RU2846964C1 - Pyrimidine derivatives - inhibitors of reproduction of viruses relating to genus orthoflavivirus - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, pharmacology and medicine, specifically to a compound selected from 4-[(2-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine, 4-[(3-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine or 4-[(4-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine. Invention also relates to use of 4-[(2-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine, 4-[(3-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine or 4-[(4-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine as inhibitors of reproduction of a virus of the genus Orthoflavivirus, the use of said compounds for the preparation of a pharmaceutical composition with antiviral activity for the treatment and/or prevention of a disease of viral etiology caused by a virus of the genus Orthoflavivirus in a patient, and a pharmaceutical composition with antiviral activity for the treatment and/or prevention of a disease of viral etiology caused by a virus of the genus Orthoflavivirus in patient containing 4-[(2-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine, 4-[(3-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine or 4-[(4-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine.

EFFECT: compounds characterized by high efficiency in inhibiting reproduction of viruses of genus Orthoflavivirus.

8 cl, 4 tbl

Description

Field of technology

This invention relates to organic chemistry, pharmacology and medicine and concerns the prevention and therapy of diseases, the etiology or pathogenesis of which are associated with viruses belonging to the genus Orthoflavivirus , using new groups of compounds of the pyrimidine series.

State of the art

Viruses of the genus Orthoflavivirus (flaviviruses) commonly circulate among blood-sucking arthropods (mosquitoes and ticks), birds, and wild animals. Through the attachment of an infected tick or mosquito bite, flaviviruses can be transmitted to humans and cause a wide range of diseases of varying severity: from mild febrile illnesses to hemorrhagic fevers and fatal central nervous system disorders. Specifically, viruses of the genus Orthoflavivirus cause diseases such as tick-borne encephalitis (TBE), yellow fever, dengue fever (including dengue shock syndrome), West Nile fever, and Zika fever.

Among natural focal flavivirus infections, TBE is a particularly significant problem on the Eurasian continent, including Europe, Russia, East Asia, and Japan. Yellow fever is endemic in the equatorial, tropical, and subtropical regions of South America and Africa, and West Nile fever occurs in Africa, Europe, the Middle East, and North America. According to the World Health Organization (WHO), more than 10,000 cases of TBE and approximately 200,000 cases of yellow fever are reported annually. Despite the availability of effective vaccines, immunization coverage is considered insufficient. Moreover, a number of cases of TBE infection have been recorded even after vaccination. The number of West Nile fever cases in the United States from 1999 to 2019 was approximately 51,000. However, West Nile fever is currently actively spreading to new territories in Europe and Russia. Furthermore, there are currently no vaccines approved for medical use against West Nile fever or many other diseases caused by flaviviruses. Although a number of small-molecule inhibitors of flavivirus reproduction are known, there are still no drugs specifically targeting flaviviruses and their molecular targets.

Thus, there is a need to develop new effective agents against diseases caused by viruses of the genus Orthoflavivirus .

Disclosure of invention

The objective of the present invention is to develop and create new effective antiviral agents that are promising for use in clinical practice for the treatment and/or prevention of diseases caused by viruses of the genus Orthoflavivirus .

The technical result of the invention consists in the development and production of compounds characterized by high efficiency in inhibiting the reproduction of viruses of the genus Orthoflavivirus , in particular, tick-borne encephalitis virus, yellow fever virus, West Nile fever virus and others.

The compounds of the invention also expand the arsenal of available antiviral agents used as inhibitors of the reproduction of a virus belonging to the genus Orthoflavivirus .

The specified technical result is achieved by means of a compound of the general formula (I):

formula (I),

or a prodrug or pharmaceutically acceptable salt thereof, where:

R ₁ is chosen independently and is:

- NH-(C _1-5 -alkyl)-(1-adamantyl);

- NH-(C _1-5 -alkyl)-(2-adamantyl);

- NH-(C _1-5 -alkyl)-OH;

;

R ₂ is chosen independently and represents C_3-6-cycloalkyl, isopropyl, alternativelyR ₂ is methyl ifR ₁ represents;

n takes values 0-2;

or compounds of the general formula (II):

formula (II),

or a prodrug or pharmaceutically acceptable salt thereof, where:

R' ₁ is chosen independently and is:

- NH-(C _1-5 -alkyl)-(1-adamantyl);

- NH-(C _1-5 -alkyl)-(2-adamantyl);

;

;

;

R' ₂ is selected independently and represents hydrogen, methyl, -NH ₂ , halogen;

n takes values 0-2;

or compounds of the general formula (III):

formula (III),

or a prodrug or pharmaceutically acceptable salt thereof, where:

Rʺ ₁ is chosen independently and is:

;

;

;

Rʺ ₂ is independently selected and is C _1-5 -alkyl;

Rʺ ₃ is independently selected and is C _1-5 -alkyl.

In particular embodiments of the invention, R ₁ is selected independently and represents:

NH-(C ₂ -alkyl)-(1-adamantyl);

- NH-(C ₂ -alkyl)-(2-adamantyl); or

- NH-(C ₂ -alkyl)-OH;

R ₂ is independently selected and is cyclopropyl, cyclohexyl or isopropyl;

n takes the value 1.

In particular embodiments of the invention, R' ₁ is selected independently and represents:

- NH-(C ₂ -alkyl)-(1-adamantyl); or

- NH-(C ₂ -alkyl)-(2-adamantyl);

R' ₂ represents hydrogen, methyl, -NH ₂ or a chlorine atom;

n takes the value 1.

In particular embodiments of the invention, Rʺ ₂ is independently selected and is methyl;

Rʺ ₃ is independently selected and represents tert -butyl.

In particular embodiments, the present invention includes compounds selected from the group:

- 4-[2-(1-adamantyl)ethylamino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide;

- 4-[2-(1-adamantyl)ethylamino]-2-cyclopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide;

- 4-[2-(1-adamantyl)ethylamino]-2-cyclohexyl-5,6,7,8-tetrahydroquinazoline 1-oxide;

- 4-[(2-hydroxyethyl)amino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide;

- 4-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]amino}-2-methyl-5,6,7,8-tetrahydroquinazoline 1-oxide;

- 4-[(2-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline;

- 4-[(3-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline;

- 4-[(4-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline;

- 4-(2-(1-adamantyl)ethylamino)-2-amino-5,6,7,8-tetrahydroquinazoline;

- 4-(2-(2-adamantyl)ethylamino)-2-amino-5,6,7,8-tetrahydroquinazoline;

- 4-(2-(1-adamantyl)ethylamino)-2-chloro-5,6,7,8-tetrahydroquinazoline;

- 4-(2-(2-adamantyl)ethylamino)-2-chloro-5,6,7,8-tetrahydroquinazoline;

- 4-(2-(2-adamantyl)ethylamino)-2-methyl-5,6,7,8-tetrahydroquinazoline;

- 4-(2-(1-adamantyl)ethylamino)-5,6,7,8-tetrahydroquinazoline;

- 4-(2-(2-adamantyl)ethylamino)-5,6,7,8-tetrahydroquinazoline;

- 4-(1-(1-adamantyl)ethylamino)-2-methyl-5,6,7,8-tetrahydroquinazoline;

- 4-[(2-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine;

- 4-[(3-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine;

- 4-[(4-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine.

The present invention also relates to the use of a compound of the invention as an inhibitor of the reproduction of a virus belonging to the genus Orthoflavivirus .

In particular embodiments of the invention, the virus is tick-borne encephalitis virus, yellow fever virus, West Nile fever virus, dengue virus, Japanese encephalitis virus, Kyasanur forest disease virus, Omsk hemorrhagic fever virus, Powassan virus.

The present invention also relates to the use of the compounds of the invention for the preparation of a pharmaceutical composition with antiviral activity for the treatment and/or prevention of a disease of viral etiology caused by a virus of the genus Orthoflavivirus in a patient.

The invention also includes pharmaceutical compositions with antiviral activity for the treatment and/or prevention of diseases of viral etiology caused by viruses of the genus Orthoflavivirus in a patient, containing an effective amount of a compound according to the invention.

In particular embodiments of the invention, the pharmaceutically acceptable excipient is a carrier, filler and/or solvent.

In particular embodiments of the invention, the patient is a human being.

The present invention also relates to a method for inhibiting the reproduction of viruses belonging to the genus Orthoflavivirus , comprising administering to a patient a therapeutically effective amount of a compound of the invention.

The invention also includes a method for the treatment and/or prevention of diseases of viral etiology caused by viruses of the genus Orthoflavivirus in a patient, comprising administering a therapeutically or prophylactically effective amount of a compound according to the invention.

The present invention also relates to the use of the compounds of the invention for the production of an agent for inhibiting the reproduction of a virus belonging to the genus Orthoflavivirus .

The present invention also includes the preparation of compounds and/or compositions of the invention.

Detailed disclosure of the invention

Definitions (terms)

For a better understanding of the present invention, certain terms used in this description of the invention are provided below. The following definitions apply throughout this document unless otherwise specified.

The scientific and technical terms used, unless otherwise specified, have the meanings generally accepted in the scientific and technical literature.

The terms "includes" and "including" are interpreted to mean "includes, among other things." These terms are not intended to be construed as meaning "consists solely of."

The term " optional " or " optional " or " optionally " as used herein means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances in which the event or circumstance occurs and instances in which it does not occur.

The term " and/or " means one, more than one, or all of the listed elements.

Also here, listing numeric ranges by endpoints includes all numbers within that range.

The genus Orthoflavivirus (family Flaviviridae ) includes enveloped RNA viruses (flaviviruses), many of which, such as tick-borne encephalitis virus (TBEV), yellow fever virus (YFV), West Nile fever virus (WNV), dengue virus, Zika virus, etc., are pathogenic and cause a number of diseases of the same name, widespread in various regions of the world.

The term "alkyl" as used herein, by itself or as part of another substituent, refers to saturated straight- or branched-chain hydrocarbon groups, including hydrocarbon groups having the specified number of carbon atoms, in particular, the term "alkyl" refers to groups typically having from one to five carbon atoms. For example, the term "C _1-3 -alkyl" includes methyl, ethyl, propyl, isopropyl, etc.

The term " cycloalkyl " as used herein refers to groups having three to six carbon atoms in a monocyclic structure. By way of illustration, cycloalkyls include, but are not limited to, the following radicals: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term " halogen " by itself or as part of another term refers to an atom of fluorine, chlorine, bromine, or iodine.

Unless otherwise stated, all occurrences of functional groups in the structures of the compounds of the invention are independently selected.

The invention contains only those combinations of substituents and derivatives that form a stable or chemically feasible compound. A stable or chemically feasible compound is one whose stability is sufficient for its synthesis and analytical detection.

Unless otherwise stated, the structures of the compounds described in the application materials also include all stereoisomers, i.e., the R- and S-isomers for each chiral center. Individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the compounds of the invention, are also the subject of the present invention. Thus, the present invention encompasses each diastereomer or enantiomer substantially free of other isomers (>90%; more preferably, >95% molar purity), as well as a mixture of such isomers.

A specific optical isomer can be obtained by separating a racemic mixture according to a standard procedure, for example, by preparing diastereomeric salts by treatment with an optically active acid or base, followed by separation of the diastereomeric mixture by crystallization, and subsequent isolation of the optically active bases from these salts. Examples of corresponding acids include tartaric, diacetyltartaric, dibenzoyltartaric, ditoluenetartaric, and camphorsulfonic acid. Another technique for separating optical isomers involves the use of a chiral chromatography column. Another possible separation method involves the synthesis of covalent diastereomeric derivatives by reacting the compounds of the invention with an optically pure acid in activated form or an optically pure isocyanate. The resulting diastereomers can be separated by methods such as chromatography, distillation, crystallization, or sublimation, and then hydrolyzed to yield an enantiomerically pure compound.

Optically active compounds of the present invention can be prepared using optically active starting materials. Such isomers can exist in the form of a free acid, a free base, or a salt.

The compounds that form the core of this invention may exist in radioisotope-labeled form, i.e., said compounds may contain one or more atoms whose atomic mass or mass number differs from the atomic mass or mass number of the most abundant natural isotopes. Radioisotopes of hydrogen and carbon include ³ H and ¹⁴ C, respectively. Compounds of the present invention that contain such radioisotopes and/or other radioisotopes of other atoms are within the scope of the present invention. Such compounds can be prepared using the methods described herein by simply replacing unlabeled reagents with the appropriate labeled reagents. Tritium, i.e., ³ H, and carbon, i.e., ¹⁴ C, radioisotopes are particularly preferred due to their ease of preparation and detection.

The compounds of the present invention may exist in free form or, if desired, in the form of a pharmaceutically acceptable salt or other derivatives (e.g., prodrugs). The term "pharmaceutically acceptable salt" in the context of this application refers to those salts that, within the framework of medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and meet a reasonable benefit-risk ratio. Such salts can be obtained either in situ during the isolation or purification of the compounds of the invention, or separately, by reacting the free acid or base of the compound of the invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, non-toxic acid salts include amino group salts formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids.

The compounds of the present invention may exist as a prodrug. In the context of the present application, the term " prodrug " means a precursor or derivative form of a compound of the invention that has improved properties, such as better solubility, reduced cytotoxicity, or increased bioavailability compared to the parent compound or drug, and is capable of being activated or converted into a more active parent form. " Prodrug group " means a group that is converted by reaction with an enzyme, gastric acid, or the like under physiological conditions in vivo to produce a compound of general formula (I), (II), or (III), i.e., a group that is converted to produce a compound of general formula (I), (II), or (III) by hydrolysis or the like caused by gastric acid or the like.

The terms " therapeutically effective amount " and " prophylactically effective amount " mean that amount of a compound administered or delivered to a patient that is most likely to exhibit the desired response to the treatment or prophylaxis of diseases caused by viruses of the genus Orthoflavivirus . The exact amount required may vary from subject to subject depending on the age, body weight, and general condition of the patient, the severity of the disease, the method of administration, combination therapy with other drugs, etc.

The term "patient" (or "subject") encompasses all mammalian species, preferably humans, that utilize the compounds of the invention, either by self-administration or by administration to the patient by another person, for the treatment and/or prevention of a disease or medical condition.

The terms “treatment” and “therapy” cover the treatment of pathological conditions in patients and include: a) blocking (stopping) the course of the disease, b) alleviating the severity of the disease, i.e. inducing regression of the disease.

The terms "prophylaxis , ""prevention," and "preventive therapy" refer to the reduction of risk factors and the prophylactic treatment of subclinical stages of the disease in humans, aimed at reducing the likelihood of developing clinical stages of the disease. Preventive therapy includes (a) primary prophylaxis, i.e., prophylactic administration of medication by individuals traveling to areas with a high risk of infection; (b) post-exposure prophylaxis, i.e., prophylactic treatment of patients who have come into contact with a carrier of the disease but who have not yet developed the clinical stage of the disease; and (c) secondary prophylaxis, i.e., preventing the recurrence of the same or a similar clinical state of the disease or reducing the risk of persistent infection.

Implementation of the invention

Examples

The specific compounds of the invention disclosed herein are provided for the purpose of illustrating the present invention so that the invention may be more fully understood. The illustrated specific examples of the compounds of the invention can be prepared by the methods described in the general synthetic schemes, examples, and known methods in the art, but these methods are not exhaustive and allow for reasonable modifications. The indicated reactions should be carried out using suitable solvents and materials. When implementing these general procedures for the synthesis of specific substances, it is necessary to take into account the functional groups present in the substances and their effect on the reaction. To obtain some substances, it is necessary to change the order of the steps or to choose one of several alternative synthetic schemes. The compounds given below should not be considered the only examples within the scope of the present invention and in no way limit the invention.

Some particular examples of compounds according to the invention are presented in Table 1.

Table 1. Examples of compounds according to the invention

Name of the compound Structure Connection number Compounds of general formula (I) 4-[2-(1-adamantyl)ethylamino]-2-cyclopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide 1d 4-[2-(1-adamantyl)ethylamino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide 1st 4-[2-(1-adamantyl)ethylamino]-2-cyclohexyl-5,6,7,8-tetrahydroquinazoline 1-oxide 1f 4-[(2-hydroxyethyl)amino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide 5a 4-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]amino}-2-methyl-5,6,7,8-tetrahydroquinazoline 1-oxide 5b Compounds of general formula (II) 4-[(2-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline 4a 4-[(3-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline 4b 4-[(4-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline 4c 4-(2-(1-adamantyl)ethylamino)-2-amino-5,6,7,8-tetrahydroquinazoline 2a 4-(2-(2-adamantyl)ethylamino)-2-amino-5,6,7,8-tetrahydroquinazoline 2b 4-(2-(1-adamantyl)ethylamino)-2-chloro-5,6,7,8-tetrahydroquinazoline 2c 4-(2-(2-adamantyl)ethylamino)-2-chloro-5,6,7,8-tetrahydroquinazoline 2d 4-(2-(2-adamantyl)ethylamino)-2-methyl-5,6,7,8-tetrahydroquinazoline 2e 4-(2-(1-adamantyl)ethylamino)-5,6,7,8-tetrahydroquinazoline 2f 4-(2-(2-adamantyl)ethylamino)-5,6,7,8-tetrahydroquinazoline 2g 4-(1-(1-adamantyl)ethylamino)-2-methyl-5,6,7,8-tetrahydroquinazoline 2h Compounds of general formula (III) 4-[(2-aminophenyl)oxy]-2-methyl-6- tert -butylpyrimidine 6d 4-[(3-aminophenyl)oxy]-2-methyl-6- tert -butylpyrimidine 6e 4-[(4-aminophenyl)oxy]-2-methyl-6- tert -butylpyrimidine 6f

General methods of synthesis

The starting compounds 8 , 9a-d , 10a-d, 11 were obtained according to previously published methods:

- KN Sedenkova, EB Averina, YK Grishin, AG Kutateladze, VB Rybakov, TS Kuznetsova, NS Zefirov, Three-component Heterocyclization of gem -Bromofluorocyclopropanes with NOBF ₄ : Access to 4-Fluoropyrimidine N -Oxides. J. Org. Chem. 2012 , 77 , 9893-9899;

- Sedenkova KN, Averina EB, Grishin YK, Bacunov AB, Troyanov SI, Morozov IV, Deeva EB, Merkulova AV, Kuznetsova TS, Zefirov NS Nitronium salts as novel reagents for the heterocyclization of gem-bromofluorocyclopropanes into pyrimidine derivatives. Tetrahedron Lett . 2015 , 56(34), 4927-4930;

- Miller, GW, & Rose, FL 1080. S-triazolopyrimidines. Part I. Synthesis as potential therapeutic agents. J Chem Soc 1963, 5642-5659;

- Sedenkova. KN; Zverev, D. V.; Nazarova, A.A.; Lavrov, MI; Radchenko, EV; Grishin, YK; Gabrel'yan, A.V.; Zamoyski, V. L.; Grigoriev, V.V.; Averina, E. B.; Palyulin, VA Novel Nanomolar Allosteric Modulators of AMPA Receptor of Bis(pyrimidine) Series: Synthesis, Biotesting and SAR Analysis. Molecules. 2022 , 27 , 8252-8273;

- Ohno, S.; Mizukoshi, K.; Komatsu, O.; Kunoh, Y.; Nakamura, Y.; Katoh, E.; Nagasaka, M. Synthesis and hypoglycemic activity of 7,8-dihydro-6H-thiopyrano(3,2-d)pyrimidine derivatives and related compounds. Chem. Pharm. Bull. 1986 , 34 , 4150-4165;

Ortega, J. A.; Arencibia, J.; Minniti, E.; Byl, J.; Franco-Ulloa, S.; Borgogno, M.; Genna, V.; Summa, M.; Bertozzi, S.; Bertorelli, R.; Armirotti, A.; Minarini, A.; Sissi, S.; Osheroff, N.; Vivo, M. Novel, Potent, and Druglike Tetrahydroquinazoline Inhibitor That Is Highly Selective for Human Topoisomerase II α over β. J. Med. Chem. 2020 , 63 , 12873-12886;

- Kim, JY; Kim, D.; Kang, S.Y.; Park, W.K.; Kim, H.J.; Jung, M.E.; Son, E. J.; Pae, A. N.; Kim, J.; Lee, J. Arylpiperazine-containing pyrimidine 4-carboxamide derivatives targeting serotonin 5-HT(2A), 5-HT(2C), and the serotonin transporter as a potential antidepressant. Bioorg Med Chem Lett. 2010 , 20 , 6439-6442.

4-Substituted tetrahydroquinazoline N-oxides 1d-f and 5a-b were prepared from the corresponding 4-fluorotetrahydroquinazoline N-oxides 9a-d . The starting heterocyclic compounds 9a-d were synthesized by three-component heterocyclization of gem-bromofluorocyclopropane 8 upon treatment with TfONO ₂ , obtained in situ from TfOH and fuming HNO ₃ in various nitriles (Scheme 1).

Scheme 1. Synthesis of compounds 1d-f , 5a-b of the invention. Reagents and conditions: (i) TfOH, _HNO3 , room temp., 48 h; (ii) diisopropylethylamine, EtOH, room temp., 30 h.

4-(Aminophenoxy)tetrahydroquinazolines 4a–c were prepared from 4-chloropyrimidine 10a by treatment with the corresponding aminophenols as shown in Scheme 2.

Scheme 2. Synthesis of compounds of the invention 4a-c . Reagents and conditions: ( iv ) Cs ₂ CO ₃ , DMF, 6 h.

4-Aminotetrahydroquinazolines 2a–h were prepared from 4-chloropyrimidines 10a–d by treatment with the corresponding amines 7a–c as shown in Scheme 3.

Scheme 3. Synthesis of compounds 2a-h _of the invention. Reagents and conditions: ( v ) _Cs2CO3 , DMF, 2 h, reflux; (vi): diisopropylethylamine, _CH3CN , room temp., 16 h.

Tert- butylpyrimidines 6d–f were prepared from 4-chloropyrimidine 11 by treatment with the corresponding amines as shown in Scheme 4.

Scheme 4. Synthesis of compounds of the invention 6d-f . Reagents and conditions: ( iv ) Cs ₂ CO ₃ , DMF, 6 h.

Solvents and materials were of reagent grade and were used without further purification. ^1H and ^13C NMR spectra were recorded on an Agilent 400-MR spectrometer at 400 MHz (400.0 and 100.6 MHz for ^1H and ^13C , respectively) at room temperature; chemical shifts δ were determined relative to the solvent ( _CDCl3 , _δH = 7.26 ppm, _δC = 77.16 ppm). When necessary, signals in the NMR spectra were assigned using 2D methods. High-resolution mass spectrometry (HRMS) was performed on a Jeol GCMate II mass spectrometer with electrospray ionization (ESI). TLC was performed on an Alugram SIL G/UV254 (Macherey-Nagel, Düren, Germany) with UV visualization. Column chromatography was performed on silica gel (Merck, particle size 0.040–0.063 mm). All other materials were commercially available.

Preparation of compounds according to the invention

General scheme for the synthesis of 4-aminotetrahydroquinazoline N -oxides 1d-f,5a-b

A mixture of 4-fluorotetrahydroquinazoline N-oxide 9a-d (0.5 mmol), the appropriate amine (0.5 mmol), and diisopropylethylamine (0.129 g, 1.0 mmol) in absolute ethanol (1 mL) was stirred overnight under argon. The reaction mixture was then diluted with water (1 mL) and extracted with dichloromethane (3 × 4 mL). The combined organic extracts were washed with water (3 × 4 mL) and dried over MgSO ₄ . The solvent was evaporated under reduced pressure; the product was isolated by preparative column chromatography (SiO ₂ ).

4-[2-(1-adamantyl)ethylamino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide (1d)

Yield 76 mg (41%). Yellowish solid, mp 102-105°C, R _f = 0.6 (CHCl ₃ -MeOH 5:1). ¹ H NMR (CDCl ₃ , δ, ppm, J , Hz): 1.28 (d, 6H, ³ J = 6.8, 2CH ₃ ), 1.34-1.42 (m, 2H, CH ₂ Ad), 1.51-1.59 (m, 6H, 3CH ₂ , Ad), 1.60-1.68 (m, 3H, 3CH ₂ , Ad), 1.68-1.76 (m, 3H, 3CH ₂ , Ad), 1.75-1.86 (m, 4H, 2CH _2, THQ), 1.92-2.01 (m, 3H, 3CH, Ad), 2.23-2.30 (m, 2H, CH ₂ , THQ), 2.87-2.95 (m, 2H, CH ₂ , THQ), 3.48-3.55 (m, 2H, CH ₂ NH), 3.92 (sept, 1H, ³ J = 6.8, CH, i- Pr), 4.59 (br.s, 1H, NH); ¹³ C NMR (CDCl ₃ , δ, ppm): 20.0 (2CH ₃ ), 20.9 (CH ₂ , THQ), 21.2 (CH ₂ , THQ), 22.2 (CH ₂ , THQ), 24.8 (CH ₂ , THQ), 28.7 (3CH, Ad), 29.3 (CH, i -Pr), 32.2 (C, Ad), 36.5 (CH ₂ Ad), 37.2 (3CH ₂ , Ad), 42.7 (3CH ₂ , Ad), 44.1 (CH ₂ NH), 111.4 (C(4a)), 153.5 (C(4)), 153.8 (C(8a)), 162.5 (C(2)). HRMS (ESI ⁺ , m/z): calculated _{for C23H35N3O} [M+H _] ⁺ 370.2853, determined 370.2858.

4-[2-(1-adamantyl)ethylamino]-2-cyclopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide (1e)

Yield 82 mg (45%). Yellowish solid, mp 107-108°C, R _f = 0.8 (CHCl ₃ -MeOH 5:1). ¹ H NMR (CDCl ₃ , δ, ppm, J , Hz): 0.95-1.12 (m, 4H, 2CH ₂ , cy-Pr), 1.21-1.32 (m, 2H, CH ₂ Ad), 1.46 (br.s, 6H, 3CH ₂ , Ad), 1.50-1.70 (m, 6H, 3CH ₂ , Ad), 1.67-1.78 (m, 4H, 2CH _2, THQ), 1.90 (br.s, 3H, 3CH, Ad), 2.28-2.27 (m, 2H, CH ₂ , THQ), 2.75-2.82 (m, 2H, CH ₂ , THQ), 2.28-2.27 (m, 2H, CH ₂ , THQ), 2.75-2.82 (br.t, 2H, ³ J = 5.8, CH ₂ , THQ), 2.82-2.94 (m, 1H, CH, cy-Pr), 3.32-3.44 (m, 2H, CH ₂ NH), 5.86 (br.s, 1H, NH); ¹³ C NMR ( _CDCl3 , δ, ppm): 10.37 (CH, cy-Pr), 10.41 (2CH2, cy-Pr), 20.9 ( _CH2 , THQ), 21.1 ( _CH2 , _THQ ), 22.3 ( _CH2 , THQ), 24.7 ( _CH2 , THQ), 28.6 (3CH, Ad), 32.0 (C, Ad), 36.3 (CH ₂ Ad), 37.1 (3CH ₂ , Ad), 42.5 (3CH ₂ , Ad), 43.6 (CH ₂ NH), 111.5 (C(4a)), 152.5 (C(8a)), 154.1 (C(4)), 159.1 (C(2)). HRMS (ESI ⁺ , m/z): calculated _{for C23H33N3O} [M+H _] ⁺ 368.2696, determined 368.2700.

4-[2-(1-adamantyl)ethylamino]-2-cyclohexyl-5,6,7,8-tetrahydroquinazoline 1-oxide (1f)

Yield 82 mg (40%). Yellowish solid, mp 96-98°C, R _f = 0.14 (light petroleum ether-EtOAc-MeOH 3:1:0.5). ¹ H NMR (CDCl ₃ , δ, ppm, J , Hz): 1.32-1.39 (m, 2H, CH ₂ Ad), 1.40-1.53 (m, 4H, 2CH ₂ , cy-Hex), 1.55 (br.s, 6H, 3CH ₂ , Ad), 1.60-1.68 (m, 3H, 3CH ₂ , Ad), 1.68-1.76 (m, 3H, 3CH ₂ , Ad), 1.73-1.85 (m, 10H, 3CH ₂ , cy-Hex + 2CH _2, THQ), 1.96 (br.s, 3H, 3CH, Ad), 2.23- 2.30 (m, 2H, CH ₂ , THQ), 2.83-2.90 (m, 2H, CH ₂ , THQ), 3.47-3.53 (m, 2H, CH ₂ NH), 3.57-3.67 (m, 1H, CH, cy-Hex), 4.67 (br.s, 1H, NH); ¹³ C NMR (CDCl ₃ , δ, ppm): 21.0 (CH ₂ , THQ), 21.3 (CH ₂ , THQ), 22.3 (CH ₂ , THQ), 24.8 (CH ₂ , THQ), 26.2 (2CH ₂ , cy-Hex), 26.4 (CH ₂ , cy-Hex), 28.7 (3CH, Ad), 29.9 (2CH ₂ , cy-Hex), 32.2 (C, Ad), 36.4 (CH ₂ Ad), 37.2 (3CH ₂ , Ad), 38.6 (CH, cy-Hex), 42.7 (3CH ₂ , Ad), 44.1 (CH ₂ NH), 111.3 (C(4a)), 152.3 (C), 153.3 (C), 160.7 (C(2)). HRMS (ESI ⁺ , m/z): calculated for C ₂₆ H ₃₉ N ₃ O [M+H] ⁺ 410.3166, determined 410.3156.

4-[(2-hydroxyethyl)amino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide (5a)

Yield 67 mg (53%). Dark yellow crystals, mp 111-112°C, Rf= 0.28 (light petroleum ether-EtOAc-MeOH 3:1:1).¹H NMR (CDCl₃+ CD₃OD, δ, ppm,J, Hz): 1.22 (d, 6H,³ J= 6.9, 2CH₃), 1.69-1.83 (m, 4H, 2CH₂, THQ), 2.31-2.38 (m, 2H, CH₂, THQ), 2.70 (br.s, 2H, OH+NH), 2.76-2.84 (m, 2H, CH₂, THQ), 3.60-3.69 (m, 2H, CH₂), 3.73-3.84 (m, 3H, CH₂+ CH,i-Pr);¹³C NMR (CDCl₃+ CD₃OD, δ, ppm): 19.8 (2CH₃), 20.8 (CH₂, THQ), 21.1 (CH₂, THQ), 22.1 (CH₂, THQ), 24.6 (CH₂, THQ), 29.2 (CH), 43.9 (CH₂NH), 61.3 (CH₂OH), 112.3 (C(4a)), 153.4 (C(8a)), 153.9 (C(4)), 162.0 (C(2)). HRMS (ESI⁺, m/z): calculated for C₁₃H₂₁N₃O₂[M+Na]⁺ 274.1526, defined 254.1528.

4-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]amino}-2-methyl-5,6,7,8-tetrahydroquinazoline 1-oxide (5b)

Yield 81 mg (54%). Brownish oil, R f = 0.10 (light petroleum ether-EtOAc-MeOH 3:1:1). ¹ H NMR (CDCl ₃ + CD ₃ OD, δ, ppm, J , Hz): 1.67-1.84 (m, 4H, CH ₂ , THQ), 2.16 (s, 3H, CH ₃ , pyrazole), 2.17 (s, 3H, CH ₃ , pyrazole), 2.17-2.24 (m, 2H, CH ₂ , THQ), 2.59 (s, 3H, CH ₃ , THQ), 2.58-2.65 (m, 2H, CH ₂ , THQ), 2.79-2.90 (m, 2H, CH ₂ ), 3.07-3.31 (m, 2H, 2NH), 3.46-3.55 (m, 2H, CH ₂ ); ¹³ C NMR (CDCl ₃ + CD ₃ OD, δ, ppm): 10.8 (2CH ₃ ), 20.2 (CH ₃ ), 20.8 (CH ₂ , THQ), 21.0 (CH ₂ , THQ), 22.1 (CH ₂ ), 23.2 (CH ₂ , THQ), 24.5 (CH ₂ , THQ), 41.4 (CH ₂ ), 112.0 (C(4a)), 112.1 (C(4'), pyrazole), 142.5 (C(3')+C(5'), pyrazole), 152.8 (C(4)), 153.5 (C(8a)), 155.3 (C(2)). HRMS (ESI ⁺ , m/z): calculated for C ₁₆ H ₂₃ N ₅ O [M+H] ⁺ 302.1975, determined 302.1981.

General scheme for the synthesis of 4-[(aminophenyl)oxy]tetrahydroquinazolines 4a-c

A mixture of 4-chloropyrimidine 10a (91 mg, 0.5 mmol), _Cs2CO3 (0.296 g, 1.0 mmol) _, and the appropriate aminophenol (109 mg, 1.0 mmol) in dry DMF (3 mL) was stirred at reflux for 24 h under argon. After this time, the reaction mixture was cooled to comp. temp., diluted with ice-water (3 mL), and extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (3 × 5 mL) and dried over _MgSO4 . The solvent was evaporated under reduced pressure; the product was isolated by preparative column chromatography ( _SiO2 ).

4-[(2-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline (4a)

Yield 71 mg (56%). Yellow solid, mp 223-225°C, R f = 0.5 (CHCl ₃ -MeOH 10:1). ¹ H NMR (CDCl ₃ , δ, ppm, J , Hz): 1.81-1.90 (m, 2H, CH ₂ , THQ), 1.90-1.97 (m, 2H, CH ₂ , THQ), 2.48-2.54 (m, 2H, CH ₂ , THQ), 2.53 (s, 3H, CH ₃ ), 2.71-2.77 (m, 2H, CH ₂ , THQ), 6.40 (br.s, 2H, NH ₂ ), 6.86 (ddd, 1H, ³ J = 8.0, ³ J = 7.1, ⁴ J = 1.6, CH, Ar), 6.68-7.04 (m, 1H, CH, Ar), 7.08 (dd, 1H, ³ J = 8.0, ⁴ J = 1.7, CH, Ar), 7.10-7.16 (m, 1H, CH, Ar); ¹³ C NMR (CDCl ₃ , δ, ppm): 22.0 (CH ₂ , THQ), 22.2 (CH ₂ , THQ), 22.3 (CH ₂ , THQ), 25.1 (CH ₃ ), 31.9 (CH ₂ , THQ), 110.1 (C(4a)), 120.3 (CH, Ar), 120.8 (CH, Ar), 122.8 (CH, Ar), 126.7 (CH, Ar), 127.8 (C, Ar), 149.4 (C, Ar), 158.0 (C), 158.1 (C), 162.9 (C). HRMS (ESI ⁺ , m/z): calculated for C ₁₅ H ₁₇ N ₃ O [M+H] ⁺ 256.1444, determined 256.1452.

4-[(3-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline (4b)

Yield 83 mg (65%). White solid, mp 91-94°C, R f = 0.1 (light petroleum ether-EtOAc 1:1). ¹ H NMR (CDCl ₃ , δ, ppm, J , Hz): 1.75-1.90 (m, 4H, 2CH ₂ , THQ), 2.44 (s, 3H, CH ₃ ), 2.62-2.71 (m, 2H, CH ₂ , THQ), 2.73-2.81 (m, 2H, CH ₂ , THQ), 3.72 (br.s, 2H, NH ₂ ), 6.41-6.45 (m, 1H, CH, Ar), 6.46-6.52 (m, 2H, 2CH, Ar), 7.12 (dd, 1H, ³ J = 8.1, ³ J = 7.9, CH, Ar); ¹³ C NMR (CDCl ₃ , δ, ppm): 21.9 (CH ₂ , THQ), 22.2 (CH ₂ , THQ), 22.4 (CH ₂ , THQ), 25.7 (CH ₃ ), 32.0 (CH ₂ , THQ), 108.3 (CH, Ar), 111.5 (CH, Ar), 111.9 (CH, Ar), 114.3 (C(4a)), 130.0 (CH, Ar), 147.8 (C, Ar), 154.3 (C, Ar), 164.4 (C(2)), 166.6 (C), 167.0 (C). HRMS (ESI ⁺ , m/z): calculated for C ₁₅ H ₁₇ N ₃ O [M+H] ⁺ 256.1444, determined 256.1449.

4-[(4-aminophenyl)oxy]-2-methyl-5,6,7,8-tetrahydroquinazoline (4c)

Yield 73 mg (57%). Black solid, mp 123-124°C, R f = 0.1 (light petroleum ether-EtOAc 1:1). ¹ H NMR (CDCl ₃ , δ, ppm, J , Hz): 1.77-1.93 (m, 4H, 2CH ₂ , THQ), 2.43 (s, 3H, CH ₃ ), 2.66-2.73 (m, 2H, CH ₂ , THQ), 2.74-2.82 (m, 2H, CH ₂ , THQ), 3.62 (br.s, 2H, NH ₂ ), 6.63-6.75 (m, 2H, 2CH, Ar), 6.88-6.99 (m, 2H, 2CH, Ar); ¹³ C NMR (CDCl ₃ , δ, ppm): 21.9 (CH ₂ , THQ), 22.2 (CH ₂ , THQ), 22.4 (CH ₂ , THQ), 25.7 (CH ₃ ), 31.9 (CH ₂ , THQ), 113.9 (C(4a)), 115.8 (2CH, Ar), 122.5 (2CH, Ar), 143.5 (C, Ar), 145.2 (C, Ar), 164.2 (C(2)), 166.1 (C), 167.4 (C). HRMS (ESI ⁺ , m/z): calculated for C ₁₅ H ₁₇ N ₃ O ₂ [M+H] ⁺ 256.1444, determined 256.1449.

General scheme for the synthesis of 4-aminotetrahydroquinazolines 2a-h

Method (v) . A mixture of 4-chloropyrimidine 10a-d (2 mmol), _Cs2CO3 ( _0.358 g, 3 mmol), and the appropriate amine (1 mmol) in dry DMF (3 mL) was heated under reflux with stirring for 2 h under argon. The reaction mixture was then cooled to room temperature, diluted with ice-water (3 mL), and extracted with ethyl acetate (3 × 15 mL). The combined organic layers were washed with saturated aqueous NaCl (1 × 15 mL) and water (1 × 15 mL) and dried over _MgSO4 . The solvent was evaporated under reduced pressure; the product was isolated by preparative column chromatography.

Method (vi) . Diisopropylethylamine (0.4 ml, 299 mg, 2 mmol) was added dropwise to a mixture of 4-chloropyrimidine (0.5 mmol) and the appropriate amine (0.45 mmol) in dry acetonitrile (5 ml) and stirred for 16 h at room temperature under argon atmosphere. The solvent was then evaporated, water (5 ml) was added to the dry residue and the mixture was extracted with ethyl acetate (3 × 10 ml). The combined organic layers were dried over MgSO ₄ . The solvent was evaporated under reduced pressure; the product was isolated by preparative column chromatography.

4-(2-(1-Adamantyl)ethylamino)-2-amino-5,6,7,8-tetrahydroquinazoline (2a)

Yield 59 mg (18%), method (v) . Yellow solid, _mp 152-153°C, R _f = 0.3 (light petroleum ether-EtOAc-MeOH=1:1:0.5). NMR spectrum ¹ H (CDCl ₃ , δ, ppm, J , Hz): 1.31-1.39 m (2H, CH ₂ , CH ₂ -Ad), 1.44-1.58 m (6H, 3CH _2, Ad), 1.63 br d (3H, ² J =12.3, 3CH ₂ , Ad), 1.72 br d. d (3H, ² J =12.3, 3CH ₂ , Ad) 1.72-1.86 m (4H, 2CH ₂ , THQ), 1.97 br. s (3H, 3CH, Ad), 2.16-2.22 m (2H, CH _2, THQ), 2.60-2.66 m (2H, CH _2, THQ), 3.35-3.52 m (2H, CH ₂ -NH), 4.86-5.03 m (1H, NH), 6.11 br. with (2H, NH ₂ ). ¹³ C NMR spectrum (CDCl ₃ , δ, ppm): 21.1 (CH _2, THQ), 21.3 (CH _2, THQ), 22.0 (CH _2, THQ), 28.1 (CH ₂ , THQ), 28.7 (3CH, Ad), 32.2 (C, Ad), 36.6 (CH ₂ -NH), 37.1 (3CH ₂ , Ad), 42.6 (3CH _{2 , Ad), 43.8 (CH 2 -Ad} ), 103.3 (C(4a), THQ), 153.6 (C(8a), THQ), 156.8 (C(2), THQ), 162.0 (C(4), THQ). HRMS (ESI ⁺ , m/z): calculated _{for C20H30N4} [ _M +H] ⁺ 327.2543, found 327.2540.

4-(2-(2-Adamantyl)ethylamino)-2-amino-5,6,7,8-tetrahydroquinazoline (2b)

Yield 62 mg (19%), method (v) . Yellow solid, _mp 147-148°C, R _f = 0.2 (light petroleum ether-EtOAc-MeOH=3:3:1). NMR spectrum ¹ H (CDCl ₃ , δ , ppm, J , Hz): 1.52 br. d (2H, ² J= 12.3, 2CH ₂ , Ad), 1.63-1.94 m (19H, 5CH, Ad + 5CH ₂ , Ad + 2CH ₂ , THQ + CH ₂ -Ad), 2.12-2.26 m (2H, CH ₂ , THQ), 2.45-2.61 m (2H, CH ₂ , THQ), 3.31-3.48 m (2H, CH ₂ -NH), 4.44-4.59 m (1H, NH), 4.85 br. s (2H, _NH2 ). ¹³ C NMR spectrum (CDCl ₃ , δ , ppm): 21.7 (CH ₂ , THQ), 22.3 ( _{CH 2, THQ), 22.6 (CH 2 ,} THQ), 28.1 (CH, Ad), 28.3 (CH, Ad), 31.1 (CH ₂ , THQ), 31.8 (2CH ₂ , Ad), 32.0 (2CH, Ad), 32.8 (CH ₂ -Ad), 38.4 (CH ₂ , Ad), 39.2 (2CH ₂ , Ad), 39.7 (CH ₂ -NH), 42.2 (CH, Ad), 102.9 (C(4a), THQ), 159.8 (C(8a), THQ), 160.1 (C(4), THQ), 161.8 (C(2), THQ). HRMS (ESI ⁺ , m/z): calculated for C ₂₀ H ₃₀ N ₄ [M+H] ⁺ 327.2543, found 327.2535.

4-(2-(1-Adamantyl)ethylamino)-2-chloro-5,6,7,8-tetrahydroquinazoline (2c)

Yield 72 mg (46%), method(vi). Colorless solid, T_pl= 200-201°C, R_f= 0.1 (light petroleum ether-EtOAc = 3:0.5). NMR spectrum¹H (CDCl₃,δ, m.d.,J, Hz): 1.30-1.42 m (2H, CH₂-Ad), 1.48-1.58 m (6H, 3CH_2,Ad), 1.63 wg (3H,² J=11.9, 3CH₂, Ad), 1.71 wt d (3H,² J=11.9, 3CH_2,Ad), 1.74-1.87 m (4H, 2CH₂, THQ), 1.96 us. s (3H, 3CH, Ad), 2.14-2.29 m (2H, CH₂, THQ), 2.56-2.74 m (2H, CH₂, THQ), 3.38-3.54 (2H,CH ₂ -NH), 4.39-4.57 m (1H, NH). NMR spectrum ¹³C (CDCl₃,δ, ppm): 21.9 (CH₂, THQ), 22.1 (2CH₂, THQ), 28.7 (3CH, Ad), 31.7 (CH₂, THQ), 32.2 (C, Ad), 36.5 (CH₂-NH), 37.1 (3CH₂, Ad), 42.6 (3CH₂, Ad), 44.1 (CH₂-Ad), 110.2 (C(4a), THQ), 157.6 (C(2), THQ), 162.0 (C(4), THQ), 163.6 (C(8a), THQ). HRMS (ESI⁺, m/z): calculated for C₂₀H₂₈ClN₃[M+H]⁺346.2045, found 346.2043.

4-(2-(2-Adamantyl)ethylamino)-2-chloro-5,6,7,8-tetrahydroquinazoline (2d)

Yield 76 mg (49%), method (vi) . Colourless solid, _mp 198-199°C, R _f = 0.2 (light petroleum ether-EtOAc = 3:1). NMR spectrum ¹ H (CDCl ₃ , δ , ppm, J , Hz): 1.52 br. d (2H, ² J= 12.5, 2CH ₂ , Ad), 1.63-1.94 m (19H, 5CH, Ad + 5CH ₂ , Ad + 2CH ₂ , THQ + CH ₂ -Ad), 2.17-2.32 m (2H, CH ₂ , THQ), 2.60-2.71 m (2H, CH ₂ , THQ), 3.39-3.51 m (2H, CH ₂ -NH), 4.58-4.72 m (1H, NH). ¹³ C NMR spectrum (CDCl ₃ , δ, ppm): 22.0 (CH ₂ , THQ), 22.1 (2CH ₂ , THQ), 28.1 (CH, Ad), 28.3 (CH, Ad), 31.7 (CH ₂ , THQ), 31.8 (2CH ₂ , Ad), 32.0 (2CH, Ad), 32.6 (CH ₂ -Ad), 38.4 (CH ₂ , Ad), 39.2 (2CH ₂ , Ad), 40.0 (CH ₂ -NH), 42.1 (CH, Ad), 102.2 (C(4a), THQ), 157.6 (C(2), THQ), 162.1 (C(4), THQ), 163.7 (C(8a), THQ). HRMS (ESI ⁺ , m/z): _{calculated for C20H28ClN3 [ M} +H] ⁺ 346.2045, found 346.2043.

4-(2-(2-Adamantyl)ethylamino)-2-methyl-5,6,7,8-tetrahydroquinazoline (2e)

Yield 124 mg (38%), method (v) . Yellow solid, _mp 164-165°C, R _f = 0.2 (light petroleum ether-EtOAc-MeOH=1:1:0.1). NMR spectrum ¹ H (CDCl ₃ , δ, ppm, J , Hz): 1.54 br. d (2H, ² J =12.0, 2CH ₂ , Ad), 1.68-1.94 m (19H, 5CH, Ad + 5CH ₂ , Ad + 2CH ₂ , THQ + CH ₂ -Ad), 2.21-2.29 m (2H, CH ₂ , THQ), 2.47 s (3H, CH ₃ ), 2.59-2.69 m (2H, CH ₂ , THQ), 3.44-3.55 m (2H, CH ₂ -NH), 4.33-4.43 m (1H, NH). ¹³ C NMR spectrum (CDCl ₃ , δ , ppm): 22.0 (CH ₂ , THQ), 22.4 (CH 2 , THQ), 22.5 (CH ₂ , THQ), 26.1 (CH ₃ ), 28.2 (CH, Ad), 28.3 ₍ CH, Ad), 31.8 (2CH ₂ , Ad + CH ₂ , THQ), 32.1 (2CH, Ad), 33.0 (CH ₂ -Ad), 38.5 (CH ₂ , Ad), 39.3 (2CH ₂ , Ad), 39.7 (CH ₂ -NH), 42.2 (CH, Ad), 108.5 (C(4a), THQ), 160.7 (C, THQ), 161.0 (C, THQ), 164.2 (C, THQ). HRMS (ESI ⁺ , m/z): calculated for C ₂₁ H ₃₁ N ₃ [M+H] ⁺ 326.2591, found 326.2582.

4-(2-(1-Adamantyl)ethylamino)-5,6,7,8-tetrahydroquinazoline (2f)

Yield 112 mg (36%), method (v) . Colorless solid, _mp 151-152°C, R _f = 0.1 (light petroleum-EtOAc = 3:0.5). NMR spectrum ¹ H (CDCl ₃ , δ , ppm, J , Hz): 1.36-1.43 m (2H, CH 2 , CH ₂ -Ad), 1.51-1.59 m (6H, 3CH ₂ , Ad), 1.64 br d (3H, 2 J =11.8, 3CH 2 , Ad), 1.72 br d (3H, 2 J =11.8, 3CH _{2 ,} Ad), 1.72 br d (3H, ² J =11.8, 3CH ₂ , Ad). d (3H, ² J =11.8, 3CH _2, Ad), 1.76-1.89 m (4H, 2CH ₂ , THQ), 1.96 br. s (3H, 3CH, Ad), 2.23-2.30 m (2H, CH ₂ , THQ), 2.67-2.74 m (2H, CH ₂ , THQ), 3.44-3.52 m (2H, CH ₂ -NH), 4.33 br. s (1H, NH), 8.43 br. s (1H, CH, THQ). ¹³ C NMR spectrum (CDCl ₃ , δ, ppm): 22.13 (CH ₂ , THQ), 22.15 (CH ₂ , THQ), 22.2 (CH ₂ , THQ), 28.7 (3CH, Ad), 31.5 (CH ₂ , THQ), 32.2 (C, Ad), 36.4 (CH ₂ -NH), 37.2 (3CH 2, Ad), 42.6 (3CH ₂ , Ad), 44.3 (CH ₂ -Ad), 111.9 (C(4a), _THQ ), 155.1 (CH, THQ), 160.5 (C(4), C(8a), THQ). HRMS (ESI ⁺ , m/z): calculated _{for C20H29N3 [ M} +H] ⁺ 312.2434, found 312.2440.

4-(2-(2-Adamantyl)ethylamino)-5,6,7,8-tetrahydroquinazoline (2g)

Yield 149 mg (48%), method (v) . Colorless solid, T _pl = 155-156 ° C, R _f = 0.5 (CH ₂ Cl ₂ -MeOH = 10:1). ^1H NMR spectrum ( _CDCl3 , δ , ppm, J , Hz): 1.49 br. d (2H, ² J= 12.3, 2CH ₂ , Ad), 1.57-1.96 m (19H, 5CH, Ad + 5CH ₂ , Ad + 2CH ₂ , THQ + CH ₂ -Ad), 2.18-2.31 m (2H, CH ₂ , THQ), 2.58-2.72 m (2H, CH ₂ , THQ), 3.35-3.51 m (2H, CH ₂ -NH), 4.48-4.65 m (1H, NH), 8.37 s (1H, CH, THQ). ¹³ C NMR spectrum (CDCl ₃ , δ, ppm): 22.15 (2CH ₂ , THQ), 22.21 (CH ₂ , THQ), 28.0 (CH, Ad), 28.2 (CH, Ad), 31.7 (2CH ₂ , Ad + CH ₂ , THQ), 31.9 (2CH, Ad), 32.6 (CH ₂ -Ad), 38.3 (CH ₂ , Ad), 39.1 (2CH ₂ , Ad), 39.8 (CH ₂ -NH), 42.2 (CH, Ad), 111.8 (C(4a), THQ), 155.3 (CH, THQ), 160.3 (C(4), THQ), 160.9 (C(8a), THQ). HRMS (ESI ⁺ , m/z): calculated _{for C20H29N3} [ _M +H] ⁺ 312.2434, found 312.2438.

4-(1-(1-Adamantyl)ethylamino)-2-methyl-5,6,7,8-tetrahydroquinazoline (2h)

Yield 75 mg (23%), method (vi) . Colorless solid, _mp 139-140°C, R _f = 0.2 (light petroleum ether-EtOAc-MeOH = 6:6:1). NMR spectrum ¹ H (CDCl ₃ , δ , ppm, J , Hz): 1.08 d (3H, ² J =6.7, CH ₃ -CH), 1.52 br d (3H, ² J =11.8, 3CH _2, Ad), 1.56-1.67 m (6H, 6CH _2, Ad), 1.71 br d. d (3H, ² J =11.8, 3CH ₂ , Ad), 1.76-1.90 m (4H, 2CH ₂ , THQ), 1.99 br. s (3H, 3CH, Ad), 2.16-2.37 m (3H, CH _2, THQ + NH), 2.45 s (3H, CH ₃ ), 2.61-2.70 m (2H, CH _2, THQ), 4.10-4.19 m (1H, CH -NH), 4.30-4.38 m (1H, NH ). ¹³ C NMR spectrum ( _CDCl3 , δ , ppm): 14.4 ( CH3 - _CH ), 21.5 (CH2, THQ), 21.8 ( _CH2 , THQ), 21.9 ( _CH2 , THQ ₎ , 25.6 (CH3), 28.0 ( _3CH , Ad), 31.2 ( _CH2 , THQ), 35.8 (C, Ad), 36.7 (3CH ₂ , Ad), 38.1 (3CH ₂ , Ad), 52.8 (CH-NH), 107.6 (C(4a), THQ), 160.0 (C, THQ), 160.3 (C, THQ), 163.5 (C, THQ). HRMS (ESI ⁺ , m/z): calculated for C ₂₁ H ₃₁ N ₃ [M+H] ⁺ 326.2591, found 326.2588.

General scheme of synthesis rubs -butylpyrimidines 6d-f

A mixture of 4-chloropyrimidine 11 (91 mg, 0.5 mmol), _Cs2CO3 (0.296 g, 1.0 mmol) _, and the appropriate aminophenol (109 mg, 1.0 mmol) in dry DMF (3 mL) was stirred at reflux for 24 h under argon. After this time, the reaction mixture was cooled to comp. temp., diluted with ice-water (3 mL), and extracted with ethyl acetate (3 × 15 mL). The combined organic extracts were washed with brine (3 × 5 mL) and dried over _MgSO4 . The solvent was evaporated under reduced pressure; the product was isolated by preparative column chromatography ( _SiO2 ).

4-[(2-Aminophenyl)oxy]-2-methyl-6- rubs -butylpyrimidine (6d)

Yield 96 mg (68%). Orange solid, _mp = 48-49°C; R _f = 0.4 (light petroleum-EtOAc = 3:1). NMR spectrum ¹ H (CDCl ₃ , δ, ppm, J , Hz): 1.27 s (9H, 3CH ₃ , t -Bu), 2.53 s (3H, CH ₃ ), 6.47 br s (1H, Pyr), 6.83 ddd (1H, ⁴ J = 2.2, ³ J = 6.7, ³ J = 7.9, CH, Ar), 6.91-7.12 m (5H, 3CH, Ar + NH ₂ ). ^13C NMR spectrum ( _CDCl3 , δ, ppm): 25.5 ( _CH3 ), 29.2 (3CH3, t-Bu), 37.3 (C, t - Bu), 98.7 (CH, Pyr), 120.2 (CH, _Ar ), 120.4 (CH, Ar), 122.4 (CH, Ar), 126.2 (CH, Ar), 128.1 (C), 148.9 (C), 160.4 (C), 165.8 (C), 177.7 (C(6), Pyr). HRMS (ESI ⁺ , m/z): calculated for C ₁₅ H ₁₉ N ₃ O [M+H] ⁺ 258.1601, found 258.1602.

4-[(3-Aminophenyl)oxy]-2-methyl-6- rubs -butylpyrimidine (6e)

Yield 88 mg (62%). Colorless solid, _mp 100-101°C; R _f = 0.4 (light petroleum ether - EtOAc = 2:1). NMR spectrum ¹ H (CDCl ₃ , δ, ppm, J , Hz): 1.28 s (9H, 3CH _3, t -Bu), 2.57 s (3H, CH ₃ ), 3.78 br. s (2H, NH ₂ ), 6.45 pseudo. t (1H, ⁴ J =2.2, CH, Ar), 6.48 ddd (1H, ⁴ J =0.8, ⁴ J =2.2, ³ J =8.0, CH, Ar), 6.54 ddd (1H, ⁴ J =0.8, ⁴ J =2.2 CH, ³ J =8.0, CH, Ar), 6.54 br. c (1H, Pyr), 7.16 ps. t. (1H, ³ J =8.0, CH, Ar). ^13C NMR spectrum ( _CDCl3 , δ, ppm): 26.2 ( _CH3 ), 29.4 (3CH3, t-Bu), 37.5 (C, t - Bu), 99.2 (CH, Pyr), 108.1 (CH, _Ar ), 111.2 (CH, Ar), 112.2 (CH, Ar), 130.4 (CH, Ar), 148.2 (C- _NH2 , Ar), 154.0 (CO, Ar), 167.8 (C(2), Pyr), 170.3 (C(4), Pyr), 180.3 (C(6), Pyr). HRMS (ESI ⁺ , m/z): calculated for C ₁₅ H ₁₉ N ₃ O [M+H] ⁺ 258.1601, found 258.1600.

4-[(4-Aminophenyl)oxy]-2-methyl-6- rubs -butylpyrimidine (6f)

Yield 86 mg (61%). Black solid, _mp 93-94°C; R _f = 0.5 (light petroleum-EtOAc = 1:1). NMR spectrum ¹ H (CDCl ₃ , δ, ppm): 1.25 s (9H, 3СH ₃ , t -Bu), 2.54 s (3H, CH ₃ ), 3.69 br s (2H, NH ₂ ), 6.48 s (1H, Pyr), 6.63-6.71 m (2H, 2CH, Ar), 6.86-6.94 m (2H, 2CH, Ar). ^13C NMR ( _CDCl3 , δ, ppm): 26.1 ( _CH3 ), 29.3 (3CH3, t-Bu), 37.4 (C, t - Bu), 98.7 (CH, Pyr), 116.0 (2CH, _Ar ), 122.2 (2CH, Ar), 144.0 (C), 144.8 (C), 167.6 (C(2), Pyr), 170.9 (C(4), Pyr), 180.0 (C(6), Pyr ₎ . _HRMS (ESI ⁺ , m/z): calculated for _C15H19N3O [M+H] ⁺ 258.1601, found 258.1597.

Characterization of the biological activity of the compounds according to the invention

Cells and viruses

Continuous pig embryo kidney cells (PEKCs) were grown in a mixture of medium 199 with Earle's salts and medium 199 with Hanks' salts (Chumakov Federal Scientific Center for R&D, Russian Academy of Sciences (Polio Institute)) supplemented with 5% heat-inactivated fetal calf serum (Gibco) and penicillin-streptomycin (Paneko LLC). Continuous African green monkey kidney cells (Vero) were grown in a medium consisting of DMEM with L-glutamine (Chumakov Federal Scientific Center for R&D, Russian Academy of Sciences (Polio Institute)) supplemented with 5% heat-inactivated fetal calf serum (Gibco) and gentamicin (Paneko LLC). Both cell lines were obtained from the collection of the Federal State Autonomous Institution “Federal Scientific Center for Research and Development of Polymers named after M.P. Chumakov of the Russian Academy of Sciences” (Institute of Poliomyelitis), Russia.

The Absettarov tick-borne encephalitis virus strain (Genbank accession number KU885457.1), the yellow fever virus strain 17D (Genbank accession number JN628279.1), and the West Nile virus strain Strix nebulosa-12 (Genbank accession number OP868929) were taken from the collection of the Chumakov Federal Scientific Center for Research and Infectious Diseases of the Russian Academy of Sciences (Polio Institute), Russia.

The studied compounds were dissolved in DMSO (VWR Life Science) to prepare stock solutions with a concentration of 5-10 mmol/L.

Cytotoxicity analysis on Vero and SPEV cells

Cytotoxicity was determined by the effect of the compounds according to the invention on cell viability and measured using the resazurin assay. When added to living cells, the dye resazurin is reduced by cellular enzymes to the fluorescent dye resorufin. The toxic effect of the compounds according to the invention is detected by a decrease in fluorescence intensity compared to control cells.

Vero or SPEV cells were seeded in 96-well culture plates and incubated for 24 hours at 37°C and 5% CO ₂ . Serial 1:2 dilutions of the compounds were prepared, starting with a concentration of 50-100 μmol/L. As a control, serial DMSO dilutions were prepared in a similar manner, starting with a concentration of 1%. DMEM medium supplemented with L-glutamine served as the solvent for the experiment on Vero cells, while a mixture of medium 199 (Earle's salts) and medium 199 (Hank's salts) with the addition of 2% inactivated fetal bovine serum served for the experiment on SPEV cells. An aqueous solution of sodium dodecyl sulfate at a concentration of 0.5 mg/mL was used as a positive control, causing 100% cell death. Equal volumes of compound dilutions were transferred to cells, after which the plates with cells were incubated at 37°C and 5% CO ₂ for 7 days to determine chronic cytotoxicity. After incubation, the cell monolayer was washed with phosphate-buffered saline, and a resazurin solution (Sigma-Aldrich) in medium 199 (based on Earle's solution) at a concentration of 25 μg/ml was added to the cells. The cells were incubated for 4 hours at 37°C and 5% CO ₂ , then the culture fluid was collected and resorufin fluorescence was measured in it at λ _ex / _em = 544/590 nm. The CC ₅₀ value was calculated using the Reed-Muench method.

Analysis of activity against TBEV

The activity against TBEV was analyzed using the plaque inhibition method.

SPEV cells were seeded in 24-well culture plates and incubated for 3 days at 37°C and 5% CO ₂ . Serial 1:4 dilutions of the compounds were prepared in 199 medium (Earle's solution), starting with a concentration of 50-100 μmol/L. As a control, serial dilutions in DMSO were prepared in a similar manner, starting with a concentration of 1%. The viral suspension was added to the resulting dilutions, and the mixtures were incubated for 1 hour at 37°C and 5% CO ₂ . The virus titer was adjusted to produce 30-60 plaque-forming units per well with cells during infection. SPEV cells were infected with the resulting mixtures and incubated with periodic shaking for 1 hour at 37°C and 5% CO ₂ . The infected cells were then covered with a 1.5% methylcellulose solution in a mixture of medium 199 (Earle's salts) and medium 199 (Hank's salts) with the addition of 2% fetal bovine serum and incubated for 6 days at 37°C and 5% CO ₂ . After incubation, the cells were uncoated, washed with phosphate-buffered saline, fixed with 96% ethanol and stained with 0.5% crystal violet solution. The EC ₅₀ value was calculated using the Reed-Muench method after plaque counting.

Analysis of activity against VZhL

Activity against VZhL was measured similarly to activity against TBEV, with minor modifications. Specifically, Vero cells were used instead of SPEV cells, and the incubation time of infected cells was increased to 7 days. The remaining stages of the study were performed as described above.

Analysis of activity against WNV

Activity against WNV was measured similarly to activity against VZhV, with minor modifications. Specifically, DMEM was used for dilution, and the incubation time for infected cells was reduced to 5 days. The remaining steps were performed as described above.

Results of the conducted research

The antiviral activity of the compounds of the invention was assessed in relation to, in particular, tick-borne encephalitis virus on SPEV cells, and tick-borne encephalitis, yellow fever and West Nile fever viruses on Vero cells using the plaque inhibition method (Tables 2-4).

Table 2. Activity against TBEV and cytotoxicity against TBEV cells of the compounds according to the invention

No. General formula (I)
R ₁ R ₂ n EC ₅₀ (VKE), μM CC ₅₀ (SPEV), μM (7 days) 1d 1 9.4 ± 1.7 11.0 ± 2.2 1st 1 5.3 ± 1.8 14.0 ± 4.1 1f 1 4.6 ± 0.8 9.37 ± 0.05 5a 1 33 ± 7 > 50 No. General formula (II)
R' ₁ R' ₂ n EC ₅₀ (VKE), μM CC ₅₀ (SPEV), μM
(7 days) 4a 1 4.59 ± 0.11 > 50 2a 1 10 ± 3 n.d.* 2b 1 14 ± 6 n.d. 2c 1 49 ± 4 >100 2d 1 10.1 ± 0.7 >100 2e 1 36.7 ± 2.8 n.d. 2h 1 24 ± 11 n.d. No. General formula (III)
Rʺ ₁ Rʺ ₂ Rʺ3 EC ₅₀ (VKE), μM CC ₅₀ (SPEV), μM
(7 days) 6d 4.2 ± 2.0 >50 6e 12 ± 5 >50 6f 22 ± 5 >50 * n.d. - no data.

Table 3. Activity against VZhL and cytotoxicity against Vero cells of the compounds of the invention

No. General formula (I)
R ₁ R ₂ n EC ₅₀ (VZHL), μM CC ₅₀ (Vero), μM
(7 days) 1st 1 8 ± 4 19.0 ± 1.8 No. General formula (II)
R' ₁ R' ₂ n EC ₅₀ (VZHL), μM CC ₅₀ (Vero), μM
(7 days) 2a 1 14 ± 8 16.50 ± 0.18 2b 1 13 ± 5 n.d. 2e 1 32 ± 3 17.23 ± 0.06 2h 1 20 ± 6 17.03 ± 0.22 * n.d. - no data.

Table 4. Activity against WNV and cytotoxicity against Vero cells of the compounds of the invention

No. General formula (I)
R ₁ R ₂ n EC ₅₀ (VZN), μM CC ₅₀ (Vero), μM
(7 days) 1d 1 4.4 ± 2.5 32 ± 4 1st 1 6.4 ± 0.3 19.0 ± 1.8 1f 1 4.6 ± 1.1 13.9 ± 0.3 5b 1 32 ± 6 > 50 No. General formula (II)
R' ₁ R' ₂ n EC ₅₀ (VZN), μM CC ₅₀ (Vero), μM
(7 days) 4a 1 21 ± 5 > 50 4b 1 10 ± 6 > 50 4c 1 10 ± 5 > 50 2a 1 2.6 ± 1.0 16.50 ± 0.18 2b 1 3.9 ± 1.6 n.d. 2c 1 3.1 ± 0.3 >100 2d 1 3.0 ± 0.3 >100 2e 1 10.7 ± 1.9 17.23 ± 0.06 2f H 1 8.2 ± 1.4 17.37 ± 0.19 2g H 1 10.9 ± 2.4 22 ± 6 2h 1 13.6 ± 2.0 17.03 ± 0.22 No. General formula (III)
Rʺ ₁ Rʺ ₂ Rʺ3 EC ₅₀ (VZN), μM CC ₅₀ (Vero), μM
(7 days) 6d 0.8 ± 0.7 >50 6e 14 ± 6 >50 6f 7.6 ± 1.0 >50 * n.d. - no data.

Thus, the results of the study of biological activity show that the compounds of the invention are characterized by high efficiency in inhibiting the reproduction of viruses belonging to the genus Orthoflavivirus , including TBEV, VZhV, WNV, and have low cytotoxicity, which, in combination with high antiviral activity, is a necessary condition for further pharmaceutical development.

PHARMACEUTICAL COMPOSITIONS

The invention also relates to pharmaceutical compositions that contain a compound of general formula (I), (II) or (III) (or a prodrug form, a pharmaceutically acceptable salt or another pharmaceutically acceptable derivative) and one or more pharmaceutically acceptable carriers, adjuvants, solvents and/or excipients that can be administered to a patient's body together with the compound that is the essence of this invention, do not reduce the pharmacological activity of this compound and are not toxic when administered in doses sufficient to deliver a therapeutic amount of the compound.

The pharmaceutical compositions disclosed in this invention comprise the compounds of this invention together with pharmaceutically acceptable carriers, which may include any solvents, diluents, dispersions or suspensions, surfactants, isotonic agents, thickeners and emulsifiers, preservatives, astringents, antibacterial agents and fungicides, sustained-release agents, lubricants, dyes, flavors and fragrances, preservatives and antioxidants, etc., the selection and ratio of which depend on the method of administration and dosage. According to known methods, the pharmaceutical compositions may be presented in various liquid (solutions, emulsions, suspensions) or solid (tablets, capsules, pills) dosage forms. Standard procedures for their preparation involve mixing the compounds of this invention with a liquid or finely divided solid carrier.

An example of tablet production is mixing the active ingredient with pharmaceutical excipients such as lactose, starch, talc, silicon dioxide, etc., forming tablets and, if necessary, coating them with sucrose or other suitable substances.

Gelatin capsules can be prepared by mixing the active compound with a solvent, dyes and stabilizers and filling soft or hard capsules with the resulting mixture, or by using the drop method, simultaneously dosing the resulting mixture and heated gelatin mass into cooled vaseline oil.

Injectable forms of the composition are usually aqueous suspensions, isotonic saline solutions or sterile injection solutions with the addition of preservatives and stabilizers.

Examples of obtaining a composition according to the invention

Method A: Tableting

To prepare 10,000 pcs. 100 mg tablets containing 0.1 mg of 4-[2-(1-adamantyl)ethylamino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide (1d) , 1 g of compound 1d is mixed with 200 g of tragacanth (binder), 549 g of calcium carbonate (filler), 200 g of starch (disintegrating agent), and 50 g of citric acid (flavoring agent). The resulting mixture is then pressed into tablets using a special machine.

Method B: Preparing Capsules

To prepare 10,000 pcs. 500 mg capsules containing 0.5 mg of 4-[2-(1-adamantyl)ethylamino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide (1d) , mix 5 g of compound 1d with 1000 g of glycerin and 3395 g of sugar syrup, then add 400 g of peppermint oil, 100 g of sodium benzoate, 50 g of ascorbic acid and 50 g of tetrazine dye. The capsules are obtained by the drop method, simultaneously dosing the resulting mixture and the heated gelatin mass (900 g) into cooled vaseline oil. This results in ready-to-use spherical capsules containing 0.5 mg of the active substance.

Method B: Preparation of injection solution

For the preparation of 1000 pcs. 2 ml ampoules containing 1 mg of 4-[2-(1-adamantyl)ethylamino]-2-isopropyl-5,6,7,8-tetrahydroquinazoline 1-oxide(1d),mix 1 G connections(1d) with 400 ml mint oil, 10 g methylcellulose, 1600 ml solution A 0.9% sodium chloride solution with 2% DMSO added, as well as 10 g of benzoic acid, is added. The resulting mixture is filtered to remove any mechanical impurities and poured into ampoules, which are then sealed and sterilized in an autoclave.

METHODS OF THERAPEUTIC APPLICATION

The compounds of the present invention exhibit activity against flaviviruses and are therefore suitable for the treatment and/or prevention of diseases caused by flaviviruses, including tick-borne encephalitis, yellow fever, West Nile fever, dengue fever, dengue shock syndrome, and Zika fever. The patient can be either humans or other mammals.

The compounds of the invention can be used as part of a pharmaceutical composition in any suitable pharmaceutical dosage form and by any suitable route of administration (intravenously, intramuscularly, orally, subcutaneously, by inhalation, intranasally and sublingually), as well as with any duration of administration necessary for the treatment and/or prevention of diseases.

The invention also relates to a pharmaceutical composition containing a daily dose of an active compound in the form of a fixed dosage unit, and to a combination containing said pharmaceutical composition or said compound. In a preferred embodiment, said composition for use in accordance with the invention is administered orally or intravenously one or more times a day in a dosage of 1 mg or more of the selected compound according to the invention. The preferred dosage is 1-1500 mg. The most preferred dosage is 10-1000 mg.

In combination with the compounds of the invention, additional pharmacologically active agents may also be used in a single or separate dosage form. The therapeutic effect of the active agents may be simultaneous or sequential and is aimed at alleviating symptoms associated with viral infections, such as fever, chills, headache, secondary infections, etc. Examples of additional active agents include antipyretics, anti-inflammatory agents, chemotherapeutic agents, antibiotics, antifungal agents, chemotherapeutic agents, interferons, cytokines, monokines, antibodies, or combinations thereof. They may be administered either simultaneously with the compound of the invention or at separate times.

Although the invention has been described with reference to the disclosed embodiments, the specific experiments described in detail are provided merely for the purpose of illustrating the present invention and should not be considered as in any way limiting the scope of the invention - various modifications can be made without departing from the spirit of the present invention.

Claims (15)

1. A compound selected from the group: - 4-[(2-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine with the structural formula: ; - 4-[(3-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine with the structural formula: ; or - 4-[(4-aminophenyl)oxy]-2-methyl-6-tert-butylpyrimidine with the structural formula: ; or its pharmaceutically acceptable salt. 2. Use of a compound according to claim 1 as an inhibitor of the reproduction of a virus belonging to the genus Orthoflavivirus . 3. The use according to claim 2, wherein the virus is dengue virus, West Nile fever virus, yellow fever virus, Japanese encephalitis virus, Kyasanur forest disease virus, tick-borne encephalitis virus, Omsk hemorrhagic fever virus, Powassan virus. 4. Use of a compound according to claim 1 for the preparation of a pharmaceutical composition with antiviral activity for the treatment and/or prevention of a disease of viral etiology caused by a virus of the genus Orthoflavivirus in a patient. 5. A pharmaceutical composition with antiviral activity for the treatment and/or prevention of a disease of viral etiology caused by a virus of the genus Orthoflavivirus in a patient, containing an effective amount of a compound according to claim 1 and at least one pharmaceutically acceptable excipient. 6. The pharmaceutical composition according to claim 5, characterized in that the pharmaceutically acceptable excipient is a carrier, filler and/or solvent. 7. The pharmaceutical composition according to claim 5, wherein the virus is dengue virus, West Nile fever virus, yellow fever virus, Japanese encephalitis virus, Kyasanur forest disease virus, tick-borne encephalitis virus, Omsk hemorrhagic fever virus, Powassan virus. 8. The pharmaceutical composition according to claim 5, wherein the patient is a human.