Novel compounds for treating viral infections

Abstract

The present invention relates to novel compounds represented by general formula (I) having the potential to treat viral infections, particularly those associated with dengue virus, their tautomerized forms, their stereoisomers, suitable pharmaceutically acceptable salts thereof, their polymorphs, pharmaceutical compositions containing them, and methods for preparing them. The compounds of the present invention are useful for treating the human or animal body by regulating viral replication. Therefore, the compounds of the present invention are suitable for treating virus-related disorders such as dengue fever.

Description

[Technical Field]

[0001] Field of Invention The present invention relates to novel compounds represented by general formula (I) having the potential to treat viral infections, particularly viral infections associated with dengue virus, their tautomerized forms, their stereoisomers, suitable pharmaceutically acceptable salts thereof, their polymorphs, pharmaceutical compositions containing them, methods for preparing them, the use of these compounds in pharmaceuticals, and intermediates involved in their preparation. [ka] [Background technology]

[0002] Background of the present invention Dengue fever, caused by the dengue virus (DENV), is one of the most important arthropod-borne human viral infections in many tropical and subtropical regions. With approximately 390 million infections each year, DENV infections pose a high health risk to the global population. The DENV genome encodes three structural proteins: capsid (C), membrane (M), and envelope (E), as well as seven non-structural proteins: NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5. There are four distinct DENV serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, each of which can infect a person during their lifetime. Infection with one serotype may provide lifelong immunity to infection with homologous DENV strains; however, it only maintains short-term immunity to heterologous infections. Dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) are life-threatening consequences of DENV infection. Severe dengue fever can lead to plasma leakage, bleeding tendencies, organ failure, shock, and sometimes death. Dengvaxia is an approved quadrivalent attenuated live dengue vaccine candidate, but its use is permitted with strict restrictions. It has shown high efficacy in preventing dengue fever caused by DENV serotypes 1-4 and is safe even in people with a history of dengue infection, i.e., seropositive individuals.

[0003] US10550123 describes a viral replication inhibitor and the process for preparing it. WO2021094563, WO2018215315, WO2018178238, WO2017046255, WO2017046258, WO2017167951, WO2016180696, and WO2016113371 describe substituted indole and indoline derivatives for the treatment of dengue fever disease.

[0004] WO2019244047 describes N-substituted tetrahydrothienopyridine derivatives and their uses. WO2018178240 describes substituted indoline derivatives as dengue virus replication inhibitors. WO2017102014 describes propenamidothiophene derivatives as flavivirus inhibitors and their uses.

[0005] Despite the widespread and long-standing global prevalence of dengue fever, there are still no specific antiviral drugs for the treatment or prevention of dengue virus infection. Therefore, there is a significant unmet medical need for preventative or therapeutic treatment of viral infections in animals, particularly those caused by the dengue virus. Compounds exhibiting excellent pan-antiviral efficacy against DENV1-4, minimal side effects, low toxicity, and a favorable ADME profile are greatly needed. [Overview of the project]

[0006] Summary of the present invention The present invention relates to novel compounds represented by general formula (I) having the potential to treat viral infections, particularly viral infections associated with dengue virus, their tautomerized forms, their stereoisomers, suitable pharmaceutically acceptable salts thereof, their polymorphs, pharmaceutical compositions containing them, and methods for preparing them. The compounds of the present invention are useful for treating the human or animal body by regulating viral replication. Therefore, the compounds of the present invention are suitable for treating virus-related disorders such as dengue fever.

[0007] Embodiments of the present invention The main object of the present invention is to provide a novel compound represented by general formula (I), its tautomerized form, its stereoisomer, a novel intermediate involved in its synthesis, a suitable pharmaceutically acceptable salt thereof, and its polymorphs.

[0008] In one embodiment, a process is provided for preparing a novel compound represented by general formula (I), its tautomerized forms, its stereoisomers, novel intermediates involved in its synthesis, a suitable pharmaceutically acceptable salt thereof, and its polymorphs. In another embodiment, a pharmaceutical composition is provided comprising a compound represented by general formula (I), a tautomer, a stereoisomer thereof, a suitable pharmaceutically acceptable salt thereof, and a polymorph thereof, having a pharmaceutically acceptable carrier, solvent, diluent, binder, disintegrant, coating agent, filler, lubricant, and / or other suitable excipient. In yet another embodiment, the use of the novel compounds of the present invention for the treatment of virus-related disorders such as dengue fever is provided by administering a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, in a therapeutically effective and non-toxic amount. In another embodiment, a method is provided for treating a virus-related disorder such as dengue fever using a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof.

[0009] Description of the present invention In a first embodiment, the present invention relates to a compound represented by general formula (I), [ka] During the ceremony, X represents an aryl ring, heteroaryl ring, or heterocyclyl ring; R1 represents hydrogen, halogen, haloalkyl, (C1-C6)alkyl, heterocyclyl, or -OR6, where (C1-C6)alkyl or heterocyclyl is independently unsubstituted or substituted with one or more preferred substituents; Y represents a carbocyclic or heterocyclic ring; these are independently unsubstituted or substituted with one or more preferred substituents selected from (C1-C6)alkyl, -OR6, and halogens; A and B represent a carbocyclic ring or a heterocyclic ring; R2 and R3 are hydrogen, hydroxy, cyano, halo, nitro, haloalkyl, (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C6)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy, -COR6, -COOR6, -OR 6、 -OSO2CH3, -OCOR6, -S(O) p R6, -NR6R7, -CONR6R7, -N(R6)COR7, -N(R6)COOR7, -N(R6)CONR6R 7、 -SO2NR6R7 and -N(R6)SO2R7 represent the substituents, which are independently unsubstituted or substituted with one or more preferred substituents; R4 is selected from hydrogen, (C1-C6) alkyl, (C3-C6) cycloalkyl, haloalkyl, and heterocyclyl, which are independently unsubstituted or substituted with one or more preferred substituents; R5 is selected from haloalkyl, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, and heterocyclylalkyl, which are independently unsubstituted or substituted with one or more preferred substituents; R6 and R7 are independently selected from hydrogen, unsubstituted or substituted (C1-C6) alkyl, (C3-C6) cycloalkyl, and haloalkyl, and together with the N atom to which they are attached, R6 and R7 may form a 5- to 8-membered heterocyclyl or heteroaryl ring.

[0010] In one embodiment, substitutions include (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, and (C3-C6)cycloalkyl; preferred substitutions are hydrogen, hydroxy, cyano, halo, nitro, haloalkyl, oxo, (C1-C6)alkyl, (C3-C6)cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy, -COR6, -COOR6, and -OR 6、 --S(O) pR6, -NR6R7, -CONR6R 7、 CON(R6)OR7, -CON(R6)SO2R 7、 -N(R6)COR7, -N(R6)COOR7, -N(R6)CONR6R 7、 It may also be selected from -SO2NR6R7, -N(R6)SO2R7 derivatives; R6 and R7 are as described above; p represents an integer from 0 to 2; l represents an integer from 1 to 4; m represents an integer from 1 to 5; n represents an integer from 1 to 4.

[0011] In a second aspect, the present invention relates to a compound of general formula (I-A);

Chemical formula

[0012] A more preferred embodiment is as disclosed below: Preferred X may be selected from aryl; Preferred Y may be selected from carbocyclic rings; Preferred A and B may be selected from carbocyclic rings or heterocyclic rings; Preferred R1, R2 and R3 may be selected from hydrogen, cyano, halogen, (C1-C6) alkyl, haloalkyl, heterocyclyl, and -OR6; Preferred R4 may be selected from hydrogen and unsubstituted or substituted (C1-C6) alkyl; Preferred R5 may be selected from unsubstituted or substituted (C1-C6) alkyl; Preferred substitutions on the (C1-C6) alkyl group may be selected from hydroxy, -COOR6, -OR6, -CONR6R7, -CON(R6)OR7, and -CON(R6)SO2R7; l represents an integer from 1 to 4; m represents an integer between 1 and 5; n represents an integer between 1 and 4.

[0013] In a further embodiment, the above-mentioned group, radical may be selected from the following: - The "alkyl" group, used either alone or in combination with other radicals, represents a linear or branched radical containing 1 to 6 carbon atoms, selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, amyl, t-amyl, n-pentyl, n-hexyl, etc.;

[0014] - An "alkenyl" group used either alone or in combination with other radicals, which is a radical containing 2 to 6 carbon atoms, more preferably selected from groups such as vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, etc., and includes linear and branched dienes and trienes;

[0015] - An "alkynyl" group used either alone or in combination with other radicals, which is a linear or branched radical containing 2 to 6 carbon atoms, more preferably selected from thienyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, etc. (The term "alkynyl" includes diynes and triynes);

[0016] - A "cycloalkyl" or "alicyclic" group used either alone or in combination with other radicals, which is a cyclic radical containing 3 to 6 carbon atoms, more preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.;

[0017] - The "haloalkyl" group is preferably selected from alkyl radicals as defined above, substituted with one or more halogens (such as fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, mono- or polyhalo-substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl groups);

[0018] - "Halo" or "halogen" means a fluorine, chlorine, bromine, or iodine atom, either by itself or as part of another substituent, unless otherwise stated;

[0019] - An "aryl" or "aromatic" group used either alone or in combination with other radicals, which is selected from a suitable aromatic system containing one, two, or three rings, where such rings may be linked in a pendant-like manner or fused, and more preferably, the group is selected from phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, etc.;

[0020] - A "carbocyclic" group used either alone or in combination with other radicals, which is selected from the groups described as "cycloalkyl," "aryl," or "aromatic";

[0021] - A “heterocyclyl” or “heterocyclic” group used either alone or in combination with other radicals, which is selected from suitable saturated, partially saturated, or unsaturated, aromatic or non-aromatic, monocyclic, bicyclic, or tricyclic groups containing one or more heteroatoms selected from nitrogen, sulfur, and oxygen, more preferably azilidinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, 4-methylpiperazinyl, 4-hydroxypiperizinyl, 2-oxopiperizinyl, 4-oxopiperizinyl, 2-oxopiperazinyl, 3-oxopiperazinyl Selected from 1, 2, 3, 4

[0022] A “heteroaryl” or “heteroaromatic” group, used either alone or in combination with other radicals, is selected from suitable monocyclic or fusion monocyclic, bicyclic, or tricyclic aromatic heterocyclic radicals containing one or more heteroatoms selected from O, N, or S, and more preferably the group is pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetra Selected from zolyl, benzofuranil, benzothienyl, indolinyl, indolyl, azaindolyl, azaindolinyl, pyrazolopyrimidinyl, azaquinazolinyl, pyridofuranil, pyridothienyl, thienopyrimidyl, quinolinyl, pyrimidinyl, pyrazolyl, quinazolinyl, pyridadinyl, triazinyl, benzimidazolyl, benzotriazolyl, phthalazinyl, naphthilidinyl, prinyl, carbazolyl, phenothiazinyl, phenoxazinyl, benzoxazolyl, benzothiazolyl, etc.

[0023] - An "aralkyl" group used either alone or in combination with other radicals, which contains an aryl radical as defined above and is directly bonded to an alkyl radical as defined above, more preferably selected from groups selected from benzyl, phenethyl, and the like;

[0024] - A "heterocyclylalkyl" group used either alone or in combination with other radicals, which is selected from groups containing a heterocyclyl radical as defined above and directly bonded to an alkyl radical as defined above;

[0025] - An alkylsulfonyloxy group, used either alone or in combination, refers to an alkylsulfonyl group directly bonded to an oxygen atom, where a suitable alkyl group as defined above is bonded to a sulfonyl radical;

[0026] - One or more preferred substituents substituted on a single carbon, or one or more preferred substituents substituted on two or more carbons;

[0027] -As used herein, the term “substituted” means that any one or more hydrogen atoms on a given atom are substituted with a group selected from the indicated groups, provided that the substitution does not exceed the normal valence of the given atom and the substitution results in a stable compound. Substituents are selected from hydrogen, deuterium, hydroxy, cyano, halo, nitro, haloalkyl, oxo, (C1-C6)alkyl, (C3-C6)cycloalkyl, aminoalkyl, alkoxyalkyl, alkenyl, alkynyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, and alkylsulfonyloxy;

[0028] -The term “stereoisomer” as used anywhere in this specification refers to the compound of the present invention exhibiting the (R) and (S) configurations;

[0029] - The term "polymorphic" refers to the ability of the compound of the present invention to exist in one or more forms or crystalline structures. Suitable groups and substituents on the group may be selected from those described anywhere in this specification.

[0030] Preferred compounds according to the present invention include, but are not limited to, the following:

[0031] 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; (+) 2-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; (+) 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid;

[0032] (-) 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(4-chlorophenyl)-2-((3-(1-((2-hydroxyethoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; (+) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; (-) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid;

[0033] 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; (+) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid;

[0034] 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)-2-methylpropyridene)amino)oxy)-2-methylpropanoic acid; 2-((((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)(cyclopropyl)methylene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)-2,2,2-trifluoroethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-methoxy-5-((2-oxo-1-phenyl-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-fluorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid;

[0035] 2-(((1-(3-((1-(2,4-dichlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(5-chloropyridine-2-yl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-morpholinospiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)acetic acid;

[0036] 2-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-3-methylbutanoic acid; 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)cyclobutane-1-carboxylic acid; 4-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid;

[0037] 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzaldehyde O-(2-hydroxyethyl)oxime;

[0038] 2-(4-chlorophenyl)-2-((3-(1-(((1-hydroxy-2-methylpropane-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzaldehyde O-(1-hydroxy-2-methylpropane-2-yl)oxime; 2-(4-chlorophenyl)-2-((3-(1-((2-hydroxy-2-methylpropoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(4-chlorophenyl)-2-((3-(1-((3-hydroxypropoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid;

[0039] 2-(((1-(3-((1-(4-chloro-2-(2-hydroxyethoxy)phenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; (+) 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; (-) 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid;

[0040] 2-(((1-(3-Methoxy-5-((1-(4-Methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-cyanophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid;

[0041] 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; (+) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide;

[0042] (+) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; (-) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide;

[0043] 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propenamide; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propenamide; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propenamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-isopropyl-2-methylpropanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-1-morpholinopropan-1-one;

[0044] 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-hydroxy-2-methylpropanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanenitrile; 2-((3-(1-(((2-(1H-tetrazole-5-yl)propane-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one;

[0045] 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanenitrile; 2-((3-(1-((2-(1H-tetrazole-5-yl)ethoxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzaldehyde O-methyl oxime; 2-(4-chlorophenyl)-2-((3-methoxy-5-(1-(methoxyimino)ethyl)phenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)acetic acid;

[0046] 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)propanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)butanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)acetic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)propanoic acid;

[0047] 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)butanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-3-methylbutanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)propanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid;

[0048] 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-3-methylbutanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)butanamide; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)butanamide;

[0049] 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-3-methyl-N-(methylsulfonyl)butanamide; 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide;

[0050] 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(4-chloro-2-methoxyphenyl)-2-((3-(1-((2-hydroxy-2-methylpropoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(4-chloro-2-methoxyphenyl)-2-((3-(1-(((1-hydroxy-2-methylpropane-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)acetamide;

[0051] 4-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; 2-(((3-Methoxy-5-((2-Oxo-1-phenyl-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)benzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((3-Methoxy-5-((1-(4-Methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)benzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((3-((1-(2,4-dichlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid;

[0052] 2-(((1-(3-methoxy-5-((2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-fluorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-Methoxy-5-((2-Oxo-1-phenyl-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-Methoxy-5-((1-(4-Methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-cyanophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide;

[0053] 2-(((1-(3-((1-(2,4-dichlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(5-chloropyridine-2-yl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethyl)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(5'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)-2,2,2-trifluoroethylidene)amino)oxy)-2-methylpropanoic acid;

[0054] 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((2-(6'-chloro-7'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-1-(4-chlorophenyl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-(6'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-Methoxy-5-((1-(6-Methoxypyridine-3-yl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-Methoxy-5-((1-(6-Methoxypyridine-3-yl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide.

[0055] The novel compounds of the present invention may be prepared using the reactions and techniques shown in the following scheme and described in this section. The reactions are carried out in solvents suitable for the reagents and materials employed and suitable for the transformations in which they act. Those skilled in the art will understand that the nature and order of the presented synthetic steps may be modified for the purpose of optimizing the formation of the compounds of the present invention. It will also be well understood that one or more reactants may be protected and deprotected by techniques known to those skilled in the art to facilitate the synthesis. It will also be understood that one or more compounds of the present invention may exist in the form of stereoisomers and / or diastereomers. Such stereoisomers and / or diastereomers, as well as their optical counterparts, are construed to be within the scope of the present invention. It will also be well understood, and this can be well understood, that one or more of these compounds may be converted into salts and other derivatives based on certain groups present on the compound. Such salts and / or other derivatives should also be construed to be within the scope of the present invention, in some cases.

[0056] Scheme 1: Synthesis of compounds represented by general formula (I) [ka] Compounds represented by general formula (II) can be prepared using general techniques for preparing spirocyclic compounds as described in the literature (J. Med. Chem. 2021, 64, 7, 3658-3676, and J. Med. Chem. 2012, 55, 7667-7685). Compounds represented by general formula (III) can be prepared by alpha-halogenation of the corresponding acetic acid derivative using various techniques described in the literature. Compounds represented by general formula (IV) can be obtained by coupling (II) with (III) using various amide bond formation techniques known in the art, such as those described in Tetrahedron 2005, 61, 10827, with appropriate modifications as needed. Compounds represented by general formula (I) can be obtained by reacting the compound represented by formula (IV) with the compound represented by (V) in a solvent such as DMF, acetonitrile, etc., in the presence of a base such as triethylamine, diisopropylethylamine, etc.

[0057] Scheme 2: Synthesis of compounds represented by general formula (I) [ka] Alternatively, the compound represented by formula (I) may be obtained by the following scheme 2. The compound represented by general formula (VII) may be prepared by coupling the compound represented by general formula (VI) and (V) in the same manner as described in scheme 1 for the coupling of the compounds represented by formulas (VI) and (V). The compound represented by general formula (VIII) may be obtained by deprotection using alkaline hydrolysis (PG=Me or Et) or debenzylation (PG=Bn) with hydrogenation in the presence of Pd-C. The compound represented by general formula (I) may then be obtained by coupling (II) with (VIII) using various amide bond formation techniques known in the art, such as those described in Tetrahedron 2005, 61, 10827, with appropriate modifications as needed.

[0058] Scheme 3: Synthesis of intermediates represented by general formula (V) [ka] The compound represented by general formula (V) can be prepared as shown in Scheme 3. The compound represented by formula (X) can be prepared by treating (IX) with hydroxylamine hydrochloride in an alcohol solvent. The compound represented by general formula (XII) can be obtained by coupling (X) with compound (XI) using general nucleophilic substitution techniques described in the literature. The compound represented by formula (V) is prepared by using a reducing agent such as stannous chloride in ethyl acetate, or by hydrogenation in the presence of Pd-C. The present invention will be illustrated in more detail by the following examples, which are provided for illustrative purposes only and should not be construed as limiting the scope of the invention. 1 ¹H NMR spectra were recorded on a Brucker Avance-400 spectrometer (400 MHz). Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS) in either CDCl3 or DMSO-d6 solution. Mass spectra (ESI-MS) were obtained on a Shimadzu LC-MS 2010-A spectrometer.

[0059] List of Abbreviations min: minute (singular or plural) RT: Room temperature (25~30℃) HMPA: Hexamethylphosphoramide DMF: Dimethylformamide DCM: Dichloromethane hrs: hours (singular or plural) BBr3: Boron tribromide DMAP: Dimethylaminopyridine EDC.HCl: N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride NBS: N-bromosuccinate LiHMDS: Lithium bis(trimethylsilyl)amide THF: Tetrahydrofuran AIBN: Azobisisobutyronitrile TMS-Cl: Trimethylsilyl chloride CCl4: Carbon tetrachloride DIBAL-H: Diisobutylaluminum hydride HATU: Azabenzotriazole tetramethyluronium hexafluorophosphate DIPEA: N,N-diisopropylethylamine Pd / C: Palladium Carbon ACN: Acetonitrile CDCl3: Deuterated chloroform Cs2CO3: Cesium Carbonate DIPEA: Diisopropylethylamine DMSO: Dimethyl sulfoxide DMSO-d6: Hexadeuterodimethylsulfoxide HCl: Hydrochloric acid NaOH: Sodium hydroxide TPP: Triphenylphosphine TFA: Trifluoroacetic acid 1 1H NMR: Proton Nuclear Magnetic Resonance J: Coupling constant in Hz Hz: Hertz

[0060] Preparation of the intermediate represented by formula (II) Preparation of 6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline](II-1) [ka] Step 1: Preparation of diethyl 2-(2-nitro-4-(trifluoromethoxy)phenyl)malonate [ka] To a stirred solution of 1-chloro-2-nitro-4-(trifluoromethoxy)benzene (50 g, 207 mmol) and diethyl malonate (37.90 ml, 101 mmol) in dry DMF (500 ml), cesium carbonate (101 g, 310 mmol) was added, and the resulting mixture was stirred at 80°C for 3-4 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 366.03 (M+H) + .

[0061] Step 2: Preparation of 2-(2-nitro-4-(trifluoromethoxy)phenyl)acetic acid [ka] To a stirred solution of the product obtained in step 1 (46.35 g, 127 mmol) in methanol (400 mL), 100 mL of aqueous solution of sodium hydroxide (20.30 g, 508 mmol) was added, and the resulting mixture was stirred at 80°C for 4 hours. After the starting materials had completely transformed, the reaction mixture was diluted with cold water and acidified with diluted HCl. The resulting solid was filtered and washed with water to obtain the title product. ESI-MS (m / z): 266.03 (M+H) + .

[0062] Step 3: Preparation of methyl 2-(2-nitro-4-(trifluoromethoxy)phenyl) acetate [ka] To a stirred solution of the product obtained in step 2 (33 g, 124 mmol) in DCM (330 mL), 0.9 mL of DMF was added at 0°C. Oxalyl chloride (6.31 mL, 73.5 mmol) was added dropwise over 10 min, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, 100 mL of methanol was added dropwise, and the mixture was stirred at room temperature for 2 hours. After the starting materials had completely transformed, the reaction mixture was diluted with cold water. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 280.05 (M+H) + .

[0063] Step 4: Preparation of methyl 1-(2-nitro-4-(trifluoromethoxy)phenyl)cyclopropane-1-carboxylic acid [ka] To a stirred solution of the product obtained in step 3 (31 g, 111 mmol) in dry DMF (310 ml) and 1,2-dibromoethane (11.54 ml, 133 mmol), cesium carbonate (109 g, 333 mmol) was added, and the resulting mixture was stirred at 120 °C for 2 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. MS (m / z): 306.07 (M+H) + .

[0064] Step 5: Preparation of 6'-(trifluoromethoxy)spiro[cyclopropan-1,3'-indoline]-2'-one [ka] To a stirred solution of the product obtained in step 4 (12.3 g, 40.3 mmol) in acetic acid (120 ml), iron powder (11.25 g, 202 mmol) was added, and the resulting mixture was stirred at 100°C for 2 hours. After the starting materials had completely transformed, the reaction mixture was filtered through Celite and washed with ethyl acetate. The organic layer was removed by distillation and diluted with cold water. The resulting solid was filtered, washed with water, dried, and column purified to obtain the title product. ESI-MS (m / z): 244.04 (M+H) + .

[0065] Step 6: Preparation of 6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline] [ka] To a stirred suspension of lithium aluminum hydride (4.92 g, 130 mmol) in dry THF (180 ml) at 0°C, a solution of the product obtained in step 5 (9 g, 37 mmol) in dry THF (90 ml) was added dropwise, and the resulting mixture was stirred at 60°C for 2 hours. After the starting materials were completely converted, the reaction mixture was diluted with 10% NaOH aqueous solution and stirred at RT for 1 hour. The reaction mixture was filtered through Celite. The filtrate was washed with water, evaporated under reduced pressure, dried, and purified by column to obtain the title product. ESI-MS (m / z): 1 H NMR (CDCl3): 6.56-6.52 (m, 2H), 6.50-6.47 (d, 1H), 3.93 (s, 1H), 3.65 (s, 2H), 1.04-0.93 (m, 4H) ESI-MS (m / z): 230.12 (M+H) + .

[0066] Preparation of 6'-methoxyspiro[cyclopropane-1,3'-indoline](II-2) [ka] Step 1: Preparation of 6-methoxyindoline-2-one [ka] To a stirred solution of ethyl 2-(4-methoxy-2-nitrophenyl) acetate (5.8 g, 24.24 mmol) in acetic acid (50 ml), iron powder (6.77 g, 121 mmol) was added, and the resulting mixture was stirred at 100°C for 2 hours. After the starting materials had completely transformed, the reaction mixture was filtered through Celite and washed with ethyl acetate. The resulting filtrate was removed by distillation, diluted with water, and filtered. The resulting solid was filtered, washed with water, dried, and column purified to obtain the title product. ESI-MS (m / z): 164.07 (M+H) + .

[0067] Step 2: Preparation of 6'-methoxyspiro[cyclopropan-1,3'-indoline]-2'-one [ka] To a stirred solution of the product obtained in Step 1 (2.5 g, 15.32 mmol) in dry THF (25 ml), N,N,N',N'-tetramethylethylenediamine (3.45 ml, 22.98 mmol) and n-butyllithium (18.39 ml, 46.0 mmol) were added dropwise at -78°C, and the mixture was stirred for 30 minutes. 1,2-dibromoethane was added dropwise at -78°C. The resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the title product. ESI-MS (m / z): 190.08 (M+H) + .

[0068] Step 3: Preparation of 6'-methoxyspiro[cyclopropane-1,3'-indoline] [ka] To a stirred solution of the product obtained in step 2 (610 mg, 3.22 mmol) in dry toluene (10 ml), vitrid (39.0 mg, 1.028 mmol) was added at 60°C, and the resulting mixture was stirred at 60°C for 2 hours. After the reaction was complete, the reaction mixture was diluted with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. ESI-MS (m / z): 176.09 (M+H) + .

[0069] The following intermediates (Table 1) were prepared in a similar manner, making full use of the appropriate starting materials and suitable modifications of the process described in the preparation of intermediates II-I and II-2 (including suitable additions and / or deletions of steps as appropriate, as necessary), within the scope of those skilled in the art.

[0070] Table 1 [Table 1]

[0071] Preparation of the intermediate represented by formula (III) Preparation of 2-bromo-2-(4-chlorophenyl)acetic acid (III-1) [ka] To a stirred solution of 2-(4-chlorophenyl)acetic acid (10 g, 58.6 mmol) in dry CCl4 (100 ml), NBS (11.48 g, 64.5 mmol), followed by AIBN (0.48 g, 2.93 mmol), was added, and the resulting mixture was refluxed for 12 hours. After the starting materials had completely transformed, the reaction mixture was cooled to 0°C, the precipitated solid was filtered, the filtrate was separated, washed with water, and dried under reduced pressure to obtain the title product. ESI-MS (m / z): 248.96 (MH).

[0072] The following intermediates (Table 2) were prepared in a similar manner, making full use of the appropriate starting materials and suitable modifications of the process described in the preparation of intermediate III-1 (including suitable additions and / or deletions of steps as appropriate, as necessary), within the scope of those skilled in the art.

[0073] Table 2 [Table 2]

[0074] Preparation of the intermediate represented by formula (VI) Preparation of methyl 2-bromo-2-(4-chlorophenyl)acetate (VI-1) [ka] To a stirred solution of 2-bromo-2-(4-chlorophenyl)acetic acid (2.5 g, 10.02 mmol) in dry DCM (15 mL), oxalyl chloride (1.03 mL, 12.02 mmol) was added, and the resulting mixture was stirred at RT for 1 hour. The reaction mixture was cooled to 0°C, methanol (0.64 mL, 20.04 mmol) was added to the reaction mixture, and the mixture was stirred at RT for 4 hours. After the starting materials had completely transformed, the reaction mixture was diluted with cold water, and the organic layer was separated. The organic layer was removed by distillation to obtain the product described in the title. ESI-MS (m / z): 263.03 (M+H) + .

[0075] Preparation of benzyl 2-bromo-2-(4-chloro-2-methoxyphenyl)acetate (VI-2) [ka] Step 1: Preparation of benzyl 2-(4-chloro-2-methoxyphenyl) acetate [ka] Potassium carbonate (6.89 g, 49.8 mmol) was added to a stirred solution of 2-(4-chloro-2-methoxyphenyl)acetic acid (5 g, 24.95 mmol) and benzyl bromide (3.26 ml, 27.4 mmol) in acetone (50 mL), and the resulting mixture was stirred at 60 °C for 4 hours. After the reaction was complete, the reaction mixture was filtered. The organic layer was removed by distillation to obtain the crude product, which was purified by column chromatography to obtain the product described in the title. ESI-MS (m / z): 291.06 (M+H) + .

[0076] Step 2: Preparation of benzyl 2-bromo-2-(4-chloro-2-methoxyphenyl) acetate [ka] To a stirred solution of the product obtained in Step 1 (3.6 g, 12.38 mmol) in dry THF (40 ml), LiHMDS in THF (27.5 ml, 27.5 mmol) was added dropwise at -78°C. Then, TMS-Cl (2.2 g, 20.64 mmol) in dry THF (4 ml) was added at -78°C, and the reaction mixture was stirred at the same temperature for 15 minutes. NBS (3.67 g, 20.64 mmol) in dry THF (30 ml) was added dropwise to the reaction mixture at -78°C, and the mixture was stirred at -78°C for 1 hour. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was removed by distillation to obtain the crude product, which was purified by column chromatography to obtain the title product.

[0077] Preparation of methyl 2-bromo-2-(4-chloro-2-methoxyphenyl) acetate (VI-3) [ka] Methyl 2-(4-chloro-2-methoxyphenyl) acetate was used as the starting material and prepared using the same process as described in step 2 of intermediate VI-2. ESI-MS (m / z): 292.95 (M+H) + .

[0078] Preparation of ethyl 2-bromo-2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)acetate (VI-4) [ka] Step 1: Preparation of ethyl 2-(4-chloro-2-hydroxyphenyl) acetate [ka] To a stirred solution of ethyl 2-(4-chloro-2-methoxyphenyl) acetate (3.6 g, 15.74 mmol) in dry DCM (50 mL), BBr3 (31.5 mL, 31.5 mmol) was added at -30°C, and the resulting mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 215.05 (M+H) + .

[0079] Step 2: Preparation of ethyl 2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl) acetate [ka] To a stirred solution of the product obtained in Step 1 (2.6 g, 12.11 mmol) in dry DMF (30 ml), (2-bromoethoxy)(tert-butyl)dimethylsilane (4.5 g, 18.17 mmol), followed by cesium carbonate (7.89 mg, 24.23 mmol), the resulting mixture was stirred at RT for 12 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 373.10 (M+H) + .

[0080] Step 3: Preparation of ethyl 2-bromo-2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl) acetate [ka] To a stirred solution of the product obtained in step 2 (2.8 g, 7.5 mmol) in dry THF (20 ml), LiHMDS in THF (15 ml, 15.01 mmol) was added dropwise at -78°C. TMS-Cl (1.31 g, 12.01 mmol) in dry THF (4 ml) was added at -78°C, and the reaction mixture was stirred at the same temperature for 15 minutes. NBS (2.01 g, 11.24 mmol) in dry THF (10 ml) was added dropwise to the reaction mixture at -78°C, and the mixture was stirred at -78°C for 1 hour. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 451.05 (M+H) + .

[0081] Preparation of ethyl 2-bromo-2-(4-methoxyphenyl)acetate (VI-5) [ka] To a stirred solution of ethyl 2-(4-methoxyphenyl) acetate (1.0 g, 5.15 mmol) in CCl4 (15 ml), benzoyl peroxide (0.062 g, 0.257 mmol) was added. NBS (1.833 g, 10.30 mmol) was added gradually, and the reaction mixture was stirred at 75-80°C for 3.0 hours. After the reaction was complete, the reaction mixture was cooled to 25°C, the solid was filtered through a Celite pad, and the solid was washed with 2 x 10 ml of CCl4. The filtrate was washed with 10 ml of water and 10 ml of brine solution, and the organic layer was dried and evaporated to obtain the title product.

[0082] Preparation of ethyl 2-bromo-2-(4-cyanophenyl) acetate (VI-6) [ka] Prepared using ethyl 2-(4-cyanophenyl) acetate as the starting material, following the same process as described in VI-5. ESI-MS (m / z): 265.97 (MH).

[0083] Preparation of methyl 2-bromo-2-(6-methoxypyridine-3-yl)acetate (VI-7) [ka] Prepared using methyl 2-(6-methoxypyridine-3-yl) acetate as the starting material, following the same process as described in VI-5. ESI-MS (m / z): 261.95 (M+H) + .

[0084] Preparation of the intermediate represented by formula (IV) Preparation of 2-bromo-2-(4-chlorophenyl)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one (IV-1) [ka] To a stirred solution of intermediate (III-1) (1.796 g, 7.20 mmol) in dry DCM (20 ml), EDC.HCl (1.380 g, 7.20 mmol) was gradually added at 0°C, followed by DMAP (0.080 g, 0.654 mmol) and intermediate (II-1) (1.5 g, 6.54 mmol). The resulting mixture was stirred at room temperature for 2 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water, and the organic layer was separated. The organic layer was washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. 1H NMR (DMSO-d6): 8.02 (s, 1H), 7.62-7.59 (m, 2H). 7.58-7.58 (m, 2H) 7.05-7.04 (m, 1H), 7.03-6.93 (m, 1H), 6.15 (s, 1H), 4.47-4.44 (m, 1H), 4.09-4.07 (m, 1H), 1.17-1.06 (m, 4H). ESI-MS (m / z): 461.95 (M+H) + .

[0085] Preparation of 2-bromo-2-(5-chloropyridine-2-yl)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one (IV-2) [ka] Step 1: Preparation of ethyl 2-(5-chloropyridine-2-yl) acetate [ka] To a stirred solution of 2-bromo-5-chloropyridine (2.50 g, 12.99 mmol) and diethyl malonate (4.56 ml, 29.9 mmol) in dioxane (30 ml), Cs2CO3 (13.97 g, 42.9 mmol) was added. Picolinic acid (0.720 g, 5.85 mmol) and copper(I) oxide (0.744 g, 5.20 mmol) were then added via RT. The reaction mixture was heated to 135°C and stirred for 24 hours. After the reaction was complete, the reaction mixture was diluted with ethyl acetate and cold water. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the product described in the title. ESI-MS (m / z): 200.04 (M+H) + .

[0086] Step 2: Preparation of sodium 2-(5-chloropyridine-2-yl)acetate [ka] To a stirred solution of the product obtained in Step 1 (0.500 g, 2.505 mmol) in methanol (1.00 ml), a solution of NaOH (0.150 g, 3.76 mmol) in water (5.00 ml) was added, and the mixture was stirred at RT for 3 hours. After the reaction was complete, the reaction mixture was freeze-dried to obtain the product described in the title.

[0087] Step 3: Preparation of 2-(5-chloropyridine-2-yl)-1-(6'-(trifluoromethoxy)spiro[cyclopropan-1,3'-indoline]-1'-yl)ethane-1-one [ka] To a stirred solution of the product obtained in step 2 (0.338 g, 1.745 mmol) in DCM (15 ml), EDC:HCl (0.502 g, 2.62 mmol), followed by II-1 (0.200 g, 0.873 mmol) and DMAP (0.075 g, 0.611 mmol) were added at 0°C. The reaction mixture was stirred at RT for 3 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. ESI-MS (m / z): 383.07 (M+H) + .

[0088] Step 4: Preparation of 2-bromo-2-(5-chloropyridine-2-yl)-1-(6'-(trifluoromethoxy)spiro[cyclopropan-1,3'-indoline]-1'-yl)ethane-1-one [ka] To a stirred solution of the product obtained in step 3 (100 mg, 0.261 mmol) in DCM (5.00 ml), NBS (46.5 mg, 0.261 mmol) was gradually added by RT and stirred for 4 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the product described in the title. ESI-MS (m / z): 462.98 (M+H) + .

[0089] The following intermediates (Table 3) were prepared in a similar manner, making full use of the appropriate starting materials and suitable modifications of the process described in the preparation of intermediates IV-1 and IV-2 (including suitable additions and / or deletions of steps as appropriate); all within the scope of the art.

[0090] Table 3 [Table 3-1] [Table 3-2]

[0091] Preparation of tert-butyl 2-(((1-(3-amino-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate (V-1) [ka] Step 1: Preparation of 3-methoxy-5-nitrobenzoic acid [ka] Lithium methanolate (14.32 g, 377 mmol) was added to a stirred solution of 3,5-dinitrobenzoic acid (20 g, 94 mmol) in dry HMPA (200 ml). The resulting mixture was stirred at RT for 16 hours, followed by 8 hours at 100°C. After the starting materials were completely converted, the reaction mixture was diluted with cold water, acidified with diluted HCl, and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 196.06 (MH).

[0092] Step 2: Preparation of 3-methoxy-5-nitrobenzoyl chloride [ka] To a stirred solution of the product obtained in Step 1 (2.4 g, 12.17 mmol) in dry DCM (20 ml), oxalyl chloride (1.3 ml, 18.26 mmol) was added, and the resulting mixture was stirred at RT for 2 hours. The excess solvent was removed by distillation to obtain the crude product, which was used directly in the next step.

[0093] Step 3: Preparation of 1-(3-methoxy-5-nitrophenyl)ethane-1-one [ka] To a stirred solution of diethyl malonate (2.03 mL, 13.36 mmol) in toluene (30 mL) was added magnesium chloride (0.74 g, 7.79 mmol), followed by triethylamine (0.72 mL, 27.8 mmol), and the reaction mixture was stirred at RT for 1 h. To this was added the product obtained in step 2 (2.4 g, 11.13 mmol) in toluene (12 mL), and the reaction mixture was stirred at RT for 12 hrs. After the starting material was completely converted, the reaction mixture was diluted with cold water and the organic layer was separated. The organic layer was removed by distillation to obtain the crude product, which was dissolved in a mixture of DMSO (30 mL) and water (5 mL) and heated at 150 °C for 4 hrs. After the starting material was completely converted, the reaction mixture was diluted with cold water and the precipitated solid was filtered and dried to obtain the title product. ESI-MS (m / z): 196.02 (M+H) + .

[0094] Step 4: Preparation of 1-(3-methoxy-5-nitrophenyl)ethan-1-one oxime [Chemical formula] To a stirred solution of the product obtained in step 3 (700 mg, 3.59 mmol) in water (15 mL) was added sodium acetate (0.915 g, 16.38 mmol), followed by hydroxylamine hydrochloride (1.2 g, 17.93 mmol), and the resulting mixture was stirred at 100 °C for 2 hrs. After the starting material was completely converted, the reaction mixture was cooled to 10 °C and the precipitated solid was filtered to obtain the title product. ESI-MS (m / z): 211.07 (M+H) + .

[0095] Step 5: Preparation of tert-butyl 2-(((1-(3-methoxy-5-nitrophenyl)ethylidene)amino)oxy)-2-methylpropanoate [Chemical formula] To a stirred solution of the product obtained in step 4 (2.5 g, 11.8 mmol) and tert-butyl 2-bromo-2-methylpropanoate (3.98 g, 17.8 mmol) in dry DMF (10 ml), potassium carbonate (2.96 g, 21.41 mmol) was added, and the resulting mixture was stirred at 90°C for 4 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the title product. ESI-MS (m / z): 353.15 (M+H) + .

[0096] Step 6: Preparation of tert-butyl 2-(((1-(3-amino-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] To a stirred solution of the product obtained in step 5 (0.5 g, 1.542 mmol) in rectified alcohol (10 ml), iron powder (2.046 g, 10.79 mmol), followed by ammonium chloride (2.046 g, 10.79 mmol), was added, and the resulting mixture was stirred at 80°C for 4 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the title product. 1 H NMR (DMSO-d6): 6.44-6.43 (t, 1H), 6.35-6.34 (d, 1H), 6.18-6.17 (d, 1H), 5.17 (s, 2H), 3.65 (s, 3H), 2.10 (s, 3H), 1.44 (s, 6H), 1.37 (s, 9H). ESI-MS (m / z): 323.21 (M+H) + ESI-MS (m / z): 323.21 (M+H) + .

[0097] Preparation of tert-butyl-2-(((3-amino-5-methoxybenzylidene)amino)oxy)-2-methylmethylpropanoate (V-2) [ka] Step 1: Preparation of methyl 3-methoxy-5-nitrobenzoic acid [ka] To a stirred solution of 3-methoxy-5-nitrobenzoic acid (10 g, 150.7 mmol) in dry DCM (100 mL), oxalyl chloride (11.12 ml, 152 mmol) was gradually added over 10 mins, and the resulting mixture was stirred at RT for 2 hours. The reaction mixture was cooled to 0°C, 15 mL of methanol was added dropwise, and the mixture was stirred at RT for 2 hours. After the starting materials had completely transformed, the reaction mixture was diluted with cold water, and the organic layer was separated. The organic layer was removed by distillation to obtain the title product.

[0098] Step 2: Preparation of 3-methoxy-5-nitrobenzaldehyde [ka] To a stirred solution of the product obtained in Step 1 (36 g, 170.1 mmol) in dry THF (300 ml), DIBAL-H in toluene (107 g, 188.2 mmol) was added dropwise at -78°C. The reaction mixture was stirred at the same temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 182.06 (M+H) + .

[0099] Step 3: Preparation of 3-methoxy-5-nitrobenzaldehyde oxime [ka] To a stirred solution of the product obtained in step 2 (0.5 g, 2.76 mmol) in water (5 ml), sodium acetate (1.83 g, 27.6 mmol), followed by hydroxylamine hydrochloride (0.959 g, 13.8 mmol), was added, and the resulting mixture was stirred at 100°C for 2 hours. After the starting materials had been completely converted, the reaction mixture was cooled to 10°C, and the precipitated solid was filtered to obtain the product described in the title. ESI-MS (m / z): 197.05 (M+H) + .

[0100] Step 4: Preparation of tert-butyl-2-(((3-methoxy-5-nitrobenzylidene)amino)oxy)-2-methylpropanoate [ka] To a stirred solution of the product obtained in step 3 (15 g, 76 mmol) and tert-butyl 2-bromo-2-methylpropanoate (21.4 ml, 115 mmol) in dry DMF (100 ml), potassium carbonate (19.02 g, 138 mmol) was added, and the resulting mixture was stirred at 90 °C for 4 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product.

[0101] Step 5: Preparation of tert-butyl-2-(((3-amino-5-methoxybenzylidene)amino)oxy)-2-methylmethylpropanoate [ka] To a stirred solution of the product obtained in step 4 (9 g, 26.6 mmol) in rectified alcohol (100 ml), iron powder (8.91 g, 160 mmol) was added, followed by ammonium chloride (8.54 g, 160 mmol). The resulting mixture was stirred at 80°C for 4 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the title product.1 1H NMR (CDCl3): 7.97 (s, 1H), 6.55 - 6.52 (m, 2H), 6.27 - 6.26 (t, 1H), 3.75 (s, 3H), 3.73 (s, 2H), 1.58 (s, 6H), 1.52 (s, 9H). ESI-MS (m / z): 309.1 (M + H) + .

[0102] Preparation of 1-(3-Amino-5-methoxyphenyl)ethan-1-one O-(2-hydroxyethyl)oxime (V-3)

Chem.

Chem.

[0103] Step 2: Preparation of 1-(3-Amino-5-methoxyphenyl)ethan-1-one O-(2-hydroxyethyl)oxime

Chem.

[0104] The following intermediates (Table 4) were prepared in a similar manner, making full use of the appropriate starting materials and suitable modifications of the process described in the preparation of intermediates V-1 to V-3 (including suitable additions and / or deletions of steps as appropriate, as necessary), within the scope of those skilled in the art.

[0105] Table 4 [Table 4-1] [Table 4-2] [Table 4-3]

[0106] Preparation of ethyl 3-(((1-(3-amino-5-methoxyphenyl)ethylidene)amino)oxy)propanoate (V-25) [ka] Step 1: Preparation of ethyl 3-(((1-(3-methoxy-5-nitrophenyl)ethylidene)amino)oxy)propanoate [ka] To a stirred solution of 1-(3-methoxy-5-nitrophenyl)ethane-1-one oxime (30 g, 143 mmol) and ethyl acrylate (15.46 ml, 143 mmol) in dry ACN (300 ml), TPP (7.49 g, 28.5 mmol) was added, and the resulting mixture was stirred at 100 °C for 45 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 311.7 (M+H) + .

[0107] Step 2: Preparation of ethyl 3-(((1-(3-amino-5-methoxyphenyl)ethylidene)amino)oxy)propanoate [ka] To a stirred solution of the product obtained in Step 1 (12.0 g, 38.7 mmol) in ethyl acetate (120 ml), tin chloride (36.7 g, 193 mmol) was added, and the resulting mixture was stirred at 60°C for 4 hours. After the reaction was complete, the reaction mixture was diluted with aqueous ammonia, and the organic layer was decanted. The organic layer was dried and removed by distillation to obtain the product described in the title. 1H NMR (DMSO-d6): 6.48-6.47 (t, J=1.6 Hz, 1H), 6.35-6.34 (t, J=1.6 Hz, 1H), 6.19-6.18 (t, J=1.6 Hz, 1H), 5.19 (s, 2H), 4.33-4.30 (t, J=6 Hz, 2H), 4.11-4.06 (q, J=7.2 Hz, 2H), 3.72 (s, 3H), 2.70-2.67 (t, J=6 Hz, 2H), 2.08 (s, 3H), 1.20-1.16 (t, J=6.8 Hz, 3H). ESI-MS (m / z): 281.15 (M+H) + .

[0108] Preparation of 3-(((1-(3-amino-5-methoxyphenyl)ethylidene)amino)oxy)propanenitrile (V-26) [ka] Prepared using the same process as described in V-25, but with acrylonitrile instead of ethyl acrylate. ESI-MS (m / z): 234.14 (M+H) + .

[0109] Preparation of 2-(((1-(3-amino-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanenitrile (V-27) [ka] It was prepared using the same process as described in V-3, but with 2-bromo-2-methylpropanenitrile instead of 2-bromoethanol. ESI-MS (m / z): 248.40 (M+H) + .

[0110] Preparation of compounds Example 1 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] Step 1: Preparation of tert-butyl 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] To a stirred solution of intermediate IV-1 (300 mg, 0.651 mmol) in DMF (5 ml), intermediate V-1 (230 mg, 0.781 mmol), followed by triethylamine (0.13 ml, 0.977 mmol), was added. The resulting mixture was stirred at 80°C for 14 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the product described in the title. ESI-MS (m / z): 702.20 (M+H) + .

[0111] Step 2: Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] To a stirred solution of the product obtained in Step 1 (15 g, 21.36 mmol) in DCM (150 mL), TFA (11.52 mL, 150 mmol) was added, and the resulting mixture was stirred at RT for 4 hours. After the starting materials had completely transformed, the reaction mixture was diluted with cold water and extracted with DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. 1 H NMR (DMSO-d6): 8.03 (s, 1H), 7.56-7.54 (d, 2H),7.45-7.43 (d, 2H), 7.00-6.98 (m, 1H), 6.92-6.90 (m, 1H), 6.63-6.61 (m, 2H), 6.39 (s, 1H), 6.32 (s, 1H), 5.50-5.48 (m, 1H), 4.56-4.54 (m, 1H), 4.08-4.05 (m, 1H), 3.65 (s, 3H), 2.08 (s, 3H), 1.42-1.41 (d, 6H), 1.12-1.04 (m, 4H). ESI-MS (m / z): 646.5 (M+H) + .

[0112] Example 2 Preparation of (+) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The enantiomers of Example 1 were separated by preparative HPLC ((YMC-Choral Amylose-C (250 x 4.6 mm) 5.0 u), 0.1% TFA in methanol-hexane (20.20), wavelength 220 nm) (t=20.20 min; ee=93.20%). 1H NMR (DMSO-d6): 8.03 (s, 1H), 7.56-7.54 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (m, 1H), 6.93-6.92 (m, 1H), 6.65-6.61 (m, 1H), 6.39 (s, 1H), 6.32 (s, 1H), 5.51-5.49 (m, 1H), 4.56-4.54 (m, 1H), 4.07-4.05 (m, 1H), 3.65 (s, 3H), 2.09 (s, 3H), 1.44-1.13 (d, 6H), 1.15-1.08 (m, 4H). ESI-MS (m / z): 646.30 (M+H) + .

[0113] Example 3 Preparation of (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The enantiomers of Example 1 were separated by preparative HPLC ((YMC-Choral Amylose-C (250 x 4.6 mm) 5.0 u), 0.1% TFA in methanol-hexane (8.764), wavelength 220 nm) (t=8.764 min; ee=95.74%). 1H NMR (DMSO-d6): 8.03 (s, 1H), 7.55-7.54 (d, 2H). 7.45-7.44 (d, 2H) 7.01-6.99 (m, 1H), 6.93-6.91 (m, 1H), 6.66-6.64 (m, 1H), 6.39 (s, 1H), 6.32 (s, 1H), 5.50-5.48 (m, 1H), 4.56-4.54 (m, 1H), 4.07-4.05 (m, 1H), 3.65 (s, 3H), 2.09 (s, 3H), 1.44-1.42 (s, 6H), 1.14-1.06 (m, 4H). ESI-MS (m / z): 646.30 (M+H) + .

[0114] Example 4 Preparation of 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] Step 1: Preparation of ethyl 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoate [ka] To a stirred solution of intermediate IV-1 (300 mg, 0.651 mmol) in DMF (5 ml), intermediate V-25 (230 mg, 0.781 mmol), followed by triethylamine (0.13 ml, 0.977 mmol), was added. The resulting mixture was stirred at 80°C for 3 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 660.12 (M+H) + .

[0115] Step 2: Preparation of 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] To a stirred solution of the product obtained in step 1 (100 mg, 0.155 mmol) in 50% methanol:THF (5 mL), 4 mL of aqueous solution of sodium hydroxide (18.57 mg, 0.46 mmol) was added, and the resulting mixture was stirred at RT for 4 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water, acidified with aqueous HCl, and extracted by DCM. The organic layer was separated, washed with water, evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the title product. 1H NMR (DMSO-d6): 8.03 (s, 1H), 7.57-7.55 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (m, 1H), 6.93-6.91 (d, 1H), 6.64-6.62 (d, 1H), 6.45-6.43 (m, 1H), 6.33 (m, 1H), 5.52 (s, 1H), 4.58-4.55 (d, 1H), 4.27 (t, 2H), 4.13-4.07 (d, 1H), 3.67 (s, 3H), 2.58 (t, 2H), 2.05 (s, 3H), 1.17-1.07 (m, 4H). ESI-MS (m / z): 632.2 (M+H) + .

[0116] Example 5 Preparation of (+) 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] The enantiomers of Example 4 were separated by preparative HPLC (column - Chiral PAK IG (250*30) mm*10 μm (Diacel), 0.1% TFA in 2-propanol: 0.1% TFA in hexane, isocratic elution (40:60), wavelength 210 nm) (t=12.990 min; ee=100%). 1H NMR (DMSO-d6): 8.03 (s, 1H), 7.57-7.55 (m, 2H), 7.46-7.44 (m, 2H), 6.99-6.98 (m, 1H), 6.93-6.91 (d, 1H), 6.64 (s, 1H), 6.43-6.42 (m, 1H), 6.33-6.32 (m, 1H), 5.52 (s, 1H), 4.58-4.55 (d, 1H), 4.27 (t, 2H), 4.10-4.07 (d, 1H), 3.67 (s, 3H), 2.58 (t, 2H), 2.05 (s, 3H), 1.15-1.07 (m, 4H). ESI-MS (m / z): 632.22 (M+H) + .

[0117] Example 6 Preparation of (-) 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] The enantiomers of Example 4 were separated by preparative HPLC (column - Chiral PAK IG (250*30) mm*10 μm (Diacel), 0.1% TFA in 2-propanol: 0.1% TFA in hexane, isocratic elution (40:60), wavelength 210 nm) (t=9.347 min; ee=100%). 1H NMR (DMSO-d6): 8.03 (s, 1H), 7.57-7.55 (m, 2H), 7.46-7.44 (m, 2H), 7.01-6.98 (m, 1H), 6.93-6.91 (d, 1H), 6.64 (s, 1H), 6.43-6.42 (m, 1H), 6.33 (m, 1H), 5.52 (s, 1H), 4.58-4.55 (d, 1H), 4.27 (t, 2H), 4.10-4.07 (d, 1H), 3.67 (s, 3H), 2.58 (t, 2H), 2.05 (s, 3H), 1.15-1.07 (m, 4H). ESI-MS (m / z): 632.21 (M+H)+.

[0118] Example 7 Preparation of 2-(4-chlorophenyl)-2-((3-(1-((2-hydroxyethoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one [ka] To a stirred solution of intermediate IV-1 (400 mg, 0.89 mmol) in DMF (5 mL), intermediate V-3 (200 mg, 0.89 mmol), followed by triethylamine (0.14 mL, 1.07 mmol), was added, and the resulting mixture was stirred at 80°C for 3 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the title product. 1H NMR (DMSO-d6): 8.03 (s, 1H), 7.58-7.56 (d, 2H), 7.46-7.44 (d, 2H), 6.96-6.92 (m, 2H), 6.72 (br, 1H), 6.64 (s, 1H), 6.43 (s, 1H), 6.32 (s, 1H), 5.52 (s, 1H), 4.64-4.58 (d, 1H), 4.10-4.07 (m, 3H), 3.84 (s, 3H), 3.74-3.60 (m, 2H), 2.09 (s, 3H), 1.24-1.09 (m, 4H). ESI-MS (m / z): 604.2 (M+H) + . The following compounds were prepared in a similar manner, making full use of the appropriate starting materials and suitable modifications of the processes described in the preparations of Examples 1-7 (including suitable additions and / or deletions of steps as appropriate, as necessary), within the scope of the art.

[0119] Example 8 Preparation of 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid [ka] The solution was prepared using intermediates IV-1 and V-2. 1 H NMR (DMSO-d6): 12.53 (br, 1H), 8.02 (s, 2H), 7.56-7.54 (d, 2H), 7.46-7.44 (d, 2H), 7.01-7.07 (d, 1H), 6.99-6.93 (t, 1H), 6.63 (s, 1H), 6.38 -6.33 (d, 2H), 5.49 (s, 1H), 4.56-4.53 (d, 1H), 4.07-4.04 (d, 1H), 3.66 (s, 3H), 1.44-1.43 (s, 6H), 1.17-1.07 (m, 4H). ESI-MS (m / z): 632.15 (M+H) + .

[0120] Example 9 Preparation of (+) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid [ka] The enantiomers of Example 8 were separated by preparative HPLC (column - Chiral PAK IG (250*30) mm*10 μm (Diacel), 2-propanol-hexane, isocratic elution (40:60), wavelength 210 nm) (t=21.069 min; ee=97.15%). 1 H NMR (DMSO-d6): 11.55 (br, 1H), 8.02 (s, 2H), 7.55-7.54 (d, 2H), 7.46-7.44 (d, 2H), 7.43-7.42 (d, 1H), 7.01-7.07 (d, 1H), 6.99-6.93 (t, 1H), 6.62 (s, 1H), 6.40 (d, 1H), 6.38 (d, 1H), 5.49 (s, 1H), 4.56-4.53 (d, 1H), 4.07-4.04 (d, 1H), 3.66 (s, 3H), 1.44-1.43 (s, 6H), 1.17-1.07 (m, 4H). ESI-MS (m / z): 632.20 (M+H) + .

[0121] Example 10 Preparation of (-) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid [ka] The enantiomers of Example 8 were separated by preparative HPLC (column - Chiral PAK IG (250*30) mm*10 μm (Diacel), 2-propanol-hexane, isocratic elution (40:60), wavelength 210 nm) (t=17.093 min; ee=94.02%). 1 H NMR (DMSO-d6): 12.53 (br, 1H), 8.02 (s, 2H), 7.56-7.54 (d, 2H), 7.46-7.44 (d, 2H), 7.01-7.07 (d, 1H), 6.99-6.93 (t, 1H), 6.62 (s, 1H), 6.39 (s, 1H), 6.33 (s, 1H), 5.49 (s, 1H), 4.56-4.53 (d, 1H), 4.07-4.04 (d, 1H), 3.66 (s, 3H), 1.44-1.43 (d, 6H), 1.17-1.07 (m, 4H). ESI-MS (m / z): 632.20 (M+H) + .

[0122] Example 11 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The preparation was carried out using intermediates IV-6 and V-1. 1H NMR (DMSO-d6): 12.45(s, 1H), 7.92(s, 1H), 7.56-7.54(d, 2H), 7.46-7.44(d, 2H), 7.31-7.12(m, 1H), 6.94-6.86 (m, 2H), 6.84-6.80 (m, 2H), 6.62-6.36 (m, 2H), 5.50-5.48 (d, 1H), 4.55-4.52 (d, 1H), 4.03-4.00 (d, 1H), 3.65 (s, 3H ), 2.09 (s, 3H), 1.45-1.43 (d, 6H), 1.10-0.85 (m, 4H). ESI-MS (m / z): 628.20 (M+H) + .

[0123] Example 12 Preparation of 2-(((3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid [ka] The preparation was carried out using intermediates IV-6 and V-2. 1 H NMR (DMSO-d6):12.60 (s, 1H), 8.02(s, 1H), 7.91(s, 1H), 7.56-7.54(d, 2H), 7.46-7.44(d, 2H), 7.31-7.095(m, 1H), 6.95-6.94 (m, 1H), 6.85-6.80 (m, 2H), 6.67 (s, 1H), 6.60 (s, 1H), 6.38-6.34 (m, 2H), 5.48 (s, 1H), 4.54-4.52 (d, 1H), 4.02-3.99 (d, 1H), 3.73 (s, 3H), 1.44 (s, 6H), 1.04-0.91 (m, 4H). ESI-MS (m / z): 614.18 (M+H) + .

[0124] Example 13 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid [ka] The preparation was carried out using intermediates IV-1 and V-16. 1 H NMR (DMSO-d6):12.68 (br, 1H), 8.03 (s, 1H), 7.57-7.55 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (d, 1H), 6.96-6.92 (t, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 6.38-6.33 (d, 2H), 5.50 (s, 1H), 4.58-4.55 (d, 1H), 4.29-4.21 (d, 2H), 2.68-2.65 (d, 1H), 1.44-1.41 (d, 6H), 1.29-1.27 (m, 3H), 1.26-1.25 (m, 1H), 1.15-1.09 (m, 3H), 0.98-0.96 (m, 3H). ESI-MS (m / z): 660.22 (M+H) + .

[0125] Example 14 Preparation of (+) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid [ka] The enantiomers of Example 13 were separated by preparative HPLC (column - Chiral PAK IG (250*30) mm*10 μm (Diacel), 2-propanol-hexane, isocratic elution (40:60), wavelength 210 nm) (t=14.496 min; ee=95.32%). 1 H NMR (DMSO-d6): 12.55 (br, 1H), 8.03 (s, 1H), 7.57-7.55 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (d, 1H), 6.96-6.92 (t, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 6.38-6.33 (d, 2H), 5.50 (s, 1H), 4.58-4.55 (d, 1H), 4.29-4.21 (d, 2H), 2.68-2.65 (d, 1H), 1.44-1.41 (d, 6H), 1.29-1.27 (m, 3H), 1.26-1.25 (m, 1H), 1.15-1.09 (m, 3H), 0.98-0.96 (m, 3H). ESI-MS (m / z): 660.20 (M+H) + .

[0126] Example 15 Preparation of (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid [ka] The enantiomers of Example 13 were separated by preparative HPLC (column - Chiral PAK IG (250*30) mm*10 μm (Diacel), 2-propanol-hexane, isocratic elution (40:60), wavelength 210 nm) (t=12.767 min; ee=94.73%). 1H NMR (DMSO-d6): 12.55 (br, 1H), 8.03 (s, 1H), 7.57-7.55 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (d, 1H), 6.96-6.92 (t, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 6.38-6.33 (d, 2H), 5.50 (s, 1H), 4.58-4.55 (d, 1H), 4.29-4.21 (d, 2H), 2.68-2.65 (d, 1H), 1.44-1.41 (d, 6H), 1.29-1.27 (m, 3H), 1.26-1.25 (m, 1H), 1.15-1.09 (m, 3H), 0.98-0.96 (m, 3H). ESI-MS (m / z): 660.20 (M+H) + .

[0127] Example 16 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)-2-methylpropyridene)amino)oxy)-2-methylpropanoic acid [ka] The preparation was carried out using intermediates IV-1 and V-14. 11H NMR (DMSO-d6): 12.56 (broad, 1H), 8.03 (singlet, 1H), 7.56 - 7.54 (doublet, 2H), 7.46 - 7.44 (multiplet, 2H), 7.01 - 6.99 (doublet, 1H), 6.93 - 6.91 (doublet, 1H), 6.32 (singlet, 1H), 6.30 (singlet, 1H), 6.21 (singlet, 1H), 5.49 (singlet, 1H), 4.55 - 4.53 (doublet, 1H), 4.07 - 4.05 (doublet, 1H), 3.64 (singlet, 3H), 1.41 - 1.40 (doublet, 3H), 1.27 - 1.24 (doublet, 6H) 1.14 - 1.02 (multiplet, 5H), 0.93 - 0.89 (doublet, 4H). ESI-MS (m / z): 674.50 (M+H) + 。

[0128] Example 17 Preparation of 2 - ((((3 - ((1 - (4 - chlorophenyl) - 2 - oxo - 2 - (6' - (trifluoromethoxy)spiro[cyclopropane - 1,3' - indoline] - 1' - yl)ethyl)amino) - 5 - methoxyphenyl)(cyclopropyl)methylene)amino)oxy) - 2 - methylpropanoic acid

Chemical Structure

[0129] Example 18 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)-2,2,2-trifluoroethylidene)amino)oxy)-2-methylpropanoic acid [ka] The solution was prepared using intermediates IV-1 and V-18. 1 H NMR (DMSO-d6): 12.91 (s,1H), 8.03 (s, 1H), 7.56-7.54 (m, 2H). 7.46-7.44 (m, 2H) 7.01-6.99 (m, 1H), 6.96-6.91 (m, 1H), 6.45-6.43 (m, 2H), 6.31 (s, 1H), 5.51-5.49 (d, 1H), 4.55-4.52 (d, 1H), 4.05-4.06 (d, 1H), 3.67(s, 3H), 1.37 (s, 6H), 1.28-1.18 (m, 1H), 1.23-1.07 (m, 4H). ESI-MS (m / z): 700.08 (M+H) + .

[0130] Example 19 Preparation of 2-(((1-(3-methoxy-5-((2-oxo-1-phenyl-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The solution was prepared using intermediates IV-3 and V-1. 1H NMR (DMSO-d6): 12.50 (br, 1H), 8.05 (s, 1H), 7.56-7.54 (m, 2H), 7.41-7.38 (m, 2H), 7.34-7.32 (d, 1H), 6.989-6.986 (d, 1H), 6.93-6.91 (d, 1H), 6.63 (s, 1H), 6.56-6.55 (d, 1H), 6.39-6.38 (m, 2H), 5.46-5.45 (d, 1H), 4.59 (s, 1H), 4.01-3.99 (d, 1H), 3.66 (s, 3H), 2.09 (s, 3H), 1.44-1.43 (d, 6H), 1.20-1.08 (m, 4H). ESI-MS (m / z): 612.2 (M+H) + .

[0131] Example 20 Preparation of 2-(((1-(3-((1-(4-fluorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The preparation was carried out using intermediates IV-4 and V-1. 1 H NMR (DMSO-d6): 12.44 (s, 1H), 8.04 (s, 1H), 7.59-7.57 (m, 2H), 7.24-7.01 (m, 2H), 6.987-6.984 (d, 1H), 6.93-6.91 (d, 1H), 6.61-6.59 (d, 2H), 6.4-6.34 (m, 2H), 5.49-5.47 (d, 1H), 4.58-4.55 (d, 1H), 4.05-4.02 (d, 1H), 3.66 (s, 3H), 2.11 (s, 3H), 1.45-1.43 (d, 6H), 1.18-1.10 (m, 4H). ESI-MS (m / z): 630.23 (M+H) + .

[0132] Example 21 Preparation of 2 - ((((1 - (3 - ((1 - (2,4 - dichlorophenyl) - 2 - oxo - 2 - (6' - (trifluoromethoxy)spiro[cyclopropane - 1,3' - indoline] - 1' - yl)ethyl)amino) - 5 - methoxyphenyl)ethylidene)amino)oxy) - 2 - methylpropanoic acid [Chemical formula] It was prepared using Intermediate IV - 5 and Intermediate V - 1. 1 H NMR (DMSO - d6): 8.01 (s, 1H), 7.67 - 7.66 (d, 1H). 7.49 - 7.44 (m, 2H) 7.03 - 7.01 (m, 1H), 6.95 - 6.93 (m, 1H), 6.57 (m, 2H), 6.43 (s, 1H), 6.17 (s, 1H), 5.59 - 5.57 (d, 1H), 4.40 - 4.37 (d, 1H), 4.26 - 4.24 (d, 1H), 3.65 (s, 3H), 2.08 (s, 3H), 1.43 (s, 6H), 1.24 - 1.07 (m, 4H). ESI - MS (m / z): 680.20 (M + H) + .

[0133] Example 22 Preparation of 2 - ((((1 - (3 - ((1 - (5 - chloropyridin - 2 - yl) - 2 - oxo - 2 - (6' - (trifluoromethoxy)spiro[cyclopropane - 1,3' - indoline] - 1' - yl)ethyl)amino) - 5 - methoxyphenyl)ethylidene)amino)oxy) - 2 - methylpropanoic acid [Chemical formula] It was prepared using Intermediate IV - 2 and Intermediate V - 1. 1H NMR (DMSO-d6): 12.46 (br, 1H), 8.62-8.61 (d, 1H), 8.02-7.96 (m, 2H), 7.61-7.59 (d, 1H), 7.00-6.92 (m, 2H), 6.77-6.75 (d, 1H), 6.65 (s, 1H), 6.42 (s, 1H), 6.34 (s, 1H), 5.64-5.62 (d, 1H), 4.55-4.53 (d, 1H), 4.33-4.31 (d, 1H), 3.66 (s, 3H), 2.09 (s, 3H), 1.45-1.44 (d, 6H), 1.18-1.09 (m, 4H). ESI-MS (m / z): 647.16 (M+H) + .

[0134] Example 23 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The preparation was carried out using intermediates IV-7 and V-1. 1 H NMR (DMSO-d6): 12.44 (s, 1H), 7.77-7.76 (d, 1H), 7.57-7.55 (d, 2H), 7.46-7.43 (d, 2H), 6.72-6.70 (d, 1H), 6.62-6.57 (m, 3H), 6.40-6.39 (d, 2H), 5.49-5.47 (d, 1H), 4.51-4.48 (d, 1H), 4.04-3.97 (m, 1H), 3.70-3.66 (d, 3H), 3.33 (s, 3H), 2.10 (s, 3H), 1.46-1.44 (d, 6H), 1.20-1.06 (m, 4H). ESI-MS (m / z): 592.19 (M+H) + .

[0135] Example 24 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-morpholinospiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The solution was prepared using intermediates IV-9 and V-1. 1 H NMR (DMSO-d6): 12.55 (s, 1H), 8.02 (s, 1H), 7.86-7.56 (d, 1H), 7.54-7.45 (d, 2H), 7.43-7.42 (d, 2H), 6.61-6.39 (m, 2H), 6.32-6.32 (d, 1H), 6.42-6.34 (d, 1H), 5.46 (s, 1H), 4.45-4.44 (d, 2H), 4.01-3.97 (m, 2H), 3.76-3.74 (m, 2H), 3.73 (s, 3H),3.73-3.72 (m, 2H), 3.03-3.02 (m, 2H), 2.09 (s, 3H), 1.24 (s, 6H), 1.12-1.13 (m, 1H), 0.96-0.95 (m, 4H). ESI-MS (m / z): 647.3 (M+H) + .

[0136] Example 25 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)acetic acid [ka] The preparation was carried out using intermediates IV-1 and V-10. 1H NMR (DMSO-d6): 12.8 (br, 1H), 8.03 (s, 1H), 7.57-7.48 (d, 2H), 7.46-7.44 (d, 2H), 7.01-7.0 (d, 1H), 6.96-6.94 (d, 1H), 6.64 (s, 2H), 6.41 (s, 1H), 6.33 (s, 1H), 5.53 (s, 1H), 4.63 (s, 2H), 4.57-4.54 (d, 1H), 4.10-4.08 (d, 1H), 3.84 (s, 3H), 2.14 (s, 3H), 1.18-1.09 (m, 4H). ESI-MS (m / z): 618.22 (M+H) + .

[0137] Example 26 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] The preparation was carried out using intermediates IV-1 and V-11. 1 H NMR (DMSO-d6): 12.65 (s, 1H), 8.03 (s, 1H), 7.56-7.54 (m, 2H), 7.47-7.43 (dd, 2H), 7.01-6.98 (m, 1H), 6.96-6.91 (m, 1H), 6.39 (s, 1H), 6.34-6.31 (m, 1H), 5.51 (s, 1H), 4.66-4.65 (m, 1H), 4.56-4.54 (m, 1H), 4.09-4.06 (m, 2H), 3.66 (s, 3H ), 3.17 (s, 1H) ), 2.125-2.124 (d, 3H), 1.42-1.39 (m, 3H), 1.24-1.08 (m, 4H). ESI-MS (m / z): 632.15 (M+H) + .

[0138] Example 27 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid [ka] The solution was prepared using intermediates IV-1 and V-12. 1 H NMR (DMSO-d6): 12.59(s, 1H), 8.70 (s, 1H), 8.03 (s, 1H), 7.56-7.54 (d, 2H), 7.45-7.43 (d, 2H), 7.03-7.01 (d, 1H), 6.93-6.91 (d, 1H), 6.63-6.62 (d, 1H), 6.40-6.39 (m, 1H), 6.34-6.31 (m 1H), 5.51 (s 1H), 4.57-4.47 (m, 1H), 4.14-4.06 (m, 2H), 3.66 (s, 3H), 2.137-2.135 (d, 3H), 1.83-1.76 (m, 2H), 1.18-1.12 (m, 2H), 1.08 (s, 2H), 0.97-0.93 (m, 3H). ESI-MS (m / z): 646.2 (M+H) + .

[0139] Example 28 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-3-methylbutanoic acid [ka] The solution was prepared using intermediates IV-1 and V-13. 1H NMR (DMSO-d6): 12.63 (s, 1H), 8.033 (s, 1H), 7.56-7.54 (m, 2H), 7.45-7.43 (m, 2H), 7.01-6.99 (d, 1H), 6.93-6.91 (d, 1H), 6.68-6.63 (m, 2H), 6.39 (s, 1H), 6.33-6.31 (d, 1H), 5.52-5.50 (m, 1H), 4.57-4.53 (m, 1H), 4.32-4.30 (m 1H), 4.10-4.06 (m, 1H), 3.66 (s, 3H), 2.11 (s, 4H), 1.36-1.35 (m, 1H), 1.08 (S, 3H), 0.99-0.85 (m, 6H). ESI-MS (m / z): 660.25 (M+H) + .

[0140] Example 29 Preparation of 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)cyclobutane-1-carboxylic acid [ka] The solution was prepared using intermediates IV-1 and V-17. 1 1H NMR (DMSO-d6): 1H NMR (DMSO-d6): 12.20 (br, 1H), 8.03 (s, 1H), 7.57-7.55 (d, 2H), 7.46-7.44 (d, 2H), 6.92-6.90 (m, 2H), 6.64-6.62 (d, 2H), 6.42-6.33 (m, 2H), 5.52-5.50 (d, 1H), 4.81-4.55 (m, 2H), 4.10-4.06 (m, 1H), 3.66 (s, 3H), 2.97-2.67 (m, 1H), 2.55-2.52 (m, 4H), 2.20-2.08 (m, 3H), 1.16-1.09 (m, 4H). ESI-MS (m / z): 658.19 (M+H) + .

[0141] Example 30 Preparation of 4-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid [ka] The solution was prepared using intermediates IV-1 and V-9. 1 H NMR (DMSO-d6): 12.2 (br, 1H), 8.03 (s, 1H), 7.58-7.55 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (m, 1H), 6.94-6.92 (d, 1H), 6.64-6.63 (d, 1H), 6.433-6.428 (d, 1H), 6.33-6.32 (d, 2H), 5.53-5.50 (d, 1H), 4.8-4.55 (d, 1H), 4.10-4.06 (m, 3H), 3.67 (s, 3H), 2.31-2.27 (t, 2H), 2.29 (s, 3H), 1.86-1.83 (m, 2H), 1.21-1.10 (m, 4H). ESI-MS (m / z): 646.17 (M+H) + .

[0142] Example 31 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The preparation was carried out using intermediates IV-10 and V-1. 1 H NMR (DMSO-d6): 12.59 (s, 1H), 7.98 (s, 1H), 7.65-7.63 (d, 1H), 7.60-7.58 (d, 2H), 7.46-7.44 (dd, 2H), 7.11-7.09 (dd, 1H), 6.64-6.60 (m, 2H), 6.40-6.36 (m 2H), 5.64-5.63 (d, 1H), 4.70-4.67 (d, 1H), 4.11-4.09 (d, 1H), 3.66 (s, 3H), 2.33-2.26 (m, 3H), 2.10 (s, 3H), 1.99 (s, 3H ), 1.44-1.442 (d, 6H). ESI-MS (m / z): 660.25(M+H) + .

[0143] Example 32 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] The solution was prepared using intermediates IV-11 and V-1. 1H NMR (DMSO-d6): 12.59 (s, 1H), 8.00 (s, 1H), 7.59-7.57 (d, 2H), 7.46-7.44 (dd, 2H), 7.37-7.35(d, 1H), 7.06-7.04 (dd, 1H), 6.65(s, 2H), 6.40-6.36 (m 2H), 5.61 (s, 1H), 4.34-4.31 (d, 1H), 3.82-3.80 (d, 1H), 3.66 (s, 3H), 2.10 (s, 3H), 1.87- 1.71 (m, 6H), 1.70-1.61 (m, 1H), 1.53-1.49 (m, 1H), 1.448-1.446 (d, 6H). ESI-MS (m / z): 674.20 (M+H) + .

[0144] Example 33 Preparation of 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] The solution was prepared using intermediates IV-10 and V-25. 1 H NMR (DMSO-d6): 12.40 (br, 1H), 7.98 (s, 1H), 7.64-7.60 (m, 3H), 7.47-7.45 (d, 2H), 7.11-7.09 (d, 1H), 6.67 (s, 1H), 6.60-6.58 (d, 1H), 6.43-6.37 (d, 2H), 5.68-5.66 (d, 1H), 4.73-4.70 (d, 1H), 4.28-4.25 (t, 2H), 4.12-4.09 (d, 1H), 3.68 (s, 3H), 2.60-2.57 (t, 2H), 2.35-2.29 (m, 3H), 2.06-2.03 (m, 4H), 2.01-1.96 (m, 2H). ESI-MS (m / z): 646.20 (M+H) + .

[0145] Example 34 Preparation of 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] The solution was prepared using intermediates IV-11 and V-25. 1 H NMR (DMSO-d6): 12.23 (s, 1H), 8.00 (s, 1H), 7.61-7.59 (m, 2H). 7.47-7.45 (m, 2H) 7.37-7.39 (m, 1H), 7.06-7.04 (m, 1H), 6.67 (s, 1H), 6.57-6.55 (m, 1H), 6.43-6.37 (d, 2H), 5.66-5.64 (d, 1H), 4.36-4.34 (d, 1H), 4.29 (m, 2H), 3.82-3.80 (d, 1H), 3.67 (s, 3H), 2.08 (s, 3H), 1.77-1.76 (m, 6H), 1.54-1.50 (m, 2H), 1.30-1.23 (m, 2H). ESI-MS (m / z): 660.25 (M+H) + .

[0146] Example 35 Preparation of 3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzaldehyde O-(2-hydroxyethyl)oxime [ka] The preparation was carried out using intermediates IV-1 and V-7. 1H NMR (DMSO-d6): 8.02 (s, 2H), 7.57-7.54 (d, 2H), 7.46-7.44 (d, 2H), 6.99-6.92 (t, 1H), 6.90-6.80 (d, 1H), 6.59 (s, 1H), 6.42-6.34 (m, 2H), 5.51 (s, 1H), 4.56-4.54 (d, 1H), 4.10-4.06 (m, 3H), 3.73 (s, 3H), 3.63-3.60 (t, 3H), 1.24-1.09 (m, 4H). ESI-MS (m / z): 590.5 (M+H) + .

[0147] Example 36 Preparation of 2-(4-chlorophenyl)-2-((3-(1-(((1-hydroxy-2-methylpropane-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one [ka] The preparation was carried out using intermediates IV-1 and V-5. 1 H NMR (DMSO-d6): 8.04 (s, 1H), 7.57-7.55 (d, 2H), 7.47-7.45 (d, 2H), 7.01-6.99 (d, 1H), 6.93-6.91 (d, 1H), 6.62 (s, 1H), 6.42 (s, 1H), 6.33 (s, 1H), 5.49 (s, 1H), 4.58-4.55 (d, 1H), 4.07-4.04 (d, 1H), 3.71 (s, 3H), 3.64 (s, 1H), 3.39 (s, 2H), 2.05 (s, 3H), 1.28-1.09 (m, 10H). ESI-MS (m / z): 632.21 (M+H) + .

[0148] Example 37 Preparation of 3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzaldehyde O-(1-hydroxy-2-methylpropane-2-yl)oxime [ka] The preparation was carried out using intermediates IV-1 and V-8. 1 H NMR (DMSO-d6): 8.06-8.01 (m, 1H), 7.73-7.70 (m, 1H), 7.58-7.53 (m, 2H), 7.47-7.45 (d, 2H), 7.23-7.13 (m, 1H), 7.03-6.96 (m, 1H), 6.88 (br, 1H), 6.67 (s, 1H), 6.42-6.35 (m, 2H), 5.48 (s, 1H), 4.59-4.56 (d, 1H), 4.14-4.09 (d, 1H), 3.85 (br, 1H), 3.67 (s, 3H), 3.39 (s, 2H), 1.35-1.30 (d, 6H), 1.22-1.02 (m, 4H). ESI-MS (m / z): 618.17 (M+H) + .

[0149] Example 38 Preparation of 2-(4-chlorophenyl)-2-((3-(1-((2-hydroxy-2-methylpropoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one [ka] The preparation was carried out using intermediates IV-1 and V-6. 1H NMR (DMSO-d6): 8.03 (s, 1H), 7.57-7.55 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (m, 1H), 6.94-6.91 (d, 1H), 6.64-6.63 (d, 2H), 6.43-6.42 (t, 1H), 6.33-6.32 (t, 1H), 5.52-5.50 (d, 1H), 4.58-4.55 (d, 1H), 4.46 (s, 1H), 4.10-4.07 (d, 1H), 3.89 (s, 2H), 3.33 (s, 3H), 2.11 (s, 3H), 1.16-1.08 (m, 10H). ESI-MS (m / z): 632.20 (M+H) + .

[0150] Example 39 Preparation of 2-(4-chlorophenyl)-2-((3-(1-((3-hydroxypropoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one [ka] The solution was prepared using intermediates IV-1 and V-4. 1 H NMR (DMSO-d6): 8.03 (s, 1H), 7.58-7.56 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (d, 2H), 6.94-6.92 (d, 2H), 6.64-6.62 (d, 1H), 6.32 (s, 1H), 5.53-5.50 (d, 1H), 4.58-4.55 (d, 1H), 4.47 (s, 1H), 4.14-4.08 (m, 3H), 3.67 (s, 3H), 3.49-3.48 (d, 2H), 2.07 (s, 3H), 1.80-1.74 (m, 2H), 1.24-1.02 (m, 4H). ESI-MS (m / z): 618.18 (M+H) + .

[0151] Example 40 Preparation of 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] Step 1: Preparation of tert-butyl 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-methoxy-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] To a stirred solution of VI-3 (400 mg, 1.36 mmol) in DMF (15 mL), intermediate V-1 (439 mg, 1.36 mmol), followed by triethylamine (0.28 mL, 2.04 mmol), was added. The resulting mixture was heated at 80°C for 3 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. ESI-MS (m / z): 535.03 (M+H) + .

[0152] Step 2: Preparation of 2-((3-(1-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-chloro-2-methoxyphenyl)acetic acid [ka] To a stirred solution of the product obtained in step 1 (600 mg, 1.12 mmol) in 50% methanol:THF (10 mL), 4 mL of aqueous sodium hydroxide (135 mg, 3.36 mmol) was added, and the resulting mixture was stirred at 40°C for 4 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water, acidified with aqueous HCl, and extracted by DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. ESI-MS (m / z): 521.03 (M+H) + .

[0153] Step 3: Preparation of tert-butyl 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] To a stirred solution of the product obtained in step 2 (250 mg, 0.48 mmol) in DMF (5 mL), intermediate II-1 (110 mg, 0.48 mmol), followed by HATU (146 mg, 1.44 mmol) and DIPEA (0.25 mL, 1.44 mmol) were added at 0-10°C. The resulting mixture was stirred at the same temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. ESI-MS (m / z): 733.10 (M+H) + .

[0154] Step 4: Preparation of 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] To a stirred solution of the product obtained in step 3 (300 mg, 0.445 mmol) in DCM (15 mL), TFA (39.2 mg, 0.979 mmol) was added, and the resulting mixture was stirred at room temperature for 4 hours. After the starting materials had completely transformed, the reaction mixture was diluted with cold water and extracted with DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. 1 H NMR (DMSO-d6): 12.60-12.39 (br, 1H), 8.02 (s, 1H), 7.35-7.33 (d, 1H), 7.15-7.14 (d, 1H), 7.05-7.02 (m, 2H), 6.99-6.98 (d, 1H), 6.66-6.64 (d, 1H), 6.58 (s, 1H), 6.40 (s, 1H), 6.23 (s, 1H), 5.60-5.58 (d, 1H), 4.42-4.40 (d, 1H), 4.09-4.06 (d, 1H), 3.65 (s, 3H), 3.34 (s, 3H), 2.12 (s, 3H), 1.44 (s, 6H), 1.18-1.09 (m, 4H). ESI-MS (m / z): 676.2 (M+H) + .

[0155] Example 41 Preparation of 2-(((1-(3-((1-(4-chloro-2-(2-hydroxyethoxy)phenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] Step 1: Preparation of tert-butyl 2-(((1-(3-((1-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)-2-ethoxy-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] To a stirred solution of intermediate VI-4 (1.3 g, 2.88 mmol) in DMF (15 mL), intermediate V-1 (0.83 mg, 2.59 mmol) was added, followed by triethylamine (1.28 mL, 8.64 mmol). The resulting mixture was heated at 80°C for 12 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. ESI-MS (m / z): 693.34 (M+H) + .

[0156] Step 2: Preparation of 2-((3-(1-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)acetic acid [ka] To a stirred solution of the product obtained in Step 1 (600 mg, 1.15 mmol) in 50% methanol:THF (10 mL), 4 mL of aqueous sodium hydroxide (131 mg, 3.39 mmol) was added, and the resulting mixture was stirred at RT for 4 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water, acidified with citric acid, and extracted by DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. ESI-MS (m / z): 665.32 (M+H) + .

[0157] Step 3: Preparation of tert-butyl(E)-2-(((1-(3-((1-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] To a stirred solution of the product obtained in step 2 (1.5 g, 2.25 mmol) in DMF (20 mL), the product obtained in intermediate II-1 (0.517 g, 2.25 mmol), followed by HATU (1.28 g, 3.38 mmol) and DIPEA (1.18 mL, 6.76 mmol) were added at 0-10°C. The resulting mixture was stirred at RT for 1 hour. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 876.38 (M+H) + .

[0158] Step 4: Preparation of 2-(((1-(3-((1-(4-chloro-2-(2-hydroxyethoxy)phenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] To a stirred solution of the product obtained in step 3 (0.8 g, 0.913 mmol) in DCM (10 mL), TFA (0.70 mL, 9.13 mmol) was added at 0°C, and the resulting mixture was stirred at RT for 4 hours. After the starting materials had been completely converted, the reaction mixture was diluted with cold water and extracted with DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. 1 H NMR (DMSO-d6): 12.6 (br, 1H), 8.03 (s, 1H), 7.41-7.39 (d, 1H), 7.146-7.141 (d, 1H), 7.04-7.02 (m, 2H), 6.982-6.979 (d, 1H), 6.69 (br, 1H), 6.62 (s, 1H), 6.40-6.396 (d, 1H), 6.29 (s, 1H), 5.73 (s, 1H), 4.46-4.44 (d, 1H), 4.19-4.15 (d, 1H), 4.09-4.04 (m, 2H), 3.99 (br, 1H), 3.78-3.73 (m, 2H), 3.65 (s, 3H), 2.09 (s, 3H), 1.44 (s, 6H), 1.18-1.10 (m, 4H). ESI-MS (m / z): 706.22 (M+H) + .

[0159] Example 42 Preparation of 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] Step 1: Preparation of ethyl 3-(((1-(3-((2-(benzyloxy)-1-(4-chloro-2-methoxyphenyl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoate [ka] To a stirred solution of intermediate VI-2 (400 mg, 1.36 mmol) in DMF (15 mL), V-25 (439 mg, 1.36 mmol), followed by triethylamine (0.28 mL, 2.04 mmol), was added. The resulting mixture was heated at 80°C for 4 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain the title product. ESI-MS (m / z): 569.20 (M+H) + .

[0160] Step 2: Preparation of 2-(4-chloro-2-methoxyphenyl)-2-((3-(1-((3-ethoxy-3-oxopropoxy)imino)ethyl)-5-methoxyphenyl)amino)acetic acid [ka] To a stirred solution of the product obtained in step 1 (500 mg, 0.879 mmol) in 50% methanol:THF (5 mL), Pd / C (94 mg, 0.879 mmol) was added, and the resulting mixture was stirred under hydrogen pressure in RT for 4 hours. After the starting materials were completely converted, the reaction mixture was filtered through a high-flow filter, and the filtrate was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the title product. ESI-MS (m / z): 479.16 (M+H) + .

[0161] Step 3: Preparation of ethyl 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoate [ka] To a stirred solution of the product obtained in step 2 (250 mg, 0.48 mmol) in DMF (5 ml), intermediate II-1 (110 mg, 0.48 mmol), followed by HATU (146 mg, 1.44 mmol) and DIPEA (0.27 mL, 1.44 mmol) were added at 0-10°C. The resulting mixture was stirred at the same temperature for 1 hour. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. ESI-MS (m / z): 690.23 (M+H) + .

[0162] Step 4: Preparation of 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] To a stirred solution of the product obtained in step 3 (270 mg, 0.391 mmol) in THF (2 mL), 2 mL of aqueous sodium hydroxide (49.3 mg, 1.174 mmol) was added, and the resulting mixture was stirred at RT for 4 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water, acidified with aqueous HCl, and extracted by DCM. The organic layer was separated, washed with water, evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the title product. 1 H NMR (DMSO-d6): 8.02 (s, 1H), 7.36-7.34 (d, 1H), 7.148-7.143 (d, 1H), 7.04-6.98 (m, 2H), 6.95-6.91 (m, 1H), 6.60 (s, 1H), 6.43 (s, 1H), 6.24 (s, 1H), 5.60 (s, 1H), 4.44-4.38 (m, 1H), 4.27 (t, 2H), 4.13-4.08 (d, 1H), 3.90 (s, 3H), 3.66 (s, 3H), 2.60 (t, 2H), 2.04 (s, 3H), 1.19-1.10 (m, 4H). ESI-MS (m / z): 662.20 (M+H) + .

[0163] Example 43 Preparation of (+) 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] The enantiomers of Example 42 were separated by preparative HPLC (column: YMC-Choral cellulose-SZ (250 × 4.6 mm) 5.0 μm) with 0.1% TFA in ethanol-hexane (0.5:95), wavelength 220 nm) (t = 22.898 min; ee = 93.60 %). 1 H NMR (DMSO-d6): 8.02 (s, 1H), 7.36-7.34 (d, 1H), 7.148-7.143 (d, 1H), 7.04-6.99 (m, 2H), 6.93-6.91 (d, 1H), 6.61 (s, 1H), 6.43 (s, 1H), 6.24 (s, 1H), 5.61 (s, 1H), 4.44-4.41 (d, 1H), 4.27 (t, 2H), 4.11-4.08 (d, 1H), 3.90 (s, 3H), 3.66 (s, 3H), 2.58 (t, 2H), 2.04 (s, 3H), 1.20-1.08 (m, 4H). ESI-MS (m / z): 662.24 (M+H) + .

[0164] Example 44 Preparation of (-) 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] The enantiomers of Example 42 were separated by preparative HPLC (column: YMC-Choral cellulose-SZ (250 × 4.6 mm) 5.0 μm) with 0.1% TFA in ethanol-hexane (0.5:95), wavelength 220 nm) (t = 15.205 min; ee = 99.14%). 1H NMR (DMSO-d6): 8.02 (s, 1H), 7.36-7.34 (d, 1H), 7.147-7.142 (d, 1H), 7.04-6.98 (m, 2H), 6.93-6.91 (d, 1H), 6.61 (s, 1H), 6.43 (s, 1H), 6.24 (s, 1H), 5.61 (s, 1H), 4.44-4.41 (d, 1H), 4.27 (t, 2H), 4.11-4.08 (d, 1H), 3.90 (s, 3H), 3.66 (s, 3H), 2.58 (t, 2H), 2.04 (s, 3H), 1.18-1.08 (m, 4H). ESI-MS (m / z): 662.21 (M+H) + .

[0165] Example 45 Preparation of 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid [ka] Step 1: Preparation of tert-butyl 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-methoxy-2-oxoethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoate [ka] Intermediates V-2 and VI-3 were used to prepare the product using the same process as described in Step 1 of Example 42. ESI-MS (m / z): 521.1 (M+H) + .

[0166] Step 2: Preparation of 2-((3-((((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)methyl)-5-methoxyphenyl)amino)-2-(4-chloro-2-methoxyphenyl)acetic acid [ka] The sample was prepared using the same process as described in Step 2 of Example 42. ESI-MS (m / z): 507.1 (M+H) + .

[0167] Step 3: Preparation of tert-butyl 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoate [ka] The sample was prepared using the same process as described in Step 3 of Example 42. ESI-MS (m / z): 718.2 (M+H) + .

[0168] Step 4: Preparation of 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid [ka] It was prepared using the same process as described in step 4 of Example 42. 1H NMR (DMSO-d6): 12.64-12.49 (br, 1H), 8.02 (s, 2H), 7.34-7.32 (d, 1H), 7.21-7.17 (d, 1H), 7.09-7.02 (m, 2H), 6.95-6.93 (d, 1H), 6.83-6.71(br, 1H), 6.54 (s, 1H), 6.39 (s, 1H), 6.26(s, 1H), 5.57 (s, 1H), 4.42-4.40 (d, 1H), 4.12-4.08 (d, 1H), 3.90 (s, 3H), 3.77 (s, 3H), 1.44 (s, 6H), 1.19-1.08 (m, 4H). ESI-MS (m / z): 662.27 (M+H) + .

[0169] Example 46 Preparation of 2-(((1-(3-methoxy-5-((1-(4-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] Step 1: Preparation of tert-butyl 2-(((1-(3-((2-ethoxy-1-(4-methoxyphenyl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] Intermediates V-1 and VI-5 were used to prepare the product by following a process similar to that described in Step 1 of Example 40. ESI-MS (m / z): 515.20 (M+H) + .

[0170] Step 2: Preparation of 2-((3-(1-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-methoxyphenyl)acetic acid [ka] It was prepared using the same process as described in Step 2 of Example 40.

[0171] Step 3: Preparation of tert-butyl 2-(((1-(3-methoxy-5-((1-(4-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] The sample was prepared using the same process as described in Step 3 of Example 40. ESI-MS (m / z): 698.20 (M+H) + .

[0172] Step 4: Preparation of 2-(((1-(3-methoxy-5-((1-(4-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] It was prepared using the same process as described in Step 4 of Example 40. 1H NMR (DMSO-d6): 8.04 (s, 1H), 7.46-7.45 (m, 2H). 6.99-6.89 (m, 4H) 6.61 (s, 1H), 6.44-6.34 (m, 3H), 5.38-5.36 (d, 1H), 4.59-4.57 (d, 1H), 3.97-3.95 (d, 1H), 3.66 (s, 3H), 3.32 (s, 3H), 2.09 (s, 3H), 1.44 (s, 6H), 1.16-1.07 (m, 4H). ESI-MS (m / z): 642.2 (M+H) + .

[0173] Example 47 Preparation of 2-(((1-(3-((1-(4-cyanophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] Step 1: Preparation of tert-butyl 2-(((1-(3-((1-(4-cyanophenyl)-2-ethoxy-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] Intermediates V-1 and VI-6 were used to prepare the product by following a process similar to that described in Step 1 of Example 40. ESI-MS (m / z): 510.26 (M+H) + .

[0174] Step 2: Preparation of 2-((3-(1-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-cyanophenyl)acetic acid [ka] Prepared using the same process as described in Step 2 of Example 40. ESI-MS (m / z): 482.23 (M+H) + .

[0175] Step 3: Preparation of tert-butyl 2-(((1-(3-((1-(4-cyanophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] The sample was prepared using the same process as described in Step 3 of Example 40. ESI-MS (m / z): 693.34 (M+H) + .

[0176] Step 4: 2-(((1-(3-(1-(4-cyanophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] It was prepared using the same process as described in Step 4 of Example 40. 1H NMR (DMSO-d6): 12.50 (br, 1H), 8.02 (s, 1H), 7.86-7.84 (d, 2H), 7.73-7.71 (d, 2H), 7.00-6.98 (m, 1H), 6.94-6.92 (d, 1H), 6.84 (br, 1H), 6.60 (s, 1H), 6.40 (s, 1H), 6.31 (s, 1H), 5.62 (s, 1H), 4.53-4.50 (d, 1H), 4.18-4.15 (d, 1H), 3.65 (s, 3H), 2.08 (s, 3H), 1.45-1.43 (d, 6H), 1.18-1.09 (m, 4H). ESI-MS (m / z): 637.24 (M+H) + .

[0177] Example 48 Preparation of 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] Step 1: Preparation of tert-butyl 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] Using intermediate II-6 and the product obtained in step 2 of Example 40, preparations were made using the same process as described in step 3 of Example 40. ESI-MS (m / z): 746.30 (M+H) + .

[0178] Step 2: Preparation of 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] It was prepared using the same process as described in Step 4 of Example 40. 1 H NMR (CDCl3): 8.10 (s, 1H), 7.40-7.37 (m, 2H), 6.98- 6.96 (m, 3H), 6.55-6.53 (m, 2H), 6.32-6.31 (m, 1H), 5.71 (s, 1H), 4.34-4.31 (d, 1H), 4.05 (s, 3H), 4.03 (s, 1H), 3.77 (s, 3H), 2.33-2.02 (m, 9H), 1.60-1.59 (d, 6H), 1.29-1.28 (t, 1H). ESI-MS (m / z): 690.27 (M+H) + .

[0179] Example 49 Preparation of 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] Step 1: Preparation of tert-butyl 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoate [ka] Using intermediate II-7 and the product obtained in step 2 of Example 40, preparations were made using the same process as described in step 3 of Example 40. ESI-MS (m / z): 760.30 (M+H) + .

[0180] Step 2: Preparation of 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid [ka] It was prepared using the same process as described in Step 4 of Example 40. 1 H NMR (CDCl3): 8.10 (s, 1H), 7.41-7.39 (d, 1H), 7.11-7.09 (m, 1H), 6.99-6.93 (m, 3H), 6.54-6.52 (d, 2H), 6.30 (s, 1H), 5.66 (s, 1H), 4.02-4.00 (m, 4H), 3.76-3.73 (m, 4H), 2.26 (s, 3H), 1.92-1.27 (m, 14H). ESI-MS (m / z): 704.26 (M+H) + .

[0181] Example 50 Preparation of 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] Step 1: Preparation of ethyl 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoate [ka] Using intermediate II-6 and the product obtained in step 2 of Example 42, preparations were made using the same process as described in step 3 of Example 42. ESI-MS (m / z): 704.2 (M+H) + .

[0182] Step 2: Preparation of 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] It was prepared using the same process as described in step 4 of Example 42. 1H NMR (DMSO-d6): 12.24 (s, 1H), 7.96(s, 1H), 7.65-7.633 (d, 1H), 7.36-7.634 (d, 1H), 7.17-7.16(m, 1H), 7.117-6.113 (m, 1H), 7.096-7.093 (m, 1H), 7.04-7.01 (m, 1H), 6.63 (s, 1H), 6.59-6.577 (d, 1H), 6.43-630 (m, 1H), 5.73-5.71 (d, 1H), 4.52-4.50 (d, 1H ), 4.29-4.26 (t, 2H), 4.19-4.16 (m 1H), 3.96 (s, 3H), 3.67 (s, 3H), 2.61-2.52 (m, 2H), 2.33-2.77 (m, 4H), 2.05 (s, 3H ), 2.00-1.96 (m, 2H ). ESI-MS (m / z): 676.20 (M+H) +

[0183] Example 51 Preparation of 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] Step 1: Preparation of ethyl 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoate [ka] Using intermediate II-7 and the product obtained in step 2 of Example 42, preparations were made using a process similar to that described in step 3 of Example 42.

[0184] Step 2: Preparation of 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid [ka] It was prepared using the same process as described in step 4 of Example 42. 1 H NMR (DMSO-d6): 12.21 (s, 1H), 8.00(s, 1H), 7.38-7.35 (m, 2H), 7.17-7.16(d, 1H), 7.06-7.02 (m, 2H), 6.62 (s, 1H), 6.56-6.54(d, 1H), 6.43 (s, 1H), 6.30 (s, 1H), 5.69-5.67 (d, 1H), 4.29-4.26 (t, 1H), 4.19-4.17 (d, 2H), 3.94 (s, 3H), 3.83-3.80 (d, 2H), 3.67 (s, 3H), 2.60-2.57 (t, 1H), 2.04 (s, 3H), 1.88-1.80 (m, 3H), 1.62-1.24 (m, 5H). ESI-MS (m / z): 690.20 (M+H) +

[0185] Example 52 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide [ka] To a stirred solution of the product obtained in Example 1 (400 mg, 0.619 mmol) in DCM (15 mL), EDC.HCl (237 mg, 1.24 mmol), followed by DMAP (7.6 mg, 0.062 mmol), was added, and the resulting mixture was stirred at RT for 1 hour. Methanesulfonamide (118 mg, 1.24 mmol) was added, and the resulting mixture was stirred at RT for 12 hours. After the starting materials had been completely converted, the reaction mixture was diluted with cold water, acidified with aqueous HCl solution, and extracted with DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the title product. 1 H NMR (DMSO-d6): 11.44 (s, 1H), 8.03 (s, 1H), 7.56-7.54 (d, 2H), 7.45-7.43 (d, 2H), 6.99-6.91 (m, 1H), 6.93-6.91 (d, 1H), 6.63 (s, 1H), 6.42-6.37 (m, 2H), 5.47 (s, 1H), 4.54-4.51 (d, 1H), 4.09-4.06 (d, 1H), 3.65 (s, 3H), .3.20 (s, 3H), 3.21 (s, 3H), 1.45-1.44 (d, 6H), 1.15-1.07 (m, 4H). ESI-MS (m / z): 723.4 (M+H) + .

[0186] Example 53 Preparation of (+) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide [ka] The enantiomers of Example 52 were separated by preparative HPLC (column: YMC-Choral cellulose-SZ (250 × 4.6 mm) 5.0 μm) in ethanol-hexane (10:90) with 0.1% TFA, wavelength 220 nm). (t = 9.658 min; ee = 99.74%) 1 H NMR (DMSO-d6): 11.44 (s, 1H), 8.03 (s, 1H), 7.56-7.54 (d, 2H), 7.45-7.43 (d, 2H), 6.99-6.91 (m, 1H), 6.93-6.91 (d, 1H), 6.63 (m, 2H), 6.32 (s, 1H), 6.42-6.37 (m, 1H), 5.47 (s, 1H), 4.54-4.51 (d, 1H), 4.09-4.06 (d, 1H), 3.65 (s, 3H), 3.21 (s, 3H), 2.15 (s, 3H), 1.45-1.44 (d, 6H), 1.15-1.07 (m, 4H). ESI-MS (m / z): 723.15 (M+H) + .

[0187] Example 54 Preparation of (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide [ka] The enantiomers of Example 52 were separated by preparative HPLC (column: YMC-Choral cellulose-SZ (250 × 4.6 mm) 5.0 μm) in ethanol-hexane (10:90) with 0.1% TFA, wavelength 220 nm) (t = 7.814 min; ee = 98.58%). 1H NMR (DMSO-d6): 11.44 (s, 1H), 8.03 (s, 1H), 7.56-7.54 (d, 2H), 7.45-7.43 (d, 2H), 6.99-6.91 (m, 1H), 6.93-6.91 (d, 1H), 6.63 (s, 2H), 6.42-6.37 (m, 2H), 5.47 (s, 1H), 4.54-4.51 (d, 1H), 4.09-4.06 (d, 1H), 3.65 (s, 3H), 3.21 (s, 3H), 2.16 (s, 3H), 1.45-1.44 (d, 6H), 1.15-1.07 (m, 4H). ESI-MS (m / z): 723.15 (M+H) + .

[0188] Example 55 Preparation of 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide [ka] The product obtained in Example 8 was prepared by following the same procedure as described in Example 52. 1 1H NMR (DMSO-d6): 1 H NMR (DMSO-d6): 12.52 (s, 1H), 8.08-8.02 (d, 2H), 7.55-7.53 (d, 2H), 7.45-7.43 (d, 2H), 7.01-6.93 (m, 1H), 6.93-6.91 (d, 1H), 6.74-6.72 (m, 1H), 6.60 (s, 1H), 6.40-6.36 (m, 2H), 5.47-4.45 (d, 1H), 4.54-4.51 (d, 1H), 4.07-4.04 (d, 1H), 3.65 (s, 3H), 3.16 (s, 3H), 1.43-1.42 (d, 6H), 1.15-1.11 (m, 4H). ESI-MS (m / z): 709.18 (M+H)+ .

[0189] Example 56 Preparation of (+) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide [ka] The enantiomers of Example 55 were separated by preparative HPLC (column - Chiral PAK IG (250*30) mm*10 μm (Diacel), 2-propanol-hexane, isocratic elution (40:60), wavelength 210 nm) (t=11.926 min; ee=98.43%). 1 H NMR (DMSO-d6): 12.52 (s, 1H), 8.08-8.03 (d, 2H), 7.56-7.54 (d, 2H), 7.45-7.43 (d, 2H), 6.99-6.91 (m, 1H), 6.93-6.91 (d, 1H), 6.74-6.72 (m, 1H), 6.63 (s, 1H), 6.42-6.37 (m, 2H), 5.47 (s, 1H), 4.54-4.51 (d, 1H), 4.09-4.06 (d, 1H), 3.65 (s, 3H), 3.21 (s, 3H), 1.45-1.44 (d, 6H), 1.15-1.07 (m, 4H). ESI-MS (m / z): 709.18 (M+H) + .

[0190] Example 57 Preparation of (-) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide [ka] The enantiomers of Example 55 were separated by preparative HPLC (column - Chiral PAK IG (250*30) mm*10 μm (Diacel), 2-propanol-hexane, isocratic elution (40:60), wavelength 210 nm) (t=9.295 min; ee=100%). 1 H NMR (DMSO-d6): 11.52 (s, 1H), 8.08 (d, 2H), 7.55-7.53 (d, 2H), 7.45-7.43 (d, 2H), 6.99-6.91 (m, 1H), 6.93-6.91 (d, 1H), 6.74-6.72 (m, 1H), 6.60 (s, 1H), 6.29-6.28 (m, 2H), 5.47 (s, 1H), 4.54-4.51 (d, 1H), 4.09-4.06 (d, 1H), 3.65 (s, 3H), 3.21 (s, 3H), 1.45-1.44 (d, 6H), 1.15-1.09 (m, 4H). ESI-MS (m / z): 709.18 (M+H) + .

[0191] Example 58 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide [ka] It was prepared using Example 31 by following the same procedure as described in Example 52. 1H NMR (DMSO-d6): 11.47(s, 1H), 7.98 (s, 1H), 7.65-7.58 (q, 3H), 7.45-7.43(d, 2H), 7.12-7.09 (dd, 1H), 6.65-6.60 (m, 2H), 6.416-6.412 (d, 2H), 5.60-5.58 (d, 1H), 4.67-4.64 (d, 1H ), 4.13-4.11 (d, 1H), 3.65 (s, 3H), 3.22 (s, 3H), 2.33-2.29 (m, 3H), 2.17 (s, 3H), 2.08-1.98 (m, 3H), 1.45-1.44 (d, 6H). ESI-MS (m / z): 737.20 (M+H) +

[0192] Example 59 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide [ka] It was prepared using Example 32, following the same procedure as described in Example 52. 1H NMR (DMSO-d6): 11.47(s, 1H), 8.01 (s, 1H), 7.59-7.57 (d, 2H), 7.45-7.42 (d, 2H), 7.38-7.35(d, 1H), 7.06-7.04 (dd, 1H), 6.64-6.58 (m, 2H), 6.42-6.40 (m, 2H), 5.57-5.54 (d, 1H), 4.30-4.27 (d, 1H ), 3.84-3.81 (d, 1H), 3.65 (s, 3H), 3.21 (s, 3H), 2.16 (s, 3H), 1.88 (s, 1H), 1.85- 1.76 (m, 3H), 1.74-1.63 (m, 3H), 1.53-1.48 (m, 1H), 1.45-1.44 (d, 6H). ESI-MS (m / z): 751.25 (M+H) + .

[0193] Example 60 Preparation of 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propenamide [ka] It was prepared using Example 45 by following the same procedure as described in Example 52. 1H NMR (DMSO-d6): 11.56 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 8.01 (d, 1H), 7.33-7.31 (d, 1H), 7.01-7.02 (m, 1H), 6.8 (s, 1H), 6.55 (s, 1H), 6.55 (s, 1H), 6.41 (s, 1H), 6.29 (s, 1H), 5.57 (s, 1H), 4.41-4.38 (d, 1H), 4.08-4.07 (d, 1H), 3.89 (s, 3H), 3.65 (s, 3H), 3.17 (s, 3H), 1.44-1.43 (d, 6H), 1.12-1.07 (m, 4H). ESI-MS (m / z): 739.30 (M+H) + .

[0194] Example 61 Preparation of 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propanamide [ka] The product obtained in Example 4 was prepared by following the same procedure as described in Example 52. 1H NMR (DMSO-d6): 11.78 (s, 1H), 8.04 (s, 1H), 7.58-7.56 (d, 2H), 7.46-7.44 (d, 2H), 7.01-6.99 (d, 1H), 6.96-6.92 (t, 1H), 6.65 (s, 1H), 6.44 (s, 1H), 6.33 (s, 1H), 5.53 (s, 1H), 4.58-4.55 (d, 1H), 4.32-4.29 (t, 2H), 4.10-4.07 (d, 2H), 3.67 (s, 3H), 3.21 (s, 3H), 2.68-2.65 (t, 2H), 2.06 (s, 3H), 1.20-1.09 (m, 4H). ESI-MS (m / z): 709.19 (M+H) + .

[0195] Example 62 Preparation of 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propanamide [ka] It was prepared using Example 51, following the same procedure as described in Example 52. 1H NMR (DMSO-d6): 11.47 (s, 1H), 8.00(s, 1H), 7.36 (s, 2H), 7.29 (s, 1H), 7.17(s, 1H), 7.04 (s, 2H), 6.62 (s, 1H), 6.56-6.54(d, 1H), 6.43 (s, 1H), 6.31 (s, 1H), 5.69-5.67 (d, 1H), 4.30 (s, 2H), 4.19-4.17 (d, 1H), 3.94 (s, 3H), 3.82-3.81 (d, 1H), 3.67 (s, 3H), 3.20 (s, 3H), 2.67 (s, 1H), 2.05 (s, 3H), 1.88-1.81 (m, 3H), 1.70-1.56 (m, 5H). ESI-MS (m / z): 767.26 (M+H) +

[0196] Example 63 Preparation of 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propanamide [ka] It was prepared using Example 42, following the same procedure as described in Example 52. 1H NMR (DMSO-d6): 11.78 (s, 1H), 8.03 (s, 1H), 7.36-7.34 (d, 1H), 7.149-7.144 (d, 1H), 7.05-7.01 (m, 2H), 6.99-6.986 (d, 1H), 6.61 (s, 1H), 6.44 (s, 1H), 6.25 (s, 1H), 5.61 (s, 1H), 4.44-4.42 (d, 1H), 4.32-4.29 (t, 2H), 4.10-4.08 (d, 2H), 3.91 (s, 3H), 3.67 (s, 3H), 3.20 (s, 3H), 2.68-2.65 (t, 2H), 2.05 (s, 3H), 1.17-1.09 (m, 4H). ESI-MS (m / z): 740.2 (M+H) + .

[0197] Example 64 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-isopropyl-2-methylpropanamide [ka] To a stirred solution of the product obtained in Example 1 (75 mg, 0.11 mmol) in 5 ml of dry DCM, DMAP (1.42 mg, 0.012 mmol) and propan-2-amine (8.23 mg, 0.139 mmol), followed by EDC-HCl (33.4 mg, 0.174 mmol), the resulting mixture was stirred at RT for 2 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water, acidified with aqueous HCl solution, and extracted with DCM. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the title product. 1H NMR (DMSO-d6): 8.02 (s, 1H), 7.55-7.53 (d, 2H), 7.45-7.43 (d, 2H), 6.98-6.90 (m, 3H), 6.60 (s, 1H), 6.40 (s, 1H), 6.33 (s, 1H), 5.47 (s, 1H), 4.65-4.54 (d, 1H), 4.05-4.03 (d, 1H), 3.83-3.94 (m, 2H), 3.65 (s, 3H), 2.15 (s, 3H), 1.38-1.36 (d, 6H), 1.17-1.08 (m, 4H), 1.03-1.02 (d, 6H). ESI-MS (m / z): 687.27 (M+H) + .

[0198] Example 65 Preparation of 2-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-1-morpholinopropan-1-one [ka] It was prepared using Example 1 by following the same procedure as described in Example 64. 1 H NMR (DMSO-d6): 8.02 (s, 1H), 7.55-7.53 (d, 2H), 7.46-7.44 (d, 2H), 6.98-6.91 (t, 1H), 6.90 (m, 1H), 6.61 (s, 1H), 6.35 (d, 2H), 5.47 (s, 1H), 4.65-4.54 (d, 1H), 4.06-4.03 (d, 1H), 3.65 (s, 3H), 3.35 (m, 4H), 3.12 (m, 4H), 2.10 (s, 3H), 1.47-1.46 (d, 6H), 1.18-1.07 (m, 2H), 1.03-1.02 (d, 3H). ESI-MS (m / z): 715.26 (M+H) + .

[0199] Example 66 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanamide [ka] It was prepared using Example 1 by following the same procedure as described in Example 64. 1 H NMR (DMSO-d6): 8.03 (s, 1H), 7.56-7.54 (m, 2H). 7.46-7.44 (m, 2H) 7.05-6.99 (m, 1H), 6.98 (m, 1H), 6.93-6.91 (m, 1H), 6.86 (m,1H), 6.64-6.62 (m, 2H), 6.41 (s, 1H), 6.33 (s, 1H), 5.50-5.48 (d, J =8.0 Hz, 1H), 4.56-4.53 (d, J =10.8 Hz, 1H), 4.07-4.04 (d, J =10.4 Hz, 1H), 3.66 (s, 3H), 2.14 (s, 3H), 1.40 (s, 6H), 1.16-1.08 (m, 4H). ESI-MS (m / z): 645.40 (M+H) +

[0200] Example 67 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-hydroxy-2-methylpropanamide [ka] Step 1: Preparation of N-(benzyloxy)-2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanamide [ka] To a stirred solution of the product obtained in Example 1 (0.20 g, 0.316 mmol) in dry DMF (5 ml), DIPEA (0.09 ml, 0.475 mmol) and O-benzylhydroxylamine (0.061 g, 0.38 mmol), followed by HATU (0.132 g, 0.348 mmol), the resulting mixture was stirred at RT for 2 hours. After the starting materials were completely converted, the reaction mixture was diluted with cold water, acidified with aqueous HCl solution, and extracted with ethyl acetate. The organic layer was separated, washed with water, and evaporated under reduced pressure to obtain the crude product, which was used directly in the next step.

[0201] Step 2: Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-hydroxy-2-methylpropanamide [ka] To a stirred solution of the product obtained in step 1 (0.30 g, 0.408 mmol) in 50% methanol:THF (5 mL), Pd / C (0.043 g, 4.08 μmol) was added, and the resulting mixture was stirred at room temperature under hydrogen pressure for 4 hours. After the starting materials were completely converted, the reaction mixture was filtered through a high flow filter, and the filtrate was evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain the title product. 1H NMR (DMSO-d6): 10.28 (s, 1H), 8.03 (s, 1H), 7.57-7.55 (d, 2H), 7.47-7.44 (d, 2H), 7.09-6.99 (t, 1H), 6.96-6.92 (m, 1H), 6.67 (s, 1H), 6.41 (s, 1H), 6.34 (s, 1H), 5.50 (s, 1H), 4.57-4.54 (d, 1H), 4.07-4.04 (d, 1H), 3.66 (s, 3H), 2.13 (s, 3H), 1.44-1.41 (d, 6H), 1.29-1.24 (d, 2H), 1.15-1.09 (m, 4H). ESI- ESI-MS (m / z): 661.21 (M+H) + .

[0202] Example 68 Preparation of 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanenitrile [ka] To a stirred solution of the product obtained from intermediate IV-1 (100 mg, 0.19 mmol) in DMF (5 ml), intermediate V-27 (48.3 mg, 0.19 mmol), followed by triethylamine (0.082 ml, 0.59.3 mmol), was added, and the resulting mixture was stirred at 80°C for 14 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. 1H NMR (DMSO-d6): 8.01 (s, 1H), 7.57 (d, 2H), 7.55-7.46 (d, 2H), 6.99-6.98 (d, 1H), 6.93-6.91 (d, 1H), 6.72-6.70 (m, 2H), 6.47-6.46 (m, 1H), 6.39-6.38 (m, 1H), 5.52-5.50 (d, 1H), 4.57-4.55 (d, 1H), 4.07-4.04 (d, 1H), 3.68 (s, 3H), 2.14 (s, 3H), 1.65 (s, 6H), 1.15-1.08 (m, 4H). ESI- ESI-MS (m / z): 627.20 (M+H) + .

[0203] Example 69 Preparation of 2-((3-(1-(((2-(1H-tetrazole-5-yl)propane-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one [ka] To a stirred solution of the product obtained in Example 68 (150 mg, 0.23 mmol) in dry DMF (10 ml), sodium azide (78 mg, 1.19 mmol), followed by ammonium chloride (64 mg, 1.19 mmol), was added, and the resulting mixture was stirred at 110°C for 14 hours. After the reaction was complete, the reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was separated, washed with water, evaporated under reduced pressure, and purified by column chromatography to obtain the title product. 1H NMR (DMSO-d6): 7.52 (s, 1H), 7.50-7.44 (d, 2H), 7.42-7.41 (d, 2H), 6.99-6.93 (d, 1H), 6.91-6.90 (d, 1H), 6.72-6.70 (m, 1H), 6.63 (s, 1H), 6.61-6.60 (m, 2H), 5.44-5.42 (d, 1H), 4.54-4.51 (d, 1H), 4.06-4.04 (d, 1H), 3.63 (s, 3H), 2.14 (s, 3H), 1.74-1.72 (d, 6H), 1.15-1.08 (m, 4H). ESI- ESI-MS (m / z): 670.25 (M+H) + .

[0204] Example 70 Preparation of 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanenitrile [ka] Intermediates IV-1 and V-26 were used to prepare the product by following a process similar to that described in Example 68. 1 H NMR (DMSO-d6): 7.57 (s, 1H), 7.55-7.46 (d, 2H), 7.44-7.43 (d, 2H), 6.99-6.98 (d, 1H), 6.93-6.91 (m, 1H), 6.91-6.90 (m, 2H), 6.65 (s, 1H), 6.35 (s, 1H), 5.54-5.51 (d, 1H), 4.57-4.55 (d, 1H), 4.26-4.24 (t, 2H), 4.08-4.06 (d, 1H), 3.67 (s, 3H), 2.89-2.86 (t, 2H), 2.11 (s, 3H), 1.15-1.09 (m, 4H). ESI- ESI-MS (m / z): 613.20 (M+H) + .

[0205] Example 71 Preparation of 2-((3-(1-((2-(1H-tetrazole-5-yl)ethoxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one [ka] The product obtained in Example 70 was prepared using the same process as described in Example 69. 1 H NMR (DMSO-d6): 7.57 (s, 1H), 7.55-7.46 (d, 2H), 7.44-7.44 (d, 2H), 6.99-6.98 (d, 1H), 6.93-6.91 (d, 1H), 6.59 (s, 1H), 6.36-6.32 (m, 2H), 5.51 (d, 1H), 4.58-4.56 (d, 1H), 4.44-4.41 (t, 2H), 4.10-4.07 (d, 1H), 3.66 (s, 3H), 3,27-3,24 (t, 2H), 1.99 (s, 3H), 1.15-1.09 (m, 4H). ESI- ESI-MS (m / z): 656.22 (M+H) + .

[0206] The following compounds were prepared in a similar manner, making full use of the appropriate starting materials and suitable modifications of the process described in the above-mentioned examples (including suitable additions and / or deletions of steps as appropriate); all within the scope of the art.

[0207] [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7] [Table A-8]

[0208] Biological data: Assay protocol for screening compounds using RT-PCR Mycoplasma-free VeroE6 cells were seeded in Complete MEM (Plain MEM + 10% FBS + 1X antibiotic) in 96-well plates at a density of 25,000 cells / well (100 μl / well), and incubated overnight at 37°C and 5% CO2. The following day, 10 6 The virus requiring PFU / mL (DENV2 NGC strain - New Guinea C) was added to cells in Plain MEM at 0.05 MOI and incubated at 37°C and 5% CO2 for 1 hour. After 1 hour, the virus was removed and the compound was added at the required concentration. After 48 hours, RNA was isolated from the supernatant. It was then reverse transcribed to cDNA, and the amount of virus was detected by RT-PCR. After denaturation at 95°C for 5 minutes, RT-PCR was performed for 45 cycles of 10 seconds at 95°C and 30 seconds at 60°C. Delta-delta-CT was calculated for all CT values. The inhibition rate was calculated by considering the delta-delta-CT of DMSO as 100% inhibition. The inhibition concentration (50%) was derived by plotting the data on a graph pad prism and performing nonlinear regression analysis.

[0209] The compound of the present invention is its DENV2 IC 50 As shown in (Table 5), it exhibits excellent antiviral efficacy.

[0210] Table 5: Bioactivity Data [Table 5-1] [Table 5-2] [Table 5-3] Examples 21, 32, 33, 34, 35, 37, 48, 49, 59, 62, 66, 68, 69, 70, 71, 72, 73, 76, 78, 98, 107, 108, 119, and 120 are DENV2 ICs in the range of less than 100 nM. 50 This shows the value.

[0211] The novel compound represented by formula (I) of the present invention, its tautomers, its stereoisomers, its suitable pharmaceutically acceptable salts, and its polymorphs can be formulated into suitable pharmaceutically acceptable compositions by combining them with suitable excipients in accordance with well-known techniques and processes and concentrations. Novel compounds represented by formula (I), their tautomers, their stereoisomers, suitable pharmaceutically acceptable salts thereof, and their polymorphs are useful as pharmaceuticals for mammalian infectious diseases, are suitable for humans and other warm-blooded animals, and may be administered orally, topically, or parenterally.

[0212] The amount of the active ingredient, i.e., the amount of the novel compound represented by formula (I), its tautomers, its stereoisomers, its suitable pharmaceutically acceptable salts, its polymorphs, and its unit dosage forms, may be broadly varied or adjusted depending on several factors, such as a particular method of administration, the potency of a particular compound, and the desired concentration.

[0213] Use of novel compounds represented by formula (I), their tautomers, their stereoisomers, suitable pharmaceutically acceptable salts thereof, and their polymorphs, for the treatment of virus-related disorders such as dengue fever.

[0214] A method for treating virus-related disorders such as dengue fever by administering therapeutically effective amounts of a novel compound represented by formula (I), its tautomers, its stereoisomers, a suitable pharmaceutically acceptable salt thereof, and its polymorphs to subjects requiring such treatment.

Claims

1. A novel compound represented by general formula (I), its tautomerized form, its stereoisomer, a suitable pharmaceutically acceptable salt thereof, and its polymorph, 【Chemistry 1】 During the ceremony, X is selected from an aryl ring, a heteroaryl ring, or a heterocyclyl ring; R 1 (C) 1 -C 6 ) alkyl, heterocyclyl, -OR 6 Selected from, here, (C 1 -C 6 Alkyl and heterocyclyl groups are independently unsubstituted or substituted with one or more preferred substituents; Y is selected from a carbocyclic ring or a heterocyclic ring; these are independently unsubstituted or substituted with one or more suitable substituents selected from (C 1 -C 6 )alkyl, -OR 6 , halogen; A and B are selected from either a carbon-cyclic or heterocyclic ring; R 2 and R 3 (C) 1 -C 6 ) alkyl, (C 2 -C 6 ) Alkenil, (C 2 -C 6 ) Alkinyl, (C 3 -C 6 )Cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy, -COR 6 ,-COOR 6 , -OR 6、 -OSO 2 CH 3 , -OCOR 6 , -S(O) p R 6 , -NR 6 R 7 ,-CONR 6 R 7 , -N(R 6 )COR 7 , -N(R 6 )COOR 7 , -N(R 6 )CONR 6 R 7、 -SO 2 NR 6 R 7 , -N(R 6 )SO 2 R 7 Selected from these, these are independently unsubstituted or substituted with one or more suitable substituents; R 4 is hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) Selected from cycloalkyl, haloalkyl, and heterocyclyl, these are independently unsubstituted or substituted with one or more preferred substituents; R 5 (C) 1 -C 6 ) alkyl, (C 3 -C 6 ) Selected from cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, and heterocyclylalkyl, these are independently unsubstituted or substituted with one or more suitable substituents; R 6 and R 7 is hydrogen, unsubstituted or substituted (C 1 -C 6 ) alkyl, (C 3 -C 6 ) independently selected from cycloalkyl and haloalkyl groups; R 6 and R 7 These, together with the N atoms attached to them, form a 5- to 8-membered heterocyclyl or heteroaryl ring; (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 6 )cycloalkyl is substituted; suitable substitutions are hydrogen, hydroxy, cyano, halo, nitro, haloalkyl, oxo, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heterocyclylalkyl, alkylsulfonyloxy, -COR 6 , -COOR 6 , -OR 6、 -S(O) p R 6 , -NR 6 R 7 , -CONR 6 R 7、 -CON(R 6 )OR 7 , -CON(R 6 )SO 2 R 7、 -N(R 6 )COR 7 , -N(R 6 )COOR 7 , -N(R 6 )CONR 6 R 7、 -SO 2 NR 6 R 7 , -N(R 6 )SO 2 R 7 selected from derivatives; R 6 and R 7 are as described above; p is selected from integers between 0 and 2; l is selected from integers between 1 and 4; m is an integer selected from 1 to 5; n is selected from integers between 1 and 4. A novel compound represented by the general formula (I), its tautomerized form, its stereoisomer, a suitable pharmaceutically acceptable salt thereof, and its polymorphs.

2. X is an aryl ring, and Y is a carbocyclic ring; A and B are carbocyclic or heterocyclic rings; R 1 , R 2 , and R 3 Hydrogen, cyano, halogen, (C 1 -C 6 ) alkyl, haloalkyl, heterocyclyl, and -OR 6 Selected from; R 4 and R 5 (C 1 -C 6 A compound represented by general formula (I) as described in claim 1, selected from alkyl groups.

3. A compound represented by the formula described in claim 1, wherein: 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; (+) 2-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; (+) 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; (-) 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(4-chlorophenyl)-2-((3-(1-((2-hydroxyethoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; (+) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; (-) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; (+) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)-2-methylpropyridene)amino)oxy)-2-methylpropanoic acid; 2-((((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)(cyclopropyl)methylene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)-2,2,2-trifluoroethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-methoxy-5-((2-oxo-1-phenyl-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-fluorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(2,4-dichlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(5-chloropyridine-2-yl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-morpholinospiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)acetic acid; 2-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-3-methylbutanoic acid; 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)cyclobutane-1-carboxylic acid; 4-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-(1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzaldehyde O-(2-hydroxyethyl)oxime; 2-(4-chlorophenyl)-2-((3-(1-(((1-hydroxy-2-methylpropane-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzaldehyde O-(1-hydroxy-2-methylpropane-2-yl)oxime; 2-(4-chlorophenyl)-2-((3-(1-((2-hydroxy-2-methylpropoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(4-chlorophenyl)-2-((3-(1-((3-hydroxypropoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chloro-2-(2-hydroxyethoxy)phenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; (+) 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; (-) 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-Methoxy-5-((1-(4-Methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-cyanophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; (+) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; (-) 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; (+) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; (-) 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclobutan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propenamide; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopentan-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propenamide; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propenamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-isopropyl-2-methylpropanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-1-morpholinopropan-1-one; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-hydroxy-2-methylpropanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanenitrile; 2-((3-(1-(((2-(1H-tetrazole-5-yl)propane-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 3-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanenitrile; 2-((3-(1-((2-(1H-tetrazole-5-yl)ethoxy)imino)ethyl)-5-methoxyphenyl)amino)-2-(4-chlorophenyl)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzaldehyde O-methyl oxime; 2-(4-chlorophenyl)-2-((3-methoxy-5-(1-(methoxyimino)ethyl)phenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)acetic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)propanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)butanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)acetic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)propanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)butanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-3-methylbutanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)propanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-3-methylbutanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)butanamide; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)butanamide; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-3-methyl-N-(methylsulfonyl)butanamide; 2-(((3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(4-chloro-2-methoxyphenyl)-2-((3-(1-((2-hydroxy-2-methylpropoxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(4-chloro-2-methoxyphenyl)-2-((3-(1-(((1-hydroxy-2-methylpropane-2-yl)oxy)imino)ethyl)-5-methoxyphenyl)amino)-1-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethane-1-one; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-N-(methylsulfonyl)acetamide; 4-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)butanoic acid; 2-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; 2-(((3-Methoxy-5-((2-Oxo-1-phenyl-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)benzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((3-Methoxy-5-((1-(4-Methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)benzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((3-((1-(2,4-dichlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxybenzylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-methoxy-5-((2-oxo-1-(tetrahydro-2H-pyran-4-yl)-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-fluorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-Methoxy-5-((2-Oxo-1-phenyl-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-Methoxy-5-((1-(4-Methoxyphenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-cyanophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(2,4-dichlorophenyl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(5-chloropyridine-2-yl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(6'-(trifluoromethyl)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-oxo-2-(5'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)-2,2,2-trifluoroethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-(difluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)propyridene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-((2-(6'-chloro-7'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-1-(4-chlorophenyl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 3-(((1-(3-((1-(4-chloro-2-methoxyphenyl)-2-(6'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)propanoic acid; 2-(((1-(3-((1-(4-chlorophenyl)-2-(6'-methoxyspiro[cyclopropane-1,3'-indoline]-1'-yl)-2-oxoethyl)amino)-5-methoxyphenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide; 2-(((1-(3-Methoxy-5-((1-(6-Methoxypyridine-3-yl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methylpropanoic acid; 2-(((1-(3-Methoxy-5-((1-(6-Methoxypyridine-3-yl)-2-oxo-2-(6'-(trifluoromethoxy)spiro[cyclopropane-1,3'-indoline]-1'-yl)ethyl)amino)phenyl)ethylidene)amino)oxy)-2-methyl-N-(methylsulfonyl)propanamide, The compound comprising the above.

4. Use of a novel compound represented by general formula (I) as described in claim 1 for the treatment of virus-related disorders selected from dengue fever.

5. Use of a compound represented by general formula (I) as described in claim 1, its tautomerized form, its stereoisomer, a suitable pharmaceutically acceptable salt thereof, and its polymorph in the manufacture of a pharmaceutical for the treatment of a virus-related disorder selected from dengue fever.

6. A pharmaceutical composition comprising a compound represented by the general formula (I) described in claim 1, its tautomerized form, its stereoisomer, a suitable pharmaceutically acceptable salt thereof, its polymorph, and a mixture thereof having a pharmaceutically acceptable carrier, solvent, diluent, binder, disintegrant, coating agent, filler, lubricant, and / or other suitable excipient.

Images