl, ~. _{The 4-} haloalkyl group, or _3⁄4 and z ₄ together with the nitrogen atom to which they are attached form a 5- to 7-membered heterocyclic group which may contain, in addition to a nitrogen atom, one or more heteroatoms selected from nitrogen and oxygen. When the other group is as defined in the above formula (I), the methacryl benzimidazole (thio) ketone represented by the formula (I) to be protected by the present invention can be prepared by the synthetic route shown in the following scheme. derivative:

 The synthesis route is based on dinitro-substituted aniline, wherein one nitro group and amino group are ortho-positions, firstly a halogenated hydrocarbon is used as a hydrocarbylating agent, and various hydrocarbyl groups or substituted hydrocarbyl groups are introduced on the amino nitrogen, and then the powder is used. Selective reduction of the amino- ortho-nitro group, followed by cyclization, acylation, and nitro reduction to obtain a benzimidazolone derivative having an amino group on the benzene ring, and finally introducing a mercapto group through a hydrocarbylation reaction. Or introducing an acyl group by esterification reaction with an acid chloride to obtain a target compound;  The compound of the formula (I) obtained by the above production method is converted into a salt by a usual method, as needed. 6. Use of a compound according to any one of claims 1 to 4 for inhibiting bacteria, wherein the bacteria are Gram-positive bacteria and Gram-negative bacteria.  7. The use according to claim 6, wherein the Gram-positive bacterium is Staphylococcus aureus (St phyloccocus aureus) Streptococci aga/flct/fle, Bacillus subtilis, Bacillus cereus BaciU cereus ; Gram-negative bacteria are Escherichia col, Pseudomonas aeruginosa ^ Salmonella (Salmonella arizonae).  8. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and/or prophylaxis of human/animal diseases caused by bacterial infections: Staphylococcus aureus, Streptococcus agalactiae, Bacillus subtilis, wax Spore 93 Replacement page (Article 26) Gram-negative bacteria are Escherichia coli, Pseudomonas aeruginosa, and Salmonella serrata.  9. Use according to claim 8 wherein the compound can be processed into powder injections, tablets, capsules or other suitable dosage forms.  10. The use of a compound according to any one of claims 1 to 4 for inhibiting fungi, wherein the fungus is Trichophyton rubrum > I Monilia albican -^ Microsporum canis) Malassezia o  11. Use of a compound according to any one of claims 1 to 4 for the manufacture of a medicament for the treatment and/or prevention of human/animal dermatological diseases caused by the following fungal infections: Trichophyton rubrum, Candida albicans, Microsporum canis And Malassezia.  12. Use according to claim 11 wherein the compound can be processed into an ointment, emulsion, powder or other suitable dosage form.  13. Use of a compound according to any of claims 1 to 4 for controlling plant diseases caused by the following phytopathogenic fungi: Botrytis cinerea, Pseudoperonospora cubensis, Erysiphe Graminis), apple anthracnose (Glomerella cingulata), cotton iFusarium oxysporium) and Phytophthora infestans iPhytophthom infestans.  14. Use according to claim 13 wherein the compound can be processed into an emulsifiable concentrate, an aqueous emulsion, a microemulsion, a wettable powder, a water-dispersible granule, a suspending agent, or other suitable dosage form. 94  Replacement page (Article 26)