JP2020050635A - Biaryl sulfonamide derivative having inhibitory activity against cell invasion of filovirus - Google Patents

Abstract

To provide: a novel compound that inhibits cell invasion of filovirus; a medicinal composition that comprises the compound; an anti-filovirus agent or an inhibitor of cell invasion of filovirus; a method for inhibiting a process of cell invasion of filovirus; and a method for treating filovirus infection.SOLUTION: The purpose is achieved by providing: a compound represented by formula (I) or a hydrate thereof; or a pharmaceutically acceptable salt or hydrate thereof of the compound.SELECTED DRAWING: None

Description

  The present invention relates to a novel compound that inhibits entry of a filovirus into a cell, a pharmaceutical composition containing the compound, an anti-filovirus agent or an inhibitor of cell entry of a filovirus, or an inhibitor of a cell entry process of a filovirus. And methods for treating filovirus infections.

  The filoviridae family, which is a family of viruses having negative single-stranded RNA as a genome, includes Ebolavirus genus and Marburg virus genus, and is a virus of the filoviridae family (hereinafter referred to as "filovirus"). Is known to cause acute and highly lethal infections in humans or monkeys. Infections caused by the Ebola virus genus virus (herein referred to as “Ebola virus”) and Marburg virus genus virus (herein referred to as “Marburg virus”) contained in filovirus are Ebola hemorrhagic fever and Also known as Marburg hemorrhagic fever.

  At present, five Ebola viruses are phylogenetically known: Zaire, Sudan, Tai Forest, Bundibugyo and Reston, and only one type of Marburg virus is known. The Ebola and Marburg haemorrhagic fever have been sporadic epidemics in Africa, and Zaire was responsible for the Ebola epidemic in West Africa, which occurred in 2013-2015. The unprecedented epidemic of Ebola in West Africa in 2014 and the spread of the disease to Europe and the United States have recognized the need and urgency for the development and prevention of Ebola virus prophylactic and therapeutic agents. I'm in a hurry. However, at present, no effective preventive or therapeutic agent against filovirus including Ebola virus and Marburg virus has been put to practical use.

Non-Patent Document 1 describes that although an unapproved drug, an antibody drug using a cocktail of various monoclonal antibodies was actually used in an Ebola virus infected person, the plasma Ebola virus load decreased over time. Have been.
Non-Patent Document 2 discloses that in a clinical trial in Africa, Favipiravir (Avigan (registered trademark) tablet), a nucleic acid analog that is a low-molecular compound developed as a therapeutic agent for influenza, was actually used in persons infected with Ebola virus. As a result, it is described that a sufficient therapeutic effect was not confirmed.
Non-Patent Document 3 describes that BCX4430, a novel synthetic adenosine analog, inhibited filovirus infection in human cells by inhibiting viral RNA polymerase function.

Non-Patent Document 4 describes that a novel low molecular weight compound GS-5732 which is a monophosphoramidic acid prodrug of an adenosine analog has antiviral activity against Ebola virus.
Non-Patent Document 5 describes that as a result of evaluating the efficacy of a pyrazinecarboxamide derivative T-705 (Favipiravir) against Ebola virus (Zaire), it suppressed replication of the virus in cells and caused rapid virus clearance in mice. Is described.
Non-Patent Document 6 describes that two novel entry inhibitors (MBX2254 and MBX2270) that inhibit Ebola virus infection have been identified.

Lyon GM, et al. Clinical care of two patients with Ebola virus disease in the United States.N. Engl. J. Med., 371 (25): 2402-2409, 2014 Sissoko D, et al. Experimental treatment with favipiravir for Ebola virus disease (the JIKI Trial): a historically controlled, single-arm proof-of-concept trial in Guinea.PLOS Med., 13 (3): e1001967, 2016 Warren TK, et al. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430.Nature, 508 (7496): 402-405, 2014 Warren TK, et al. Therapeutic efficacy of the small molecule GS-5743 against Ebola virus in rhesus monkeys.Nature, 531 (7594): 381-385, 2016 Oestereich L, et al. Successful treatment of advanced Ebola virus infection with T-705 (favipiravir) in a small animal model.Antiviral Res., 105: 17-21, 2014 Basu A, et al. Novel small molecule entry inhibitors of Ebola virus. J. Infect. Dis., 212 (Suppl 2): S425-S434, 2015

  The present invention relates to a novel compound that inhibits entry of a filovirus into a cell, a pharmaceutical composition containing the compound, an anti-filovirus agent or an inhibitor of cell entry of a filovirus, or an inhibitor of a cell entry process of a filovirus. It is an object to provide a method, a method for treating a filovirus infection, and the like.

  Since filoviruses differ greatly in antigenicity between species, most of the monoclonal antibodies produced worldwide to date, including the antibody described in Non-Patent Document 1, are specific to Zaire, Not effective against other filoviruses. In addition, in the development of antibody drugs, there is a problem that the limits of mass production and restrictions such as cost are large. On the other hand, Favipiravir is expected to be an effective RNA polymerase inhibitor against a wide variety of RNA viruses including filovirus, and although its antiviral effect was confirmed in a mouse model infected with Ebola virus, Non-Patent Document 2 As described above, no sufficient antiviral effect was confirmed in clinical trials in Africa. In addition, Favipiravir has been confirmed to have side effects, and thus it is known that Favipiravir has a limitation even in use as a therapeutic agent for influenza.

  Thus, the present inventors have aimed at the practical application of effective prophylactic and therapeutic agents for the next generation of filovirus, and have continued research with an emphasis on the cell entry mechanism of filovirus. It was newly found to inhibit the cell entry process. Based on such knowledge, the present inventors have continued intensive studies, analyzed the structure-activity relationships of various biarylsulfonamide derivatives, optimized the structures of the compounds, and continued the research. As a result, the present invention was completed.

That is, the present invention relates to the following:
[1] Formula (I):
Where:
R ¹ is NO ₂ , NR ³ R ⁴ , or Het;
R ² is
Where
R ^{3 to} R ⁶ are each independently H, Alk, or Ar;
R ⁷ is H, Alk, or COOAlk;
Het is a monocyclic, bicyclic, or tricyclic heterocyclic group having 1-3 N and / or O, wherein the heterocyclic group is optionally R ⁸ and / or R ⁹ may be substituted where R ⁸ and R ⁹ are each, independently, H, Alk, or COOAlk;
Alk is each independently a linear or branched alkyl group having 1 to 10 carbon atoms,
Ar is an aryl group optionally substituted by halogen;
Or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.

[2] Het
The compound of [1] or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.
[3] The compound of [1] or [2] or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt thereof, wherein R ³ and R ⁴ are each independently a methyl group or an ethyl group. Hydrate.
[4] The compound of [1] to [3], wherein R ⁵ and R ⁶ are each Alk, and Alk is each independently a linear or branched alkyl group having 1 to 4 carbon atoms. A hydrate or a pharmaceutically acceptable salt of the compound or a hydrate thereof.

[5] R ² is
Or a hydrate thereof or a pharmaceutically acceptable salt of the compound or a hydrate thereof.

[6] R ¹ is NO ₂ , NH ₂ ,
The compound of [1] to [5] or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.

[7] The following chemical structural formula:
Or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.

[8] A pharmaceutical composition comprising the compound of [1] to [7] or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.
[9] The pharmaceutical composition of [8], for preventing and / or treating a viral infection.
[10] The pharmaceutical composition of [9], wherein the viral infection is an acute viral infection.
[11] The pharmaceutical composition of [10], wherein the acute viral infection is Ebola hemorrhagic fever.
[12] The pharmaceutical composition of [9], wherein the virus is a filovirus.
[13] The pharmaceutical composition of [12], wherein the filovirus is an Ebola virus.

[14] An antiviral agent comprising the compound of [1] to [7] or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.
[15] A virus cell entry inhibitor comprising the compound of [1] to [7] or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.
[16] A method for inhibiting the virus cell entry process using the compound of [1] to [7] or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.

  The compounds of the present invention can inhibit entry of filoviruses, including Ebola virus and Marburg virus, into cells, thereby inhibiting filovirus replication in cells. In addition, since the effect of the compound of the present invention on inhibiting the entry of a filovirus into cells is specific to the filovirus and its toxicity is low, infectious diseases associated with the filovirus with extremely high selectivity, such as Ebola hemorrhagic fever and Marburg It can be used for prevention and treatment of hemorrhagic fever. In addition, the compound of the present invention can inhibit cell entry regardless of the species of filovirus, and can therefore be used as a general antiviral agent for filovirus. Furthermore, the compound of the present invention is a biarylsulfonamide derivative, which is a low molecular weight compound, and thus can be industrially produced at a lower cost as compared with an antibody drug or the like. It can supply cheaply to domestic and foreign markets including certain African countries.

FIG. 1 shows a schematic diagram of a vesicular stomatitis virus (VSV) pseudotype system capable of measuring the cell entry inhibitory activity of a filovirus.

Hereinafter, the present invention will be described in detail.
Unless defined otherwise herein, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referred to herein are hereby incorporated by reference in their entirety. In the case of inconsistencies between the publication referred to in this specification and the description of this specification, the description of this specification shall control.

<1> Compound of the Present Invention In one aspect, the present invention provides the following formula (I):
Where:
R ¹ is NO ₂ , NR ³ R ⁴ , or Het;
R ² is
Where
R ^{3 to} R ⁶ are each independently H, Alk, or Ar;
R ⁷ is H, Alk, or COOAlk;
Het is a monocyclic, bicyclic, or tricyclic heterocyclic group having 1-3 N and / or O, wherein the heterocyclic group is optionally R ⁸ and / or R ⁹ may be substituted where R ⁸ and R ⁹ are each, independently, H, Alk, or COOAlk;
Alk is each independently a linear or branched alkyl group having 1 to 10 carbon atoms,
Ar is an aryl group optionally substituted by halogen;
Or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.

R ¹ is NO ₂ , NR ³ R ⁴ or Het, preferably NO ₂ , NH ₂ ,
And particularly preferably NO ₂ ,
It is.

R ² is
Wherein R ^{5 to} R ⁷ are preferably each independently a methyl group or an ethyl group. R ² is particularly preferably
It is.

R ^{3 to} R ⁶ are each independently H, Alk, Ar, or COOAlk, preferably H, Alk, or Ar, and particularly preferably a methyl group or an ethyl group.
R ⁷ is H, Alk, Ar, or COOAlk, preferably H, Alk, or COOAlk, and particularly preferably a methyl group or an ethyl group.
In some embodiments, R ³ is a methyl or ethyl group.
In some embodiments, R ³ and R ⁴ are each independently a methyl or ethyl group.
In some embodiments, R ⁵ and R ⁶ are each Alk, wherein Alk is each independently a straight-chain or branched alkyl group having 1 to 4 carbon atoms.
In some ^embodiments, R 5 to R ⁷ is a methyl group or an ethyl group.
In some embodiments, NR ³ R ⁴ is N (CH ₃ ) ₂ or N (CH ₂ CH ₃ ) ₂ .

“Het” is a monocyclic, bicyclic, or tricyclic heterocyclic group having 1 to 3 N and / or O, wherein the heterocyclic group optionally includes R ⁸ and And / or may be substituted by R ⁹ . Here, R ⁸ and R ⁹ are each independently H, Alk or COOAlk, preferably H, a methyl group, an ethyl group, or COO-t-butyl. “Het” is particularly preferably
It is.

“Alk” represents a straight-chain or branched alkyl group having 1 to 10 carbon atoms, and preferably represents a straight-chain or branched alkyl group having 1 to 4 carbon atoms. Specific examples include a methyl group, an ethyl group, an isopropyl group, a t-butyl group, an n-butyl group, an isobutyl group, an s-butyl group, and the like, and preferably a methyl group, an ethyl group, an isopropyl group, and a t-butyl group. Butyl group and the like.
“COOAlk” represents an alkoxycarbonyl group in which a straight-chain or branched alkyl having 1 to 10 carbon atoms is bonded to an ester, preferably a straight-chain or branched alkoxycarbonyl group having 1 to 4 carbon atoms. Represents Specifically, for example, a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, an s-butoxycarbonyl group, a t-butoxycarbonyl group, and the like are exemplified, and preferably t- Butoxycarbonyl group.
“Ar” represents an aryl group that may be substituted with any substituent. A preferred substituent is Hal. In the present invention, "aryl" or "aryl group" refers to an aromatic ring group derived from an aromatic hydrocarbon, such as a monocyclic ring, a condensed ring, or a polycyclic ring in which a single ring is bonded by a single bond, Preferably it is a phenyl group.

Particularly preferred embodiments of the compound of the present invention can be obtained by combining the above preferred embodiments of the respective substituents.
The compound represented by the formula (I) or a salt thereof may be an anhydride or may form a solvate such as a hydrate. The term “solvation” as used herein refers to a phenomenon in which a solute molecule or ion strongly attracts a solvent molecule adjacent thereto in a solution to form one molecular population. For example, when the solvent is water, hydration is called hydration. The solvate may be a hydrate or a non-hydrate. As the non-hydrate, alcohol (for example, methanol, ethanol, n-propanol), dimethylformamide and the like can be used.

As described above, the compounds of the present invention can be used for the prevention and treatment of infectious diseases associated with filovirus. Therefore, the compound represented by the formula (I) or a solvate thereof, or a pharmaceutically acceptable salt of the compound or a solvate thereof is also included in the present invention. In the present specification, the term "compound of the present invention" refers to not only the compound represented by the formula (I) but also a solvate thereof or a pharmaceutically acceptable salt or pharmaceutically acceptable salt of the compound, unless otherwise specified. It is understood that the solvates are also included.
Pharmaceutically acceptable salts of the compounds of formula (I) include, for example, hydrochloride, hydrobromide, hydroiodide, phosphate, phosphonate, sulfate, methanesulfone Acid salts, sulfonic acid salts such as p-toluenesulfonic acid salt, acetate salts, citrate salts, malate salts, tartrate salts, succinate salts, carboxylate salts such as salicylates, or sodium salts, potassium salts and the like Alkali metal salts; alkaline earth metal salts such as magnesium salts and calcium salts; and ammonium salts such as ammonium salts, alkyl ammonium salts, dialkyl ammonium salts, trialkyl ammonium salts, and tetraalkyl ammonium salts. These salts can be produced by methods known in the art, for example, by contacting the compound with an acid or base that can be used for producing a pharmaceutical.

When the compound of the present invention is obtained as a free form, it can be converted into a salt which may be formed by the compound or a hydrate or solvate thereof according to a conventional method.
When the compound of the present invention is obtained as a salt, hydrate or solvate of the compound, it can be converted to a free form of the compound according to a conventional method.
The compound of the present invention includes all isotopes of the compound represented by the formula (I). The isotope of the compound of the present invention is one in which at least one atom is substituted by an atom having the same atomic number (proton number) and a different mass number (sum of the number of protons and neutrons). Examples of atoms having isotopes that may be included in the compounds of the present invention include H, C, N, O, P, S, F, Cl, and the like, and include ² H, ³ H, ¹³ C, and ¹⁴ , respectively. ^{C, 15 N, 17 O,} 18 O, 35 S, 18 F and the like are included. In particular, radioactive isotopes, such as ³ H, ¹¹ C, ¹⁴ C, and ¹⁸ F, which decay by emitting radioactivity or positrons, are useful in, for example, tissue distribution tests of pharmaceuticals or compounds in vivo.

Stable isotopes are safe to use because they do not decay, have little change in abundance, and have no radioactivity. The isotope of the compound of the present invention can be converted by a conventional method by replacing the reagent used in the synthesis with a reagent containing the corresponding isotope.
The compounds of the present invention also include prodrug forms known in the art. Here, a "prodrug" of a compound of the present invention is understood to mean a compound of formula (I) or a pharmaceutically acceptable salt thereof which is converted, after administration, under physiological conditions, by enzymatic or non-enzymatic degradation. A derivative of the compound of formula (I). Prodrugs may be inactive when administered to a patient, but are present in vivo in converted form into the active compound of formula (I).

Prodrugs known in the art include, for example, those that change to a desired drug form when a specific pH is reached or by the action of an enzyme. Typical prodrugs are compounds that generate free acids in vivo, for example, compounds that have hydrolyzable ester residues that are hydrolyzed in vivo to generate free acids. Such hydrolyzable ester residues are not limited to these. For example, when the free hydrogen in the carboxyl group is a C1-C4 alkyl group, a C2-C7 alkanoyloxymethyl group, a C4-C9 1- (alkanoyl Oxy) ethyl group, C5-C10 1-methyl-1- (alkanoyloxy) -ethyl group, C3-C6 alkoxycarbonyloxymethyl group, C4-C7 1- (alkoxycarbonyloxy) ethyl group, C5-C8 1-methyl-1- (alkoxycarbonyloxy) ethyl group, C3-C9 N- (alkoxycarbonyl) aminomethyl, C4-C10 1- (N- (alkoxycarbonyl) amino) ethyl group, 3-phthalidyl group , 4-crotonolactonyl group, γ-butyrolactone-4-yl group, di-N, N- (C _1-2 ) a Alkylamino _{(C 2-3)} alkyl group (e.g. N, N-dimethylaminoethyl group), a carbamoyl - _{(C 1-2)} alkyl group, N, N-di _{(C 1-2)} alkylcarbamoyl - _{(C 1-} including residues with ₂₎ an alkyl group, piperidino _{(C 2-3)} alkyl group, a pyrrolidino _{(C 2-3)} alkyl group, or a morpholino _{(C 2-3)} carboxyl moiety substituted with an alkyl group.

The compounds described in the following table are compounds for which the present inventors have actually shown their cell entry inhibitory activity.

Particularly preferred compounds of the present invention include the compounds listed in the table below.

<Typical manufacturing method>
The compound of the present invention can be produced, for example, according to the following method, but the method of producing the compound of the present invention is not limited thereto. In addition, the order of reaction steps such as introduction of a substituent can be changed as necessary. In addition, as a raw material compound used in the production, a commercially available compound may be used, or may be produced by an ordinary method as needed.

In the formulas representing the following reaction steps, R ^{1 to} R ⁸ are as defined in formula (I).
Other abbreviations used in the following schemes have their ordinary meanings as would be understood by a person skilled in the art.
Abbreviations commonly used in the following general synthesis methods and examples, and names of reagents and solvents corresponding to the chemical formulas are described below.
EtOAc Ethyl acetate MeI Methyl iodide EtI Ethyl iodide i-PrI Isopropyl iodide MeOH Methanol NaH Sodium hydride TEA Triethylamine DMAP N, N-dimethyl-4-aminopyridine THF Tetrahydrofuran DMF N, N-dimethylformamide DMSO Dimethyl sulfoxide

The compounds of the present invention can be prepared according to the following scheme.

[Step 1]
Step 1 is an alkylation reaction.
This step is an N-alkylation reaction by alkylation of 5-methoxy-2-nitrobenzeneamine to form a pyrrole ring or a nucleophilic substitution reaction on a fluorine group of 2-fluoro-4-methoxy-1-nitrobenzene.
1-Pyrrole conversion of 5-methoxy-2-nitrobenzeneamine can be synthesized by causing non-dehydration with 2,5-dimethoxytetrahydrofuran or 2,5-hexadione under acidic conditions or the like.

The reaction temperature can be raised to 300 ° C. by using a microwave synthesizer, preferably 150 ° C. to 170 ° C. under microwave irradiation, and the reaction time is 10 to 20 minutes.
After completion of the reaction, water is poured into the reaction solution, and the mixture is extracted with an organic solvent such as ethyl acetate. The organic layer is washed with water and saturated saline, and dried with a desiccant such as sodium sulfate. After removing the drying agent by filtration, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography, and dried under reduced pressure to obtain the desired compound of the present invention.
Further, an N-alkylation reaction can be caused by a nucleophilic substitution reaction for a fluorine group of 2-fluoro-4-methoxy-1-nitrobenzene.
This reaction proceeds in a high yield by stirring the amino derivative in a solvent from 0 degree to heating.

It proceeds in the presence of the amino derivative itself without the addition of a base, but is promoted by the addition of a base and proceeds with good yield.
The base is not particularly limited as long as it is a base known in the art, and examples thereof include inorganic bases such as sodium hydride, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, and organic bases such as pyridine, TEA, and DIPEA. And the like, and preferred is sodium hydride.
The solvent that can be used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include ethanol, DMSO, THF, DMF, DMA, dioxane, acetonitrile, and mixtures thereof, and ethanol is preferable.

[Step 2]
Step 2 is a catalytic reduction reaction of a nitro group to an amine.
In this step, in the presence of a hydrogenation catalyst such as a nickel catalyst or a palladium catalyst, by reacting an aromatic compound having a nitro group (nitro derivative obtained in step 1) with a reducing agent serving as a hydrogen source, The nitro group in the compound is reduced to an amino group.
As the hydrogenation catalyst used in the reaction, for example, a palladium catalyst such as 5% palladium carbon or 10% palladium carbon or a nickel catalyst can be used, and preferably 10% palladium carbon.
Under general nitro group reduction conditions, hydrogen gas is often used as a hydrogen source, but in this step, the reaction can also be performed using 1,4-cyclohexadiene as a hydrogen source. Therefore, hydrogen gas or 1,4-cyclohexadiene can be used as a hydrogen source, and preferably 1,4-cyclohexadiene. For example, the method described in Bioorganic and medicinal chemistry letters, 12, 22, 3309-3312; It can be implemented for reference. For its use, use 10 equivalents.

As the solvent, for example, alcoholic solvents such as methanol and ethanol can be used, and methanol is preferable.
The reaction temperature ranges from room temperature to the boiling point of the solvent, and further includes reaction conditions up to 300 ° C. by using a microwave synthesizer, preferably 120 ° C. to 140 ° C. using a microwave synthesizer, and the reaction time is 10 minutes. It is.
After the completion of the reaction, the palladium carbon is removed by filtration, the reaction solution is distilled off, the obtained residue is purified by silica gel column chromatography, and the aniline derivative obtained by drying under reduced pressure is used in the next step. .

[Step 3]
Step 3 is a sulfonamidation step by reacting the aniline derivative obtained in step 2 with sulfuryl chloride.
In this step, by reacting the aniline derivative obtained in Step 2 with sulfuryl chloride in the presence of a pyridine solvent, it is possible to synthesize a sulfonamidated derivative.
The reaction temperature can be from room temperature to the boiling point of the solvent, and the reaction temperature can be up to 300 ° C. by using a microwave synthesizer, preferably from 120 ° C. to 180 ° C. for 10 minutes under microwave irradiation.
After the completion of the reaction, water is poured into the reaction solution, and the mixture is extracted with an organic solvent such as ethyl acetate. After the desiccant is removed by filtration, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography, and the sulfonamide derivative obtained by drying under reduced pressure is used in the next step.

[Step 4]
This is a step of alkylating a sulfonamide to an amino group.
This step can be performed by reacting the sulfonamidated derivative obtained in Step 3 with an alkylating agent in the presence of a base.
As the alkylating agent, R ² I or R ² Br (where R ² is the same as R ² in the above formula (I)) can be used.
The base that can be used is not particularly limited as long as it is a base known in the art. For example, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, hydride Examples include inorganic bases such as calcium, and organic bases such as t-BuOK, t-BuONa, pyridine, TEA, DIPEA, LDA, LiHMDS, and n-BuLi, and preferably sodium carbonate or cesium carbonate.

The solvent that can be used is not particularly limited as long as it does not adversely affect the reaction, and examples thereof include toluene, xylene, n-hexane, cyclohexane, DMF, DMA, EtOAc, DMSO, dichloromethane, carbon tetrachloride, THF, dioxane, and acetonitrile. And mixtures thereof, preferably DMF.
The reaction temperature can be from room temperature to the boiling point of the solvent, and the reaction temperature can be up to 300 ° C. by using a microwave synthesizer, preferably from 120 ° C. to 180 ° C. for 10 minutes under microwave irradiation.
After completion of the reaction, water is poured into the reaction solution, and the mixture is extracted with an organic solvent such as ethyl acetate. The organic layer is washed with water and saturated saline, and dried with a desiccant such as sodium sulfate. After removing the drying agent by filtration, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography, and dried under reduced pressure to obtain the desired compound of the present invention.

<Synthesis of starting compounds>
The starting compound of the compound of the present invention can be easily obtained by purchasing a commercially available compound or synthesizing it using a known method.
As described above, an example of the method for producing the compound of the formula (I) according to the present invention has been described. It can be performed by applying ordinary chemical operations such as recrystallization and various types of chromatography.

<2> Pharmaceutical composition of the present invention As described above, the compound of the present invention can inhibit the entry of a virus, particularly a filovirus, into cells. Can be suitably used for the prevention and / or treatment of Accordingly, the present invention in one aspect relates to a pharmaceutical composition comprising a compound of the present invention or a solvate thereof, or a pharmaceutically acceptable salt of the compound or a solvate thereof. In particular, the compounds of the present invention have a remarkably low IC ₅₀ value in inhibiting the entry of viruses, particularly filoviruses into cells, and some compounds have low cardiotoxicity and metabolic stability in vivo. It has been found by the present inventors that they also have suitable properties as an active ingredient of a pharmaceutical composition in terms of height and the like.

  The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier in addition to the compound of the present invention. As used herein, the term "pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid vehicle diluents or encapsulating materials that are capable of suffering a filovirus infection ( For example, mammals). As used herein, the term "acceptable" refers to compositions that, under normal conditions of use, do not react with each other in a manner that substantially diminishes the pharmaceutical effectiveness of the composition. It means that the components in the product and the target compound can be mixed. A pharmaceutically acceptable carrier must of course have sufficiently high purity and sufficiently low toxicity to be suitable for administration to the subject to be treated, preferably an animal, more preferably a mammal. .

Examples of materials that can be used as pharmaceutically acceptable carriers include sugars such as lactose, glucose, sucrose; starches such as corn starch, potato starch; celluloses and derivatives such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose; Tragacanth gum powder; malt; gelatin; talc; solid lubricants such as stearic acid and magnesium stearate; calcium sulfate; Polyalcohols such as mannitol and polyethylene glycol; alginic acid; emulsifiers such as TWEEN; wetting agents such as lecithin; coloring agents; fragrances; Agents; antioxidants; preservatives; pyrogen-free water; isotonic saline solution; and phosphate buffer and the like.
When the pharmaceutical composition of the present invention is used as a therapeutic or prophylactic agent for viral infection, the method of administration is oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), Intracisternal, vaginal, intraperitoneal, intravesical, topical (drip, powder, ointment, gel or cream) administration and inhalation (buccal or nasal spray).

The dosage forms include, for example, tablets, capsules, granules, powders, pills, aqueous and non-aqueous oral solutions and suspensions, and non-aqueous tablets filled into containers adapted to be divided into individual doses. Oral solutions are included. Dosage forms may also be adapted for various modes of administration, including controlled release formulations, such as subcutaneous implantation.
The above-mentioned preparations are produced by known methods using additives such as excipients, lubricants (coating agents), binders, disintegrants, stabilizers, flavoring agents, diluents and the like.
Examples of the excipient include, but are not limited to, starch such as starch, potato starch, and corn starch, lactose, crystalline cellulose, calcium hydrogen phosphate, and the like.

Examples of the coating agent include, but are not limited to, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin.
Examples of the binder include, but are not limited to, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients.

Examples of the disintegrant include, but are not limited to, compounds similar to the above-mentioned excipients and croscarmellose sodium, sodium carboxymethyl starch, chemically modified starch and cellulose such as cross-linked polyvinyl pyrrolidone, and the like. Can be mentioned.
Examples of the stabilizer include, but are not limited to, paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenol; Phenols such as cresol; thimerosal; dehydroacetic acid; and sorbic acid.
Flavoring agents include, but are not limited to, commonly used sweeteners, sour agents, flavors, and the like.

Further, the solvent for producing the liquid preparation is not limited to this, but for example, ethanol, phenol, chlorocresol, purified water, distilled water, and the like can be used.
Examples of the surfactant or emulsifier include, but are not limited to, polysorbate 80, polyoxyl stearate 40, lauromacrogol, and the like.
The mechanism by which the compounds of the present invention inhibit the entry of viruses, especially filoviruses, into cells is not clearly understood. Without being bound by theory, it is conceivable, for example, to act on glycoproteins on the surface of the virus to inhibit its function.

  When the pharmaceutical composition of the present invention is used as a therapeutic or prophylactic agent for viral infection, the amount of the compound of the present invention or a salt or solvate thereof may vary depending on symptoms, age, body weight, relative health, It depends on the existence of other medications, administration method, and the like. For example, for patients (warm-blooded animals, especially humans), the generally effective amount is, as an active ingredient (compound of the present invention), in the case of an oral preparation, preferably 0.001-1000 mg / kg of body weight per day, More preferably, it is 0.01 to 300 mg / kg of body weight, and the daily usage is preferably in the range of 1 to 800 mg for an adult patient of normal weight. In the case of a parenteral preparation, the amount is preferably 0.001 to 1000 mg / kg of body weight, more preferably 0.01 to 300 mg / kg of body weight per day. It is desirable to administer this once or several times a day according to the symptoms.

The pharmaceutical composition of the present invention is for prevention and / or treatment of a viral infection, preferably for prevention and / or treatment of an acute viral infection, and more preferably for Ebola hemorrhagic fever. And / or for the prevention and / or treatment of Marburg hemorrhagic fever, and more preferably for the prevention and / or treatment of Ebola hemorrhagic fever.
The pharmaceutical composition of the present invention is for prevention and / or treatment of a viral infection, wherein preferably, the virus is a filovirus, more preferably, the virus is an Ebola virus or a Marburg virus. Yes, and more preferably, the virus is an Ebola virus.

<3> Antiviral Agent of the Present Invention As described above, the compound of the present invention can inhibit the virus, particularly the filovirus, from invading cells, and thus cannot infect the cells with the virus. As a result, the growth of the virus can be suppressed. Accordingly, the present invention in one aspect relates to an antiviral agent comprising a compound of the present invention or a solvate thereof, or a pharmaceutically acceptable salt of the compound or a solvate thereof. The antiviral agent means an agent having an effect of suppressing the growth of a virus in vitro and / or in vivo. Preferably, the virus is a filovirus, more preferably, the virus is an Ebola virus or Marburg virus, even more preferably, the virus is an Ebola virus.

<4> Cellular entry inhibitor of virus of the present invention In one aspect, the present invention provides a compound of the present invention or a solvate thereof, or a pharmaceutically acceptable salt of the compound or a solvate of a virus containing a virus containing the compound. Related to inhibitors. The virus cell entry inhibitor means a substance having an action of inhibiting entry of a virus into cells in vitro and / or in vivo. Preferably, the virus is a filovirus, more preferably, the virus is an Ebola virus or Marburg virus, even more preferably, the virus is an Ebola virus.

<5> Method of Inhibiting Virus Cell Invasion Process of the Present Invention In one aspect, the present invention relates to a method of inhibiting a virus cell invasion process, wherein one or more compounds of the present invention are added to a virus. a method comprising the step of contacting in vitro and / or in vivo.

<6> Method for preventing and / or treating viral infection of the present invention In one aspect, the present invention relates to a method for preventing and / or treating a viral infection in a subject, comprising one or more of Administering to a subject in need thereof an effective amount of a compound of the present invention. The viral infection is preferably an acute viral infection, more preferably Ebola and / or Marburg hemorrhagic fever, even more preferably Ebola. When the pharmaceutical composition of the present invention is used as a therapeutic or prophylactic agent for viral infection, the amount of the compound of the present invention depends on the symptoms, age, body weight, relative health, presence of other medications, administration. It may vary depending on the method and the like. For example, for patients (warm-blooded animals, especially humans), the generally effective amount is preferably 0.001-1000 mg per kg of body weight per day as an active ingredient (compound of the present invention) as an active ingredient (compound of the present invention). It is preferably 0.01 to 300 mg / kg of body weight, and the daily dose is preferably in the range of 1 to 800 mg for a normal weight adult patient, for example when the subject is a human. In the case of a parenteral preparation, the amount is preferably 0.001 to 1000 mg / kg of body weight, more preferably 0.01 to 300 mg / kg of body weight per day. It is desirable to administer this once or several times depending on the symptoms.

Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Examples.
The microwave reaction was performed using a Biotage Initiator and a snap-cap reaction vial. Maximum power settings include air cooling of the reaction vessel to avoid temperature rises due to microwaves.
Biotage's Isolera Prime was used for purification of the synthesized compound, and Biotage's SNAP cartridge was used for the purification column.
Mass spectrum data was obtained using Waters SQ Detector2.

The NMR analysis was performed using JNM-ECP00 (400 MHz) manufactured by JEOL. The NMR data was shown in ppm (parts per million) (δ), and the deuterium lock signal from the sample solvent was referenced.
Commercial reagents were used without further purification. Room temperature refers to a range of about 20 to 30 degrees. All non-aqueous reactions were performed in anhydrous solvents under a nitrogen or argon atmosphere. Concentration under reduced pressure or solvent evaporation was performed using a rotary evaporator.
In the preparation of the compound, when there was a possibility that an undesired side reaction might occur, the functional group was protected by a protecting group as necessary, and after the target molecule was prepared, the protecting group was removed. The selection and desorption operations of the protecting group were performed, for example, by the method described in Greene and Wuts, “Protective Groups in Organic Synthesis” (5th edition, John Wiley & Sons 2014).

[Example 1]
Compound No. 1-1
2- (2,5-dimethyl-1H-pyrrol-1-yl) -4-methoxy-1-nitrobenzene
2- (2,5-dimethyl-1H-pyrrol-1-yl) -4-methoxy-nitrobenzene
5-Methoxy-2-nitro-1-benzeneamine (168 mg, 1.0 mmol), 2,5-hexanedione (342 mg, 3.0 mmol), acetic acid (3.0 mL) were placed in a Biotage 5 mL snap-cap reaction vial. In addition, after attaching an aluminum cap, the mixture was heated and stirred at 170 ° C. for 20 minutes in a microwave reactor.

After cooling to room temperature, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (Biotage KP-SIL 10 g, 5% → 10% ethyl acetate / hexane, eluted with 15 column volumes) to give the title compound, 2 -(2,5-Dimethyl-1H-pyrrol-1-yl) -4-methoxy-1-nitrobenzene was obtained as an orange oil (139.3 mg, yield 56%).
1H-NMR (400 MHz, CDCl3) δ: 8.10 (d, J = 8.8 Hz, 1H), 7.04 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.83 (d, J = 2.4 Hz, 1H) , 5.92 (s, 2H), 3.91 (s, 3H), 1.97 (s, 6H)
LCMS: m / z 247 (M + H) ⁺

[Example 2]
Compound No. 1-2
1- (1-methylethyl) -4- (5-methoxy-2-nitrophenyl) -1-piperazine
1- (1-methylethyl) -4- (5-methoxy-2-nitrophenyl) -1-piperazine
2-Fluoro-4-methoxy-1-nitrobenzene (100 mg, 0.58 mmol), 1- (1-methylethyl) -piperazine (150 mg, 1.16 mmol) and ethanol (3.0 mL) were combined with Biotage's 5 mL snap cap. After adding an aluminum cap to the reaction vial, the mixture was heated and stirred at 160 ° C. for 20 minutes in a microwave reactor.
After cooling to room temperature, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (Biotage KP-SIL 10 g, 0% → 5% methanol / chloroform, eluted with 15 column volumes) to give the title compound, 1- (1-Methylethyl) -4- (5-methoxy-2-nitrophenyl) -1-piperazine was obtained as a colorless powder (163 mg, yield 99%).
1H-NMR (400 MHz, CDCl3) δ: 7.95 (d, J = 8.8 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H), 6.49 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H) , 3.85 (s, 3H), 3.08 (t, J = 4.8 Hz, 4H), 2.73 (m, 1H), 2.69 (t, J = 4.8 Hz, 4H), 1.08 (d, J = 6.4 Hz, 6H)
LCMS: m / z 280 (M + H) ⁺

[Example 3]
Compound No. 1-3
5-methoxy-2-nitro-N, N-diphenylbenzeneamine
5-methoxy-2-nitro-N, N-diphenyl-benzeneamine
Using diphenylamine instead of 1- (1-methylethyl) -piperazine under the same conditions as in Example 2, the title compound, 5-methoxy-2-nitro-N, N-diphenylbenzeneamine, was converted into a colorless powder (69 mg). , Yield 73%).
1H-NMR (400 MHz, CDCl3) δ: 7.88 (d, J = 7.6 Hz, 1H), 7.23 (t, J = 7.6 Hz, 4H), 6.99-7.06 (m, 6H), 6.69 (m, 2H), 3.77 (s, 3H)
LCMS: m / z 321 (M + H) ⁺ .

[Example 4]
Compound No. 1-4
9- (3-methoxy-2-nitrophenyl) -9H-carbazole
9- (3-methoxy-2-nitrophenyl) -9H-carbazole
The title compound, 9- (3-methoxy-2-nitrophenyl) -9H-carbazole was converted to yellow under the same conditions as in Example 2 by using carbazole instead of 1- (1-methylethyl) -piperazine. Obtained as a powder (172.2 mg, 92%).
1H-NMR (400 MHz, CDCl3) δ: 8.26 (d, J = 9.6 Hz, 1H), 8.13 (d, J = 7.6 Hz, 2H), 7.39 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.6 Hz, 2H), 7.13 (m, 4H), 3.91 (s, 3H)
LCMS: m / z 319 (M + H) ⁺ .

[Example 5]
Compound No. 2-1
N ² , N ² -diphenyl-4-methoxy-1,2-benzenediamine
N ² , N ² -diphenyl-4-methoxy-1,2-benzenediamine
Compound No. 1-3 (65 mg, 0.20 mmol), 1,3-cyclohexadiene (163 mg, 2, 03 mmol), 10% palladium on carbon (7 mg), and methanol (3 mL) were added to a Biotage 20 mL snap-cap reaction vial. After attaching the aluminum cap, the mixture was heated and stirred at 130 ° C. for 10 minutes using a microwave synthesizer.
After cooling to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (Biotage ULTRA 10 g, 5% → 20% ethyl acetate / hexane, eluted with 15 column volumes) to give the title compound, N ² , ^{N 2} - diphenyl-4-methoxy-1,2-benzenediamine as a colorless powder (36,3mg, 61% yield).
1H-NMR (400 MHz, CDCl3) δ: 7.22 (t, J = 7.6 Hz, 4H), 7.04 (d, J = 8.0 Hz, 4H), 6.94 (t, J = 7.2 Hz, 2H), 6.75 (d, J = 8.4 Hz, 1H), 6.70 (dd, J = 8.4 Hz, J = 2.8 Hz, 1H), 6.62 (d, J = 2.8 Hz, 1H), 3.67 (s, 3H), 3.20 (brs, 2H)
LCMS: m / z 291 (M + H) ⁺

[Example 6]
Compound No. 2-2
9- (3-methoxy-2-aminophenyl) -9H-carbazole
9- (3-methoxy-2-aminophenyl) -9H-carbazole
The title compound, 9- (3-methoxy-2-aminophenyl) -9H-carbazole, was converted to a colorless oil by using compound No. 1-4 instead of compound No. 1-3 under the same conditions as in Example 5. 60, 7 mg, 85%).
1H-NMR (400 MHz, CDCl3) δ: 8.15 (d, J = 7.6 Hz, 2H), 7.42 (t, J = 7.2 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 6.92 (m, 2H), 6.84 (d, J = 2.4 Hz, 1H), 3.74 (s, 3H), 3.30 (brs, 2H)
LCMS: m / z 289 (M + H) ⁺ .

[Example 7]
Compound No. 3-1
N- [2- (1H-pyrrole) -4- (methoxy-phenyl) benzenesulfonamide
N- [2- (1H-pyrrole) -4-methoxy-phenyl] benzenesulfonamide
4-methoxy-2- (1H-pyrrol-1-yl) benzenamine (55.0 mg, 0.29 mmol), benzenesulfonyl chloride (61.9 mg, 0.35 mmol) synthesized by a known method, DMAP (4. (0 mg, 0.029 mmol) and 2 ml of pyridine were added to a 5 mL snap-cap reaction vial manufactured by Biotage, and after attaching an aluminum cap, the mixture was heated and stirred at 160 ° C. for 20 minutes using a microwave synthesizer.
The reaction suspension was poured into 1N hydrochloric acid (100 mL), extracted with ethyl acetate (30 mL), and the organic layer was washed with water and brine, and then dried over sodium sulfate. The desiccant was removed by filtration, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (Biotage KP-SIL 10 g, 5% → 20% ethyl acetate / hexane, eluted with 15 column volumes) to give the title compound. , N- [2- (1H-pyrrole) -4- (methoxy-phenyl) benzenesulfonamide as a colorless oil (92.0 mg, 96% yield).
1H-NMR (400 MHz, CDCl3) δ: 7.68 (d, J = 8.8 Hz, 1H), 7.49-7.56 (m, 3H), 7.39 (t, J = 8.0 Hz, 2H), 6.92 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.66 (d, J = 2.4 Hz, 1H), 6.30 (brs, 1H), 6.20 (t, J = 2.4 Hz, 2H), 6.14 (t, J = 2.4 Hz, 2H), 3.76 (s, 3H)
LCMS: m / z 329 (M + H) ⁺ .

Example 8
Compound No. 3-2
N- [2- (2,5-dimethyl-1H-pyrrole) -4-methoxy-phenyl) -benzenesulfonamide
N- [2- (2,5-dimethyl-1H-pyrrol-1-yl) -4-methoxy-phenyl] benzenesulfonamide
Under the same conditions as in Example 7, 2- (2,5-dimethyl-1H-pyrrol-1-yl) synthesized by a known method instead of 4-methoxy-2- (1H-pyrrol-1-yl) benzenamine. Yl) -4-methoxy-benzeneamine to give the title compound, N- [2- (2,5-dimethyl-1H-pyrrole) -4-methoxy-phenyl) -benzenesulfonamide, as a colorless oil (39. (5 mg, 44%).
1H-NMR (400 MHz, CDCl3) δ: 7.80 (d, J = 9.2 Hz, 1H), 7.66-7.70 (m, 2H), 7.53 (m, 1H), 7.38-7.42 (m, 2H), 6.95 (dd , J = 9.2 Hz, J = 3.2 Hz, 1H), 6.60 (d, J = 3.2 Hz, 1H), 5.93 (brs 1H), 5.89 (s, 2H), 3.76 (s, 3H), 1.55 (s, 6H)
LCMS: m / z 357 (M + H) ⁺ .

[Example 9]
Compound No. 3-3
N- [4-methoxy 2- (1-piperidinyl) -phenyl] benzenesulfonamide
N- [4-methoxy-2- (1-piperidinyl) -phenyl] benzenesulfonamide
4-methoxy-2- (1-piperidinyl) benzeneamine synthesized by a known method in place of 4-methoxy-2- (1H-pyrrol-1-yl) benzenamine under the same conditions as in Example 7 Was used to obtain the title compound, N- [4-methoxy-2- (1-piperidinyl) -phenyl] benzenesulfonamide, as a colorless powder (856 mg, 60%).
1H-NMR (400MHz, CDCl3) δ: 7.75 (m, 1H), 7.73 (m, 1H), 7.67 (brs, 1H), 7.57 (d, J = 8.8 Hz, 1H), 7.48 (m, 1H), 7.38 (m.2H), 6.65 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.59 (d, J = 2.8 Hz, 1H), 3.73 (s, 3H), 2.30 (brt, J = 4.8 Hz, 4H), 1.55 (brt, J = 4.0 Hz, 4H), 1.49 (brs, 2H)
LCMS: m / z 347 (M + H) ⁺ .

[Example 10]
Compound No. 3-4
N- [4-methoxy2- (4-morpholinyl) -phenyl] benzenesulfonamide
N- [4-methoxy-2- (4-morpholinyl) -phenyl] -benzenesulfonamide
Under the same conditions as in Example 7, 4-methoxy-2- (4-morpholinyl) -benzeneamine synthesized by a known method was used instead of 4-methoxy-2- (1H-pyrrol-1-yl) benzenamine. Use to give the title compound, N- [4-Methoxy-2- (4-morpholinyl) -phenyl] benzenesulfonamide, as a colorless powder (43.9 mg, 75%).
1H-NMR (400MHz, CDCl3) δ: 7.75 (m, 1H), 7.72 (m, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.53 (brs, 1H), 7.50 (m, 1H), 7.40 (m, 2H), 6.71 (dd, J = 8.4 Hz, J = 3.2 Hz, 1H), 6,62 (d, J = 3.2 Hz, 1H), 3.76 (s, 3H), 3.67 (t, J = 4.4 Hz, 4H), 2.35 (brs, 4H)
LCMS: m / z 349 (M + H) ⁺ .

[Example 11]
Compound No. 3-5
N- [2- (diethylamino) -4-methoxyphenyl] benzenesulfonamide
N- [2- (diethylamino) -4-methoxyphenyl] -benzenesulfonamide
N ² , N ² -Diethyl-4-methoxy-1,2 synthesized by a known method in place of 4-methoxy-2- (1H-pyrrol-1-yl) benzenamine under the same conditions as in Example 7. Using -benzenediamine gave the title compound, N- [2- (diethylamino) -4-methoxyphenyl] benzenesulfonamide, as a colorless oil (36.5 mg, 78%).
1H-NMR (400MHz, CDCl3) δ: 8.04 (brs, 1H), 7.77 (m, 2H), 7.62 (d, J = 8.8 Hz, 1H), 7.46 (m, 1H), 7.39 (m, 2H), 6.67 (d, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 3.75 (s, 3H), 2.59 (q, J = 7.2 Hz, 4H), 0.72 (t, J = 7.2 Hz, 6H)
LCMS: m / z 336 (M + H) ⁺ .

[Example 12]
Compound No. 3-6
N- [4-methoxy-2- [4- (1-methylethyl) -1-piperazinyl] benzenesulfonamide
N- [4-methoxy-2- [4- (1-methylethyl) -1-piperazinyl] -benzenesulfonamide
Under the same conditions as in Example 7, 4-methoxy-2- [4- (1-methylethyl) synthesized by a known method instead of 4-methoxy-2- (1H-pyrrol-1-yl) benzenamine By using -1-piperazinyl] -benzeneamine, the title compound, N- [4-methoxy-2- [4- (1-methylethyl) -1-piperazinyl] benzenesulfonamide, was converted into a brown powder (208.0 mg, 93 %).
1H-NMR (400MHz, CDCl3) δ: 7.74 (m2H), 7.70 (brs, 1H), 7.56 (m, 1H), 7.50 (m, 1H), 7.39 (m, 2H), 6.68 (m, 2H) , 3.73 (s, 3H), 2.30−2.95 (m, 9H), 1.17 (d, J = 6.0 Hz, 6H)
LCMS: m / z 390 (M + H) ⁺ .

Example 13
Compound No. 3-7
N- ^{[N 2,} N 2 - diphenyl-4-methoxy-1,2-benzenediamine] benzenesulfonamide
N- [N ² , N ² -diphenyl-4-methoxy-1,2-benzenediamine] -benzenesulfonamide
Under the same conditions as in Example 7, compound 2-1 and N ² , N ² -diphenyl-4-methoxy-1,2- instead of 4-methoxy-2- (1H-pyrrol-1-yl) benzenamine were used. the title compound by using benzene ^{diamine, N- [N 2, N 2} - diphenyl-4-methoxy-1,2-benzenediamine] benzene sulfonamide was obtained as a colorless powder (35.5mg, 83%).
1H-NMR (400 MHz, CDCl3) δ: 7.64 (d, J = 8.8 Hz, 1H), 7.58 (brd, J = 7.2 Hz, 2H), 7.50 (brt, J = 7.6 Hz, 1H), 7.34 (brt, J = 8.0 Hz, 2H), 7.14 (brt, J = 7.2 Hz, 4H), 6.97 (brt, J = 7.2 Hz, 2H), 6.74 (dd, J = 9.2 Hz, J = 2.8 Hz, 1H), 6.62 (brd, J = 8.8Hz, 4H), 6.47 (d, J = 3.2Hz, 1H), 6.30 (brs, 1H), 3.66 (s, 3H)
LCMS: m / z 431 (M + H) ⁺ .

[Example 14]
Compound No. 3-8
N- [9- (3-methoxy-2-aminophenyl) -9H-carbazole] benzenesulfonamide
N- [9- (3-methoxy-2-9H-carbazole) -phenyl-benzenesulfonamide
Under the same conditions as in Example 7, but instead of 4-methoxy-2- (1H-pyrrol-1-yl) benzenamine, compound 2-2, 9- (3-methoxy-2-aminophenyl) -9H-carbazo The title compound, N- [9- (3-methoxy-2-aminophenyl) -9H-carbazole] benzenesulfonamide, was obtained as a colorless powder (69.6 mg, 90%) by using benzene.
1H-NMR (400 MHz, CDCl3) δ: 8.10 (m, 2H), 7.93 (d, J = 9.2 Hz, 1H), 7.24-7.35 (m, 7H), 7.07 (m, 3H), 6.73 (d, J = 2.8 Hz, 1H), 6.63 (m, 2H), 6.22 (brs, 1H), 3.74 (s, 3H)
LCMS: m / z 429 (M + H) ⁺ .

[Example 15]
Compound No. 4-1
N- (4-methoxy-2-nitro-phenyl) -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- (4-methoxy-2-nitro-phenyl) -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide (50.0 mg, 0.16 mmol) synthesized according to a known synthesis method, N, N-dimethylaminopropyl chloride (58) synthesized according to a known synthesis method 0.5 mg, 0.48 mmol), sodium carbonate (25.0 mg, 0.24 mmol), and anhydrous DMF (2.5 mL) were added to a Biotage 5 mL snap-cap reaction vial, and after attaching an aluminum cap, using a microwave synthesizer. Heating and stirring were performed at 130 ° C. for 10 minutes.

The reaction suspension was poured into water (50 mL), extracted with ethyl acetate (30 mL × 2), and the organic layer was washed with water and brine, and then dried over sodium sulfate. After the desiccant was removed by filtration, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (Biotage KP-SIL 10 g, 0% → 10% methanol / chloroform, eluted with 15 column volumes) to give the title. The compound, N- (4-methoxy-2-nitro-phenyl) -N- [3- (dimethylamino) propyl] benzenesulfonamide, was obtained as a colorless oil (55.9 mg, 87% yield).
1H-NMR (400 MHz, CDCl3) δ: 7.56-7.63 (m, 3H), 7.43-7.49 (m, 2H), 7.35 (d, J = 3.2 Hz, 1H), 7.00 (dd, J = 8.8 Hz, J = 3.2 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1 H), 3.86 (s, 3H), 3.79 (brs, 1H), 3.53 (brs, 1H), 2.50 (brs, 2H), 2.28 ( brs, 6H), 1.85 (brs, 2H)
LCMS: m / z 394 (M + H) ⁺

[Example 16]
Compound No. 4-2
N- [3- (dimethylamino) propyl] -N- (2-amino-4-methoxy-phenyl) benzenesulfonamide
N− [3- (dimethylamino) propyl] −N− (2-amino-4-methoxy-phenyl) −benzenesulfonamide
Using the compound number 4-1 instead of the compound number 1-3 under the same conditions as in Example 5, the title compound, N- [3- (dimethylamino) propyl] -N- (2-amino-4- Methoxy-phenyl) benzenesulfonamide was obtained as a colorless powder (408.0 mg, 80%).
1H-NMR (400MHz, CDCl3) δ: 7.59-7.67 (m, 3H), 7.47-7.53 (m, 2H), 6.31 (d, J = 2.0 Hz, 1H), 6.08-6.12 (m, 2H), 4.25 (brs, 2H), 4.01 (m, 1H), 3.72 (s, 3H), 3.38 (m, 1H), 3.14−3.27 (m, 2H), 2.75 (brs, 6H), 2.14 (m, 1H) , 1.82 (m, 1H)
LCMS: m / z 364 (M + H) ⁺ .

[Example 17]
Compound No. 4-3
N- [2- (1H-pyrrol) -4-methoxy-phenyl) -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- [2- (1H-pyrrole) -4-methoxy-phenyl] -N- [3- (dimethylamino) propyl] -benzenesulfonamide
Under the same conditions as in Example 15, but instead of N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide, Compound No. 3-1 and N- [2- (1H-pyrrole) -4- (methoxy- The title compound, N- [2- (1H-pyrrole) -4-methoxy-phenyl) -N- [3- (dimethylamino) propyl] benzenesulfonamide, was obtained by using phenyl) benzenesulfonamide as a colorless oil (42). 0.3 mg, 79%).
1H-NMR (400 MHz, CDCl3) δ: 7.79 (d, J = 7.2 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.53 (t, J = 7.2 Hz, 2H), 7.06 (t, J = 1.6 Hz, 2H), 6.88 (d, J = 1.6 Hz, 1H), 6.72−6.79 (m, 2H), 6.30 (t, J = 2.0 Hz, 2H), 3.80 (s, 3H), 3.37 ( brs, 1H), 3.13 (brs, 1H), 2.10 (s, 6H), 2.10 (brs, 1H), 1.94 (brs, 1H), 1.30 (brs, 2H)
LCMS: m / z 414 (M + H) ⁺ .

[Example 18]
Compound No. 4-4
N- [2- (2,5-dimethyl-1H-pyrrole) -4-methoxy-phenyl) -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- [2- (2,5-dimethyl-1H-pyrrol) -1-yl-4-methoxy-phenyl] -N- [3- (dimethylamino) propyl] -benzenesulfonamide
Compound No. 3-2 and N- [2- (2,5-dimethyl-1H-pyro- ) -4-methoxy-phenyl) -benzenesulfonamide to give the title compound, N- [2- (2,5-dimethyl-1H-pyrrol) -4-methoxy-phenyl) -N- [3 -(Dimethylamino) propyl] benzenesulfonamide was obtained as a colorless oil (19.2 mg, 46%).
1H-NMR (400 MHz, CDCl3) δ: 7.71 (d, J = 7.2 Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.2 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.77 (d, J = 2.8 Hz, 1H), 5.94 (s, 2H), 3.82 (s, 3H) , 3.08 (brs, 2H), 2.06 (s, 6H), 2.02 (s, 6H), 1.97 (brs, 2H), 1.50 (brs, 2H),
LCMS: m / z 443 (M + H) ⁺ .

[Example 19]
Compound No. 4-5
N- [4-methoxy2- (1-piperidinyl) -phenyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- [4-methoxy-2- (1-piperidinyl) -phenyl] -N- [3- (dimethylamino) propyl] -benzenesulfonamide
Compound No. 3-3, N- [4-methoxy-2- (1-piperidinyl) -phenyl] instead of N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide under the same conditions as in Example 15. By using benzenesulfonamide, the title compound, N- [4-methoxy-2- (1-piperidinyl) -phenyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide, was obtained as a colorless oil (11.3 mg, 40%).
1H-NMR (400MHz, CDCl3) δ: 7.87 (m, 2H), 7.55 (m, 1H), 7.49 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 6.61 (d, J = 2.4 Hz, 1H), 6.49 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 3.85 (brs, 1H), 3.77 (s, 3H), 3.60 (brs, 1H), 2.99 (brs, 2H), 2.66 (brs, 2H), 2.12 (brs, 2H), 2.08 (s, 6H), 1.58 (brs, 2H), 1.51 (brs, 6H)
LCMS: m / z 432 (M + H) ⁺ .

[Example 20]
Compound No. 4-6
N- [4-methoxy2- (4-morpholinyl) -phenyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- [4-methoxy-2- (4-morpholinyl) -phenyl] -N- [3- (dimethylamino) propyl] -benzenesulfonamide
Compound No. 3-4, N- [4-methoxy-2- (4-morpholinyl) -phenyl] instead of N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide under the same conditions as in Example 15. The title compound, N- [4-methoxy2- (4-morpholinyl) -phenyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide was obtained using benzenesulfonamide as a colorless oil (11.1 mg, 28%).
1H-NMR (400 MHz, CDCl3) δ: 7.85 (m.2H), 7.57 (m, 1H), 7.51 (m, 2H), 6.87 (d, J = 8.4 Hz), 1H), 6,63 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.4 Hz, J = 2.4 Hz, 1H), 3.82 (brs, 1H), 3.77 (s, 3H), 3.73 (brs, 4H), 3.55 (brs, 1H), 3.15 (brs, 2H), 2.76 (brs, 2H), 2.14 (brs, 2H), 2.09 (s, 6H), 1.50 (m, 2H),
LCMS: m / z 434 (M + H) ⁺ .

[Example 21]
Compound No. 4-7
N- [2- (diethylamino) -4-methoxyphenyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- [2- (diethylamino) -4-methoxyphenyl] -N- [3- (dimethylamino) propyl] -benzenesulfonamide
Compound Nos. 3-5 and N- [2- (diethylamino) -4-methoxyphenyl] benzenesulfone instead of N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide under the same conditions as in Example 15. The title compound, N- [2- (diethylamino) -4-methoxyphenyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide was converted to a colorless oil (9.0 mg, 20%) by using an amide. Obtained.
1H-NMR (400 MHz, CDCl3) δ: 7.90 (m, 2H), 7.57 (m, 1H), 7.51 (m, 2H), 6.89 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 2.8 Hz, 1H), 6.41 (dd, J = 8.4 Hz, J = 2.8 Hz, 1H), 3.87 (brs, 1H), 3.77 (s, 3H), 3.62 (brs, 1H), 3.11 (q, J = 7.2 Hz, 4H), 2.10 (brs, 2H), 2.07 (s, 6 H), 1.46 (m, 2H), 0.99 (t, J = 7.2 Hz, 6H)
LCMS: m / z 421 (M + H) ⁺ .

[Example 22]
Compound No. 4-8
N- [2- (diethylamino) -4-methoxyphenyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- [2- (dimethylamino) -4-methoxyphenyl] -N- [3- (dimethylamino) propyl] -benzenesulfonamide
N- [2- (Dimethylamino) -4-methoxyphenyl synthesized according to a known synthesis method in place of N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide under the same conditions as in Example 15. ] Benzenesulfonamide to give the title compound, N- [2- (diethylamino) -4-methoxyphenyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide as a colorless oil (51.9 mg, 70 %).
1H-NMR (400 MHz, CDCl3) δ: 7.86 (m, 2H), 7.57 (m, 1H), 7.51 (m, 2H), 6.74 (d, J = 8.4 Hz, 1H), 6.49 (d, J = 2.8 Hz, 1 H), 6.33 (dd, J = 8.4 Hz, J = 2.8 Hz, 1H), 3.76 (s, 3H), 3.70 (brs, 1H), 3.54 (brs, 1H), 2.80 (s, 6H) , 2.15 (t, J = 7.2 Hz, 2H), 2.10 (s, 6H), 1.55 (brs, 2H)
LCMS: m / z 392 (M + H) ⁺ .

[Example 23]
Compound No. 4-9
N- [4-methoxy-2- [4- (1-methylethyl) -1-piperazinyl] -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- [4-methoxy-2- [4- (1-methylethyl) -1-piperazinyl] -N- [3- (dimethylamino) -propyl] -benzenesulfonamide
Under the same conditions as in Example 15, but instead of N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide, compound 3-6, N- [4-methoxy-2- [4- (1-methyl Ethyl) -1-piperazinyl] benzenesulfonamide gives the title compound, N- [4-methoxy-2- [4- (1-methylethyl) -1-piperazinyl] -N- [3- (dimethylamino) [Propyl] benzenesulfonamide was obtained as a colorless oil (32.9 mg, 51%).
1H-NMR (400 MHz, CDCl3) δ: 7.84 (m2H), 7.56 (m, 1H), 7.49 (m, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 3.2 hz , 1H), 6.49 (dd, J = 8.8 Hz, J = 3.2 Hz, 1H), 3.79 (brs, 1H), 3.74 (s, 3H), 3.56 (brs, 1H), 3.21 (brs, 2H), 2.84 (brs, 2H), 2.72 (7th, J = 6.8 Hz, 1H), 2.63 (brs, 4H), 2.14 (m, 2H), 2.09 (s, 6H), 1.50 (m, 2H), 1.10 (d, (J = 6.8 Hz, 6H)
LCMS: m / z 475 (M + H) ⁺ .

[Example 24]
Compound No. 4-10
N- ^{[N 2,} N 2 - diphenyl-4-methoxy-1,2-benzenediamine]-N-[3- (dimethylamino) propyl] benzenesulfonamide
N- [N ² , N ² -diphenyl-4-methoxy-1,2-benzenediamine] -N- [3- (dimethylamino) -propyl] -benzenesulfonamide
Compound 3-7, N- [N ² , N ² -diphenyl-4-methoxy-1] instead of N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide under the same conditions as in Example 15. , the title compound by using a 2-benzenediamine] ^{benzenesulfonamide, N- [N 2, N 2} - diphenyl-4-methoxy-1,2-benzenediamine]-N-[3- (dimethylamino) propyl] Benzenesulfonamide was obtained as a colorless oil (35.1 mg, 97%).
1H-NMR (400 MHz, CDCl3) δ: 7.65 (d, J = 6.8 Hz, 2H), 7.51 (t, J = 7.6 Hz, 1H), 7.39 (t, J = 8.0 Hz, 2H), 7.20 (t, J = 7.2 Hz, 4H), 7.00 (d, J = 7.6 Hz, 4H), 6.97 (t, J = 7.6 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 6.80 (d, J = 2.8 Hz, 1H), 6.64 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 3.71 (s, 3H), 2.93 (m, 1H), 2.77 (m, 1H), 2.03 (s, 6H) , 1.85 (m, 2H), 1.10 (m, 2H)
LCMS: m / z 516 (M + H) ⁺ .

[Example 25]
Compound No. 4-11
N- [9- (3-methoxy-2-aminophenyl) -9H-carbazole] -N- [3- (dimethylamino) propyl] benzenesulfonamide
N- [9- (3-methoxy) -2-9H-carbazole] -phenyl-N- [3- (dimethylamino) propyl] -benzenesulfonamide
Under the same conditions as in Example 15, instead of N- (4-methoxy-2-nitro-phenyl) benzenesulfonamide, compound 3-8, N- [9- (3-methoxy-2-aminophenyl)- By using 9H-carbazole] benzenesulfonamide, the title compound, N- [9- (3-methoxy-2-aminophenyl) -9H-carbazole] -N- [3- (dimethylamino) propyl] benzenesulfonamide, was obtained. Obtained as a colorless oil (63.5 mg, 86%).
1H-NMR (400 MHz, CDCl3) δ: 8.12 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 7.2 Hz, 1H), 7.34-7.42 (m, 5H), 7.27 (t, J = 7.6 Hz, 3H), 7.20 (t, J = 7.6 Hz, 3H), 7.10 (dd, J = 7.2 Hz, J = 2.8 Hz, 1H), 6.92 (d, J = 2.8 Hz, 1H), 3.80 (s, 3H), 2,94 (brs, 2H), 1.98 (s, 6H), 1.80 (brt, J = 7.2 Hz, 2H), 1.44 (m, 2H)
LCMS: m / z 514 (M + H) ⁺ .

[Example 26]
Compound No. 4-12
N- [2- (1H-pyrrol-1-yl)]-4- (methoxyphenyl) -N-[(1-t-butoxycarbonyl-4-piperidinyl) -methyl] benzenesulfonamide
N- [2- (1H-pyrrol-1-yl)]-4- (methoxyphenyl) -N-[(1-t-butoxycarbonyl-4-piperidinyl) methyl] -benzenesulfonamid
Under the same conditions as in Example 17, tert-butyl 4- (bromomethyl) piperidine-1-carboxylate synthesized according to a known synthesis method instead of dimethylaminopropyl chloride, and Compound Nos. 3-1 and N- [2 By using-(1H-pyrrol) -4- (methoxy-phenyl) benzenesulfonamide, the title compound N- [2- (1H-pyrrol-1-yl)]-4- (methoxyphenyl)- N-[(1-tert-butoxycarbonyl-4-piperidinyl) -methyl] benzenesulfonamide was obtained as a colorless oil (136.8 mg, 79%).
1H-NMR (400 MHz, CDCl3) δ: 7.81 (d, J = 7.2 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 7.55 (t, J = 8.0 Hz, 2H), 7.06 (brs, 2H), 6.87 (brs, 1H), 6.76 (brd, J = 8.8 Hz, 2H), 6.28 (brs, 2H), 3.95 (brs, 2H), 3.81 (s, 3H), 2.88 (brs, 1H), 2.40 (brs 1H), 2.30 (t, J = 12.4 Hz, 1H), 1.40 (s, 9H), 1.24 (m, 2H), 1.02 (m, 2H), 0.88 (m, 1H), 0.70 (m, 1H)
LCMS: m / z 526 (M + H) ⁺

[Example 27]
Compound No. 4-13
N- [2- (1H-pyrrol-1-yl)]-4- (methoxyphenyl) -N-4-piperidinylmethyl-benzenesulfonamide
N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N-4-piperidinylmethyl-benzenesulfonamid
To a solution of compound number 4-12 (125.0 mg, 0.23 mmol) in chloroform (2 mL) was added trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature for 1 hour.
The reaction solution was concentrated under reduced pressure, extracted with chloroform (30 mL), washed with a saturated aqueous solution of sodium bicarbonate, water and brine, and dried over sodium sulfate. After the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure to give the title compound N- [2- (1H-pyrrol-1-yl)]-4- (methoxyphenyl) -N-4-piperidinylmethyl-benzenesulfonamide. Was obtained as a colorless powder (101.1 mg, 100% yield).
1H-NMR (400 MHz, CDCl3) δ: 7.81 (d, J = 7.6 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 2H), 6.99 (t, J = 2.0 Hz, 2H), 6.86 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 9.2 Hz, 1H), 6.77 (dd, J = 9.2 Hz, J = 2.8 Hz, 1H), 6.26 (t, J = 2.0 Hz, 2H), 3.81 (s, 3H), 2.99 (dd, J = 12.8 Hz, J = 7.6 Hz, 1H), 2.91 (d, J = 4.8 Hz, 1H), 2.88 (dd , J = 9.2 Hz, J = 3.6 Hz, 1H), 2.79 (brd, J = 12.8 Hz, 1H), 2.30 (td, J = 12.0 Hz, J = 2.4 Hz, 1H), 2.20 (td, J = 12.0 Hz, J = 1.6 Hz, 1H), 1.55 (brs, 1H), 1.23 (brd, J = 9.6 Hz, 1H), 1.01 (brd, J = 12.8 Hz, 2H), 0.84 (ddd, J = 24.0 Hz, 11.6 Hz, 4.0 Hz, 1H), 0.69 (ddd, J = 24.0 Hz, J = 12.0 Hz, J = 4.0 Hz, 1H)
LCMS: m / z 426 (M + H) ⁺

[Example 28]
Compound No. 4-14
N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N-[(1-ethyl-4-piperidinyl) methyl] -benzenesulfonamide
N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N-[(1-ethyl-4-piperidinyl) methyl] -benzenesulfonamid
To a solution of compound number 4-13 (40.0 mg, 0.094 mmol) in anhydrous THF (5 mL) was added 60% sodium hydride (10 mg, 0.1 mmol) and ethyl iodide (29.1 mg, 0.19 mmol). ) And stirred at room temperature for 16 hours.

The reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The obtained organic layer was washed with water and a saturated saline solution, and then dried over sodium sulfate. After the desiccant was removed by filtration, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (Biotage Ultra 10 g, 0% → 20% methanol / chloroform, eluted with 15 column volumes) to give the title compound, N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N-[(1-ethyl-4-piperidinyl) methyl] -benzenesulfonamide was converted to a colorless oil (5 0.6 mg, 13% yield).
1H-NMR (400 MHz, CDCl3) δ: 7.81 (d, J = 8.4 Hz, 2H), 7.61 (t, J = 6.8 Hz, 1H), 7.53 (t, J = 8.4 Hz, 2H), 7.01 (s, 2H), 6.83 (d, J = 2.8 Hz, 1H), 6.82 (d, J = 8.8 Hz, 1H), 6.78 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.26 (s, 2H) , 3.80 (s, 3H), 3.02 (dd, J = 12.8 Hz, J = 7.6 Hz, 1H), 2.90 (dd, J = 13.2 Hz, J = 3.6 Hz, 1H), 2.80 (d, J = 11.2 Hz , 1H), 2.72 (d, J = 10.8 Hz, 1H), 2.32 (q, J = 7.2 Hz, 2H), 1.69 (t, J = 11.6 Hz, 1H), 1.60 (t, J = 10.0 Hz, 1H ), 1.25 (d, J = 12.8 Hz, 1H), 1.05 (m, 2H), 1.03 (t, J = 7.2 Hz, 3H), 0.92 (brs, 2H)
LCMS: m / z 454 (M + H) ⁺

[Example 29]
Compound No. 4-15
N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N-[(1-methyl-4-piperidinyl) methyl] -benzenesulfonamide
N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N-[(1-methyl-4-piperidinyl) methyl] -benzenesulfonamid
Using the same conditions as in Example 28 but using methyl iodide instead of ethyl iodide, the title compound N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N- [(1-Methyl-4-piperidinyl) methyl] -benzenesulfonamide was obtained as a pale yellow oil (18.5 mg, 59%).
1H-NMR (400 MHz, CDCl3) δ: 7.81 (d, J = 7.6 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 2H), 7.10 (t, J = 2.0 Hz, 2H), 6.87 (d, J = 2.8 Hz, 1H), 6.75 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 6.27 (t, J = 2.0 Hz, 2H), 3.80 (s, 3H), 3.29 (dd, J = 13.2 Hz, J = 9.6 Hz, 1H), 3.05 (d, J = 10.8 Hz, 1H), 2.96 (d , J = 11.6 Hz, 1H), 2.83 (dd, J = 13.2 Hz, J = 4.0 Hz, 1H), 2.45 (s, 3H), 2.10 (m, 2H), 1.45 (m, 1H), 1.25 (m , 3H), 1.03 (brs, 1H)
LCMS: m / z 440 (M + H) ⁺

[Example 30]
Compound No. 4-16
N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N- [3- (diethylamino) propyl] benzenesulfonamide
N- [2- (1H-pyrrol-1-yl)]-4-methoxyphenyl) -N- [3- (diethylamino) propyl] -benzenesulfonamid
The same procedure as in Example 17 was repeated, except that N, N-dimethylaminopropyl chloride was used in place of N, N-dimethylaminopropyl chloride to obtain the title compound N- [2- (1H-pyrro-propyl). 1-yl)]-4-methoxyphenyl) -N- [3- (diethylamino) propyl] benzenesulfonamide was obtained as a colorless oil (91.1 mg, 62%).
1H-NMR (400 MHz, CDCl3) δ: 7.76 (d, J = 7.6 Hz, 2H), 7.60 (t, J = 7.6 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 6.98 (t, J = 2.0 Hz, 2H), 6.87 (d, J = 2.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.74 (dd, J = 8.8 Hz, J = 2.8 Hz, 1H), 6.28 (t, J = 2.0 Hz, 2H), 3.79 (s, 3H), 3.19 (t, J = 8.0 Hz, 2H), 2.32 (q, J = 7.2 Hz, 4H), 2.09 (q, J = 7.6 Hz , 2H), 1.25 (5th, J = 7.2 Hz, 2H), 0.86 (t, J = 7.2 Hz, 6H)
LCMS: m / z 443 (M + H) ⁺

[Example 31]
Measurement of Ebola Virus Infection Rate The function of the surface glycoprotein (GP) of Ebola and Marburg virus (filovirus) is essential for the entry process into all cells and is deeply involved in the pathogenicity of the virus. Therefore, establishment of infection can be completely inhibited by suppressing cell invasion mediated by surface glycoproteins.
Using the pseudotype system of vesicular stomatitis virus (VSV), the compound can be screened for its inhibitory effect on infection. The specificity of the filovirus to the pseudotyped virus (the right virus in FIG. 1) was confirmed using the index of the inhibitory effect on the replication of the VSV parent strain (the left virus in FIG. 1) as an index. This system has already been established and is used for screening for neutralizing activity of monoclonal antibodies (Takada A et al. A system for functional analysis of Ebola virus glycoprotein. Proc Natl Acad Sci USA 94: 14764-9, 1997). Nakayama E et al. Antibody-dependent enhancement of Marburg virus infection. J Infect Dis 204 Suppl 3: S978-85, 2011). Briefly, the system converts a virus (VSVΔG ^* -G) in which the region encoding the G protein gene is replaced with a modified GFP gene in a full-length cDNA clone of the VSV genome into a plasmid that expresses the filovirus GP. It was prepared by infecting the introduced 293T cells and collecting the supernatant after incubation.
Using the above pseudo-type system, the activity of compounds that inhibit the cell entry process of Ebola virus was evaluated.

The procedure is as follows.
1. The compound synthesized in the above example, which was serially diluted, was mixed with a pseudotype VSV (GFP expression) having a surface glycoprotein of Ebola virus (Zaire species).
2. Pseudotype VSV mixed with the compound was added to VeroE6 cells on a 96-well plate at about 1000 IU / well to infect.
3.18 hours later, the number of GFP-expressing cells was measured for each well using an IN cell Analyzer, and the infection inhibition efficiency was calculated with the number of GFP-positive cells in control wells (no compound, negative control) as 100%.
The results are shown in the table below. In all the tested compounds, infection inhibition of 10% or more at 5 μM and 50% or more at 1.25 μM was confirmed.

Claims (16)

Formula (I):
Where:
R ¹ is NO ₂ , NR ³ R ⁴ , or Het;
R ² is
Where
R ^{3 to} R ⁶ are each independently H, Alk, or Ar;
R ⁷ is H, Alk, or COOAlk;
Het is a monocyclic, bicyclic, or tricyclic heterocyclic group having 1-3 N and / or O, wherein the heterocyclic group is optionally R ⁸ and / or R ⁹ may be substituted where R ⁸ and R ⁹ are each, independently, H, Alk, or COOAlk;
Alk is each independently a linear or branched alkyl group having 1 to 10 carbon atoms,
Ar is an aryl group optionally substituted by halogen;
Or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof. Het,
The compound according to claim 1 or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof. ^3. The compound according to claim 1, wherein R ³ and R ⁴ are each independently a methyl group or an ethyl group, or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof. . The method according to any one of claims 1 to 3, wherein R ⁵ and R ⁶ are each Alk, and Alk is each independently a linear or branched alkyl group having 1 to 4 carbon atoms. A compound or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof. R ² is
The compound according to any one of claims 1 to 4, or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof. R ¹ is NO ₂ , NH ₂ ,
The compound according to any one of claims 1 to 5, or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof. The following chemical structural formula:
The compound according to claim 1 or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof, represented by the formula:   A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.   The pharmaceutical composition according to claim 8, for prevention and / or treatment of a viral infection.   The pharmaceutical composition according to claim 9, wherein the viral infection is an acute viral infection.   The pharmaceutical composition according to claim 10, wherein the acute viral infection is Ebola hemorrhagic fever.   The pharmaceutical composition according to claim 9, wherein the virus is a filovirus.   13. The pharmaceutical composition according to claim 12, wherein the filovirus is an Ebola virus.   An antiviral agent comprising the compound according to any one of claims 1 to 7 or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.   A virus cell entry inhibitor comprising the compound according to any one of claims 1 to 7, or a hydrate thereof, or a pharmaceutically acceptable salt of the compound or a hydrate thereof.   A method for inhibiting the cell entry process of a virus, using the compound or a hydrate thereof according to any one of claims 1 to 7 or a pharmaceutically acceptable salt of the compound or a hydrate thereof.