CN117917240A - Use of compounds for the treatment of herpes simplex virus infection and related diseases or conditions - Google Patents

Abstract

The present invention provides the use of a compound of formula (I) or an isomer, salt, N-oxide, metabolite, solvate, salt of a solvate, crystalline form, prodrug, complex, co-crystal, co-amorphous or isotopic form thereof in the manufacture of a medicament for the treatment or prophylaxis of herpes simplex virus infection and associated diseases or conditions in a subject,Wherein R ₁、R₂、R₃、R₄、R₅、R₆、R₇, X, m and n are as defined herein. The compounds described herein have the effect of inhibiting herpes simplex virus type 1 and herpes simplex virus type 2.

Description

Use of compounds for the treatment of herpes simplex virus infection and related diseases or conditions

Technical Field

The present invention relates to the use of a salt, crystalline form, prodrug or isotopic form comprising a specific compound or an isomer, salt, N-oxide, solvate, salt of a solvate thereof, for the manufacture of a medicament for the treatment or prophylaxis of a herpes simplex virus infection and associated diseases or conditions in a subject.

Background

In the acute infectious diseases, most of the infectious diseases are viral infectious diseases, and the incidence rate and the death rate of the viral infectious diseases are high. Individuals such as viruses are extremely tiny, lack independent metabolic capability, and exist parasitically as pathogenic microorganisms. Viruses are of a wide variety, and at present, many viruses with high infectivity and pathogenicity to human beings have been found, and the viruses often cause local and even global infectious diseases to outbreak, and have great harm to human society, such as herpes simplex virus. Some viruses can also infect animals, causing various light to severe diseases, and at the same time, animals become sources of infection for these viruses, making humans overwhelm them.

Herpes simplex virus (herpes simplex virus, HSV) is a typical representation of herpes viruses and is known as dermatitis blisters, i.e. herpes simplex, occurring in the acute phase of infection. Herpes simplex virus can cause a variety of diseases in humans, such as gingivitis (gingivostomatitis), keratoconjunctivitis (keratoconjunctivitis), encephalitis (ENCEPHALITIS), infection of the reproductive system and neonatal infections.

In view of the foregoing, there is a great need in the art to develop inhibitors for inhibiting replication of herpes simplex virus for use in the treatment of herpes simplex virus infections and diseases or conditions associated therewith.

Disclosure of Invention

The present invention provides a solution to the above problems existing in the prior art.

In a first aspect of the invention there is provided the use of a compound of formula (I), or an isomer, salt, N-oxide, metabolite, solvate, salt of a solvate, crystalline form, prodrug, complex, co-crystal, co-amorphous or isotopic form thereof, in the manufacture of a medicament for the treatment or prophylaxis of a herpes simplex virus infection and associated diseases or conditions in a subject,

Wherein the method comprises the steps of

Each R ₁、R₂、R₃、R₄、R₅、R₆、R₇ is independently H or substituted or unsubstituted C ₁-C₆ alkyl;

X is halogen;

m is 0,1,2 or 3;

n is 0, 1,2, 3,4 or 5.

In another aspect of the invention there is provided the use of a compound of formula (I) or an isomer, salt, N-oxide, metabolite, solvate, salt of a solvate, crystalline form, prodrug, complex, co-crystal, co-amorphous or isotopic form thereof in the manufacture of a medicament for inhibiting herpes simplex virus.

The inventive research shows that the compound has the effect of inhibiting the herpes simplex virus and has good potential effect in the aspect of treating or preventing the herpes simplex virus infection and related diseases or symptoms thereof.

Drawings

FIG. 1 is a statistical graph of the activity of compounds in biological examples to inhibit herpes simplex virus.

FIG. 2 is an X-ray powder diffraction pattern of crystalline form A of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 3 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form A of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 4 is an X-ray powder diffraction pattern of crystalline form B of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 5 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form B of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 6 is an X-ray powder diffraction pattern of crystalline form C of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 7 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form C of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 8 is an X-ray powder diffraction pattern of crystalline form D of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 9 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form D of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 10 is an X-ray powder diffraction pattern of crystalline form E of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 11 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form E of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 12 is an X-ray powder diffraction pattern of crystalline form F of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 13 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form F of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 14 is an X-ray powder diffraction pattern of crystalline form G of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 15 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form G of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 16 is an X-ray powder diffraction pattern of crystalline form H of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 17 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form H of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 18 is an X-ray powder diffraction pattern of crystalline form I of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 19 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form I of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 20 is an X-ray powder diffraction pattern of crystalline form J of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 21 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form J of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 22 is an X-ray powder diffraction pattern of crystalline form K of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 23 is a Thermogravimetric (TGA) and Differential Scanning Calorimetric (DSC) profile of crystalline form K of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione.

FIG. 24 is an X-ray powder diffraction pattern of crystalline form A of compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid.

Detailed Description

The term "herpes simplex virus" belongs to the subfamily alphavirus of the herpesviridae, has typical morphological structural characteristics of the herpesvirus, has a core of double-stranded linear DNA, is composed of a long fragment and a short fragment, has a length of about 150kb, can code more than 100 polypeptides, and has a part of polypeptides closely related to virus infection and cell destruction. The number of viral envelope glycoproteins is 11, gB, gC, gD, gE, gG, gH, gI, gL, gK and gM respectively, which play an important role in volatilizing the virus during the pathogenic process and are also the main antigens for inducing the immune response of the organism. The viruses can be classified into herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) according to antigenicity differences, the herpes simplex virus type 1 is mainly obtained from foci of lips, and the herpes simplex virus type 2 can be separated from foci of genitals. In particular, the herpes simplex virus comprises (e.g., is selected from) herpes simplex virus type 1 and/or herpes simplex virus type 2; preferably, herpes simplex virus type 1 (HSV-1) is herpes simplex virus type 1 GDV011; and/or, herpes simplex virus type 2 (HSV-2) is herpes simplex virus type 2 GDV017.

Herpes simplex virus type 1 causes local damage to the orofacial area, particularly on the mucous membranes (mouth and throat), at the skin mucosal edges (lips), and on the cornea (eyes). HSV-2 infection is mostly found in the genital tract.

Herpes simplex virus infection and its related diseases or conditions include diseases or conditions caused by herpes simplex virus, e.g., it includes (e.g., is selected from the group consisting of): clinical herpes (primary and recurrent), herpetic eczema (primary), traumatic herpes (primary or recurrent), gingivitis (primary), vulvovaginitis (primary, recurrent), genital herpes (primary, recurrent), keratoconjunctivitis (primary and recurrent), meningoeencephalitis (primary), neonatal herpes simplex virus infection, aseptic meningitis, and/or herpes labialis, etc.

In the present invention, inhibition of herpes simplex virus may be performed in a subject or in vitro. Inhibition of herpes simplex virus in a subject may be accomplished to treat or prevent herpes simplex virus infection and related diseases or conditions. Forms of inhibiting herpes simplex virus in vitro, including positive control drugs, research drugs and the like used for resisting the herpes simplex virus, are used in activities such as in vitro biological activity research and the like.

The invention also includes the combination of the compound of formula (I) with other antiviral agents (e.g. interferon, acyclovir, valacyclovir, etc.) or agents for the treatment of bacterial infections (e.g. antibiotics) for the treatment or prophylaxis of herpes simplex virus infections and diseases or conditions associated therewith, for the manufacture of a pharmaceutical combination or pharmaceutical composition for use in combination.

The compounds of the present application may exist in an isomer, such as a stereoisomer (enantiomer, diastereomer, cis-trans isomer), depending on the structure thereof. The present application thus relates to enantiomers or diastereomers and their respective mixtures. The stereoisomerically pure constituents can be separated in a known manner from such mixtures of enantiomers and/or diastereomers.

When the compounds of the present application may exist as optical isomers, the compounds of the present application are generally substantially pure optical isomers.

If the compounds of the present application are in tautomeric forms, the present application encompasses all tautomeric forms.

The compounds of the application may be present in free form, for example as a free base or as a free acid or as a zwitterion, or may be present in the form of a salt. The salt may be any salt commonly used in pharmacy, organic or inorganic addition salts, in particular any physiologically acceptable organic or inorganic addition salt.

For the purposes of the present application, preferred salts are the physiologically acceptable salts of the compounds according to the application. However, salts which are not suitable for pharmaceutical use per se but which can be used, for example, for the isolation or purification of the compounds according to the application are also included.

The term "physiologically acceptable salts" refers to the relatively non-toxic, inorganic or organic acid addition salts of the compounds described herein, see for example S.M. Berge et al, "Pharmaceutical Salts", J.Pharm. Sci.1977,66,1-19.

Physiologically acceptable salts of the compounds according to the application encompass acid addition salts of inorganic acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, disulphonic acid, sulphamic acid, phosphoric acid, nitric acid, or salts with organic acids, the organic acid is, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, caproic acid, heptanoic acid, undecanoic acid, dodecanoic acid, benzoic acid, salicylic acid, 2- (4-hydroxybenzoyl) -benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, octanoic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectate acid, persulfuric acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, pantothenic acid, mucic acid, succinic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphate, aspartic acid, sulfosalicylic acid or thiocyanic acid. Particularly preferred are p-toluene sulfonic acid and/or fumarate salts.

The application includes all possible salts of the compounds of the application, which are single salts or any mixture of the salts in any ratio, for example 3:1, 2:1, 1:1, 1:2.

Solvates are, for the purposes of the present application, terms for those forms of the compounds of the present application which form complexes with solvent molecules by coordination in solid or liquid form. Hydrates are a specific form of solvate in which coordination with water occurs. In the context of the present application, hydrates are preferred as solvates.

The application also includes all suitable isotopic forms of the compounds of the present application. Isotopic forms of the compounds of the present application are defined as: a compound in which at least one atom is replaced with an atom having the same atomic number but an atomic mass different from the atomic mass usually or mainly existing in nature. Examples of isotopes that can be incorporated into compounds of the application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2H (deuterium), ³ H (tritium )、¹³C、¹⁴C、¹⁵N、¹⁷O、¹⁸O、³²P、³³P、³³S、³⁴S、³⁵S、³⁶S、¹⁸F、³⁶Cl、⁸²Br、¹²³I、¹²⁴I、¹²⁹I and ¹³¹ i. Certain isotopic variants of compounds of the application, such as those incorporating one or more radioisotopes such as ³ H or ¹⁴ C, are particularly preferred for use in the study of drug and/or matrix tissue distribution.

In addition, prodrugs of the compounds of the present application are also encompassed by the present application. The term "prodrug" encompasses compounds which may be biologically active or inactive themselves, but which are converted (e.g. by metabolism or hydrolysis) during their residence time in the body to the compounds described herein. Prodrugs of the compounds of the present application may be produced, for example, by replacing suitable functional groups present in the compounds of the present application with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in Design of Prodrugs of H.Bundgaard (Elsevier, 1985)).

The compounds of the present application may be in solid form, such as amorphous, crystalline (either single crystalline or polymorphic) or mesogenic (mesomorph).

As used herein, the term "amorphous form" refers to an amorphous solid state form of a substance.

As used herein, the term "crystalline form" refers to a crystalline solid state form of a substance, i.e., a crystalline form of the same molecule, and as a result of the arrangement or conformation of the molecules in the crystal lattice. In particular, the crystalline form may be a single crystalline form or a polymorphic form.

Furthermore, the present application includes all possible polymorphs (single polymorphs or mixtures of more than one polymorphs in any ratio) of the compounds of the present application.

As used herein, the term "polymorph" refers to a crystal structure in which molecules can crystallize in different crystal package arrangements and all have the same elemental composition. For example, the same material has two or more spatial arrangements and unit cell parameters, forming multiple crystalline forms.

As used herein, the term "mesogenic form" refers to a substance (e.g., liquid crystal) that exists in a state between liquid and solid states. In the mesogenic form, the same molecules of the substance may be oriented in an organized manner (e.g., crystalline), and the substance may flow like a liquid.

Thus, the present application includes all possible salts, crystalline forms, metabolites, hydrates, solvates, prodrugs (e.g. esters) and diastereoisomeric forms of the compounds of the application, either as a single salt, crystalline form, metabolite, hydrate, solvate, prodrug (e.g. ester) or diastereoisomeric form, or as a mixture of more than one salt, crystalline form, metabolite, hydrate, solvate, prodrug (e.g. ester) or diastereoisomeric form in any ratio.

The compounds of the application intended for pharmaceutical use may be administered as crystalline or amorphous products, or mixtures thereof. Compositions, for example as solid suppositories, powders or films, can be obtained by processes such as precipitation, crystallization, freeze-drying, spray-drying or evaporative drying. Microwave or radiation drying may be used for this purpose.

The compounds of the application may be admixed with physiologically acceptable/pharmaceutically acceptable excipients to form pharmaceutical compositions, the choice of which is dependent upon the intended method of administration of the pharmaceutical composition (e.g., oral, inhalation, topical, nasal, rectal, transdermal or injectable administration).

As used herein, the term "physiologically acceptable/pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the active ingredient (e.g., a compound of the application) being administered.

For the purposes of the present invention, unless otherwise indicated, substituents have the following meanings:

The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Substituents are only in their possible chemical positions and the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, the substituents may be one or more groups independently selected from C ₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₁-C₆ alkylthio, C ₁-C₆ alkylamino, halogen, mercapto, hydroxy, nitro, cyano, C ₃-C₆ cycloalkyl, C ₂-C₆ heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate groups.

The term "halogen", "halogen atom" or "halo" means fluorine, chlorine, bromine and iodine, in particular bromine, chlorine or fluorine, preferably chlorine or fluorine.

The term "C ₁-C₆ alkyl" denotes a straight-chain or branched alkyl group having the specifically specified number of carbon atoms (e.g., one, two, three, four, five or six carbon atoms), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl. If the number of carbon atoms is not specified, the term "alkyl" generally denotes a straight-chain or branched alkyl group having from 1 to 9, in particular from 1 to 6, preferably from 1 to 4, carbon atoms. In particular, the alkyl group has 1,2, 3, 4, 5 or 6 carbon atoms ("C ₁-C₆ -alkyl"), for example methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, pentyl, isopentyl, hexyl, 2-methylbutyl, 1-ethylpropyl, 1, 2-dimethylpropyl, neopentyl, 1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2, 3-dimethylbutyl, 1, 3-dimethylbutyl or 1, 2-dimethylbutyl. Preferably, the alkyl group has 1,2 or 3 carbon atoms ("C ₁-C₃ -alkyl"), such as methyl, ethyl, n-propyl or isopropyl.

As used herein, the term "subject" refers to an animal, including but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. In particular, the subject is 0 years old or older, 1 year old or older, 2 years old or older, 4 years old or older, 5 years old or older, 10 years old or older, 12 years old or older, 13 years old or older, 15 years old or older, 16 years old or older, 18 years old or older, 20 years old or older, 25 years old or older, 30 years old or older, 35 years old or older, 40 years old or older, 45 years old or older, 50 years old or older, 55 years old or older, 60 years old or older, 65 years old or older, 70 years old or older, 75 years old or older, 80 years old or older, 85 years old or older, 90 years old or older, 95 years old or older, 100 years old or older, or 105 years old or older.

In a specific embodiment, the subject is a human, such as a child (e.g., a human aged 0-18 years or a human aged 0-14 years), an adult (e.g., a human aged 19-59 years), or an elderly human (e.g., a human aged 60 years or older).

In a particular embodiment, in the compound of formula (I), R ₁ and R ₂ are each independently unsubstituted C ₁-C₆ alkyl, preferably each independently methyl.

In a particular embodiment, in the compounds of formula (I), R ₃、R₄、R₅、R₆、R₇ are each independently H.

In a particular embodiment, in the compound of formula (I), each X may be the same or different. For example, in the compound of formula (I), the substituents X on the indazole ring may be the same or different from each other, the substituents X on the benzene ring in the benzyl group may be the same or different from each other, and the substituents X on the indazole ring and the substituents X on the benzene ring in the benzyl group may be the same or different.

In a particular embodiment, in the compound of formula (I), the substituent X on the indazole ring may be the same or different from the substituent X on the benzene ring in the benzyl group. Specifically, in the compound of formula (I), the substituents X on the indazole ring are each independently fluorine or chlorine, preferably chlorine; and/or the substituents X on the benzene ring in the benzyl group are each independently fluorine or chlorine, preferably fluorine.

In a specific embodiment, in the compound of formula (I), m is 1 or 2, for example 1. Specifically, when m is 2, the substituent X on the indazole ring is a 4, 6-position substituent, a 4, 7-position substituent, or a 6, 7-position substituent. Specifically, when m is 2, the substituents X on the indazole ring are the same or different independently of each other. More specifically, when m is 2, X is a 4, 6-dichloro substituent, 4, 7-dichloro substituent, 6, 7-dichloro substituent, 4, 6-difluoro substituent, 4, 7-difluoro substituent, 6, 7-difluoro substituent, 4-chloro-6-fluoro substituent, 4-fluoro-6-chloro substituent, 4-chloro-7-fluoro substituent, 4-fluoro-7-chloro substituent, 6-chloro-7-fluoro substituent, or 6-fluoro-7-chloro substituent. Specifically, when m is 1, X is a 4-position substituent, a 6-position substituent, or a 7-position substituent. More specifically, when m is 1, X is a 4-fluoro substituent, a 4-chloro substituent, a 6-fluoro substituent, a 6-chloro substituent, a 7-fluoro substituent, or a 7-chloro substituent.

In a specific embodiment, in the compound of formula (I), n is 2, 3 or 4, for example 3.

In a specific embodiment, in the compound of formula (I), when n is 3, X is a2, 3, 4-position substituent, a2, 3, 6-position substituent, a2, 4, 5-position substituent, a2, 5, 6-position substituent, a3, 4, 5-position substituent, a3, 5, 6-position substituent, or a4, 5, 6-position substituent. Specifically, when n is 3, the substituents X on the benzene ring in the benzyl group are the same or different, preferably the same, independently of each other. More specifically, when n is 3, X is a2, 3, 4-trifluoro substituent, a2, 3, 6-trifluoro substituent, a2, 4, 5-trifluoro substituent, a2, 5, 6-trifluoro substituent, a3, 4, 5-trifluoro substituent, a3, 5, 6-trifluoro substituent, or a4, 5, 6-trifluoro substituent, preferably a2, 4, 5-trifluoro substituent.

In a specific embodiment, the compound of formula (I) has the following structure:

Wherein R ₁、R₂, X and n are as defined above in the present application.

In a specific embodiment, the compound of formula (I) is

Or a salt, isomer, N-oxide, metabolite, solvate, salt of a solvate, crystalline form, prodrug, complex, co-crystal, co-amorphous or isotopic form thereof.

Specifically, the compound of formula (I) isAn amorphous form, a crystalline form (which may be a single crystalline form or a polymorphic form) or an isotopic form (e.g., a deuterated isotopic form); or an amorphous form, a crystalline form (which may be a single crystalline form or a polymorphic form) or an isotopic form (such as a deuterated isotopic form) of a salt thereof (e.g., fumarate); or an amorphous form, a crystalline form (which may be a single crystalline form or a polymorphic form) or an isotopic form (e.g., a deuterated isotopic form) of complexes thereof with other compounds (e.g., fumaric acid); or in the form of a co-crystal or isotope with other compounds such as fumaric acid.

In particular, specific compounds encompassed by the compound of formula (I) (e.g., the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione) and methods for their preparation are known in the art.

For example, the specific compound may be in a crystalline form selected from one of form a, form B, form C, form D, form E, form F, form H, form I, form G, form J, form K, or a mixture of two or more thereof;

Wherein,

Form a is characterized by using Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any three or more of 4.30, 12.30, 12.87, 24.61;

form B is characterized by the use of Cu-ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° including 22.20, 23.26, 26.86;

Form C is characterized by using Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any three or more of 11.26, 12.55, 18.85, 19.49;

The crystal form D is characterized in that Cu-K alpha radiation is used, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2 theta value +/-0.2 degrees comprise more than any three of 9.89, 12.83, 13.67 and 15.41;

Form E is characterized by the use of Cu-ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° including 6.60, 9.63, 13.25;

Form F is characterized by using Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any three or more of 7.44, 8.16, 14.65, 21.51;

form H is characterized by using Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any three or more of 9.16, 11.69, 19.52, 24.00;

form I is characterized by the use of Cu-ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° including 12.98, 13.24, 26.11;

Form G is characterized by the use of Cu-ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° including 8.76, 10.89, 17.73;

form J is characterized by the use of Cu-ka radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° including 17.00, 26.42, 27.99;

Form K is characterized by the use of Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any three or more of 8.29, 8.83, 14.27, 23.56.

Specifically, the crystalline forms of the compounds of the present application were characterized using an X-ray powder diffractometer PANALYTICAL EMPYREAN (PANALYTICAL, NL) with a2 theta scan angle from 3 deg. to 45 deg., a scan step size of 0.013 deg., a test time of 5 minutes 8 seconds, a light pipe voltage and current of 45kV and 40mA, respectively, and a sample pan of zero background sample pan.

In particular, the crystalline form of the compounds of the present application is a single crystalline form (e.g., form a or form E); or the crystalline form of the compound of the application is a mixture (e.g., polymorphic form) comprising at least form a and/or form E. For example, the crystalline form of the compounds of the present application is a mixture (e.g., polymorph) consisting of form a and one or more other crystalline forms different from forms a and E, a mixture (e.g., polymorph) consisting of form a, form E, and optionally one or more other crystalline forms different from forms a and E, or a mixture (e.g., polymorph) consisting of form E and one or more other crystalline forms different from forms a and E.

As used herein, the term "other crystalline forms other than forms a and E" refers to crystalline forms of the compounds of the present application that are different from forms a and E, preferably pharmaceutically acceptable crystalline forms of the compounds of the present application that are different from forms a and E.

In particular, the crystalline form of the compounds of the present application may be a solvate. In particular, crystalline form a or I of the compounds of the present application may be a solvate.

The term "solvates" refers to those forms of the crystalline forms of the compounds of the present application that are used to form complexes with molecules of solvents (e.g., water, organic solvents such as DMF, formic acid, toluene, etc.) by coordination. Hydrates are a specific form of solvate in which coordination with water occurs. For example, the solvate may be a hydrate.

In particular, the crystalline form of the compounds of the present application may be anhydrate. Specifically, crystalline form C, E or K of the compounds of the present application may be anhydrate.

Specifically, the characteristic diffraction peak of the X-ray powder diffraction pattern expressed as 2 theta value + -0.2 DEG using Cu-K alpha radiation also includes any one or more of 10.65, 13.79, 20.67.

Specifically, form a uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 4.30, 10.65, 12.30, 12.87, 13.79, 20.67, 24.61.

More specifically, form a uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 13.19, 14.94, 18.91, 24.95.

Specifically, the differential scanning calorimetric profile of form A has endothermic peaks at 167.3 ℃ + -2 ℃, 202.5 ℃ + -2 ℃, 211.2 ℃ + -2 ℃ and 239.0 ℃ + -2 ℃.

Specifically, the thermogravimetric profile of form a loses less than 6% (specifically 5.2%) of weight when heated to 150 ℃ ± 2 ℃ and undergoes decomposition at 275 ℃ ± 2 ℃.

In a specific embodiment, form B uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further comprise any one or more of 11.65, 15.92, 20.38.

In a specific embodiment, form B uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 11.65, 15.92, 20.38, 22.20, 23.26, 26.86.

Specifically, form B uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 8.57, 12.40, 16.18, 17.18.

Specifically, the differential scanning calorimetry pattern of form B has endothermic peaks at 155.2 ℃ ± 2 ℃, 219.9 ℃ ± 2 ℃ and 239.0 ℃ ± 2 ℃ and exothermic peaks at 221.9 ℃ ± 2 ℃.

Specifically, the thermogravimetric profile of form B loses less than 9% (specifically 8.6%) of weight when heated to 200 ℃ ± 2 ℃ and undergoes decomposition at 275 ℃ ± 2 ℃.

Specifically, form C uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 12.80, 16.27, 26.91.

Specifically, form C uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 11.26, 12.55, 12.80, 16.27, 18.85, 19.49, 26.91.

More specifically, form C uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 10.47, 10.93, 18.17, 18.49.

Specifically, the differential scanning calorimetry pattern of form C has endothermic peaks at 218.6 ℃ ± 2 ℃ and 239.0 ℃ ± 2 ℃ and exothermic peaks at 221.7 ℃ ± 2 ℃.

Specifically, the thermogravimetric profile of form C loses less than 0.5% (specifically 0.4%) when heated to 150 ℃ ± 2 ℃ and undergoes decomposition at 275 ℃ ± 2 ℃.

Specifically, form D uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 13.98, 19.85, 25.02.

Specifically, form D uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 9.89, 12.83, 13.67, 13.98, 15.41, 19.85, 25.02.

More specifically, form D uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 7.53, 22.05, 22.73, 25.94.

Specifically, the differential scanning calorimetric profile of form D has endothermic peaks at 146.2.+ -. 2 ℃, 150.7.+ -. 2 ℃, 160.4.+ -. 2 ℃, 220.0.+ -. 2 ℃ and 240.1.+ -. 2 ℃ and exothermic peaks at 222.3.+ -. 2 ℃.

Specifically, the thermogravimetric profile of form D loses less than 12% (specifically 11.5%) of weight when heated to 200 ℃ ± 2 ℃ and disintegrates at 275 ℃ ± 2 ℃.

In particular, form E uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 16.21, 17.56, 19.87.

In particular, form E uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 6.60, 9.63, 13.25, 16.21, 17.56, 19.87.

More specifically, form E uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 23.34, 24.55, 26.08.

Specifically, the differential scanning calorimetry pattern of form E has an endothermic peak at 238.7 ℃ ± 2 ℃.

Specifically, the thermogravimetric profile of form E did not lose weight (specifically 0%) when heated to 200 ℃ ± 2 ℃ and decomposed at 275 ℃ ± 2 ℃.

Specifically, form F uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 19.70, 24.61, 26.62.

Specifically, form F uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 7.44, 8.16, 14.65, 19.70, 21.51, 24.61, 26.62.

More specifically, form F uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 16.33, 19.35, 22.72, 29.58.

Specifically, the differential scanning calorimetry pattern of form F has endothermic peaks at 208.1 ℃ ± 2 ℃ and 239.1 ℃ ± 2 ℃ and exothermic peaks at 210.3 ℃ ± 2 ℃.

Specifically, the thermogravimetric profile of form F loses less than 10% (specifically 9.6%) when heated to 150 ℃ ± 2 ℃ and disintegrates at 275 ℃ ± 2 ℃.

Specifically, form G uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 15.18, 26.53, 27.42.

Specifically, form G used Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° included 8.76, 10.89, 15.18, 17.73, 26.53, 27.42.

Specifically, form G uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 7.57, 12.59, 18.85, 21.30.

Specifically, the differential scanning calorimetric pattern of form G has endothermic peaks at 140.2.+ -. 2 ℃, 219.9.+ -. 2 ℃ and 238.9.+ -. 2 ℃ and exothermic peaks at 142.4.+ -. 2 ℃ and 225.7.+ -. 2 ℃.

Specifically, the thermogravimetric profile of form G loses less than 17% (specifically 16.4%) of weight when heated to 200 ℃ ± 2 ℃ and undergoes decomposition at 275 ℃ ± 2 ℃.

Specifically, form H uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 15.12, 18.61, 22.01.

Specifically, form H uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 9.16, 11.69, 15.12, 18.61, 19.52, 22.01, 24.00.

More specifically, form H uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 14.33, 17.88, 25.78.

Specifically, the differential scanning calorimetric profile of form H has an endothermic peak at 145 ℃ + -2 ℃, 227.5 ℃ + -2 ℃, 239.4 + -2 ℃ and an exothermic peak at 239 ℃ + -2 ℃.

Specifically, the thermogravimetric profile of form H loses less than 15% (specifically 14.4%) of weight when heated to 200 ℃ ± 2 ℃ and undergoes decomposition at 275 ℃ ± 2 ℃.

Specifically, the characteristic diffraction peak of the X-ray powder diffraction pattern expressed as 2 theta value + -0.2 DEG using Cu-K alpha radiation also includes any one or more of 4.35, 19.99, 29.26.

Specifically, form I uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 4.35, 12.98, 13.24, 19.99, 26.11, 29.26.

More specifically, form I uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 7.03, 10.94, 25.61.

Specifically, the differential scanning calorimetry pattern of the crystal form I has endothermic peaks at 165.4+/-2 ℃, 209.3+/-2 ℃ and 239.5+/-2 ℃ and exothermic peaks at 213.8 +/-2 ℃.

Specifically, the thermogravimetric analysis of form I loses less than 3% (specifically 2.1%) of weight when heated to 150 ℃ ± 2 ℃ and undergoes decomposition at 275 ℃ ± 2 ℃.

Specifically, form J uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 16.58, 28.07, 28.14, 29.88.

Specifically, form J uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include 16.58, 17.00, 26.42, 27.99, 28.07, 28.14, 29.88.

More specifically, form J uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 26.11, 29.94, 34.78.

Specifically, the differential scanning calorimetry pattern of form J has endothermic peaks at 132.9 ℃ + -2 ℃, 227.8 ℃ + -2 ℃ and 239.1 ℃ + -2 ℃ and exothermic peaks at 197.7 ℃ + -2 ℃ and 231.0 ℃ + -2 ℃.

Specifically, the thermogravimetric profile of form J loses less than 11% (specifically 10.4%) when heated to 200 ℃ ± 2 ℃ and disintegrates at 275 ℃ ± 2 ℃.

Specifically, form K uses Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values±0.2° further include any one or more of 10.47, 12.60, 17.13.

Specifically, form K uses Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values±0.2° include 8.29, 8.83, 10.47, 12.60, 14.27, 17.13, 23.56.

More specifically, form K uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° further include any one or more of 12.27, 15.67, 17.43, 19.90.

Specifically, the differential scanning calorimetry pattern of form K has an endothermic peak at 228.2 ℃ ±2 ℃.

Specifically, the thermogravimetric profile of form K loses less than 1.5% (specifically 1.2%) when heated to 200 ℃ ± 2 ℃ and decomposes at 275 ℃ ± 2 ℃.

In particular, the specific compounds encompassed by the compounds of formula (I) (e.g., the compounds (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione) may be in crystalline form, which crystalline forms and processes for their preparation are described in WO2022/138987A1 and/or WO2022/138988A1, the above-mentioned patent applications being incorporated herein by reference.

For example, the isotopic form of the particular compound described above may be represented by any one of the following structural formulas:

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Specifically, deuterated isotopic forms of the specific compounds described above, methods of preparation, and the like are described in CN114507221a, which is incorporated herein by reference.

For example, the salt of the above specific compound (e.g., compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione) is maleate, fumarate or tosylate, and reference may be made to the descriptions of WO2022/138987A1 and/or WO2022/138988A1, the above-mentioned patent application being incorporated herein by reference. The crystalline forms of the salts of the above specific compounds are selected from the crystalline forms of the fumarate or tosylate salts of the compounds, the specific structures and methods of preparation of which are described in WO2022/138987A1 and/or WO2022/138988A1, the above-mentioned patent applications being incorporated herein by reference.

Specifically, the crystalline form of the salt of the compound of the application is a single crystalline form; or the crystalline form of a salt of a compound of the application is a mixture comprising at least two crystalline forms (e.g., polymorphs). Preferably, the crystalline form of the salt of the compound of the application is a single crystalline form or a polymorph of the fumarate salt of the compound, for example as a mixture of two crystalline forms of the fumarate salt of the compound.

In particular, the crystalline form of a salt of a compound of the application may be a solvate.

In particular, the crystalline form of a salt of a compound of the application may be anhydrate.

The application also includes complexes or co-crystals or co-amorphous forms of each particular compound encompassed by the application with other molecules, which may be other active compounds, co-crystal formations, and the like.

The term "co-crystal" refers to crystals of an Active Pharmaceutical Ingredient (API) and a co-crystal former (cocrystals former, CCF) bonded by hydrogen bonding, van der waals forces, pi-pi conjugation, or halogen bonding, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

The term "co-amorphous" refers to a single-phase amorphous binary or multi-component system having a single glass transition temperature (Tg) formed by non-covalent bonds, ionic bonds, or no interaction forces of an Active Pharmaceutical Ingredient (API) with other physiologically acceptable small molecule substances (e.g., API ₂ or small molecule pharmaceutical excipients, etc.), wherein the active pharmaceutical ingredient and the other physiologically acceptable small molecule substances are solid at room temperature. These components are intimately mixed together at the molecular level in the co-amorphous, nor are there fixed stoichiometric ratios between the components. The "co-amorphous" samples can be prepared by melt and solvent-based processes such as spray drying, solvent evaporation, freeze drying, supercritical fluid precipitation, melt quenching, hot melt extrusion, ball milling, cryogenic milling, and the like. X-ray powder diffraction (XRPD) together with Differential Scanning Calorimetry (DSC) can be used to identify whether a sample is "co-amorphous" after preparation, for example by measuring the absence of bragg peaks and the occurrence of a single glass transition temperature.

In one embodiment, the crystalline forms of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid are used.

Specifically, the crystalline form is crystalline form a, which uses cu—kα radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values±0.2° include any three selected from 10.94, 19.06, 23.50, 24.66.

Preferably, crystalline form a, which uses Cu-ka radiation, further comprises any one or more of 9.5, 13.81, 18.61, 22.59, 23.8, or further comprises any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, or further comprises any one or more of 14.73, 20.87, 21.49, 21.97, 25.39, of the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 °.

More preferably, crystalline form a uses Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any one or more of 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59, 23.8, or further include any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, and/or further include any one or more of 14.73, 20.87, 21.49, 21.97, 25.39.

Most preferably, crystalline form a uses Cu-ka radiation and the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° is shown in fig. 24.

Specifically, the molar ratio of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione to fumaric acid in the crystalline form (e.g., crystalline form A) is 1:1.

In a specific embodiment, the application provides the use of the crystalline forms (e.g., crystalline form a) of the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid of the application in the manufacture of a medicament for the treatment or prophylaxis of herpes simplex virus infection and its associated diseases or disorders in a subject; preferably, the use is in the manufacture of a medicament for inhibiting herpes simplex virus.

The crystalline forms of the above compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid may be referred to in CN114591304A, the above patent application being incorporated herein by reference.

The various embodiments described herein, or of different preferred classes of embodiments, may be combined arbitrarily unless otherwise indicated.

The present invention is illustrated below by way of examples, but it should not be construed that the scope of the inventive subject matter is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention. The compounds or reagents used in the following examples are commercially available or may be prepared by conventional methods known to those skilled in the art; the laboratory apparatus used is commercially available.

Examples

I. preparation example

1. (6E) Preparation of (E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-e-2, 4-dione

To a solution of 6-ethylsulfanyl-3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazine-2, 4 (1H, 3H) -dione (450 mg,1.091 mmol) and 6-chloro-2-methyl-2H-indazol-5-amine (258 mg, 1.319 mmol) in THF (10 mL) was first added drop-wise LHMDS (1M in THF, 1.00mL,1.00 mmol) at 0deg.C, stirred for 30min, then LHMDS (1M in THF, 1.00mL,1.00 mmol) was added drop-wise with continuous stirring. The reaction mixture was stirred at 0 ℃ for 2.5h, followed by 40min at room temperature. The reaction was quenched with aqueous NH ₄ Cl and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried over MgSO ₄ and concentrated under reduced pressure. The residue was recrystallized from methylene chloride/isopropyl ether (5:1 by volume) and subsequently dried in vacuo to give a pale pink solid. The pale pink solid was dispersed in 5mL of isopropanol, stirred, heated to reflux, cooled and suction filtered. The resulting cake was dried in vacuo to give (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione (380.1 mg) as a solid.

2. (6E) Preparation of each of the crystalline forms of (E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-e-2, 4-dione

2.1 Preparation method of Crystal form A

20.6Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione prepared in the above preparation example in solid form was weighed, added to 10.0mL of ethylene glycol dimethyl ether to be completely dissolved, and then left open at room temperature for 2 weeks, followed by centrifugal separation (10000 rpm,4 min) to give crystalline form A of the compound of the present application.

2.2 Preparation method of Crystal form B

15.0Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione prepared in the above preparation example in solid form was weighed, 0.8mL of dioxane was added to completely dissolve, 4.0mL of n-heptane was then added to the solution rapidly, stirring was carried out at room temperature for 1 hour, and after centrifugation (10000 rpm,4 min), the solid was dried in vacuo at room temperature to give form B of the compound of the present application.

2.3 Preparation method of Crystal form C

15.0Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione prepared in the above preparation example in solid form was weighed, added to 0.8mL of dioxane to completely dissolve, 4.0mL of isopropyl ether was then added to the solution, stirred at room temperature for 1 hour, and after centrifugation (10000 rpm,4 min), the solid was dried in vacuo at room temperature to give form C of the compound of the present application.

2.4 Preparation method of crystal form D

19.5Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione prepared in the above preparation example in solid form was weighed, added to 0.2mL of DMF, allowed to dissolve completely, then left open at room temperature for 2 weeks, and then centrifuged (10000 rpm,4 min) to give crystalline form D of the compound of the present application.

2.5 Preparation method of Crystal form E

20.6Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione in solid form prepared in the above preparation example was weighed, added to 10.0mL of ethyl acetate, stirred at room temperature for 1 week, and after centrifugation (10000 rpm,4 min), the solid was dried in vacuo at room temperature to give crystalline form E of the compound of the present application.

2.6 Preparation method of crystal form F

15.0Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione prepared in the above preparation example in solid form was weighed, added to 0.6mL of tetrahydrofuran to completely dissolve it, then 3.0mL of toluene was added to the solution, stirred at room temperature for 1 hour, and after centrifugation (10000 rpm,4 min), the solid was dried in vacuo at room temperature to give crystalline form F of the compound of the present application.

2.7 Preparation method of Crystal form G

15.0Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione prepared in the above preparation example in solid form was weighed, added to 0.8mL of dioxane to completely dissolve it, then 2.4mL of n-heptane was slowly added dropwise to the solution, stirred at room temperature for 1 hour, and after centrifugation (10000 rpm,4 min), the solid was dried in vacuo at room temperature to give crystalline form G of the compound of the present application.

2.8 Preparation method of crystal form I

19.8Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione prepared in the above preparation example in solid form was weighed, added to 3.0mL of acetone, allowed to dissolve completely, and then left open at room temperature for 2 weeks to give crystalline form I of the compound of the present application.

2.9 Preparation method of crystal form J

14.9Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione prepared in the above preparation example in solid form was weighed, added to 0.5mL of butyl formate to completely dissolve it, then 0.5mL of methylene chloride was added to the solution, stirred at room temperature for 1 week, and after centrifugation (10000 rpm,4 min), the solid was dried in vacuo at room temperature to give crystalline form J of the compound of the present application.

2.10 Preparation method of crystal form K

15.0Mg of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione in solid form prepared in the above preparation example was weighed, added to 1.0mL of methanol, stirred at room temperature for 1 week, and after centrifugation (10000 rpm,4 min), the solid was dried in vacuo at room temperature to give form K of the compound of the present application.

3. (6E) Preparation of crystalline forms of (E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-e-2, 4-dione and fumaric acid

(6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione fumaric acid solid form (15.2 mg) was taken and 1.0mL of acetone was added to prepare a suspension, the suspension was stirred at room temperature for 7 days, the suspension was separated, and the solid was dried in vacuo to give a white solid crystalline form A having an XRPD pattern as shown in FIG. 24.

Biological examples

Cytotoxicity test

1. Cells (i.e., vero cells) were seeded in 96-well plates and incubated in a carbon dioxide incubator at 37 ℃.

2. The compound (i.e., 6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and crystalline form A of fumaric acid) were diluted to different concentrations in culture medium, inoculated into 96-well plates, and 4 wells were repeated for each sample.

3. After 24 hours of treatment of the samples (i.e., solutions of compounds at different concentrations), the cell activity was measured using the CCK8 method, the toxicity of the compounds to the cells was calculated, and the IC ₅₀ value was calculated.

The specific experimental method is as follows:

Vero african green monkey kidney cell CCL-81) was derived from the chinese collection of typical cultures. Culture medium: MEM medium +10% fetal bovine serum.

Crystalline form a of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid was dissolved in 0.1% DMSO and then dissolved in 100 μl MEM medium (containing 10% fetal calf serum) to a final concentration of 10 μΜ,20 μΜ, 50 μΜ, 100 μΜ, 150 μΜ, 300 μΜ, with solvent 0.1% DMSO as a blank control, and MEM medium (containing 10% fetal calf serum) as a negative control.

After digestion of the corresponding host cells, the concentration was adjusted to 5X 10 ⁶/mL, inoculated into 96-well plates at 100. Mu.L/well, and each plate was left with a row of blank wells as a system control and incubated in a carbon dioxide incubator at 37 ℃.

After 24 hours, the plates were removed entirely, medium was removed, and sample and control DMSO were added to the plates separately, 6 wells at each concentration. MEM medium (containing 10% fetal bovine serum) was added to the control wells of the system.

After 48 hours, the activity of the cells was examined using the CCK8 method. The liquid in each well was removed, MEM medium (10% fetal bovine serum) containing 10% CCK8 reagent was added to each well, and after 2 hours of incubation in a 5% carbon dioxide incubator at 37℃the absorbance was measured at 450nm using a microplate reader.

The viability of Vero cells was 89.24% after 48 hours of treatment of cells with the compound at a maximum concentration of 300 μm. Results: for host cell Vero cells, the tested compounds have IC ₅₀ values greater than 300. Mu.M.

Conclusion: the tested compounds are non-cytotoxic to the cells tested (i.e., vero cells) over a relatively wide concentration range, with good safety.

Antiviral experiment

1. Sample preparation

After digestion of the corresponding host cells, the concentration was adjusted to 5X 10 ⁶/mL, inoculated into 12-well plates with 1mL per well. After 24 hours, various concentrations of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and crystalline form A (0.1. Mu.M, 0.5. Mu.M, 0.75. Mu.M, 1. Mu.M, 30. Mu.M) of fumaric acid were mixed with appropriate titres of virus liquid at room temperature and the virus titres used in the experiments are given in Table 1. The medium in the 12-well plate was removed, and the cells were washed with PBS, and PBS was removed, and a mixture of virus and drug was added to the 12-well plate for cell infection. DMSO was used as a blank and serum-free MEM medium was used as a negative control. 2 hours after infection, the solution containing the virus in the well plate was removed and replaced with MEM medium (containing 10% fetal bovine serum) containing crystalline form A of the corresponding concentrations of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- (2, 4, 5-trifluorobenzyl) -1,3, 5-triazin-E-2, 4-dione and fumaric acid. After more than half of the cells in DMSO-treated wells of the control group in the 12-well plate had cytopathic effect (cytopathic effect, CPE), the supernatant from each well was collected and the supernatant collected was used to infect the corresponding host cells for TCID ₅₀ assay. Three wells per concentration.

2. The titre of the virus was determined using TCID ₅₀ as follows:

Corresponding host cells are inoculated into a 96-well plate according to the amount of 2X 10 ⁴ cells/well, and the titer can be measured after the cell confluency reaches more than 70%. The virus stock was first diluted according to a 10-fold gradient from 10 ^-1 to 10 ^-7. After the completion of dilution, the culture broth in the 96-well plate was discarded, and the virus dilutions were added to the 96-well plate, 100. Mu.L of the virus broth was added to each well, 8 wells were repeated for each dilution, and serum-free MEM (minimum essential medium) was added to 8 wells as a negative control, and incubated in an incubator containing 5% carbon dioxide at 37℃for 1 hour. After completion of incubation, the supernatant was discarded, and 100. Mu.L of MEM containing 2% FBS was added to each well, and the mixture was incubated in an incubator at 37℃with 5% CO ₂ for a period of time determined depending on the type of virus. The occurrence of cytopathic effect (CPE) in each well was then observed with an inverted microscope and the number of CPE-positive wells per dilution was recorded. Finally, the titer of the virus was calculated according to the Reed-Muench calculation method (Stephan, 1977) and the virus inhibition was calculated according to the following formula.

Inhibition = (1-viral titer in drug-treated group/viral titer in vehicle-treated group) ×100%

The half-maximal effective concentration of the compound against the virus (EC ₅₀) was determined as follows:

EC ₅₀ calculation method: firstly, calculating the Inhibition rate corresponding to each concentration by using EXCEL software, then opening GRAPHPAD PRISM 8.0.0 software, creating a Group chart ①, inputting a medicine concentration value in an X column, inputting the corresponding Inhibition rate in a Group A column, clicking analysis ze ②, clicking Transform concentrations (X), clicking OK, ③ clicking Transform to logarithms, clicking OK, ④ clicking Transform X to perform curve fitting, clicking analysis ze, clicking OK, ⑤ clicking Dose-response-Inhibition, clicking Log (inhibitor) vs. response-Variable slope (four parameters), clicking OK, and viewing the fitted EC ₅₀ value in a non-lin fit column.

Therapeutic Index (TI) =half toxic concentration (IC ₅₀)/half effective concentration (EC ₅₀)

TABLE 1 anti-herpes simplex virus experiments and results thereof

Table 1, below

Sequence number	Viral titer	Infectious virus titer	Infection time	Host cell half CPE
					1	3.2×107TCID50/ml	3.2×106TCID50/ml	2h	About 4d appear
2	5.0×107TCID50/ml	1.0×107TCID50/ml	2h	About 4d appear

Conclusion:

As can be seen from the above table and FIG. 1, the test compounds have inhibitory effects on both herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2).

The titer of the type 1 herpes simplex virus (GDV 011) after being treated by 30 mu M of the test compound is reduced from 10 ^6.70TCID₅₀/mL to undetectable, and the titer of the type 2 herpes simplex virus (GDV 017) after being treated by 30 mu M of the test compound is reduced from 10 ^7.73TCID₅₀/mL to 10 ^1.68TCID₅₀/mL.

The test compound has an EC ₅₀ value of less than 0.1 μm for herpes simplex virus type 1 (GDV 011) and an EC ₅₀ value of less than 0.1 μm for herpes simplex virus type 2 (GDV 017).

The therapeutic index TI of the test compound to the herpes simplex virus is more than 3000.

Conclusion: the tested compounds have an inhibitory effect on the corresponding herpes simplex virus in host cells and have high therapeutic safety.

The foregoing embodiments have been provided for the purpose of illustrating the general principles of the present invention, and are not meant to limit the scope of the invention, but to limit the scope of the invention.

Claims (9)

1. The use of a compound of formula (I), or an isomer, salt, N-oxide, metabolite, solvate, salt of a solvate, crystalline form, prodrug, complex, co-crystal, co-amorphous or isotopic form thereof, in the manufacture of a medicament for the treatment or prophylaxis of a herpes simplex virus infection and associated diseases or conditions in a subject,

Wherein the method comprises the steps of

Each R ₁、R₂、R₃、R₄、R₅、R₆、R₇ is independently H or substituted or unsubstituted C ₁-C₆ alkyl;

X is halogen;

m is 0,1,2 or 3;

n is 0, 1,2, 3,4 or 5;

preferably, the substituents are one or more groups independently selected from C ₁-C₆ alkyl, C ₁-C₆ alkoxy, C ₁-C₆ alkylthio, C ₁-C₆ alkylamino, halogen, mercapto, hydroxy, nitro, cyano, C ₃-C₆ cycloalkyl, C ₂-C₆ heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate;

preferably, each X is the same or different from each other.

2. The use according to claim 1, wherein R ₁ and R ₂ are each independently unsubstituted C ₁-C₆ alkyl; and/or, R ₃、R₄、R₅、R₆、R₇ are each independently H.

3. Use according to claim 1 or2, wherein X is fluorine or chlorine; m is 1 or 2; and/or n is 2,3 or 4.

4. The use according to any one of claims 1-3, wherein when n is 3, X is a2, 3, 4-position substituent, a2, 3, 6-position substituent, a2, 4, 5-position substituent, a2, 5, 6-position substituent, a 3,4, 5-position substituent, a 3,5, 6-position substituent, or a 4,5, 6-position substituent.

5. The use according to any one of claims 1 to 4, wherein the compound of formula (I) is

Or a salt, isomer, N-oxide, metabolite, solvate, salt of a solvate, crystalline form, prodrug, complex, co-crystal, co-amorphous or isotopic form thereof.

6. The use according to claim 5, wherein the compound of formula (I) forms a crystalline form with fumaric acid;

Preferably, the crystalline form is crystalline form a, which uses Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any three selected from 10.94, 19.06, 23.50, 24.66;

Preferably, crystalline form a, which uses Cu-ka radiation, further comprises any one or more of 9.5, 13.81, 18.61, 22.59, 23.8, or further comprises any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, or further comprises any one or more of 14.73, 20.87, 21.49, 21.97, 25.39, characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 °;

More preferably, crystalline form a uses Cu-ka radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° include any one or more of 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59, 23.8, or further include any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, and/or further include any one or more of 14.73, 20.87, 21.49, 21.97, 25.39;

Most preferably, crystalline form a uses Cu-ka radiation and an X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° is shown in fig. 24;

And/or the number of the groups of groups,

Preferably, the molar ratio of the compound of formula (I) to fumaric acid in the crystalline form is 1:1.

7. The use according to any one of claims 1-6, wherein the herpes simplex virus comprises herpes simplex virus type 1 and/or herpes simplex virus type 2; preferably, herpes simplex virus type 1 (HSV-1) is herpes simplex virus type 1 GDV011; and/or, herpes simplex virus type 2 (HSV-2) is herpes simplex virus type 2 GDV017.

8. The use according to any one of claims 1-7, wherein the herpes simplex virus infection and its associated diseases or disorders include diseases or disorders caused by herpes simplex virus, such as clinical herpes (primary and recurrent), herpetic eczema (primary) and traumatic herpes (primary or recurrent), gingivitis (primary), vulvovaginitis (primary, recurrent), genital herpes (primary, recurrent), keratoconjunctivitis (primary and recurrent), meningoepithymitis (primary), neonatal herpes simplex virus infection, aseptic meningitis, and/or herpes labialis.

9. The use of any one of claims 1-8, wherein the subject is a human, such as a child, adult, or elderly human.