RU2780103C1 - Antiviral remedies for treatment and prevention of hiv infection - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to a combination for the treatment or prevention of HIV-mediated diseases, including therapeutically effective amount of a compound of the formula I and at least one compound selected from a group including HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists, and inhibitors of viral penetration to a cell, as well as to a method for the treatment or prevention of HIV-mediated diseases.

EFFECT: new combination for the treatment or prevention of HIV-mediated diseases is developed, including therapeutically effective amount of a compound of the formula I and at least one compound selected from a group including HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists, and inhibitors of viral penetration to a cell, which can be used in the treatment or prevention of HIV-mediated diseases.

17 cl, 68 ex, 1 tbl

Description

The field of technology to which the invention belongs

The present invention relates to pyrimidine derivatives having HIV replication inhibiting properties. The invention provides new pyrimidine compounds of formula I for the treatment and prevention of HIV-mediated diseases. The invention also relates to methods for their preparation and pharmaceutical compositions containing them. The invention also relates to the use of these compounds for the treatment and prevention of HIV in subjects suffering from HIV infection (human immunodeficiency virus), or at risk of contracting HIV infection.

State of the art

Compounds structurally related to the present antiviral compounds are described in the prior art: List of sources:

J. Guillemont et al., WO 2006/035068 published April 6, 2006,

J. Guillemont et al., WO 2006/035067 published April 6, 2006,

J. Guillemont et al., WO 2006/045828 published May 4, 2006,

J. Guillemont et al., WO 2006/035369 published April 6, 2006,

ON THE. De Kock and P. Wigerinck, WO 2006/094930, published September 14, 2006.

ON THE. De Kock and P. Wigerinck, WO 2006/087387 published August 24, 2006.

P.A.J. Jansen et al., J. Med Chem., 48(6), 1901-1909 (2005)

K. Das et al., J. Med. Chem., 47(10), 2550-2660 (2004).

J. Guillemont et al., J. Med. Chem., 48(6), 2072-2079 (2005).

The essence of the invention

The present invention relates to a compound of formula I

where R ¹ is selected independently and represents H-, -CN, CN-CH=CH-;

Χ ¹ , X ² are a substituent of the form (CH ₂ ) _n , and n is chosen independently for Χ ₁ , X ₂ and can take values from 1 to 3;

Υ ¹ is selected independently and represents -O-, -S-, -S(=O)-, -S(=O) ₂ -, or substituents of the form:

or

R ^b is independently selected and is -H, substituted or unsubstituted -C1-C ₆ -alkyl, substituted or unsubstituted -C ₁ -C ₆ -alkenyl, substituted or unsubstituted -C ₆ -aryl, substituted or unsubstituted -5÷6- membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and/or O, forbidden or unsubstituted -C ₃ -C ₉ -cycloalkyl, or substituted or unsubstituted 4÷9-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and/or O; or its pharmaceutically acceptable salts.

Compounds of formula I inhibit HIV-1 reverse transcriptase and can be used in a method for the prevention and treatment of HIV-mediated diseases.

The present invention also relates to a composition containing compounds of formula I, which can be used for the prevention and treatment of HIV-mediated diseases. The present invention also relates to compounds of formula I which can be used in single drug treatment or in combination treatment with other antiviral agents.

In one embodiment, the present invention relates to one of the following compounds

Disclosure of invention

In one embodiment, the present invention relates to a compound of formula I

, where R ¹ is selected independently and represents H-, -CN, CN-CH=CH-;

Χ ¹ , X ² are a substituent of the form (CH2)n, and n is chosen independently for Χ ₁ , X ₂ and can take values from 1 to 3;

Υ ¹ is selected independently and represents -O-, -S-, -S(=O)-, -S(=O) ₂ -, or substituents of the form:

or

R ^b is independently selected and is -H, substituted or unsubstituted -C ₁ -C ₆ -alkyl, substituted or unsubstituted -C ₁ -C ₆ -alkenyl, substituted or unsubstituted -C ₆ -aryl, substituted or unsubstituted -5÷6 -membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and/or O, substituted or unsubstituted -C ₃ -C ₉ -cycloalkyl, or substituted or unsubstituted 4÷9-membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and/or O; or its pharmaceutically acceptable salts,

where Rb can be attached to the rest of the molecule through a linker of the form (CH ₂ ) _n , n is selected from 1 to 3.

In another embodiment, the present invention to the compound of formula I

where R1 is independently selected and is H, CN, CN-CH=CH, C=O, CH=CH-COOH, substituted or unsubstituted 4-6 membered heterocyclyl containing 1-2 O heteroatoms; aminocarbonyl; _NH2 ; substituted or unsubstituted C _1-6 alkyl; halogen; substituted or unsubstituted C _1-6 alkyloxy; NHR ⁹ ; NR ⁹ R ¹⁰ ; -C(=O)-NHR ⁹ ; -C(=O)-NR ⁹ R ¹⁰ ; -C(=O)-R ⁹ ; -CH=N-NH-C(=O)-R ⁹ ; substituted or unsubstituted C _1-6 alkyloxyC _1-6 alkyl, substituted or unsubstituted C _2-6 alkenyl; substituted or unsubstituted C _2-6 alkynyl; -C(=N-O-R ⁸ )-C _1-4 alkyl; R ⁷ and -Rb-R ⁷ ;

X ¹ , X ² is a substituent of the form (CH ₂ ) _n , with n being chosen independently for X ₁ , X ₂ ;

Υ ¹ is Selected independently and represents -O-, -S-, -S(=O)-, -S(=O) ₂ -, or substituents of the form:

or

R ^b is selected independently and is -H, cyano, aminocarbonyl, substituted or unsubstituted -C ₁ -C ₆ -alkyl, substituted or unsubstituted -C ₂ -C ₆ -alkenyl, substituted or unsubstituted -C ₂ -C ₆ -alkynyl, substituted or unsubstituted -C ₃ -C ₆ -aryl, substituted or unsubstituted 4-6-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and/or O, substituted or unsubstituted -C ₃ -C ₉ -cycloalkyl, substituted or unsubstituted 4-9 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and/or O, R ⁷ or R ⁹ ,

where Rb can be attached to the rest of the molecule through a linker of the form (CH ₂ ) _n

R ⁷ - represents a monocyclic, bicyclic or tricyclic, saturated, partially saturated or aromatic carbocycle or monocyclic, bicyclic or tricyclic, saturated, partially saturated or aromatic 4-6 membered heterocycle containing from 1 to 4 heteroatoms independently selected from the group S , N and O, where each of the mentioned carbocyclic or heterocyclic fragments may be optionally substituted with one, two, three, four or five substituents, each of which is independently selected from halogen, hydroxy, mercapto, C _1-6 alkyl, hydroxyC _1-6 alkyl, aminoC _1-6 alkyl, mono- and di(C _1-6 alkyl)aminoC _1-6 alkyl, formyl, C _1-6 alkylcarbonyl, C _3-7 cycloalkyl, C _1-6 alkyloxy, C _1-6 alkyloxycarbonyl , C _1-6 alkylthio, cyano, nitro, polyhaloC _1-6 alkyl, polyhaloC _1-6 alkyloxy, aminocarbonyl, -C(=N-O-R ⁸ ), R*7a, -Rb-R ^7a , and R ^7a -C _1-4 alkyl;

R ^7a is a monocyclic, bicyclic or tricyclic, saturated, partially saturated or aromatic carbocycle or a monocyclic, bicyclic or tricyclic, saturated, partially saturated or aromatic 4-6 membered heterocycle containing from 1 to 4 heteroatoms independently selected from the group S, N and O, where each of the mentioned carbocyclic or heterocyclic fragments may be optionally substituted with one, two, three, four or five substituents, each independently selected from halogen, hydroxy, mercapto, C _1-6 alkyl, hydroxyC _1-6 alkyl , aminoC _1-6 alkyl, mono- or di(C _1-6 alkyl)aminoC _1-6 alkyl, formyl, C _1-6 alkylcarbonyl, C _3-7 cycloalkyl, C _1-6 alkyloxy, C _1-6 alkyloxycarbonyl, C _1-6 alkylthio, cyano, nitro, polyhaloC _1-6 alkyl, polyhaloC _1-6 alkyloxy, aminocarbonyl and -CH(=N-O-R ⁸ );

R ⁸ is hydrogen, C _1-4 alkyl, aryl or arylC _1-4 alkyl.

Each of R ⁹ and R ¹⁰ independently represents hydrogen; cyano, aminocarbonyl, hydroxy; C _1-6 alkyl; C _1-6 alkyloxy; C _1-6 alkylcarbonyl; C _1-6 alkyloxycarbonyl; amino; mono- or di(C _1-6 alkyl)amino; mono- or di(C _1-6 alkyl)aminocarbonyl; -CH(=NR ¹¹ )

or R ⁷ , where each of the above C _1-6 alkyl groups may optionally, hiding each, be substituted with one or two substituents each independently selected from hydroxy, C _1-6 alkyloxy, hydroxyC _1-6 alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, cyano, amino, aminocarbonyl, imino, mono- and di(C _1-4 alkyl)amino, polyhalomethyl, polyhalomethyloxy; polyhalomethylthio, S(=O) _p R ⁸ , -NH-S(=O) _p R ⁸ , -C(=O)R ⁸ , -NHC(=O)H, -C(=O)NHNH ₂ , NHC (=O)R ⁸ , C(=NH)R ⁸ , R ⁷

where the substituents R1, Rb are each independently selected from the group consisting of: COO-isobutyl, OH, CN, NH ₂ , C _1-4 -alkoxy, C _1-4 alkyl, 4-6-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from the group S, N and O, wherein said heteroaryl is unsubstituted or substituted with CN, NH ₂ , OH, C _1-6 alkyl, O or R ^c ; BOC, COOH, R ^c , C _3-6 aryl, optionally substituted with CN, NH ₂ , OH, O or OCH ₂ C≡CH, 4-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, S and O , O, N, SC _1-6 -alkyl, halogen, NR ⁹ R ¹⁰ , -C(=O)-NR ⁹ R ¹⁰ , -C(=O)-C _1-6 alkyl.

R ^c is NHCOO-C _1-6 -alkyl,

n can take values from 1 to 3.

In another embodiment, the present invention provides a compound according to claim 1 wherein R1 is independently selected and is H, CN, CN-CH=CH, C=O, CH=CH-COOH, a 4-6 membered heterocyclyl containing 1 -2 O heteroatoms;

R ^b is chosen independently and is:

-N,

substituted or unsubstituted -C ₁ -C ₆ -alkyl, substituted or unsubstituted -C ₁ -C ₆ -alkenyl, substituted or unsubstituted -C ₃ -C ₆ -aryl,

substituted or unsubstituted -5-6-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from N, S and/or O,

substituted or unsubstituted -C ₃ -C ₉ -cycloalkyl, or

substituted or unsubstituted 4-9 membered heterocyclyl containing 1 to 4 heteroatoms independently selected from N, S and/or O,

Wherein said Rb substituents are each independently selected from the group consisting of:

COO-isobutyl,

_NH2 ,

CN,

C1-4-alkoxy,

4-6-membered heteroaryl containing from 1 to 4 heteroatoms independently selected from the group S, N and O, while the specified heteroaryl is unsubstituted or substituted by OH, C _1-6 -alkyl, O or Rc;

WOC; COOH;

R ^c ;

C _3-6 -aryl, possibly substituted by OH, O or OCH ₂ C≡CH,

4-6 membered heterocyclyl containing 1-2 heteroatoms selected from N and

O,

Ο,Ν,

SC _1-6 -alkyl, halogen,

The remaining substituents are defined in the present invention.

In another embodiment, the present invention relates to a compound of the present invention wherein R ¹ is independently selected and is H, -CN, -CH=CH-CN, -C=O, or -CH=CH-COOH.

In another embodiment, the present invention provides a compound of the present invention wherein R ¹ is independently selected and is a 4-6 membered heterocyclyl containing 1-2 O heteroatoms.

In another embodiment, the present invention provides a compound of the present invention wherein R ¹ is oxetane, tetrahydrofuran or tetrahydropyran.

In another embodiment, the present invention relates to the compound of the present invention, in which Υ ¹ represents -O-, -S-, -S(=O)- or -S(=O) ₂ -.

In another embodiment, the present invention provides a compound of the present invention wherein Y1 is a substituent of the form:

or

In another embodiment, the present invention provides a compound of the present invention wherein Y ¹ is a substituent of the form:

In another embodiment, the present invention provides a compound of the present invention wherein Rb is substituted or unsubstituted methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, sec-butyl, t-butyl, or pentyl, wherein the substituents are defined in the present invention.

In another embodiment, the present invention provides a compound of the present invention wherein Rb is substituted or unsubstituted ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2 -methyl-2-propenyl, where the substituents are defined in the present invention.

In another embodiment, the present invention relates to the compound of the present invention, in which Rb represents a substituted or unsubstituted phenyl, where substituents are defined in the present invention.

In another embodiment, the present invention provides a compound of the present invention wherein Rb is substituted or unsubstituted thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl, benzo[b]thienyl, isobenzofuranyl, isoindolyl, benzimidazolyl, where substituents are defined in the present invention.

In another embodiment, the present invention provides a compound of the present invention wherein Rb is substituted or unsubstituted cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octanyl, spiro[5.5]undecanyl, wherein the substituents are as defined herein.

In another embodiment, the present invention provides a compound of the present invention wherein Rb is a substituted or unsubstituted pyrimidine, piperidine, azetidine, morpholine, piperazine, pyrrolidine, tetrahydropyran, furan, pyrrole, pyrazine, imidazole, or pyrazole.

In another embodiment, the present invention provides a compound of the present invention wherein Y ¹ is a substituent of the form:

a Rb представляет собой замещенный или незамещенный -5÷6-членный-гетероарил или гетероциклил, содержащие от 1 до 4 гетероатомов, независимо выбранных из N, S и/или О, где заместители определены в настоящем изобретении.

a Rb is a substituted or unsubstituted -5÷6-membered heteroaryl or heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and/or O, where the substituents are defined in the present invention.

In another embodiment, the present invention provides a compound of the present invention wherein Y ¹ is a substituent of the form:

a Rb представляет собой замещенный или незамещенный -С₃-С₆-арил или замещенный или незамещенный -С₃-С₉-циклоалкил, где заместители определены в настоящем изобретении.

a Rb is substituted or unsubstituted -C ₃ -C ₆ -aryl or substituted or unsubstituted -C ₃ -C ₉ -cycloalkyl, where the substituents are defined in the present invention.

In another embodiment, the present invention relates to a compound selected from:

4-((4-(2,6-dimethylphenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)amino)-benzonitrile

4-(2,6-dimethylphenoxy)-N-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

4-(((6-Benzyl-4-(4-cyano-2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)methyl ethyl ester ) benzoic acid

4-(((6-Benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)methyl)benzoic acid ethyl ester

4-(((7-Benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile

N-(1-benzylpiperidin-4-yl)-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydroquinazolin-2-amine

N-(1-benzylpiperidin-4-yl)-4-(2,6-dimethylphenoxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-amine

4-((2-((4-cyanophenyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

4-((4-(4-Formyl-2,6-dimethylphenoxy)-7-methyl-5,6,7,8-tetrahydro[3,4-d]pyrimidin-2-yl)amino)benzonitrile

tert-Butyl 4-(4-(1,3-dioxalan-2-yl)-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4, 5-d]azepine-7(6Н)-carboxylate

tert-Butyl 2-((4-cyanophenyl)amino)-4-(4-formyl-2,6-dimethylphenioxy)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H) -carboxylate

tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

4-((2-((4-Cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5- dimethylbenzonitiryl

Ethyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5Н)-carboxylate

(E)-3-(4-((7-(tert-Butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d] azepin-4-yl)oxy)-3,5-dimethylphenyl)acrylic acid

tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H) -carboxylate

4-((2-((4-Cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

tert-Butyl 2-((4-cyanophenyl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimido[4,5-d]azepin- 7(6H)-carboxylate

4-((2-((4-Cyanophenyl)amino)-7-picolinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-isonicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-nicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(pyridin-3-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(pyridin-4-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

tert-Butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d ]azein-7-carbonyl)piperidine-1-carboxylate

4-((2-((4-Cyanophenyl)amino)-7-(piperidine-4-carbonyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile

tert-Butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7 (6H)-yl)piperidine-1-carboxylate

4-((2-((4-Cyanophenyl)amino)-7-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile

4-((6-(2-Aminoacetyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3, 5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-6-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 4-yl)oxy)-3,5-dimethylbenzonitrile

4-({2-[(4-cyanophenyl)amino]-6-[2-(morpholin-4-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-4- yl}oxy)-3,5-dimethylbenzonitrile

4-({2-[(4-cyanophenyl)amimo|-6-[2-(4,4-difluoropiperidin-1-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3-d] pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(cyclopropanecarbonyl)-5,6,7,8-tetrahydro-[4,3-d]pyrimidin-4-yl)oxy)-3.5 -dimethylbenzonitrile

4-({2-[(4-cyanophenyl)amino]-6-(morpholine-4-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)- 3,5-dimethylbenzonitrile

4-({2-[(4-cyanophenyl)amino]-6-(4-methylpiperazin-1-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy )-3,5-dimethylbenzonitrile

tert-Butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine -7-carbonyl)pyrrolidine-1-carboxylate

(R)-tert-Butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5 -d]azepine-7-carbonyl)pyrrolidine-1-carboxylate

(S)-tert-Butyl 2-(4-(4-Cyano-2,6-dimethyphenoxy)-2-((cyanophenyl)amino)-6,7.8,9-tetrahydro-5H-pyrimido[4,5-d ]azepine-7-carbonyl)pyrrolidine-1-carboxylate

4-((2-((4-Cyanophenyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine -4-yl)oxy)-3,5-dimethylbenzonitrile

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(5-methylfuran-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d] azepin-4-yl)oxy)-315-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(1-methyl-1H-pyrrol-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5 -d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(4-hydroxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(1-methoxypropan-2-yl)'b,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-4 -yl)oxy)-3,5-dimethylbenzonitrile

tert-Butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6 -carbonyl)pyrrolidine-1-carboxylate

4-((2-((4-Cyanophenyl)amino)-6-(pyrrolidin-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile

4-((6-(Azetidine-3-carbonyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydr®pyrido[4,3-d]pyrimidin-4-yl)oxy )-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-6-(pyrazine-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)okei)- 3,5-dimethylbenzonitrile

(S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-1-oxopropan-2-yl)carbamate

(S)-4-((6-(2-Aminopropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy )-3,5-dimethylbenzonitrile

(S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-1-oxo-3-phenylpropan-2-yl)carbamate

(S)-4-((6-(2-Amino-3-phenylpropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4 -yl)oxy)-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(2-morpholinoethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile

(R)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate

tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cranophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H) -yl)-4-(methylthio)-1-oxobutan-2-yl)carbamate

4-({6-[2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-[(4-cyanophenyl)amino]-5H,6H,7H,8H-pyrido[4,3- d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

4-((6-(2-Amino-3-(1H-pyrazol-4-yl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

tert-Butyl 4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido [4,3-d]pyrimidin-6(5H)-yl)-3-oxopropyl)-1H-pyrazole-1-carboxylate

(R)-4-((6-(2-Amino-3-hydroxypropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4 -yl)oxy)-3,5-dimethylbenzonitrile

(S)-Tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)carbamate

(S)-4-((6-(2-Amino-3-(4-hydroxyphenyl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

(S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-3-methyl-1-oxobutan-2-yl)carbamate

(R)-4-((6-(2-Amino-3-methylbutanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4 -yl)oxy)-3,5-dimethylbenzonitrile

(R)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-4-methyl-1-oxopentan-2-yl)carbamate

(8)-4-((6-(2-Amino-4-methylpentanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4 -yl)oxy)-3,5-dimethylbenzonitrile

(S)-Di-tert-butyl (6-(4-(4-cyano-2,6-dshetylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d] pyrimidin-6(5H)-yl)-6-oxohexane-1,5-diyl)dicarbamate

(S)-4-((2-((4-Cyanophenyl)amino)-6-(2,6-diaminohexanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyridin-4-yl )hydroxy)-3,5-dimethylbenzonitrile

4-((7-(2-Chloroacetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile

Methyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-4-cyanophenyl)amino)-8,9-dihydro-5Н-pyrimido[4,5-d]azepin-7(6Н) -carboxylate

4-((2-((4-Cyanophenyl)amino)-7-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)- 3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-6-(pyridin-4-yl)acetyl)-516,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-6-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-6-(2-hydroxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3, 5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-6-(2-(prop-2-yn-1-yloxy)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d] pyrimidin-4-yl)oxy)-3,5-dimethylylbenzonitrile

3-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H) -yl) propanoic acid

4-((7-Allyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile

4-((7-Acetyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile

4-((7-(2-(1H-Imidazol-1-yl)acetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5- Azepin-4-yl) oyuei)-3,5-dimethylbenzonitrile

4-((2-((4-Cyanophenyl)amino)-7-(2-(methyl-1H-imidazol-1-yl)acetyl)-6,7,8,9-tetrahydro-5H-pyrimido[4, 5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-5Н,6Н,7Н,8Н-pyrido[4,3-d]pyrimidine-6-sulfonamide

methyl 2-{2-[(4-cyanopheNIp)amino]-4-(4-formyl-2,6-dimethylphenoxy)-5H,6H,7H,8H,9H-pyrimido [4,5-d]azepine-7 -yl}-2-oxoacetate

4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-(oxan-4-yl)-4aH,5H,6H,7H,8H,8aH-pyrido [4,3 -d]pyrimidine-6-carboxamide.

In another embodiment, the present invention relates to a compound of the present invention, which includes at least one isotope.

In another embodiment, the present invention provides a compound of the present invention in free base form.

or a pharmaceutically acceptable salt selected from the group consisting of salts of the amino group formed with inorganic acids such as hydrochloric, hydrobromic, phosphoric, sulfuric and perchloric acids, or formed with organic acids such as acetic, oxalic, maleic, tartaric, succinic or malonic acids,

or pharmaceutically acceptable salts: adipinate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, gansulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate , hexanate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropioate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanate, valeriate,

or a pharmaceutically acceptable salt containing alkali and/or alkali metal or non-toxic ammonium, quaternary ammonium and amine cations,

or pharmaceutically acceptable com prepared using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

In another embodiment, the present invention provides a compound of the present invention for use as a reverse transcriptase inhibitor.

In another embodiment, the present invention relates to a compound of the present invention for use as a drug having antiviral activity against HIV.

In another embodiment, the present invention provides a compound of the present invention for the preparation of a medicament having antiviral activity against HIV.

In another embodiment, the present invention relates to a pharmaceutical composition having reverse transcriptase activity, comprising a compound of the present invention in a therapeutically effective amount and at least one carrier, excipient or diluent.

In another embodiment, the present invention relates to a pharmaceutical composition for the treatment or prevention of HIV, comprising at least one compound of the present invention in a therapeutically effective amount and at least one carrier, excipient or diluent.

In another embodiment, the present invention relates to a pharmaceutical composition having activity against HIV reverse transcriptase, comprising a compound of the present invention in a therapeutically effective amount, and at least one compound selected from the group including HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside inhibitors reverse transcriptase, CCR5 antagonists and inhibitors of viral entry into the cell.

In another embodiment, the present invention provides a pharmaceutical composition having activity against HIV reverse transcriptase, wherein the HIV reverse transcriptase contains at least one mutation compared to wild-type HIV, comprising a compound of the present invention in a therapeutically effective amount.

In another embodiment, the present invention relates to a pharmaceutical composition having activity against HIV reverse transcriptase, wherein the HIV reverse transcriptase has reduced sensitivity to efavirenz, nevirapine, doravirine, or delavirdine, comprising a compound of the present invention in a therapeutically effective amount.

In another embodiment, the present invention relates to a pharmaceutical composition for obtaining funds. For the treatment or prevention of HIV, comprising at least one compound of the present invention in a therapeutically effective amount and a pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to the use of a compound of the present invention for the preparation of an agent for the treatment or prevention of HIV.

In another embodiment, the present invention relates to the use of a composition of the present invention for the preparation of an agent for the treatment or prevention of HIV.

In another embodiment, the present invention provides a method for treating or preventing HIV, comprising the use of a compound of the present invention.

In another embodiment, the present invention relates to a method of treating or preventing HIV, comprising the use of a composition of the present invention.

In another embodiment, the present invention provides a method for treating or preventing an HIV infection, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention.

In another embodiment, the present invention relates to said method of treatment or prophylaxis, wherein said therapeutically effective amount of a compound means a daily dose that is from about 0.1 to about 500 mg/kg of body weight when administered parenterally.

In another embodiment, the present invention relates to the specified method of treatment or prevention, in which the daily dose can be administered as a single dose or 1-5 divided doses.

In another embodiment, the present invention relates to a combination for the treatment or prevention of HIV-mediated diseases, comprising a therapeutically effective amount of a compound of the present invention and at least one compound selected from the group including HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists and inhibitors of viral entry into the cell.

In another embodiment, the present invention relates to a method for treating or preventing an HIV-related disease, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention and at least one compound selected from the group consisting of HIV protease inhibitors. , nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists, and viral entry inhibitors.

In another embodiment, the present invention provides a method for inhibiting HIV reverse transcriptase in an HIV-infected subject, comprising administering to the subject in need of treatment a therapeutically effective amount of a compound of the present invention.

In another embodiment, the present invention relates to a method for preparing a pharmaceutical composition of the present invention, which includes mixing the compounds of the present invention with pharmaceutically acceptable carriers.

The term "as defined above" means the broadest definition of each group specified in the Summary of the Invention or in the broadest claim or in this specification. In the other embodiments below, each embodiment has substituents that do not necessarily retain the most general scope specified in the Summary of the Invention or in the present specification.

Unless otherwise indicated, the technical and scientific terms used in the description of the present invention have the meanings known to the person skilled in the art to which the invention pertains. The description includes references to various techniques and materials known to the person skilled in the art. Goodman and Gilman, The Pharmacological Basis of Therapeutics, 13th ed., McGraw Hffl Companies Inc., New York (2017) is the standard document that addresses the general patterns of pharmacology. In the implementation of the present invention can be used in any suitable materials and/or methods known to the person skilled in the art. However, the description of the present invention describes the preferred materials and methods. Materials, reagents, etc., mentioned in the description and in the examples are commercial preparations, unless otherwise indicated.

As used herein, the term "compound of the present invention" or "compound of the present invention" refers to at least one compound mentioned in the present invention, as well as any combination thereof, including double combination, ternary combination, etc.

In the description of the invention, for example, in any section of the application or in the claims, the terms "include(s)" and "comprising" have their conventional meaning. Those. the terms roughly correspond to "comprising at least" or "comprising at least". In relation to the method, the term "comprising" means that the method includes at least the mentioned stages. With respect to a compound or composition, the term "comprising" means that the compound or composition includes at least the indicated features or components, but may also include additional features or components.

The term "approximately" as used in the description of the application means approximately, about, example"© or approximately. The term "approximately" used in connection with a numerical interval means that the maximum and minimum values of the interval have the specified values. In general, the term "approximately" is used to indicate the allowable changes in the numerical value above and below the specified value by 20%.

As used in the description, the indication of a range of numerical values is intended to mean that the invention can be used at any value within the specified range. Thus, a variable that is discrete in nature can have any integer value within a specified interval, including the end values of the interval. Similarly, a variable that is continuous in nature may have any actual value within a specified interval, including the end values of the interval. For example, a variable that is described as having values from 0 to 2 could mean 0, 1, or 2 if it is a discrete value, and could have values of 0.0, 0.1, 0.01, 0.001, or any other actual values if it is a continuous variable.

If any group (for example, R1) is contained in the fragment or in any of the specified formula or in any of the described compounds more than once, and the described compounds are used or claimed in the present invention, then its meaning in each case is independent. In addition, combinations of substituents and/or variables are only allowed if the resulting compounds are stable compounds.

In one embodiment, the present invention provides a compound of formula I, where R1, X ¹ , X2, Y are as defined above. The terms "as defined above" and "as indicated above" mean variables included by reference in the broadest definition of variables specified in the Summary of the Invention or in the broadest claim.

In another embodiment, the present invention provides a compound which is the free base or pharmaceutically acceptable salt of a compound of the present invention.

In another embodiment, the present invention provides a method for treating an HIV infection or preventing an HIV infection, which comprises administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, wherein R1, X ¹ , X2, Y1 are as defined above. .

In another embodiment, the present invention provides a method for the treatment or prevention of HIV-related diseases, which consists in the fact that the subject in need of treatment is administered a therapeutically effective amount of a compound of formula I, where R1, X ¹ , X2, Y1 have the meanings indicated above, and at least one compound selected from the group consisting of HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists, and viral entry inhibitors.

In another embodiment, the present invention provides a method for inhibiting HIV reverse transcriptase in an HIV-infected subject, comprising administering to the subject in need of treatment a therapeutically effective amount of a compound of formula I, wherein R1, X ¹ , X2, Y1 are above.

In another embodiment, the present invention provides a method for inhibiting HIV reverse transcriptase in an HIV-infected subject, wherein the HIV reverse transcriptase contains at least one mutation compared to wild-type HIV, which is that the subject in need of treatment is administered therapeutically an effective amount of a compound of formula I, wherein R1, X ¹ , X2, Y1 are as defined above.

In another embodiment, the present invention provides a method for inhibiting HIV reverse transcriptase in an HIV-infected subject, wherein the HIV reverse transcriptase has reduced sensitivity to efavirenz, nevirapine, or delavirdine, in that a therapeutically effective amount is administered to the subject in need of treatment. compounds of formula I, where R ¹ , X ¹ , X ² , Y ¹ have the meanings given above.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula I, where R ¹ , X ¹ , X ² , Y ¹ are as defined above, and at least one carrier, excipient or diluent.

The following definitions apply in this document unless otherwise stated. In addition, unless otherwise indicated, all occurrences of functional groups are chosen independently, two occurrences can be either the same or different.

The term "alkyl", by itself or as part of another substituent, refers to straight or branched chain saturated hydrocarbon groups, including hydrocarbon groups having the number of carbon atoms indicated (i.e. C _1-6 -alkyl means from one to six carbon atoms) . Examples of alkyls include methyl, ethyl, n-propyl, isopropyl.

The term alkynyl, by itself or as part of another substituent, refers to hydrocarbon groups in which at least one carbon-carbon bond is a triple bond, while the remaining bonds may be single, double or additional triple bonds, including hydrocarbon groups, from 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, and so on.

The term "alkenyl", by itself or as part of another substituent, refers to hydrocarbon groups in which at least one carbon-carbon bond is a double bond, while the remaining bonds may be either single bonds or additional double bonds, including hydrocarbon groups containing from 2 to 6 atbm of carbon. Examples of alkenyl groups include ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and the like.

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

The terms "carboxyl", "carboxy", or "hydroxycarbonyl" refer to the -COOH group.

The terms "alkoxy" and "alkyloxy" by themselves or in phrases refer (unless otherwise indicated) to aliphatic radicals of the form alkyl-O-, in which alkyl is defined above. Illustrative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, isopentoxy, neopentoxy, t-pentoxy, hexoxy -, isohexoxy, heptoxy, octoxy, and the like. Preferred alkoxy groups are methoxy and ethoxy.

Monocyclic, bicyclic or tricyclic saturated carbocycle is a cyclic system consisting of 1, 2 or 3 cycles, and the specified cyclic system consists of only carbon atoms and the specified cyclic system contains only single bonds; monocyclic, bicyclic or tricyclic partially saturated carbocycle is a cyclic system consisting of 1, 2 or 3 cycles, and the specified cyclic system consists of only carbon atoms and includes at least a double bond, provided that the cyclic system is not an aromatic ring system ; monocyclic, bicyclic or tricyclic aromatic carbocycle is an aromatic ring system consisting of 1, 2 or 3 cycles, and the specified ring system consists of only carbon atoms; the term "aromatic" is very well known to those skilled in the art and means cyclic conjugated systems containing 4n+2 electrons, i.e. 6, 10, 14, etc. r electrons (Hückel's rule); monocyclic, bicyclic or tricyclic saturated heterocycle is a cyclic system consisting of 1, 2 or 3 cycles and including at least one heteroatom selected from O, N or S, and the specified cyclic system contains only simple bonds; monocyclic, bicyclic or tricyclic partially saturated heterocycle is a cyclic system consisting of 1, 2 or 3 cycles and comprising at least one heteroatom selected from O, N or S and at least one double bond, provided that the cyclic the system is not an aromatic ring system; a monocyclic, bicyclic or tricyclic aromatic heterocycle is an aromatic ring system consisting of 1, 2 or 3 cycles and containing at least one heteroatom selected from O, N or S.

Specific examples of monocyclic, bicyclic or tricyclic saturated cariocycles are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4.2.0]-octanyl, cyclononanyl, cyclodecanyl, decahydronaphthalenyl, tetradecahydroanthracenyl, and the like. Preferred are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, more preferred are cyclopentyl, cyclohexyl, cycloheptyl.

Specific examples of monocyclic, bicyclic or tricyclic partially saturated carbocycles are cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[4,2,0]octenyl, cyclononenyl, cyclodecenyl, octahydronaphthalenyl, 1,2,3,4-tetrahydronaphthalenyl, 1 ,2,3,4,4a,9,9a,10-octahydroanthracenyl and the like.

Specific examples of monocyclic, bicyclic or tricyclic aromatic carbocycles are phenyl, naphthalenyl, anthracenyl. Preferred is phenyl.

Конкретными примерами моноциклических, бициклических или трициклических насыщенных гетероциклов являются тетрагидрофуранил, пирролидинил, диоксоланил, имидазолидинил, тиазолидинил, тетрагидротиенил, дигидрмивйзолил, изотиазолидинил, изоксазолидинил, оксадиазолидинил, триазолидинил, тиадиазолидинил, пиразолидинил, пиперидинил, гескагидропиримидинил, гексагидропиразинил, диоксанил, морфолинил, дитианил, тиофорфолинил, piperazinyl, trithianyl, decahydroquinolinyl, octahydroindolyl, and the like. Preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, dihydrooxazolyl, triazolidinyl, piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl. Especially preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl.

Specific examples of monocyclic, bicyclic and tricyclic partially saturated heterocycles are pyrrolinyl, imidazolinyl, pyrazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxoli-1,2,3-dihydro-1,4-benzodioxinyl, indolinyl and the like. Preferred are pyrrolinyl, imidazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benavedioxolyl, indolinyl.

Specific examples of monocyclic, bicyclic, or tricyclic aromatic heterocycles are azetyl, oxetylidene, rsrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiaeolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, пиранил, сензофурил, изобензофурил, бензотиенил, изобенэотиенил, индолизинил, индолил, изоиндолил, бензоксазолил, бензимидазолил, индазолил, бензизоксазолил, бензизотиазолил, бензопиразолил, бензоксадиазолил, бензотиадиазолил, бензотриазолил, пуринил, хинолинил, изохинолинил, циннолинил, хинолизинил, фталазинил, хиноксалинил, хиназолинил, naphthyridinyl, pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, isoxazolopyrazinyl, isoxazolopyrazinyl, isoxazolopyrazinyl азинил, имидазопиразинил, пирролопиримидинил, тиенопиримидинил, фуропиримидинил, изотиазолопиримидинил, тиазолопиримидинил, изоксазолопиримидинил, оксазолопиримидинил, пиразолопиримидинил, имидазопиримияинил, пирролопиридазинил, тиенопиридазинил, фуропиридазинил, изотиазолопиридазинил, тишолопиридазинил, изоксазолопиридазинил, оксазолопиридазинил, пиразолопиридазинил, имидазопиридазинил, оксадиазолопиридил, тиадиазолопиридил, триазолопиридил, оксадиазолопиразинил, тиадиазолопиразинил, триазолопиразинил, оксадиазогнэпиримидинил, тиадиазолопиримидинил, триазолопиримидинил, оксадиазолопиридазинил, тиадиазолопиридазинил, триазолопиридазинил, имидазосазолил, имидазотиазолил, имидазоимидазолил, изоксазолотриазинил, изотиазолотриазинил, пиразолотриазинил, оксазолотриазинил, тиазолотриазинил, имидазотриазинил, оксадиазолотриазинил, тиадиазолотриазинил, триазолотриазинил, карбазолил, акридинил, феназинил, фенотиазинил, феноксазинил и т. P.

Preferred aromatic heterocycles are monocyclic or bicyclic aromatic heterocycles. Monocyclic, bicyclic or tricyclic aromatic heterocycles of interest are pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, изобензофурил, бензотиенил, изобенэотиенил, индолил, изоиндолил, бензоксазолил, бензимидазолил, индазолил, бензизоксазолил, бензизотиазолил, бензопиразолил, бензоксадиазолил, бензотиадиазолил, бензотриазолил, пуринил, хинолинил, изохинолинил, фталазинил, хиноксалинил, хиназолинил, бензопиранил, гпирролопиридил, тиенопиридил, фуропиридил, изотиазолопиридил, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrayulopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, изотиазолопиримидинил, тиалопиримидинил, изоксазолопиримидинил, оксазолопиримидинил, пиразолопиримидинил, имидазопиримидинил, оксадиазолопиридил, тиадиазолопиридил, триазолониридил, оксадиазолопиразинил, тиадиазолопиразинил, триазолопиразинил, оксадиазолопиримидииил, тиадиазолопиримидинил, триазолопиримидинил, карбазолил, акридинил, фенотиазинил, феноксазинил и т.п.

The term "cycloalkyl" as used herein refers to groups having from 3 to 12 carbon atoms in a mono- or polycyclic structure, including spirocycles. By way of illustration, cycloalkyls include, but are not limited to, the following radicals: cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octanyl, spiro[5.5]undecanyl, which, as with other aliphatic or heteroaliphatic or heterocyclic substituents, may be substituted.

The term "heterocycle", "heterocyclyl" or "heterocyclic" means herein non-aromatic mono- or polycyclic systems (saturated or partially unsaturated) having from three to twelve atoms containing N, O or S heteroatoms. The heterocycle may be attached to the basic fragment of the molecule through a nitrogen atom (N-heterocyclyl) or through a carbon atom. The heterocycles may also be substituted. In particular, the heterocycle may be, without limitation, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, 1,1 -dioxo-thiomorpholin-4-yl, azepanil, diazepanil, homopiperazinyl, oxazepanil, 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-azabicyclo [3.3.1]nonyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, or 3-thia-9-azabicyclo[3.3.1]nonyl. Specific examples of heterocycles are also dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydro-pyridinyl, dihydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and 2-oxa-5-aza-bicyclo[2.2.1]heptyl. The term "cycloalkenyl" means in this document a partially unsaturated cycloalkyl containing from 5 to 12 carbon atoms, having in its composition from one to two double carbon-carbon bonds.

The term "aryl" as used herein means groups containing an aromatic ring having five to ten carbon atoms. Examples of aryl cyclic groups are phenyl and naphthyl.

The term "heteroaryl", "heteroaryl ring" as used herein means a stable heterocyclic and polyheterocyclic aromatic moiety having 5-10 ring atoms. The heteroaryl group may be substituted or unsubstituted and may consist of one or more rings. Possible substituents include, among other things, any of the previously mentioned substituents. Exemplary heteroaryl rings are five- and six-membered monocyclic groups such as thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl, and the like; as well as polycyclic heterocyclic groups such as benzo[b]thienyl, isobenzofuranyl, isoindolyl, benzimidazolyl, and the like. The term "heteroaryl" can be used equivalently with the terms "heteroaryl ring" or "heteroaromatic".

An aryl group or a heteroaryl group (including the heteroaryl portion of heteroaralkyl or heteroaralkoxy moieties and the like) may have one or more substituents. Examples of a suitable substituent on an unsaturated carbon atom of an aryl or heteroaryl group include, but are not limited to, halogen (F, Gl, Br, or I), C _1-3 -alkyl, -CN, -OH, -C _1-3 -alkyl, and others. , as indicated in the present invention.

Carbocycles or heterocycles referred to in the definition of R ⁷ or R ^7a may be attached to the remainder of the molecule of formula (I) through any suitable cyclic carbon atom or heteroatom, unless specifically indicated otherwise. Thus, for example, if the heterocycle is imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, etc., or if the carbocycle is naphthalenyl, it may be 1-naphthalinyl, 2-naphthalinyl, etc. .d.

If any of the substituents (eg R ⁷ ) occurs more than once in the same compound, each of the definitions of that substituent is independent.

The term "substituted" shall mean that one or more hydrogen atoms on the atom or group referred to as "substituted" is replaced by any of the listed groups, provided that said atom is of normal valency, or that the valency of the corresponding group atom being substituted is not redundant, and that substitution leads to a stable connection©. The term "substituted or unsubstituted" means that the compound or substructure is either unsubstituted or substituted, as defined in the application, with one or more substituents, as mentioned or as defined below.

As used herein, alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, and heteroaryl groups, as well as other substructures containing at least one hydrogen atom, may be substituted with one or more substituents:

-F, -Cl, -Br, -CN, -OH, -NO ₂ , -NH ₂ , -CF ₃ , -CHF ₂ , -CH ₂ F, -C ₁ -C ₄ -alkyl, -C ₂ -C ₄ -alkenyl, -C ₂ -C ₄ -alkynyl, -C ₃ -C ₉ -cycloalkyl, -4 + 9-membered heterocyclyl attached through C or N-atoms, -phenyl, -5 + 6-membered heteroaryl , attached through C or N-atoms, -OR ^z , -N(R ^z ) ₂ , -NRz-C(=O)-R ^z , -NR ^z -S(=O) ₂ -R ^z , -SR ^z , -C(=O)-R ^z , -C(=O)-OR ^z , -C(=O)-N(R ^z ) ₂ , -OC(=O)-R ^z , -OC(=O )-(NR ^z ) ₂ , -SO-N(R ^z ) ₂ , -SO ₂ -R ^z , in which each R ^{z is} independently selected and represents -H, -C ₁ -C ₆ -alkyl, -C ₃ -C ₉ -cycloalkyl, -5÷6-membered heteroaryl containing from 1 to 4 heteroatoms, independently selected from N, S and/or O, or substituted or unsubstituted 4+9-membered heterocyclyl containing from 1 to 4 heteroatoms;

Another group from which substituents may be selected is:

4-6-членный гетероциклил, содержащий 1-2 гетероатома, выбранных из N и О, О, атом азота, S-C_1-6-алкил, галоген. Данное изобретение содержит только такие комбинации заместителей и производных, которые образуют стабильное или химически возможное соединение. Стабильным или химически возможным соединением называется такое соединение, стабильности которого достаточно для его синтеза и аналитического детектирования. Предпочтительные соединения данного изобретения являются достаточно стабильными и не разлагаются при температуре до 40°С в отсутствие химически активных условий, в течение, по крайней мере, одной недели.COO-isobutyl, NH ₂ , CN, C _1-4 -alkoxy, 4-6 membered heteroaryl containing from 1 to 4 heteroatoms independently selected from the group S, N and O (17.18, 67.45, 60) , wherein said heteroaryl is unsubstituted or substituted with —OH, C _1-6 alkyl, O, or Rc; BOC, COOH, Rc, C _3-6 -aryl, optionally substituted by OH, O, or

4-6-membered heterocyclyl containing 1-2 heteroatoms selected from N and O, O, nitrogen atom, SC _1-6 -alkyl, halogen. This invention contains only such combinations of substituents and derivatives that form a stable or chemically possible connection. A stable or chemically possible compound is a compound whose stability is sufficient for its synthesis and analytical detection. Preferred compounds of this invention are sufficiently stable and do not decompose at temperatures up to 40°C in the absence of reactive conditions, for at least one week.

Some compounds of this invention may exist in tautomeric forms, and this invention includes all such tautomeric forms of such compounds, unless otherwise indicated.

For example, the compounds of the present invention may exist as tautomers 1-3 in dynamic equilibrium. Under normal conditions, their separation is impossible, therefore, the pharmacological properties of the compounds of the present invention are a combination of the effects of tautomers.

An example of tautomeric forms of the compounds of the invention is:

Unless otherwise indicated, the structures depicted here also include all stereoisomers, ie R- and S-isomers for each asymmetric center. In addition, individual stereochemical isomers, as well as enantiomers and diastereomeric mixtures of the present compounds, are also the subject of this invention. Thus, the present invention embraces each diastereomer or enantiomer substantially free of other isomers (>90% and preferably >95% molar purity), as well as a mixture of such isomers.

A particular 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 mixture of diastereomers by crystallization, followed by isolating the optically active bases from these salts. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric and camphorsulfonic acid. Another technique for separating optical isomers is to use a chiral chromatographic column. In addition, another separation method involves the synthesis of covalent diastereomeric molecules by reacting compounds of the invention with an optically pure acid in activated form or an optically pure isocyanate. The resulting diastereomers can be separated by conventional means, such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to obtain an enantiomerically pure compound.

Optically active compounds of this invention can be obtained using optically active starting materials. Such isomers may be in free acid, free base, ester or salt form.

The present invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention in which one or more atoms are replaced by atoms having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number normally found in nature.

Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen such as ² H and ³ H, carbon such as ¹¹ C, ¹³ C and ¹⁴ C, chlorine such as ³⁶ Cl, fluorine such as ¹⁸ F, iodine such as ¹²³ I and ¹²⁵ I, nitrogen such as ¹³ N and ¹⁵ N, oxygen such as 150, 170 and 180, phosphorus such as ³² P, and sulfur such as ³⁵ S.

Certain isotopically labeled compounds of the present invention, for example those containing a radioactive isotope, are used in drug and/or substrate tissue distribution studies. In particular, radioactive isotopes such as tritium, i.e. ³ H, and carbon-14, i.e. 14 C, are used for this purpose, due to the ease of their introduction and the availability of means for their detection.

Substitution with heavier isotopes such as deuterium, i.e. 2H, may provide certain therapeutic effects due to metabolic stability, such as increased in vivo half-life or reduced dosing rates, and therefore may be preferred in some cases.

The isotopically labeled compounds of the invention can be prepared by conventional methods known to those skilled in the art, or by methods analogous to those described in the accompanying synthetic method examples, using the appropriate isotopically labeled reagents in place of the previously unlabeled reagent.

Thus, the present invention also relates to the use of the compounds of the present invention for diagnostics, including drug distribution of the present invention or determination of targets having affinity for the compounds of the present invention, in particular isotopically labeled compounds of the present invention.

The term "wild type" as used herein means a strain of the HIV virus that has a dominant genotype, is present in the normal population and is resistant to reverse transcriptase inhibitors. The term "wild-type reverse transcriptase" as used herein means a reverse transcriptase expressed by a wild-type strain that has been sequenced and listed in the SwissProt database under number P03366.

The term "reduced sensitivity" as used herein means an approximate change in sensitivity of an isolate of a particular viral strain by a factor of 10 or more compared to that observed with a wild-type virus under similar experimental conditions.

Compounds of the present invention are obtained using the methods shown in the diagrams and described in the section The implementation of the invention. The starting materials and reagents used in the preparation of these compounds are commercial reagents supplied by companies such as Acros Organics, Alfa Aesar, Lancaster, Merck and Sigma-Aldrich and others, or they are obtained by known methods according to the methods described in the literature, such , as Fieser and Fieser, Reagents for Organic Synthesis, VWey & Sons: New York, vols. 1-21, R.C. LaRock, Comprehensive Organic Transformations, 2nd ed., Wiley-VCH, New York (1999), Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.), vols. 1-9 Pergamon, Oxford (1991), Comprehensive Heterocyclic Chemistry, A.R. Katritzky and C.W. R.ees (Eds) Pergamon, Oxford, vol. 1-9 (1984), Comprehensive Heterocyclic Chemistry II, A.R. Katritzky and C.W. Rees (Eds), Pergamon, Oxford, vols. 1-11 (1986); and Reaxis, but not limited to. The following reaction schemes are merely illustrative of some methods for the synthesis* of the compounds of the present invention, and various modifications of these reaction schemes can be developed and proposed by a person skilled in the art with reference to the materials of this application.

The starting materials and intermediates in these reaction schemes can be obtained and, if necessary, purified by appropriate methods, including, but not limited to, filtration, distillation, crystallization, chromatography, and the like. Such materials can be characterized by appropriate methods, including physical constants and spectral data.

Unless otherwise indicated, the reactions described in the application specification are preferably carried out under an inert gas atmosphere at atmospheric pressure at a temperature of from about -78°C to about 150°C, more preferably from about 0°C to about 125°C, and most preferably usually at room temperature, for example at about 20°C.

Some compounds in these schemes are presented with the inclusion of generalized substituents, however, for a specialist it is quite obvious that the nature of the groups R can vary in accordance with the structure of the various compounds of the present invention. In addition, the reaction conditions are typical and alternative conditions are also well known. It is understood that the sequence of reactions in the following examples does not limit the scope of the invention specified in the claims.

Pharmaceutically acceptable solvates according to the invention include those wherein the solvent may be isotopically substituted, eg D ₂ O, d6-acetone, d6-DMSO.

The term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvate-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

The term "hydrate" refers to a complex where the solvent molecules are water.

The compounds of the present invention may exist in free form or, if required, in the form of a pharmaceutically acceptable salt or other derivative. The term “pharmaceutically acceptable salt” as used herein refers to those salts which, within the scope of the Conducted Medical Decision, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reaction, etc., and meet a reasonable ratio of benefit. and risk. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts can be obtained in situ during the isolation or purification of the compounds of the invention, and can also be obtained separately by reacting the free acid or free base of the compound of the invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable non-toxic acid salts are amino 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, or obtained by others. methods used in this area, for example, using ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanate, hydroiodide, 2-hydroxy-tansulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nishginate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanate, valeriate and the like. Typical alkali and alkaline earth metal salts contain sodium, lithium, potassium, calcium, magnesium and others. In addition, pharmaceutically acceptable salts may contain, if desired, non-toxic ammonium, quaternary ammonium and amine cations derived from counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

The compounds of the present invention may exist as pharmaceutically acceptable esters. The term "pharmaceutically acceptable esters" refers to derivatives of the compounds of the present invention in which the carboxy group has been converted to an ether. Lower alkyl, lower hydroxyalkyl, lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono- or di-lower-alkyl-amino-lower-alkyl, morpholino-lower-alkyl, pyrrolidino-lower-alkyl, piperidino-lower -alkyl, piperazino-lower-alkyl, lower-alkyl-piperazino-lower-alkyl and aryl ethers are examples of suitable esters. Specific esters are methyl, ethyl, propyl, butyl and benzyl esters. The term "pharmaceutically acceptable esters" also encompasses compounds of the present invention in which the hydroxy groups have been converted to the corresponding esters with organic or inorganic acids such as nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like, which are non-toxic to living organisms.

If one of the starting materials or compounds of the present invention contains one or more functional groups that are not stable or reactive under the reaction conditions of one or more of the reaction steps, the corresponding protecting groups (as described, for example, in "Protective Groups in Organic Chemistry" by TW Greene and PGM ^Wutts , 3rd Ed., 1999, Wiley, New York) may be administered prior to the critical step using methods well known in the art. Such protecting groups can be removed at a later stage of the synthesis using standard methods described in the literature. Examples of protecting groups are tert-butoxycarbonyl (Boe), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teos), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

The compound of the present invention can contain several asymmetric centers and may be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, mixtures of diastereoisomers, diastereomeric racemates, or mixtures of diastereomeric racemates.

The term "asymmetric carbon atom" means a carbon atom with four different substituents. According to the Kahn-Ingold-Prelog rules, an asymmetric carbon atom can be in the "R" or "S" configuration.

Another embodiment of the present invention relates to pharmaceutical compositions or medicaments containing compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to obtain such compositions and medicaments. In one example, the compounds of the present invention can be prepared by mixing at room temperature, appropriate pH and at the desired degree of purity, with physiologically acceptable carriers, for example, carriers that are non-toxic to recipients in the doses and concentrations used, in a galenic form of administration. The pH of the composition depends primarily on the particular use and concentration of the compound, but may preferably range from about 3 to about 8. In another embodiment, the compounds of the present invention are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized preparation, or as an aqueous solution.

The compositions are formulated, dosed and administered in accordance with good medical practice. Factors considered herein include the particular disorder being treated, the particular mammal being treated, the clinical condition of the particular patient, the cause of the disorder, the site of delivery of the agent, route of administration, schedule of administration, and other factors known to practitioners.

The compounds of the invention may be administered by any suitable route, including orally, topically (including buccally and sublingually), rectally, vaginally, transdermally, parenterally, subcutaneously, intraperitoneally, intrapulmonaryly, intradermally, intrathecally and epidurally and intranasally. Parenteral infusions include intramuscular, intravenous, intra-arterial, intraperitoneal or subcutaneous administration.

The compounds of the present invention may be administered in any convenient administration form, such as tablets, powders, capsules, rasps, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, and the like. Such compositions may contain conventional pharmaceutical ingredients such as diluents, carriers, pH modifiers, sweeteners, excipients and other active agents.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, for example, Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Compositions may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, coating agents, glidants, processing aids, colorants, sweeteners , perfumes, flavors, diluents, and other known additives to provide an elegant presentation of a drug (eg, a compound of the present invention or a pharmaceutical composition thereof) or aid in the manufacture of a pharmaceutical product (eg, a drug).

Thus, the present invention also relates to:

A compound of the present invention for use as a therapeutically active substance;

A compound of the present invention for use as a reverse transcriptase inhibitor;

Compound of the present invention for use as a drug having antiviral activity against HIV

A pharmaceutical composition containing a compound of the present invention and a therapeutically inert carrier;

The use of a compound of the present invention for the treatment or prevention of HIV;

A pharmaceutical composition having activity against HIV reverse transcriptase, comprising a compound of the present invention in a therapeutically effective amount, and at least one compound selected from the group consisting of HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists, and inhibitors of viral entry into the cell;

The use of a compound of the present invention for the preparation of a medicament for the treatment or prevention of HIV;

A compound of the present invention for the treatment or prevention of HIV; and

A method of treating or preventing HIV which comprises administering an effective amount of a compound of the present invention to a patient in need thereof.

Modification of the compounds of the invention to render them more soluble in water or other carrier is achieved using fairly simple procedures (salt formation, esterification, etc.) that are well known to the person skilled in the art. In addition, one skilled in the art may modify the route of administration and course of treatment with a particular compound in order to regulate the pharmacokinetics of the compound of the invention in order to achieve maximum therapeutic effect on the patient.

The term "therapeutically effective amount", as used in the description of the application, means the amount necessary to reduce the intensity of the symptoms of the disease in the patient. The progression of HIV infection is recorded by measuring the viral load (RNA) or the level of T-cells. The dose is changed in accordance with individual requirements in each case. The dose may vary widely depending on a variety of factors such as the severity of the disease being treated, the age and relative health of the subject, the patient's use of other drugs, the route and form of administration, and the experience and skill of the attending physician. When administered orally, a suitable daily dose is from about 0.01 to about 100 mg/kg of body weight for single drug treatment and/or combination therapy. A preferred daily dose is from about 0.1 to about 500 mg/kg of body weight, more preferably from 0.1 to 100 mg/kg of body weight, and most preferably from 1.0 to about 10 mg/kg of body weight. Thus, for administration to a patient weighing 70 kg, the dose is from about 7 mg to about 0.7 g per day. The daily dose may be administered as a single dose or in 1-5 divided doses. Usually treatment begins with the introduction of doses not exceeding the optimal dose. Then the dose is gradually increased until the optimal effect on the individual patient is reached. Those skilled in the art, without much experimentation, based on their experience and the description of the present invention, can determine the therapeutically effective amount of the compounds of the present invention required for a given disease in a particular patient.

The active compound of the invention, or a salt thereof, may be administered in combination with another antiviral agent such as a nucleoside reverse transcriptase inhibitor or an HIV protease inhibitor. When the active compound or a derivative or salt thereof is administered in combination with another antiviral agent, the activity of the combination may exceed that of the parent compound. In combination therapy, such administration can be carried out simultaneously or sequentially with the administration of nucleoside derivatives. Therefore, the term "simultaneous introduction", as used in the description of the application, includes the introduction of agents at the same time or at different times. Two or more agents may be administered simultaneously in a single dosage form containing two or more active ingredients, or two or more dosage forms each containing a single active agent may be administered almost simultaneously.

References to treatment are intended to include prophylaxis as well as treatment of observed conditions. In addition, the term treatment of HIV infection as used herein also includes the treatment or prevention of a disease or condition associated with or mediated by HIV infection, or its clinical symptoms.

The pharmaceutical preparations are preferably unit dosage forms. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, where the package contains discrete amounts of the drug, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dose may be a capsule, tablet, cachet, or lozenge, or may be a package containing a specified amount of any of these forms.

Implementation of the invention

The invention is illustrated by the following non-limiting examples. The following examples and preparations are given to clarify the essence of the invention and to facilitate its practical application.

EXAMPLES

General Procedure for Substituting a Sulfo Group for an Activated Amine (Reaction XIX)

To a solution of formamide (3.9 mmol, 1 equiv.) in DMF (15 mL) was added NaH (7 mmol, 1.8 equiv.) at 0°С. The reaction mixture is stirred at room temperature. 20 minutes. The mixture is then cooled again to 0°C and the sulfone (3.9 mmol, 1.0 eq.) is added to it. The reaction mixture was stirred for 8 hours, then the organic solvent was evaporated, water was added to the residue (pH=9). The formed precipitate is filtered and washed with water. The precipitate is dissolved in methylene chloride and purified using chromatography using Hex:EA (1:1) as eluent.

General Procedure for Alkylation of Substituted Tetrahydropyrimidine Derivatives (Reaction XX)

Pyrimidine free base (1 mmol, 1 eq.) and alkyl bromide (1.1 mmol) are placed in a 50 ml round bottom flask equipped with an efficient reflux condenser with a calcium chloride tube. The mixture is boiled until the entire mass is solidified. The hydrobromide of the target product is formed. At the end of the reaction, cool the flask and pour in portions (while cooling to avoid strong heating) a solution of 1 g of sodium hydroxide in 20 ml of water. The separated product is separated in a separating funnel, chloride is added, the organic phase is washed with water, dried over anhydrous sodium sulfate. The organic solvent is removed under reduced pressure and the residue is purified using chromatography using Hex:EA (1:3) as eluent.

Example 1

Synthesis of 4-((7-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)benzonitrile

1-(tert-Butyl) 4-ethyl 3-oxopiperidine-1,4-dicarboxylate (27)

Hydrochloride 26 (59.6 g, 0.2 mol, 1 equiv.) was dissolved in ethanol (400 ml) and triethylamine (27.8 ml, 0.2 mol, 1 equiv.) was added, stirred for 5 minutes. Then 5% Pd/C (5 g) was added to the reaction mass. The reaction mixture is degassed and the debenzylation reaction is carried out in a hydrogen atmosphere. The reaction mixture was stirred for 3 days, then Boc ₂ O (43.6 g, 0.2 mol, 1 eq.) was added. The reaction is stirred for 3 hours, then passed through a pad of celite, cold water (250 ml) and methylene chloride (500 ml) are added. The organic layer is separated, washed twice with water (2×150 ml), dried over anhydrous sodium sulfate, the drying agent is filtered off, and the organic solvent is removed on a rotary evaporator under reduced pressure. The residue is purified by column chromatography using Hex:EA(3:1) as eluent. Rf=0.6.

Mass = 20 g.

Yield = 52%

tert-Butyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (28)

To a solution of sodium ethoxide obtained by dissolving Na (1.95 g, 81 mmol, 3.0 equiv.) in absolute ethanol (100 ml.) was added thiourea (3.22 g, 42 mmol, 1.5 equiv.) and ketoester (27) (7.67 g, 2 B.2 mmol, 1.0 equiv.). The reaction mixture was boiled for 8 hours, then the mixture was cooled to room temperature and Mel (1.76 ml, 28.2 mmol, 1 eq.) was added dropwise from a separating funnel with stirring. After completion of the addition of the alkylating agent, the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, the residue was dissolved in water. When the aqueous solution was acidified with citric acid to pH 3–4, a precipitate formed, which was filtered off, washed successively with water, hexane, ethyl acetate, and ether.

Weight = 7.8 g.

Yield = 85%

tert-Butyl 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate (29)

Pyrimidine 28 (5.69 g, 19.1 mmol, 1 eq.) was dissolved in 80 ml of DMF, then triethylamine (TEA) (2.66 ml, 19.1 mmol, 1 eq.) was added and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate ( RuBor) (9.9 g, 19.1 mmol, 1 eq.). The reaction mixture is stirred for 5 hours, then poured into ethyl acetate and the organic phase is washed with saturated sodium hydrogen carbonate solution. The organic layer was evaporated and purified by column chromatography using Hex:EA (3:1) as eluent.

Mass = 4.6 g.

Yield = 68%.

tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (30)

Pyrimidine 29 (4.1 g, 8.5 mmol, 1 equiv.) was dissolved in DMF (50 ml), then phenol 21 (1.24 g, 8.5 mmol, 1 equiv.) and cesium carbonate (2.76 g, 8.5 mmol, 1 equiv.) were added. . The reaction mixture is stirred for 8 hours, then poured into ethyl acetate and washed with water.

The organic layer was evaporated and purified by column chromatography using Hex:EA (3:1) as eluent.

Mass = 3.2 g.

Yield = 85%.

LCMS (M+H)=402

tert-Butyl 4-(4-iiano-2,6-dimethylphenoxy)-2-(methylsulfonyl)-5,8-dihydro-pyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (31)

To a solution of pyrimidine 30 (3.0 g, 7 mmol, 1 equiv.) in methylene chloride (50 ml) at 0°C was added m-chloroperbenzoic acid (mCPBA) (3.8 g, 21.1 mmol, 3 equiv.). The reaction mixture is stirred for 24 hours. Then add to the mixture to stop the reaction of a saturated aqueous solution of NaHCO ₃ . The resulting product is extracted with methylene chloride. The organic phase is evaporated on a rotary evaporator and purified using column chromatography using Hex:EA (1:1) as eluent.

Weight = 2.2 g

Yield = 54%

¹ H NMR (400 MHz, DMSO-d ₆ , δ, ppm): 1.46 (s, 9 H), 2.11 (s, 6 H), 2.98 (t, J=5A Hz, 2 H), 3.12 (s, 3 H), 3.76 (t, J=5.5 Hz, 2 H), 4.72 (br. s, 2 H), 7.72-7.78 (m, 3 H)

LCMS (M+H)=434

tert-Butyl 2-((4-cyanophenyl)amino)-4-(2,6-dimethylphenoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylate (32)

To a solution of formamide 32 (0.51 g, 3.9 mmol, 1 equiv.) in DMF (15 mL) was added NaH (0.28 g, 7 mmol, 1.8 equiv.) at 0°C. The reaction mixture is stirred at room temperature. 20 minutes. Then the mixture was again cooled to 0°С and sulfone 31 (1.8 g, 3.9 mmol, 1.0 equiv.) was added to it. The reaction mixture was stirred for 8 hours, then the organic solvent was evaporated, water was added to the residue (pH=9). The formed precipitate is filtered and washed with water. The residue is dissolved in methylene chloride and purified using chromatography using Hex:EA (1:1) as eluent.

Mass = 520 mg

Hex:EA (3:1).

Rf=0.6. Mass = 20 g.

Yield = 52%

tert-Butyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (28)

To a solution of sodium ethoxide obtained by dissolving Na (1.95 g, 81 mmol, 3.0 equiv.) in absolute ethanol (100 ml.) was added thiourea (3.22 g, 42 mmol, 1.5 equiv.) and ketoester (27) (7.67 g, 28.2 mmol, 1.0 eq.). The reaction mixture was boiled for 8 hours, then the mixture was cooled to room temperature and Mel (1.76 ml, 28.2 mmol, 1 eq.) was added dropwise from a separating funnel with stirring. After completion of the addition of the alkylating agent, the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, the residue was dissolved in water. When the aqueous solution was acidified with citric acid to pH 3–4, a precipitate formed, which was filtered off, washed successively with water, hexane, ethyl acetate, and ether.

Weight = 7.8 g.

Yield = 85%

tert-Butyl 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7 (6H)-carboxylate (29)

Pyrimidine 28 (5.68 g, 19.1 mmol, 1 eq.) was dissolved in 80 ml DMF, then triethylamine (TEA) (2.66 ml, 19.1 mmol, 1 eq.) was added and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate ( RuBor) (9.9 g, 19.1 mmol, 1 eq.).

The reaction mixture is stirred for 5 hours, then poured into ethyl acetate and the organic phase is washed with saturated sodium hydrogen carbonate solution. The organic layer was evaporated and purified by column chromatography using Hex:EA (3:1) as eluent.

Mass = 4.6 g.

Yield = 68%.

tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (30)

Pyrimidine 29 (4.1 g, 8.5 mmol, 1 equiv.) was dissolved in DMF (50 ml), then phenol 21 (1.24 g, 8.5 mmol, 1 equiv.) and cesium carbonate (2.76 g, 8.5 mmol, 1 equiv.) were added. . The reaction mixture is stirred for 8 hours, then poured into ethyl acetate and washed with water.

The organic layer was evaporated and purified by column chromatography using Hex:EA (3:1) as eluent.

Mass = 3.2 g.

Yield = 85%.

LCMS (M+H)=402

tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-(methylsulfonyl)-5,8-dihydro-pyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (31)

To a solution of pyrimidine 30 (3.0 g, 7 mmol, 1 equiv.) in methylene chloride (50 ml) at 0°C was added m-chloroperbenzoic acid (mCPBA) (3.8 g, 21.1 mmol, 3 equiv.). The reaction mixture is stirred for 24 hours. Then add to the mixture to stop the reaction of a saturated aqueous solution of NaHCO ₃ . The resulting product is extracted with methylene chloride. The organic phase is evaporated on a rotary evaporator and purified using column chromatography using Hex:EA (1:1) as eluent.

Weight = 2.2 g

Yield = 54%

¹ H NMR (400 MHz, DMSO-d ₆ , δ, ppm): 1.46 (s, 9 H), 2.11 (s, 6 H), 2.98 (t, J=5.4 Hz, 2 H), 3.12 (s, 3 H), 3.76 (t, J=5.5 Hz, 2 H), 4.72 (br. s, 2 H), 7.72-7.78 (m, 3 H)

LCMS (M+H)=434

tert-Butyl 2-((4-cyanophenyl)amino)-4-(2,6-dimethylphenoxy)-5,8-dihydropyrido[3,4-(1]pyrimidine-7(6H)-carboxylate (32)

To a solution of formamide 32 (0.51 g, 3.9 mmol, 1 equiv.) in DMF (15 mL) was added NaH (0.28 g, 7 mmol, 1.8 equiv.) at 0°C. The reaction mixture is stirred at room temperature. 20 minutes. The mixture is then cooled again to 0°C and sulfone 31 (1.8 g, 3.9 mmol, 1.0 fl.) is added thereto. The reaction mixture was stirred for 8 hours, then the organic solvent was evaporated, water was added to the residue (pH=9). The formed precipitate is filtered and washed with water. The precipitate is dissolved in methylene chloride and purified using chromatography using Hex:EA (1:1) as eluent.

Mass = 520 mg

Yield = 42%

4-(((4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido{3,4-d]pyrimidin-2-yl)amino)-benzonitrile hydrochloride (33)

Pyrimidine 32 (500 mg) was dissolved in methanol with saturated hydrogen chloride, stirred for an hour, the organic solvent was evaporated, the precipitate formed was recrystallized from ethanol.

Mass = 500 mg

Yield = 96%

4-(((7-Benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile (BB 0273459)

Pyrimidine 20 as a free base (500 mg, 1 mmol, 1 equiv.) and benzyl bromide (205.5 mg, 1.1 mmol) are placed in a 100 ml round bottom flask equipped with an efficient reflux condenser with a calcium chloride tube. The mixture is boiled until the entire mass is solidified. The hydrobromide of the target N-benzyl pyrimidine is formed. At the end of the reaction, cool the flask and pour in portions (while cooling to avoid strong heating) a solution of 1 g of sodium hydroxide in 20 ml of water. The separated product is separated in a separating funnel, chloride is added, the organic phase is washed with water, dried over anhydrous sodium sulfate. The organic solvent is removed under reduced pressure and the residue is purified using chromatography using Hex:EA (1:3) as eluent.

Mass = 300 mg

Yield = 58%

VV 0273459

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 1.95-2.13 (m, 6 H), 2.78 (br. s, 2 H), 3.43 (br. s, 2 H), 3.47 - 3.57 (m, 2 N), 3.64 - 3.79 (m, 2 N), 7.19 - 7.46 (m, 12 N)

LCMS m/z(M+H): 462.

Hex:EA(3:1). Rf=0.6.

Mass = 20 g.

Yield = 52%

tert-Butyl 4-hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (28)

To a solution of sodium ethoxide obtained by dissolving Na (1.95 g, 81 mmol, 3.0 equiv.) in absolute ethanol (100 ml.) was added thiourea (3.22 g, 42 mmol, 1.5 equiv.) and ketoester (27) (7.67 g, 28.2 mmol, 1.0 eq.). The reaction mixture was boiled for 8 hours, then the mixture was cooled to room temperature and Mel (1.76 ml, 28.2 mmol, 1 eq.) was added dropwise from a separating funnel with stirring. After completion of the addition of the alkylating agent, the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, the residue was dissolved in water. When the aqueous solution was acidified with citric acid to pH 3–4, a precipitate formed, which was filtered off, washed successively with water, hexane, ethyl acetate, and ether.

Weight = 7.8 g.

Yield = 85%

tert-Butyl 4-((1Н-benzo[1,2,3]triazol-1 -yl)oxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6Н) -carboxylate (29)

Pyrimidine 28 (5.68 g, 19.1 mmol, 1 eq.) was dissolved in 80 ml DMF, then triethylamine (TEA) (2.66 ml, 19.1 mmol, 1 eq.) was added and benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate ( RuBor) (9.9 g, 19.1 mmol, 1 eq.). The reaction mixture is stirred for 5 hours, then poured into amyl acetate and the organic phase is washed with saturated sodium hydrogen carbonate solution. The organic layer was evaporated and purified by column chromatography using Hex:EA (3:1) as eluent.

Mass = 4.6 g.

Yield = 68%.

tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (30)

Pyrimidine 29 (4.1 g, 8.5 mmol, 1 equiv.) was dissolved in DMF (50 ml), then phenol 21 (1.24 g, 8.5 mmol, 1 equiv.) and cesium carbonate (2.76 g, 8.5 mmol, 1 equiv.) were added. . The reaction mixture is stirred for 8 hours, then poured into ethyl acetate and washed with water. The organic layer was evaporated and purified by column chromatography using Hex:EA (3:1) as eluent.

Mass = 3.2 g.

Yield = 85%.

LCMS (M+H)=402

tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-(methylsulfonyl)-5,8-dihydro-pyrido[3,4-d]pyrimidine-7(6Н)-carboxylate (31)

To a solution of pyrimidine 30 (3.0 g, 7 mmol, 1 equiv.) in methylene chloride (50 ml) at 0°C was added m-chloroperbenzoic acid (mCPBA) (3.8 g, 21.1 mmol, 3 equiv.). The reaction mixture is stirred for 24 hours. Then add to the mixture to stop the reaction of a saturated aqueous solution of NaHCO ₃ . The resulting product is extracted with methylene chloride. The organic phase is evaporated on a rotary evaporator and purified using column chromatography using Hex:EA (1:1) as eluent.

Weight = 2.2 g

Yield = 54%

¹ H NMR (400 MHz, DMSO-d ₆ , δ, ppm): 1.46 (s, 9 H), 2.11 (s, 6 H), 2.98 (t, J=5.4 Hz, 2 H), 3.12 (s, 3 H), 3.76 (T, J=5.5 Hz, 2 H), 4.72 (br. s, 2 H), 7.72-7.78 (m, 3 H)

LCMS (M+H)=434

tert-Butyl 2-((4-cyanophenyl)amino)-4-(2,6-dimethylphenoxy)-5,8-dihydropyri"to[3,4-d]pyrimidine-7(6Н)-carboxylate (32)

To a solution of formamide 32 (0.51 g, 3.9 mmol, 1 equiv.) in DMF (15 mL) was added NaH (0.28 g, 7 mmol, 1.8 equiv.) at 0°C. The reaction mixture is stirred at room temperature. 20 minutes. Then the mixture was again cooled to 0°С and sulfone 31 (1.8 g, 3.9 mmol, 1.0 equiv.) was added to it. The reaction mixture was stirred for 8 hours, then the organic solvent was evaporated, water was added to the residue (pH=9). The formed precipitate is filtered and washed with water. The residue is dissolved in methylene chloride and purified using chromatography using Hex:EA (1:1) as eluent.

Mass = 520 mg

Yield = 42%

4-(((4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)-benzonitrile hydrochloride (33)

Pyrimidine 32 (500 mg) was dissolved in methanol with saturated hydrogen chloride, stirred for an hour, the organic solvent was evaporated, the precipitate formed was recrystallized from ethanol.

Mass = 500 mg

Yield = 96%

4-(((7-Benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile (BB 0273459)

Pyrimidine 20 free base (500 mg, 1 mmol, 1 equiv.) and benzyl bromide (205.5 mg, 1.1 mmol) are placed in a 100 ml round bottom flask equipped with an efficient reflux condenser with a calcium chloride tube. The mixture is boiled until the entire mass is solidified. The hydrobromide of the target N-benzyl pyrimidine is formed. At the end of the reaction, cool the flask and pour in portions (while cooling to avoid strong heating) a solution of 1 g of sodium hydroxide in 20 ml of water. The separated product is separated in a separating funnel, chloride is added, the organic phase is washed with water, dried over anhydrous sodium sulfate. The organic solvent is removed under reduced pressure and the residue is purified using chromatography using Hex:EA (1:3) as eluent.

Mass = 300 mg

Yield = 58%

VV 0273459

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 1.95 - 2.13 (m, 6 H), 2.78 (br. s, 2 H), 3.43 (br. s, 2 H), 3.47 - 3.57 (m, 2 N), 3.64 - 3.79 (m, 2 N), 7.19 - 7.46 (m, 12 N)

LCMS m/z(M+H): 462.

Example 2

Synthesis of 4-((2-((4-cyanophenyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0273774

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 1.26 (s, 3H), 2.18 (s, 6H), 2.20-2.22 (m, 2H), 3.12-3.15 (m, 2H), 7.22 (d, J=8.2 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.55 (s, 2H).

Mass yield - 4.5 mg (8%)

LCMS m/z(M+H):411.

Example 3

Synthesis of 4-((4-(4-Formyl-2,6-dimethylphenoxy)-7-methyl-5,6,7,8-tetrahydro[3,4-d]pyrimidin-2-yl)amino)benzonitrile

VV 0273775

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 1.26 (s, 3H), 2.18-2.20 (m, 2H), 2.23 (s, 6H), 3.14-3.18 (m, 2H), 3.74 - 3.78 (m, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.76 (s, 2H), 10.07 (s, 1H).

Mass yield - 8.2 mg (12%)

LCMS m/z(M+H):413

Example 4

Synthesis of tert-Butyl 4-(4-(1,3-dioxalan-2-yl)-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5Н-pyrimido[4 ,5-d]azepine-7(6Н)-carboxylate

VV 0273892

1H NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 1.51 (s, 1H), 2.09 (s, 6H), 2.20-2.42 (m, 1H), 2.94-3.18 (m, 4H), 3.66 (br. s, 4H), 4.06 (t, J=12.3 Hz, 2H), 4.36 (dd, J=10.97 Hz, 4.86 Hz, 2H), 5.55 (s, 1H), 7.08 (s, 1H) , 7.16 (d, J=8.56 Hz, 2H), 7.30 (s, 2H), 7.41 (d, J=8.74 Hz, 2H),

Mass yield - 0.0043 g (12%)

LCMS m/z (M+H): 572.

Example 5

Synthesis of tert-Butyl 2-((4-cyanophenyl)amino)-4-(4-formyl-2,6-dimethylphenioxy)-8,9-dihydro-5Н-pyrimido[4,5-d]azepine-7(6Н )-carboxylate

VV 0273943

1Н NMR (400 MHz, CDCl3 _, δ, ^ppm ): 1.51 (s, 9Н), 2.19 (s, 6Н), 3.09 (br. s, 4Н), 3.68 (br. s, 4Н), 7.12 (br. s, 1H), 7.30 (s, 4H), 7.70 (s, 2H), 10.02 (s, 1H).

Mass yield - 0.056 g (12%)

LCMS m/z(M+H): 514.

Example 6

Synthesis of tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

VV 0273961

NMR ¹ H (400 MHz, CDCl ₂ , δ, ppm): 1.53 (s, 9H), 2.16 (s, 6H), 2.82 - 2.89 (m, 2 H), 3.81 (t, J=5.6 Hz , 2H), 4.62 (br. s, 2H), 7.39 (d, J=8.8 Hz, 4H), 7.48 (s, 2H).

Mass yield - 2.87 g. (46%)

LCMS m/z (M+H): 497.

Example 7

Synthesis of 4-((2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0273963

¹ H NMR (400 MHz, DMSO-d ₆ , δ ppm): 2.11 (s, 6H), 3.02 (t, J=5.8 Hz, 2 H), 3.50 (d, J=5.2 Hz, 2H) , 4.31 (br. s, 2H), 7.47 (br. s, 4 H), 7.79 (br. s, 2 H).

Mass yield - 2.08 (96%)

LCMS m/z (M+H): 397.

Example 8

Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(methylsulfonyl)-77,6,7,8-tetrahydropyrido[4,3-b]pyrimidin-4-yl)oxy)-3,5 -dimethylbenzonitiryl

VV 0273964

1H NMR (400 MHz, CDCl ³ _, δ, ppm): 2.16 (s, 6H), 2.98 (s, 3H), 3.04 (t, J=5.8 Hz, 2H), 3.67-3.72 (m , 2H), 4.50 (s, 2H), 7.34-7.40 (m, 2H), 7.41-7.45 (m, 2H), 7.49 (s, 2H)

Mass yield - 0.072 g (84%)

LCMS m/z (M+H): 475.

Example 9

Synthesis of Ethyl 4-{4-cyano-2,78-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5Н)-carboxylate

VV 0273965

¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 1.33 (t, J=7.1 Hz, 3H), 2.17 (s, 6 H), 2.89 (t, J=5.5 Hz, 2H), 3.86 (t, J=5.7 Hz, 2H), 4.24 (q.v., J=7.1 Hz, 2H), 4.67 (s, 2H), 7.39 (d, J=8.9 Hz, 4H), 7.49 (s, 2H )

Mass yield - 0.056 g (56%)

LCMS m/z (M+H): 468.

Example 10

Synthesis of (E)-3-(4-((7-(tert-Butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d ]azepin-4-yl)oxy)-3,5-dimethylphenyl)acrylic acid

VV 0273969

1H NMR ⁽ 400 MHz, DMSO-d ₆ , δ, ppm): 1.40 (br.s, 9H), 2.07 (s, 6H), 3.02 (br.s, 4H), 3.59 (br.s , 4Н), 6.56 (d., J=16.0 Hz, 1Н), 7.27-7.39 (m, 2Н), 7.40-7.52 (m, 2Н), 7.53-7.67 (m, 2Н), 9.95-10.09 (m, 1H).

Example 11

Synthesis -Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-80,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H) -carboxylate

VV 0273972

1Н NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 1.51 (s, 9Н), 2.14 (s, 6Н), 3.06-3.10 (m, 4Н), 3.65-3.68 (m, 4Н), 7.07 (br.s, 1H), 7.29-7.35 (m, 2H), 7.36-7.42 (m, 2H), 7.48 (s, 2H),

Mass yield - 0.462 g (24%)

LCMS m/z (M+H): 511.

Example 12.

Synthesis of 4-((2-((4-cyanophenyl)amino)-6,7,8,81-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile dihydrochloride

VV 0273976

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 2.11 (s, 6H), 3.14-3.45 (m, 8H), 7.43 (s, 4H), 7.78 (s, 2H), 9.79 (br.s, 2H), 10.12 (br.s, 1H),

Mass yield - 0.237 g (92%)

LCMS m/z (M+H): 411.

Synthesis of tert-Butyl 2-((4-cyanophenyl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimido[4,5-d]azepine -7(6H)-carboxylate

VV 0274009

1Н NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 1.51 (s, 9Н), 2.10-2.17 (m, 6Н), 3.08 (br. s, 4Н), 3.67 (br. s, 4Н ), 5.90-5.46 (m, 1H), 7.63-7.04 (m, 8H),

Mass yield - 0.06 g (8%)

LCMS m/z (M+H): 537.

Example 13

Synthesis of 4(2-((4-Cyanophenyl)amino)-7-picolinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3,5 -dimethylbenzonitrile

VV 0274010

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 2.01-2.08 (m, 3H), 2.12 (s, 3H), 3.08 (d, J=2.4 Hz, 2H), 3.17 ( d, J=3.7 Hz, 2H), 3.63 (br.s, 2H), 3.83-3.97 (m, 2H), 7.42 (d, J=7.8 Hz, 4H), 7.50 (t, J=5.8 Hz, 1H ), 7.59 (d, J=7.7 Hz, 1H), 7.78 (d, J=13.8 Hz, 2H), 7.90-8.00 (m, 1H), 8.62 (d, J=4.3 Hz, 1H), 10.09 (br .s, 1H),

Mass yield - 0.072 g (29%)

LCMS m/z (M+H): 516.

Example 14

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-isonicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3 ,5-dimethylbenzonitrile

VV 0274011

1Н NMR ⁽ 400 MHz, DMSO-d ₆ , δ, ppm): 2.05 (s, 3Н), 2.12 (s, 3Н), 3.05 (br. s, 2Н), 3.12-3.24 (m, 2Н ), 3.51 (br.s, 2H), 3.82-3.96 (m, 2H), 7.32-7.51 (m, 6H), 7.78 (d, J=14.6 Hz, 2H), 8.69 (d, J=4.8 Hz, 2Н), 10.10 (d, J=4.0 Hz, 1Н).

Mass yield - 0.067 g (32%)

LCMS m/z (M+H): 516.

Example 15

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-nicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3 ,5-dimethylbenzonitrile

VV 0274012

1Н NMR ⁽ 400 MHz, DMSO-d ₆ δ, ppm): 2.04 (s, 3Н), 2.12 (br. s, 3Н), 3.06 (br. s, 2Н), 3.19 (br. s, 2Н ), 3.58 (br.s, 2H), 3.90 (br.s, 2H), 7.41 (d, J=11.6 Hz, 4H), 7.50 (dd, J=7.5, 5.0 Hz, 1H), 7.77 (d, J=14.4 Hz, 2H), 7.87 (d, J=6.7 Hz, 1H), 8.60-8.71 (m, 2H), 10.10 (br.s, 1H).

Mass yield - 0.055 g (30%)

LCMS m/z (M+H): 516.

Example 16

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-5Н-pyrimido[4,5-d]azepin-4- yl)oxy)-3,5-dimethylbenzonitrile

VV 0274014

¹ H NMR (400 MHz, DMSO-d ₆ , δ, ppm): 2.08 (s, 6H), 2.72 (d, J=7.5 Hz, 4H), 3.01 (d, J=8.5 Hz, 4H) , 3.80 (s, 2H), 7.27 (dd, J=6.7, 5.2 Hz, 1H), 7.40 (s, 4H), 7.54 (d, J=7.8 Hz, 1H), 7.72-7.84 (m, 3H), 8.50 (d, J=4.2 Hz, 1H), 10.04 (s, 1H).

Mass yield - 0.106 g (78%)

LCMS m/z (M+H): 502.

Example 17.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(pyridin-3-ylmethyl)-6(7,8,9-tetrahydro-5Н-pyrimido[4,5-d]azepin-4- yl)oxy)-3,5-dimethylbenzonitrile

VV 0274015

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 2.08 (s, 6H), 2.67 (d, J=6.3 Hz, 4H), 3.00 (dd, J=6.3, 2.6 Hz, 4H), 3.71 (s, 2H), 7.33-7.46 (m, 5H), 7.71-7.82 (m, 3H), 8.48 (dd, J=4.7, 1.5 Hz, 1H), 8.56 (d, >1.5 Hz, 1Н), 10.04 (s, 1Н).

Mass yield - 0.090 g (64%)

LCMS m/z (M+H): 502

Example 18.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(pyridin-4-ylmethyl)-6,7,8,9-tetrahydro-5Н-pyrimido[4,5-d]azepin-4- yl)oxy)-3,5-dimethylbenzonitrile

VV 0274016

¹ H NMR (400 MHz, DMSO-d ₆ , δ, ppm): 2.09 (s, 6H), 2.68 (d, J=5.8 Hz, 4H), 3.02 (d, J=6.2 Hz, 4H) , 3.72 (s, 2H), 7.33-7.46 (m, 6H), 7.78 (s, 2H), 8.54 (d, J=5.6, 2H), 10.04 (s, 1H).

Mass yield - 0.095 g (66%)

LCMS m/z (M+H): 502.

Synthesis of 4-((2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0274021

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.09 (br. s, 6H), 2.73-3.08 (m, 8H), 7.41 (br. s, 4H), 7.77 (br. .s, 2Н), 9.99 (br.s, 1Н),

Mass yield - 0.174 g (96%)

LCMS m/z (M+H):411

Example 19.

Synthesis of tert-Butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5- d]azein-7-carbonyl)piperidine-1-carboxylate

VV 0274025

¹ H NMR (400 MHz, CDCl ₃ , δ, ppm): 1.47 (s, 9H), 1.64-1.90 (m, 5H), 2.14 (d, J=1.6 Hz, 6H), 2.64-2.89 ( m, 3Н), 3.03-3.22 (m, 4Н), 3.70-3.91 (m, 4Н), 4.05-4.34 (m, 2Н), 7.05-7.16 (m, 1Н), 7.33 (t, J=8.4 Hz, 2H), 7.36-7.42 (m, 2H), 7.48 (d, J=4.5 Hz, 2H).

Mass yield - 0.230 g (55%)

LCMS m/z (M+H): 622.

Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(piperidine-4-carbonyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-4- yl)oxy)-3,5-dimethylbenzonitrile dihydrochloride

VV 0274026

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 1.78 (br.s, 4H), 2.09 (br.s, 6H), 2.81-3.16 (m, 7H), 3.23 (br.s, 2H), 3.62-3.90 (m, 4H), 7.41 (br.s, 4H), 7.78 (br.s, 2H), 8.86 (br.s, 1H), 9.27 (br.s, 1Н), 10.08 (br. s, 1Н).

Mass yield - 0.090 g (80%)

LCMS m/z (M+H): 522.

Example 20.

Synthesis of tert-Butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine- 7(6H)-yl)piperidine-1-carboxylate

VV 0274027

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 1.26-1.46 (m, 11H), 1.68 (d, J=11.0 Hz, 2H), 2.08 (s, 6H), 2.58- 2.83 (m, 7H), 2.94 (br.s, 4H), 3.91–4.08 (m, 2H), 7.41 (s, 4H), 7.78 (s, 2H), 10.01 (s, 1H).

Mass yield - 0.203 g (82%)

LCMS m/z (M+H): 594.

Example 93.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4- yl)oxy)-3,5-dimethylbenzonitrile trihydrochloride

VV 0274028

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 1.97-2.19 (m, 8H), 2.35 (d, J=11.9 Hz, 2H), 2.94 (q, J=11.1 Hz, 2Н), 3.09 (dd, J=16.5, 6.54 Hz, 1Н), 3.24-3.36 (m, 1Н), 3.37-3.53 (m, 5Н), 3.58-3.70 (m, 2Н), 3.71-3.87 (m, 2Н), 7.44 (s, 4Н), 7.79 (s, 2Н), 9.25 (d, J=10.2 Hz, 1Н), 9.40 (d, J=9.1 Hz, 1Н), 10.14 (br.s, 1Н), 12.13 (br. s, 1H).

Mass yield - 0.182 g (87%)

LCMS m/z (M+H): 494.

Example 94.

Synthesis of 4-((6-(2-Aminoacetyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3 ,5-dimethylbenzonitrile

VV 0274061

1Н NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 2.18 (s, 6Н), 2.82-3.11 (m, 2Н), 3.56-3.88 (m, 2Н), 3.90-4.27 (m, 2Н ), 4.49-4.87 (m, 2H), 7.41 (s, 4H), 7.49 (s, 2H).

Mass yield - 0.029 g (26%)

LCMS m/z (M+H): 453

Example 95.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-6-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine -4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0274052

1H NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 1.90 (br.s, 1H), 2.34 (br.s, 1H), 2.57-2.69 (m, 2H), 3.12-3.28 (m , 2H), 3.43-3.55 (m, 2H), 3.57-3.74 (m, 2H), 3.94-4.24 (m, 1H), 4.31-4.54 m, 2H), 4.65-4.88 (m, 1H), 7.05 (d, J=7.5 Hz, 2 H), 7.19 (d, J=7.1 Hz, 2 H), 7.26 (s, 2 H).

Mass yield - 0.005 g (12%)

LCMS m/z (M+H): 510

Example 24.

Synthesis of tert-Butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5Н-pyrimido[4,5-d] azepine-7-carbonyl)pyrrolidine-1-carboxylate

VV 0274063

1Н NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 1.25 (br. s, 9Н), 1.36 (s, 3Н), 1.59-1.91 (m, 3Н), 2.02-2.14 (m , 6H), 2.14-2.33 (m, 1H), 2.74-3.33 (m, 5H), 3.36-4.06 (m, 5H), 4.58-4.78 (m, 1H), 7.41 (br.s, 4H), 7.78 (br. s, 2H), 9.96–10.16 (m, 1H).

Mass yield - 0.128 g (57%)

LCMS m/z (M+H): 608

Example 25.

Synthesis of (R)-tert-Butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4, 5-d]azepine-7-carbonyl)pyrrolidine-1-carboxylate

VV 0274064

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 1.25 (br. s, 6H), 1.36 (s, 3H), 1.58-1.91 (m, 3H), 2.02-2.15 (m , 6H), 2.15-2.34 (m, 1H), 2.76-3.32 (m, 5H), 3.36-4.05 (m, 5H), 4.54-4.79 (m, 1H), 7.41 (br.s, 4H), 7.78 (d, J=2.4 Hz, 2H), 9.97-10.17 (m, 1H).

Mass yield - 0.103 g (52%)

LCMS m/z (M+H): 608.

Example 26.

Synthesis of (S)tert-Butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5 -d]azepine-7-carboxylate)pyrrolidine-1-carboxylate

VV 0274065

1Н NMR (400 MHz, DMO-d ₆ , δ, ^ppm ): 1.25 (br. s, 6Н), 1.36 (s, 3Н), 1.58-1.92 (m, 3Н), 2.03-2.14 (m , 6H), 2.14-2.34 (m, 1H), 2.79-3.33 (m, 5H), 3.35-4.03 (m, 5H), 4.53-4.78 (m, 1H), 7.41 (br.s, 4H), 7.77 (br. s, 2H), 9.93–10.16 (m, 1H).

Mass yield - 0.098 g (50%)

LCMS m/z (M+H): 608

Example 99.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d] azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0274072

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 1.40-1.74 (m, 4H), 2.09 (s, 6H), 2.77 (br.s, 4H), 2.97 (br.s , 4H), 3.19–3.46 (m, 3H), 3.81–3.96 (m, 2H), 7.41 (s, 4H), 7.78 (s, 2H), 10.00 (br. s, 1H).

Mass yield - 0.096 g (82%)

LCMS m/z (M+H): 495

Example 100.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(5-methylfuran-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d] azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0274073

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 2.14 (s, 6H), 2.30 (s, 3H), 2.64-2.82 (m, 4H), 3.08 (d, J=6.7 Hz, 4H), 3.68 (s, 2H), 5.92 (br.s, 1H), 6.11 (d, J=2.8 Hz, 1H), 7.14 (s, 1H), 7.24-7.33 (m, 2H), 7.34-7.41 (m, 2H), 7.47 (m, 2H).

Mass yield - 0.038 g (44%)

LCMS m/z (M+H): 505

Example 101.

Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(1-methyl-1H-pyrrol-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimido[4, 5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0274074

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 2.15 (s, 6H), 2.68 (dd, J=12.2 Hz, 10.3 Hz, 4H), 2.94-3.14 (m, 4H), 3.59 (s, 2H), 3.74 (s, 3H), 6.00-6.05 (m, 1H), 6.07 (t, J=3.0 Hz, 1H), 6.61-6.70 (m, 1H), 7.12 (s, 1H), 7.24-7.33 (m, 2H), 7.34-7.42 (m, 2H), 7.48 (s, 2H).

Mass yield - 0.152 g (38%)

LCMS m/z (M+H): 504

Example 102.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(4-hydroxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl} hydroxy)-3,5-dimethylbenzonitrile

VV 0274075

1H NMR ⁽ 400 MHz, DMSO-d ₆ , δ, ppm): 2.08 (s, 6H), 2.62 (br.s, 4H), 2.98 (br.s, 4H), 3.53 (br.s , 2Н), 6.72 (d, J=8.3 Hz, 2Н), 7.14 (d, J=8.0 Hz, 2Н), 7.40 (s, 4Н), 7.77 (s, 2Н), 9.30 (br.s, 1Н) , 10.03 (s, 1H).

Mass yield - 0.042 g (24%)

LCMS m/z (M+H): 517

Example 103.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(1-methoxypropan-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepmn- 4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0274080

1Н NMR (400 MHz, CDCl ³ _, δ, ppm): 1.06 (d, J=5.8 Hz, 3Н), 2.04-2.27 (m, 6Н), 2.81 (br. s, 4Н), 3.04 ( br.s, 5H), 3.32 (br.s, 1H), 3.36 (br.s, 3H), 3.51 (d, J=6.7 Hz, 1H), 7.14 (br.s, 1H), 7.24-7.33 ( m, 2H), 7.36 (d, J=7.90 Hz, 2H), 7.47 (br.s, 2H).

Mass yield - 0.128 g (48%)

LCMS m/z (M+H): 483

Example 104.

Synthesis of 4-((7-(Cyanomethyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy) -3,5-dimethylbenzonitrile

VV 0274095

1Н NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.10 (s, 6Н), 2.72 (br. s, 4Н), 3.03 (br. s, 4Н), 3.89 (s, 2Н ), 7.42 (br.s, 4H), 7.78 (s, 2H), 10.05 (br.s, 1H).

Mass yield - 0.042 g (24%)

LCM-S m/z (M+H): 450

Example 33.

Synthesis of tert-Butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 6-carbonyl)pyrrolidine-1-carboxylate

VV 0274097

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 1 40-1.48 (m, 9H), 2.18 (s, 6H), 2.80-3.09 (m, 2H), 3.64-4.00 (m, 2H), 4.59-4.92 (m, 2H), 5.25-5.63 (m, 1H), 7.34-7.44 (m, 4H), 7.48 (s, 2H).

Mass yield - 0.068 g (67%)

LCMS m/z (M+H): 494 (M-Boc).

Example 106.

Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(pyrrolidin-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy) -3,5-dimethylbenzonitrile

VV 0274098

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 1.91 (br. s, 3H), 2.07-2.17 (m, 6H), 2.78-2.98 (m, 2H), 3.10-3.32 (m, 2H), 3.90 (br.s, 2H), 4.50-4.85 (m, 3H), 7.46 (br.s, 4H), 7.79 (s, 2H), 8.35-8.63 (m, 1H), 10.12 (br. s, 2H).

Mass yield - 0.032 g (88%)

LCMS m/z (M+H): 494

Example 107.

Synthesis of 4-((6-(Azetidine-3-carbonyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy) -3,5-dimethylbenzonitrile

VV 0274099

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.10 (s, 6H), 2.73-2.91 (m, 2H), 3.00-3.56 (m, 1H), 3.65 (s, 2H ), 4.05–4.09 (m, 2H), 4.25–4.31 (m, 2H), 4.68 (s, 2H), 7.46 (br.s, 4H), 7.79 (s, 2H).

Mass yield - 0.075 g (52%)

LCMS m/z (M+H): 480

Example 108.

Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(pyrazine-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy) -3,5-dimethylbenzonitrile

VV 0274100

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.19 (s, 6H), 3.00-3.14 (m, 2H), 3.73-4.31 (m, 2H), 4.84-5.05 (m , 2 H), 7.32–7.60 (m, 9H).

Mass yield - 0.012 g (20%)

LCMS m/z (M+H): 503

Example 37.

Synthesis of (S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5H)-yl)-1-oxopropan-2-yl)carbamate

VV 0274101

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 1.35-1.49 (m, 9H), 1.61 (s, 3H), 2.17 (s, 6H), 2.55-2.86 (m, 1H ), 3.07 (br.s, 2H), 3.62-4.07 (m, 2H), 4.56 (s, 2H), 4.94-5.57 (m, 2H), 7.35 (br.s, 2H), 7.39-7.44 (m , 2H), 7.48 (s, 2H).

Mass yield - 0.075 g (52%)

LCMS m/z (M+H): 468 (M-Boc).

Example 110.

Synthesis of (S)-4-((6-(2-Aminopropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl) hydroxy)-3,5-dimethylbenzonitrile

VV 0274102

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 1.28-1.44 (m, 3H), 2.11 (s, 6H), 2.74-2.84 (m, 1H), 3.73-4.03 (m , 2H), 4.49-4.61 (m, 2H), 4.71-4.77 (m, 2H), 7.46 (br.s, 4H), 7.79 (s, 2H), 7.94 (s, 1H), 8.33 (br.s.). s, 2H).

Mass yield - 0.0233 g (88%)

LCMS m/z (M+H): 468

Example 39.

Synthesis of (S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5H)-yl)-1-oxo-3-phenylpropan-2-yl)carbamate

VV 0274103

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 1.41-1.51 (m, 9H), 2.15-2.20 (m, 6H), 2.83-2.96 (m, 2H), 3.38-4.01 (m, 6H), 4.47-4.96 (m, 4H), 6.90-7.14 (m, 2H), 7.41 (br. s, 6H), 7.50 (m, 3H).

Mass yield - 0.082 g (63%)

LCMS m/z (M+H): 544 (M-Boc).

Example 112.

Synthesis of (S)-4-((6-(2-Amino-3-phenylpropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]gthyrimidine- 4-yl)oxy)-3,5-dimethylbenzonitrile

VV 0274111

1Н NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.09 (br.s, 6H), 2.59-2.82 (m, 1H), 3.15 (br.s, 2H), 3.33-3.60 (m, 1H), 3.67-4.08 (m, 1H), 4.40-4.56 (m, 2H), 4.79 (br.s, 2H), 7.26 (m, 5H), 7.43 (br.s, 4H), 7.79 (br.s, 2H), 8.46 (br.s, 2H), 10.10 (br.s, 1H).

Mass yield - 0.078 g (86%)

LCMS m/z (M+H): 544

Example 113.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(2-morpholinoethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl) hydroxy)-3,5-dimethylbenzonitrile

VV 0274118

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 2.14 (s, 6H), 2.52 (br. s, 4H), 2.58 (t, J=6.90 Hz, 2H), 2.70-2.86 ( m, 6H), 3.00-3.12 (m, 4H), 3.73 (t, J=4.5, 4H), 7.09 (s, 1H), 7.28-7.33 (m, 2H), 7.34-7.40 (m, 2H), 7.48 (s, 2H).

Mass yield - 0.014 g (24%)

LCMS m/z (M+H): 524

Example 42.

Synthesis of (R)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5H)-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate

VV 0274119

1Н NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 1.45 (s, 9Н), 2.17 (s, 6Н), 3.71-4.17 (m, 4Н), 4.59-5.03 (m, 3Н), 5.37-5.77 (m, 1H), 7.31-7.45 (m, 4H), 7.49 (s, 2H).

Mass yield - 0.011 g (42%)

LCMS m/z (M+H): 484 (M-Boc).

Example 43.

Synthesis of tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5Н )-yl)-4-(methylthio)-1-oxobutan-2-yl)carbamate

VV 0274120

1Н NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 1.43 (br. s, 10Н), 2.07 (s, 3Н), 2.11-2.23 (m, 6Н), 2.45-2.68 (m, 2Н ), 3.72-4.14 (m, 2H), 4.47-4.73 (m, 1H), 4.80-5.02 (m, 2H), 5.23-5.52 (m, 1H), 7.39 (d, J=4.6 Hz, 4 H) , 7.48 (br. s, 2H), 8.01 (s, 2H).

Mass yield - 0.089 g (55%)

LCMS m/z (M+H): 528 (M-Voc)

Example 44.

Synthesis of 4-((6-(2-Amino-3-(1H-pyrazol-4-yl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3 -d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 2.11 (br. s, 6H), 2.60 - 3.01 (m, 2H), 3.05 - 3.42 (m, 2H), 3.84 - 4.29 (m, 3H), 4.51 - 4.64 (m, 1H), 4.77 - 5.00 (m, 2H), 7.46 (s, 4H), 7.80 (s, 2H), 8.44 (br.s, 2H), 9.13 ( s, 1H), 10.05 (br.s, 1H).

Mass yield - 0.005 g (8%)

LCMS m/z (M+H): 534

Example 45.

Synthesis of tert-Butyl 4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8- dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-oxopropyl)-1H-pyrazole-1-carboxylate

1H NMR (400 MHz, CDCl ³ _, δ, ppm): 1.36 - 1.48 (m, 9H), 1.50 - 1.65 (m, 9H), 2.15 (s, 6H), 3.02 - 3.21 (m, 1H ), 3.61 - 3.95 (m, 1H), 4.01 - 4.28 (m, 1H), 4.45 - 4.69 (m, 1H), 4.75 - 4.84 (m, 1H), 4.88-5.01 (m, 1H), 5.04-5.18 (m, 1H), 5.42-5.58 (m, 1H), 7.14 (s, 1H), 7.20 (s, 1H), 7.35-7.44 (m, 4H), 7.48 (s, 2H).

Mass yield - 0.032 g (33%)

LCMS m/z (M+H): 534 (M-2Boc)

Example 46.

Synthesis of (R)-4-((6-(2-Amino-3-hydroxypropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 4-yl)oxy)-3,5-dimethylbenzonitrile

1H NMR ⁽ 400 MHz, DMSO-d ₆ , δ, ppm): 2.13 (s, 6H), 2.71 - 3.01 (m, 2H), 3.74 (br.s, 2H), 3.95 (br.s , 2H), 4.52 - 4.68 (m, 2H), 4.80 (br.s, 2H), 7.46 (br.s, 4H), 7.79 (s, 2H), 8.30 (br.s, 3H).

Mass yield - 0.008 g (85%)

LCMS m/z (M+H): 484

Example 47.

Synthesis of (S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5H)-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)carbamate

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 1.43 (d, J=6.9 Hz, 9H), 2.17 (br. s, 6H), 2.61 - 2.85 (m, 2H), 3.03 - 3.45 (m, 1H), 3.56 - 3.80 (m, 1H), 3.92 - 4.22 (m, 1H), 4.37 - 4.64 (m, 1H), 4.69 -5.02 (m, 2H), 5.36 - 5.53 (m, 1H ), 6.59 - 6.75 (m, 2H), 6.97 - 7.10 (m, 2H), 7.35 (d, J=15.5 Hz, 4H), 7.48 (s, 2H).

Mass yield - 0.055 g (40%)

LCMS m/z (M+H): 560 (M-Boc).

Example 48.

Synthesis of (S)-4-((6-(2-Amino-3-(4-hydroxyphenyl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3 -d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

1H NMR ⁽ 400 MHz, DMSO-d ₆ , δ, ppm): 2.09 (br.s, 6H), 2.59 - 2.82 (m, 1H), 3.15 (br.s, 2H), 3.33 - 3.60 (m, 1H), 3.67 - 4.08 (m, 1H), 4.40 - 4.56 (m, 2H), 4.79 (br.s, 2H), 7.26 (m., 5H), 7.43 (br.s, 4H), 7.79 (br.s, 2H), 8.46 (br.s, 2H), 10.10 (br.s, 1H).

Mass yield - 0.048 g (90%)

LCMS m/z (M+H): 560

Example 49.

Synthesis of (R)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5H)-yl)-3-methyl-1-oxobutan-2-yl)carbamate

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 0.90 - 1.07 (m, 6H), 1.38 - 1.47 (m, 9H), 1.79 - 2.08 (m, 1H), 2.12 - 2.25 (m, 6H), 2.98 - 3.27 (m, 1H), 3.76 - 4.07 (m, 2H), 4.44 - 4.73 (m, 2H), 5.22 -5.53 (m, 1H), 7.33 - 7.44 (m, 4H) , 7.48 (s, 2H).

Mass yield - 0.042 g (52%)

LCMS m/z (M+H): 496 (M-Boc).

Example 50.

Synthesis of (R)-4-((6-(2-Amino-3-methylbutanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 4-yl)oxy)-3,5-dimethylbenzonitrile

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 1-36 - 1.48 (m, 2H), 1.53 - 1.86 (m, 4H), 2.08 - 2.22 (s, 6H), 3.02 - 3.29 (m, 2H), 3.75 - 4.08 (m, 2H), 4.51 - 5.06 (m, 4H), 5.30 (s, 1H), 7.31 - 7.45 (m, 4H), 7.48 (s, 2H).

Mass yield - 0.038 g (92%)

LCMS m/z (M+H): 496

Example 51.

Synthesis of (S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine -6(5H)-yl)-4-methyl-1-oxopentan-2-yl)carbamate

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 0.88-1.13 (m, 6H), 1.35-1.48 (m, 9H), 1.58 (d, J=1.4 Hz, 2H), 2.16 ( s, 6H), 2.99 - 3.26 (m, 1H), 3.72 - 4.27 (m, 2H), 4.64 - 4.98 (m, 3H), 5.30 (s, 1H), 7.33 - 7.45 (m, 4H, 7.45 - 7.56 (m, 2H).

Mass yield - 0.064 g (56%)

LCMS m/z (M+H): 510 (M-Voc

Example 52.

Synthesis of (S)-4-((6-(2-Amino-4-methylpentanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 4-yl)oxy)-3,5-dimethylbenzonitrile

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 0.82 - 0.99 (m, 6H), 1.49 - 1.86 (m, 3H), 2.12 (s, 6H), 2.71 - 3.11 (m , 2H), 3.65 - 4.11 (m, 2H), 4.70 (s, 2H), 7.46 (br.s, 4H), 7.79 (s, 2H), 8.28 (br.s, 2H)

Mass yield - 0.060 g (90%)

LCMS m/z(M+H): 510

Example 53.

Synthesis of (S)-Di-tert-butyl (6-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d ]pyrimidin-6(5Н)-yl)-6-oxohexane-1,5-diyl)dicarbamate

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 1.22 - 1.76 (m, 22H), 1.70 - 1.87 (m, 2H), 2.13 (s, 6H), 2.62 - 2.80 (m , 2H), 2.84 - 3.12 (m, 2H), 3.75 - 3.88 (m, 2H), 4.50 - 4.60 (m, 2H), 7.46 (br.s, 4H), 7.80 (s, 2H), 8.02 - 8.14 (m, 2H), 8.34-8.38 (m, 3H).

Mass yield - 0.022 g (18%)

LCMS m/z (M+H): 525 (M-2 Vos)

Example 54.

Synthesis of (S)-4-((2-((4-Cyanophenyl)amino)-6-(2,6-diaminohexanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4- yl)oxy)-3,5-dimethylbenzonitrile

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 1.30 - 1.66 (m, 4H), 1.71 - 1.85 (m, 2H), 2.12 (s, 6H), 2.63 - 2.79 (m , 2Н), 2.85 - 3.09 (m, 2Н), 3.77 - 4.04 (m, 2Н), 4.53 - 4.59 (m, 2Н), 7.46 (br.s, 4Н), 7.79 (s, 2Н), 8.01 - 8.14 (m, 3H), 8.36-8.40 (m, 3H)

Mass yield - 0.018 g (85%)

LCMS m/z (M+H): 525

Example 55.

Synthesis of (S)-4-((6-(2-Amino-4-(methylthio)butanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d ]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

1Н NMR ⁽ 400 MHz, DMSO-d ₆ , δ, ppm): 2.08 (s, 3Н), 2.15 (br. s, 6Н), 2.51 - 2.73 (m, 2Н), 2.80 - 3.07 (m , 2Н), 3.79 - 4.08 (m, 2Н), 4.47 - 4.57 (m, 2Н), 4.81 - 5.01 (m, 2Н), 7.46 (br.s, 4Н), 7.79 (s, 2Н), 8.40 (br. .s, 2H)

Mass yield - 0.076 g (82%)

LCMS m/z (M+H): 528

Example 56.

Synthesis of 4-((7-(2-Chloroacetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl) hydroxy)-3,5-dimethylbenzonitrile

1H NMR ⁽ 400 MHz, DMSO-d ₆ , δ, ppm): 2.10 (s, 6H), 3.02 (br.s, 2H), 3.13 (br.s, 2H), 3.75 (br.s , 4H), 4.49 (br.s, 2H), 7.42 (br.s, 4H), 7.78 (br.s, 2H), 10.06 (br.s, 1H).

Mass yield - 0.045 g (57%)

LCMS m/z (M+H): 487

Example 57.

Synthesis Methyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-4-cyanophenyl)amino)-8,9-dihydro-5Н-pyrimido[4,5-d]azepin-7(6Н )-carboxylate

1Н NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.09 (s, 6Н), 3.03 (br. s, 4Н), 3.64 (s, 7Н), 7.41 (s, 4Н), 7.77 (s, 2H), 10.06 (s, 1H).

Mass yield - 0.095 g (82%)

LCMS m/z (M+H): 469

Example 58.

Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy) -3,5-dimethylbenzonitrile

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.10 (br. s, 6H), 2.94 (s, 3H), 3.02-3.20 (m, 4H), 3.40-3.59 (m , 4H), 7.42 (s, 4H), 7.78 (s, 2H), 10.09 (s, 1H).

Mass yield - 0.08 g (75%)

LCMS m/z (M+H): 489

Example 59.

Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]lirimidin-4-yl)oxy) -3,5-dimethylbenzonitrile

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 2.12 (s, 6 H), 2.90 (dd, J=15.1 Hz, 4.8 Hz, 4H), 3.71 (s, 2H), 3.81 ( s, 2H), 7.31–7.41 (m, 6H), 7.45 (s, 2H), 8.58–8.60 (m, 2H).

Mass yield - 0.026 g (38%)

LCMS m/z (M+H): 488

Example 60.

Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy) -3,5-dimethylbenzonitrile

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 2.12 (s, 6H), 2.80 - 3.00 (m, 4H), 3.71 (s, 2H), 3.81 (s, 2H), 7.28 - 7.41 (m, 4H), 7.46 (s, 2H), 7.50 (dd, J=7.9 Hz, 4.8 Hz, 1H), 7.77 (d, J=7.8 Hz, 1H), 8.19 (dt, J=7.9 Hz, 1.9 Hz, 1H), 8.53-8.68 (m, 1H).

Mass yield - 0.030 g (40%)

LCMS m/z (M+H): 488

Example 61.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-6-(2-hydroxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3 ,5-Dimethylbenzonitrile

1H NMR (400 MHz, CDCl ³ _, δ, ppm): 2.14 (s, 6H), 3.00 (d, J=6.6 Hz, 4H), 3.83 (br.s, 2H), 4.01 (s , 2Н), 6.83 - 6.92 (m, 2Н), 7.02 - 7.11 (m, 2Н), 7.33 - 7.36 (m, 2Н), 7.39 - 7.44 (m, 2Н), 7.47 (s, 2Н).

Mass yield - 0.033 g (41%)

LCMS m/z (M+H): 503

Example 62.

Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(2-(prop-2-yn-1-yloxy)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d ]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

1Н NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 2.13 (s, 6Н), 2.51 (dt, J=10.6 Hz, 2.4 Hz, 2Н), 2.90 (s, 4Н), 3.78 (s , 2Н), 3.87 (s, 2Н), 4.75 (dd, J=8.3 Hz, 2.4 Hz, 2Н), 6.95 - 7.07 (m, 2Н), 7.25 - 7.33 (m, 4Н), 7.33 - 7.38 (m, 2H), 7.45 (s, 2H).

Mass yield - 0.062 g (70%)

LCMS m/z (M+H): 541

Example 63.

Synthesis of 3-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H )-yl) propanoic acid

1H NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.01-2.22 (m, 6H), 2.60-2.82 (m, 2H), 3.16 (br. s, 10H), 7.43 (br. .s, 4H), 7.79 (s, 2H), 10.09 (br.s, 1H).

Mass yield - 0.09 g (33%)

LCMS m/z (M+H): 483

Example 64.

Synthesis of 4-((7-Allyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3 ,5-dimethylbenzonitrile

NMR ¹ H (400 MHz, CDCl ₃ , δ, ppm): 2.15 (s, 6H), 2.61-2.81 (m, 4H), 3.07 (br. s, 4H), 3.19 (d, J=6.2 Hz, 2H), 5.15-5.29 (m, 2H), 5.82-6.03 (m, 1H), 7.11 (s, 1H), 7.28-7.33 (m, 2H), 7.34-7.41 (m, 2H), 7.48 ( s, 2H).

Mass yield - 0.011 g (17%)

LCMS m/z (M+H): 451

Example 65.

Synthesis of 4-((7-Acetyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3 ,5-dimethylbenzonitrile

1H NMR ⁽ 400 MHz, DMSO-d ₆ , δ, ppm): 2.10 (br.s, 9H), 2.98 (br.s, 2H), 3.09 (br.s, 2H), 3.70 (br.s, 2H .s, 4H), 7.41 (br.s, 4H), 7.78 (br.s, 2H), 10.06 (br.s, 1H).

Mass yield - 0.074 g (69%)

LCMS m/z (M+H): 453

Example 66.

Synthesis of 4-((7-(2-(1H-Imidazol-1-yl)acetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5 -d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

NMR ¹ H (400 MHz, DMSO-d ₆ , δ, ppm): 2.11 (d, J=10.2 Hz, 6H), 3.03 (br. s, 2H), 3.17 (br. s, 2H), 3.76 (br.s, 4H), 5.13 (d, J=6.1 Hz, 2H), 6.90 (br.s, 1H), 7.10 (d, J=7.40 Hz, 1H), 7.43 (d, J=5.8 Hz , 4H), 7.61 (d, J=6.7 Hz, 1H), 7.79 (d, J=6.7 Hz, 2H), 10.08 (br.s, 1H).

Mass yield - 0.011 g (21%)

LCMS m/z(M+H): 519

Example 67.

Synthesis of 4-((2-((4-Cyanophenyl)amino)-7-(2-(methyl-1H-imidazol-1-yl)acetyl)-6,7,8,9-tetrahydro-5H-pyrimido[4 ,5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile

1Н NMR (400 MHz, DMSO-d ₆ , δ, ^ppm ): 2.00-2.23 (m, 9H), 2.92-3.25 (m, 4H), 3.77 (br. s, 4H), 5.02 (d , J=13.0 Hz, 2H), 6.69 (d, J=5.2 Hz, 1H), 6.96 (d, J=11.4 Hz, 1H), 7.43 (d, J=6.8 Hz, 4H), 7.79 (d, J =7.5 Hz, 2H), 10.08 (br.s, 1H).

М=0.038 g. (41%)

LCMS m/z (M+H): 533

Example 68.

Synthesis of 4-((6-(2-Amino-3-(1H-imidazol-5-yl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3 -d]pyrimidiH-4-yl)oxy)-3,5-dimethylbenzonitrile

1Н NMR (400 MHz, CDCl ₃ , δ, ^ppm ): 2.42 (s, 5Н), 2.51 - 2.68 (m, 1Н), 2.73 - 2.92 (m, 1Н), 3.01 - 3.30 (m, 2Н ), 3.74 - 3.96 (m, 2H), 4.05 - 4.33 (m, 1H), 4.61 - 4.77 (m, 1H), 4.82 - 4.97 (m, 1H), 6.94 (d, J=0.9 Hz, 1H), 7.37 (s, 2H), 7.47 (dd, J=4.9, 1.0 Hz, 1H), 7.63 (d, J=8.7 Hz, 2H), 7.83 (d, 2H)

М=0.006 g (33%)

LCMS m/z (M+H): 535

The evaluation of the suppression of HIV reproduction/protection of human cells by the studied preparations against HIV was carried out by determining the change in the concentration of living cells in the experimental wells with MT-4 cells infected with HIV-1, as well as by the production of the p24 viral protein when different concentrations of the compounds according to item 1 were added.

The antiviral activity of the drugs was determined against HIV-1 subtype A strain 12RU 69831 when the cell culture was infected with a constant dose of the virus corresponding to 300 CCID50.

The results of determining the IC50 of the compounds according to p. 1 are shown in table 1.

The features claimed in the description of the invention or in the claims, expressed in special forms and terms for the implementation of the claimed function or method or method to achieve the claimed result, can be used alone or in any combination of such features to carry out the invention in its various forms.

The present invention has been described with reference to illustrations and examples for the purpose of explaining and understanding the essence of the invention. For a person skilled in the art it seems obvious that within the scope and claimed claims, various changes and modifications are possible. Therefore, it is understood that the description of the application only illustrates the invention and does not limit its scope. The scope of the invention is defined with reference to the claimed claims, including all equivalents claimed by the claims.

All patents, patent applications and publications cited in the specification are incorporated herein by reference in their entirety in each case to the same extent as if each patent, patent application and publication were cited separately.

Claims (119)

1. Combination for the treatment or prevention of HIV-related diseases, comprising a therapeutically effective amount of a compound of formula I and at least one compound selected from the group consisting of HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists and inhibitors of viral penetration into the cell, where the compound of formula I has the following chemical structure:

X ¹ , X ² are a Deputy of the form (CH ₂ ) _n , and n is chosen independently for X ₁ , X ₂ and can take values from 1 to 3; Y ¹ is selected independently and represents -O-, or substituents of the form:

where the substituents R1, Rb are each independently selected from the group consisting of: H, CN, CN-CH=CH-, C=O, CH=CH-COOH, substituted or unsubstituted C _1-6 alkyl; substituted or unsubstituted C _2-6 alkenyl; substituted or unsubstituted C _2-6 alkynyl; substituted or unsubstituted C _1-6 alkyloxy; halogen; NHR ⁹ ; NR ⁹ R ¹⁰ ; -C(=O)-NHR ⁹ ; -C(=O)-NR ⁹ R ¹⁰ ; -C(=O)-R ⁹ ; R ⁷ which is selected from a monocyclic, bicyclic or saturated or aromatic carbocycle or a monocyclic, bicyclic saturated or aromatic 4-6 membered heterocycle containing from 1 to 2 heteroatoms independently selected from the group S, N and O, where each of said carbocyclic or heterocyclic moieties may be optionally substituted with one or two substituents each independently selected from halo, hydroxy, C _1-6 alkyl, C _1-6 alkyloxycarbonyl, aminocarbonyl, OCH ₂ C≡CH, NHCOO-C _1-6 -alkyl, -Rb-R ^7a , where R ^7a represents a monocyclic or aromatic carbocycle or a monocyclic, bicyclic, saturated, or aromatic 4-6 membered heterocycle containing from 1 to 2 heteroatoms independently selected from the group N and O, where each of the mentioned carbocyclic or heterocyclic fragments can be optionally substituted with one, two, each independently selected from halo, hydroxy, C _1-6 alkyl, C _1-6 alkyloxycarbonyl, or NHCOO-C _1-6 alkyl; or R ⁹ where each R ⁹ independently represents hydrogen; cyano, aminocarbonyl, hydroxy; C _1-6 alkyl; C _1-6 alkyloxy, C _1-6 alkylcarbonyl; C _1-6 alkyloxycarbonyl; amino; mono(C _1-6 alkyl)amino; or R ⁷ , where each of the above C _1-6 alkyl groups may optionally be, each individually, substituted with one or two substituents each independently selected from hydroxy, C _1-6 alkyloxy, carboxyl, C _1-6 alkyloxycarbonyl, amino, a R ¹⁰ selected from R ⁷ selected from monocyclic 6-membered saturated heterocycle containing 1 O atom, monocyclic 6-membered aromatic carbocycle, bicyclic aromatic 6-membered carbocycle and aromatic 6-membered heterocycle containing 2 N atoms, COO-tert-butyl, COOH, NHCOO-C _1-6 -alkyl, where Rb can be attached to the rest of the molecule through a linker of the form (CH ₂ ) _n , n can take values from 1 to 3, while the compound of formula ( 1) may be represented by a pharmaceutically acceptable salt thereof. 2. The combination according to claim 1, where R1 is independently selected and represents H, CN, CN-CH=CH, C=O, CH=CH-COOH, 4-6-membered heterocyclyl containing 1-2 O heteroatoms; R ^b is chosen independently and is: -H, substituted or unsubstituted -C ₁ -C ₆ -alkyl or unsubstituted -C ₁ -C ₆ -alkenyl, substituted or unsubstituted C ₆ -aryl, substituted or unsubstituted -5-6-membered heteroaryl, containing from 1 to 2 heteroatoms independently selected from N, S and/or O, substituted or unsubstituted -C ₃ cycloalkyl, or substituted or unsubstituted 4-9 membered heterocyclyl containing from 1 to 2 heteroatoms independently selected from N and/or O, where said Rb substituents are each independently selected from the group consisting of: COO-tert-butyl, NH ₂ , C _1-4 -alkoxy, 4-6-membered heteroaryl containing from 1 to 2 heteroatoms independently selected from the group N and O, while the specified heteroaryl is not substituted or substituted by C 1 -alkyl. WOC; COOH; the remaining radicals are as defined in paragraph 1. 3. The combination of claim 1 wherein R ¹ in the compound of formula I is independently selected and is H, -CN, -CH=CH-CN, -C=O, or -CH=CH-COOH. 4. The combination according to claim 1, wherein R ¹ in the compound of formula I is independently selected and is a 4-6 membered heterocyclyl containing 1-2 O heteroatoms. 5. The combination according to claim 3, wherein R ¹ in the compound of formula I is oxetane. 6. The combination according to claim 1, wherein Y ¹ in the compound of formula I is -O-. 7. The combination according to claim 1 in which Y ¹ in the compound of formula I are substituents of the form:

8. The combination according to claim 1, in which Y ¹ in the compound of formula I represents substituents of the form:

9. The combination according to claim 1 wherein Rb in the compound of formula I is substituted or unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl or pentyl, wherein the substituents are as follows: defined in paragraph 1. 10. The combination according to claim 1, wherein Rb in the compound of formula I is substituted or unsubstituted phenyl, where the substituents are as defined in claim 1. 11. The combination according to claim 1, wherein Rb in the compound of formula I is substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, isobenzofuranyl, benzimidazolyl, furan, where the substituents are as defined in claim 1. 12. The combination according to claim 1, wherein Rb in the compound of formula I is a substituted or unsubstituted piperidine, azetidine, morpholine, tetrahydropyran. 13. The combination according to claim 1, in which Y ¹ in the compound of formula I represents substituents of the form:

a Rb is a substituted or unsubstituted 5-6 membered heteroaryl or heterocyclyl containing from 1 to 2 heteroatoms independently selected from N, S and/or O, where the substituents are defined in paragraph 1. 14. The combination according to claim 1, in which Y ¹ in the compound of formula I represents substituents of the form:

a Rb is substituted or unsubstituted C ₆ -aryl, -5-6-membered heteroaryl or -C ₃ - -cycloalkyl, where the substituents are defined in paragraph 1. 15. Combination according to claim 1, in which the compound of formula I is selected from: 4-(((6-Benzyl-4-(4-cyano-2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)methyl ethyl ester ) benzoic acid 4-(((6-Benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)methyl)benzoic acid ethyl ester 4-(((7-Benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile 4-((2-((4-cyanophenyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((4-(4-Formyl-2,6-dimethylphenoxy)-7-methyl-5,6,7,8-tetrahydro[3,4-d]pyrimidin-2-yl)amino)benzonitrile tert-Butyl 4-(4-(1,3-dioxalan-2-yl)-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4, 5-d]azepine-7(6Н)-carboxylate tert-Butyl 2-((4-cyanophenyl)amino)-4-(4-formyl-2,6-dimethylphenioxy)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H) -carboxylate tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate 4-((2-((4-Cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5- dimethylbenzonitiryl Ethyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5Н)-carboxylate (E)-3-(4-((7-(tert-Butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d] azepin-4-yl)oxy)-3,5-dimethylphenyl)acrylic acid tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H) -carboxylate 4-((2-((4-Cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile tert-Butyl 2-((4-cyanophenyl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimido[4,5-d]azepin- 7(6H)-carboxylate 4-((2-((4-Cyanophenyl)amino)-7-picolinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-isonicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-nicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(pyridin-3-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(pyridin-4-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile tert-Butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d ]azein-7-carbonyl)piperidine-1-carboxylate 4-((2-((4-Cyanophenyl)amino)-7-(piperidine-4-carbonyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl )hydroxy)-3,5-dimethylbenzonitrile tert-Butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7 (6H)-yl)piperidine-1-carboxylate 4-((2-((4-Cyanophenyl)amino)-7-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-(1]azepin-4- yl)oxy)-3,5-dimethylbenzonitrile 4-((6-(2-Aminoacetyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3, 5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-6-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine- 4-yl)oxy)-3,5-dimethylbenzonitrile 4-({2-[(4-cyanophenyl)amino]-6-[2-(morpholin-4-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-4- yl}oxy)-3,5-dimethylbenzonitrile 4-({2-[(4-cyanophenyl)amino]-6-[2-(4,4-difluoropiperidin-1-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3-d] pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(cyclopropanecarbonyl)-5,6,7,8-tetrahydro-[4,3-d]pyrimidin-4-yl)oxy)-3.5 -dimethylbenzonitrile 4-({2-[(4-cyanophenyl)amino]-6-(morpholine-4-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)- 3,5-dimethylbenzonitrile 4-({2-[(4-cyanophenyl)amino]-6-(4-methylpiperazin-1-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy )-3,5-dimethylbenzonitrile tert-Butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine -7-carbonyl)pyrrolidine-1-carboxylate (R)-tert-Butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5 -d]azepine-7-carbonyl)pyrrolidine-1-carboxylate (S)-tert-Butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5Н-pyrimido[4,5 -d]azepine-7-carbonyl)pyrrolidine-1-carboxylate 4-((2-((4-Cyanophenyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine -4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(5-methylfuran-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine -4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(1-methyl-1H-pyrrol-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5 -d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(4-hydroxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(1-methoxypropan-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-4 -yl)oxy)-3,5-dimethylbenzonitrile tert-Butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-6 -carbonyl)pyrrolidine-1-carboxylate 4-((2-((4-Cyanophenyl)amino)-6-(pyrrolidin-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile 4-((6-(Azetidine-3-carbonyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-6-(pyrazine-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile (S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5H)-yl)-1-oxopropan-2-yl)carbamate (S)-4-((6-(2-Aminopropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy )-3,5-dimethylbenzonitrile (S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-1-oxo-3-phenylpropan-2-yl)carbamate (S)-4-((6-(2-Amino-3-phenylpropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4 -yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(2-morpholinoethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile (R)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H) -yl)-4-(methylthio)-1-oxobutan-2-yl)carbamate 4-({6-[2-amino-3-(1H-imidazol-5-yl)propanoyl]-2-[(4-cyanophenyl)amino]-5H,6H,7H,8H-pyrido[4,3- d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile 4-((6-(2-Amino-3-(1H-pyrazol-4-yl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile tert-Butyl 4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido [4,3-d]pyrimidin-6(5H)-yl)-3-oxopropyl)-1H-pyrazole-1-carboxylate (R)-4-((6-(2-Amino-3-hydroxypropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4 -yl)oxy)-3,5-dimethylbenzonitrile (S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-3-(4-hydroxyphenyl)-1-oxopropan--2-yl)carbamate (S)-4-((6-(2-Amino-3-(4-hydroxyphenyl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3- d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (R)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-3-methyl-1-oxobutan-2-yl)carbamate (R)-4-((6-(2-Amino-3-methylbutanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4 -yl)oxy)-3,5-dimethylbenzonitrile (S)-tert-Butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine- 6(5Н)-yl)-4-methyl-1-oxopentan-2-yl)carbamate (S)-4-((6-(2-Amino-4-methylpentanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-4 -yl)oxy)-3,5-dimethylbenzonitrile (S)-Di-tert-butyl (6-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d] pyrimidin-6(5H)-yl)-6-oxohexane-1,5-diyl)dicarbamate (S)-4-((2-((4-Cyanophenyl)amino)-6-(2,6-diaminohexanoyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl )hydroxy)-3,5-dimethylbenzonitrile 4-((7-(2-Chloroacetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile Methyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H) -carboxylate 4-((2-((4-Cyanophenyl)amino)-7-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)- 3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-6-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-6-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-6-(2-hydroxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3, 5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-6-(2-(prop-2-yn-1-yloxy)benzyl)-5,6,7,8-tetrahydropyrido[4,3-d] pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 3-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5-d]azepine-7(6H) -yl) propanoic acid 4-((7-Allyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile 4-((7-Acetyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile 4-((7-(2-(1H-Imidazol-1-yl)acetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5- d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-Cyanophenyl)amino)-7-(2-(methyl-1H-imidazol-1-yl)acetyl)-6,7,8,9-tetrahydro-5H-pyrimido[4, 5-d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-5Н,6Н,7Н,8Н-pyrido[4,3-d]pyrimidine-6-sulfonamide methyl 2-{2-[(4-cyanophenyl)amino]-4-(4-formyl-2,6-dimethylphenoxy)-5H,6H,7H,8H,9H-pyrimido[4,5-d]azepine-7 -yl}-2-oxoacetate 4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-N-(oxan-4-yl)-4aH,5H,6H,7H,8H,8aH-pyrido[4 ,3-d]pyrimidine-6-carboxamide. 16. The combination according to any one of paragraphs. 1-15, in which the compound of formula I is in the form of a pharmaceutically acceptable salt obtained using counterions such as halides, hydroxides, carboxylates, sulfates. 17. A method for the treatment or prevention of HIV-related diseases, which consists in the fact that the subject in need of treatment is administered a combination according to any one of paragraphs. 1-16.