EA045845B1 - ANTIVIRAL DRUGS FOR TREATMENT AND PREVENTION OF HIV INFECTION - Google Patents

Description

Field of technology to which the invention relates

The present invention relates to pyrimidine derivatives having HIV replication inhibitory properties. The invention provides new pyrimidine compounds of formula I intended 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., application WO 2006/035068, published April 6, 2006,

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

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

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

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

ON THE. De Koek and R Wigerinck, application 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

(I) where R1 is independently selected and represents 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; NHR ⁹ ; NR9R ¹⁰ ; substituted or unsubstituted C _2-6 alkenyl; substituted or unsubstituted C _2-6 alkynyl;

X1, X ₂ represent a substituent of the form (CH ₂ ) _n , with n being chosen independently for X1, X ₂ ;

Y 1 is independently selected and represents -O- or substituents of the form:

Rb is independently selected 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 4-9 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and/or O, ^R7 , where Rb can be attached to the rest of the molecule through a linker of the form ( _CH2 ) _n ,

R ⁷ represents C ₃ -cycloalkyl;

R ⁹ and R ¹⁰ are each independently hydrogen; cyano, C _1-6 alkyl; C _2-6 alkylcarbonyl; amino; wherein each of the above C _1-6 alkyl groups may optionally be substituted with hydroxy;

where the substituents R1, Rb are each independently selected from the group including COO-isobutyl, OH, CN, NH ₂ , C _1-4 alkoxy, 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 C _1-6 alkyl, BOC, COOH, C _3-6 aryl, possibly substituted with OH, or OCH ₂ C=CH, 4-6-membered heterocyclyl containing 1-3 a heteroatom selected from N, S and O, O, N, halogen;

- 1 045845 n can take values from 1 to 3, or its pharmaceutically acceptable salt, or isotopes.

The 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-related 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

Structural formula Name 0272161 ^Н з ^С ^Г Yr NN 0 II N 4-((4-(2.6- dimethylphenoxy)-6,7dihydro-5Hcyclopenta[d]pyrimidin-2yl)amino)-benzonitrile 0272208 ίγγγ 4-(2.6- dimethylphenoxy)-N(piperidin-4-yl)-6,7dihydro-5H- cyclopenta[c1]pyrimidine n-2-amine 0273457 0 Π Ν. /Ν. Αχ G sn ₃ γ Ar Gn 4-(((6benzyl-4-(4-cyano-2,6dimethylphenoxy)5,6,7,8tetrahydropyrido[4,3c1]pyrimidin-2yl)amino)methyl)benzoic acid ethyl ester 0273458 I ^w o > o /=o VY ' b 4-(((6benzyl-4-(2,6dimethylphenoxy)5,6,7,8tetrahydropyrido[4,3c1]pyrimidin-2yl)amino)methyl)benzoic acid ethyl ester 0273459 A fΊ i Y 7 pY H 4-(((7-Benzyl-4-(2,6dimethylphenoxy)5,6,7,8tetrahydropyrido[3,4c1]pyrimidin-2yl)amino)methyl)benzone itrile

- 2 045845

- 3 045845

- 4 045845

- 5 045845

0273964 Yj D 1 / ? Il? Φ II N 4-((2-((4Cyanophenyl)amino)-6(methylsulfonyl)5,6,7,8tetrahydropyrido[4,3с1]pyrimidin-4yl)oxy)-3,5dimethylbenzonitiryl 0273965 Yj o A X 1 ^Ah N Ethyl 4-(4-cyano-2,6dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3c1]pyrimidine-6(5H)carboxylate 0273969 0 H,C Ji ³ OH o G ^CH 3 T Jf Y° ^-A ^X 'N' ^/X 'N c N (E)-3-(4-((7-(tert- Butoxycarbonyl)-2-((4cyanophenyl)amino)6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3,5dimethylphenyl)acrylic acid

- 6 045845

0273972 tert-Butyl 4-(4-cyano2,6-dimethylphenoxy)-2((4cyanophenyl)amino)8,9-dihydro-5Hpyrimido[4,5-c1]azepine7(6H)-carboxylate 1 1 N 0273976 ⁰ ΊΓ hn^YS YZ^N^NH ό II N 4-((2-((4- Cyanophenyl)amino)6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3,5dimethylbenzonitrile 0274009 A°y°Y J tert-Butyl 2-((4cyanophenyl)amino)-4(4-(2-cyanovinyl)-2,6dimethylphenoxy)-8,9dihydro-5Hpyrimido[4,5-c1]azepine7(6H)-carboxylate 0274010 bq^· b Ao 4-((2-((4- Cyanophenyl)amino)-7picolinoyl-6,7,8,9tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3,5dimethylbenzonitrile 0274011 z^4 O^L^o Q - 4 z 4-((2-((4- Cyanophenyl)amino)-7isonicotinoyl-6,7,8,9tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3,5dimethylbenzonitrile

- 7 045845

0274012 ΛΑ? ⁿ N 4-((2-((4- Cyanophenyl)amino)-7nicotinoyl-6,7,8,9tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3,5dimethylbenzonitrile 0274014 b 4-((2-((4- Cyanophenyl)amino)-7(pyridin-2-ylmethyl)6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3,5dimethylbenzonitrile 0274015 Tj ^X ---NH ^J ? N 4-((2-((4Cyanophenyl)amino)-7(pyridin-3-ylmethyl)6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3,5dimethylbenzonitrile

- 8 045845

- 9 045845

- 10 045845

- 11 045845

- 12 045845

0274057 o°^| / ^N \ to Λ -Dk N NH ό II N 4-({2-[(4cyanophenyl)amino]-6(4-methylpiperazine-1 carbonyl)- 5H,6H,7H,8Hpyrido[4,3с1]pyrimidin-4yl}oxy)-3,5dimethylbenzonitrile 0274063 b o^L-/ tert-Butyl 2-(4-(4Cyano-2,6dimethylphenoxy)-2((cyanophenyl)amino)6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepine7carbonyl)pyrrolidine1-carboxylate 0274064 ^NChiral XyVAxS N (E)-tert-Butyl 2-(4-(4Cyano-2,6dimethylphenoxy)-2((cyanophenyl)amino)6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepine7- carbonyl)pyrrolidine 1-carboxylate

- 13 045845

(8)-tert-Butyl 2-(4-(4Cyano-2,6dimethylphenoxy)-2((cyanophenyl)amino)6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepine7carbonyl)pyrrolidine1- carboxylate

4-((2-((4Cyanophenyl)amino)-7(tetrahydro-2H-pyran4-yl)-6,7,8,9tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3,5dimethylbenzonitrile

Synthesis of 4-((2-((4Cyanophenyl)amino)-7(5-methylfuran-2yl)methyl)-6,7,8,9tetrahydro-5Hpyrimido[4,5-c1]azepin4-yl)oxy)-3, 5dimethylbenzonitrile

- 14 045845

- 15 045845

- 16 045845

- 17 045845

0274103 x^NChiral o. „V CK ,ΝΗ L F. N NH : N (5)-tert-Butyl (1-(4-(4cyano-2,6- dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3c!]pyrimidin-6(5H)-yl)1-oxo-3-phenylpropan2-yl)carbamate 0274111 ^NChiral ΐ Fi %NH, < A. — ² — N NH ό II N (S)-4-((6-(2-Amhho-3phenylpropanoyl)-2-((4cyanophenyl)amino)5,6,7,8- tetrahydropyrido[4,3с!]pyrimidin-4yl)oxy)-3,5- dimethylbenzonitrile 0274118 ^N fx V A A xx N NH ? N 4-((2-((4- Cyanophenyl)amino)-7(2-morpholinoethyl)6,7,8,9-tetrahydro-5Hpyrimido[4,5-c!]azepin4-yl)oxy)-3,5dimethylbenzonitrile 0274119 χΝ Chi Yjj Η 1 1 / ^N ΗΟ' ^Χ ^Α ^χ> ^ ^ν ' ^Χ ^| ^/ ^ ^Ν XFr^ CX ,NH L Ji xF XJ X^ xx χ XX F ^H (R)-TpeT-Butyl (1-(4-(4cyano-2,6- dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3c!]pyrimidin-6(5H)-yl)3-hydroxy-1oxopropan-2yl)carbamate 0274120 XM Yy 0 II 1 χΝ 1^1 I Ol ck.nh L xk Al γ X^N N ^^x 1 h tert-Butyl (1-(4-(4cyano-2,6- dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3c!]pyrimidin-6(5H)-yl)4-(methylthio)-1oxobutan-2yl)carbamate 0275622 ^N ο ^oxX4 | NfYl I ^NH NH ₂ L Λ xT ² N NH 0 II N 4-({6-[2-amino-3-(1Ni midazol-5yl)propanoyl]-2[(4-cyanophenyl)amino]5H,6H,7H,8Hpyrido[4,3с!]pyrimidin-4yl}oxy )-3,5dimethylbenzonitrile

- 18 045845

4-((6-(2-Amino-3-(1Hpyrazol-4yl)propanoyl)-2-((4cyanophenyl)amino)5,6,7,8tetrahydropyrido[4,3с1]pyrimidin-4yl)oxy)-3, 5dimethylbenzonitrile tert-Butyl 4-(2-((tertbutoxycarbonyl)amino)-3-(4-(4-cyano-2,6dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3c1]pyrimidine -6(5H)-yl)3-oxopropyl)-1 hlpyrazole-1-carboxylate

(R)-4-((6-(2-Amhho-3hydroxypropanoyl)-2((4cyanophenyl)amino)5,6,7,8tetrahydropyrido[4,3с1]pyrimidin-4yl)oxy)-3,5dimethylbenzonitrile

(B)-tert-Butyl (1-(4-(4cyano-2,6dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3c1]pyrimidin-6(5H)-yl)3- (4-hydroxyphenyl)-1oxopropane--2yl)carbamate

- 19 045845

Rl-tert-Butyl 1-4-4cyano-2,6dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3cPpyrimidin-6(5H)-yl)3-methyl-1-oxobutan-2yl )carbamate (B)-Di-tert-butyl (6-(44-cyano-2,6dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3a1pyrimidin-6(5H)-yl)6 -oxohexane-1,5diylshicarbamate (5)-4-((2-((4Cyanophenyl)amino)-6S)-4-6-2-AMINO-4methylpentanoyl)-2-((4cyanophenyl)amino)5,6,7 ,8tetrahydropyrido[4,3a]pyrimidin-4yl)oxy)-3,5dimethylbenzonitrile diaminohexanoyl)5,6,7,8tetrahydropyrido[4,3a]pyrimidin-4yl)oxy)-3,5dimethylbenzonitrile oil -2- 4cyanophenyl)amino)5 ,6,7,8tetrahydropyrido[4,3cPpyrimidin-4yl)oxy)-3,5dimethylbenzonitrile

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

Ch (5)-tert-Butyl (1-(4-(4cyano-2,6dimethylphenoxy)-2-((4cyanophenyl)amino)7,8-dihydropyrido[4,3a]pyrimidin-6(5H)-yl)4 -methyl-1-oxopentan2-yl)carbamate (o)-4-((6-(2-Amino-3-(4hydroxyphenyl)propane

- 20 045845

- 21 045845

- 22 045845

- 23 045845

4-7-Acetyl-2-4cyanophenyl)amino)6,7,8,9-tetrahydro-5Hpyrimido[4,5-a]azepin4-yl)oxy)-3,5dimethylbenzonitrile

4- 7- 2-(1H-Imidazol1-yl)acetyl)-2-((4cyanophenyl)amino)6,7,8,9-tetrahydro-5Hpyrimido[4,5-a]azepin4-yl)oxy)- 3,5dimethylbenzonitrile

4-((2-((4Cyanophenyl)amino)-72-(methyl-1 H-imidazol1-yl)acetyl)-6,7,8,9tetrahydro-5Hpyrimido[4,5-a]azepin4-yl)oxy) -3,5dimethylbenzonitrile

4-(4-cyano-2,6dimethylphenoxy)-2-[(4cyanophenyl)amino]-Moxan-4-yl)4aH,5H,6H,7H,8H,8aHpyrido [4,3a]pyrimidine-6carboxamide methyl 2-{ 2-4cyanophenyl)amino]-4(4-formyl-2,6dimethylphenoxy)5H,6H,7H,8H,9Hpyrimido [4,5a]azepin-7-yl}-2□xoacetate

4-(4-cyano-2,6dimethylphenoxy)-2-[(4cyanophenyl)amino]5H,6H,7H,8Hpyrido[4,3a]pyrimidine-6sulfonamide

- 24 045845

Disclosure of the Invention

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

where R1 is independently selected and represents 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; NHR ⁹ ; NR ⁹ R ¹⁰ ; substituted or unsubstituted C _2-6 alkenyl; substituted or unsubstituted C _2-6 alkynyl;

X1, X ₂ represent a substituent of the form (CH ₂ )n, and n is chosen independently for X1, X ₂ ;

Y1 is independently selected and represents -O- or substituents of the form:

Rb is independently selected 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 4-9 membered heterocyclyl containing from 1 up to 4 heteroatoms independently selected from N, S and/or O, ^R7 , where Rb can be attached to the rest of the molecule through a linker of the form ( _CH2 ) _n ,

R ⁷ represents C ₃ -cycloalkyl;

R ⁹ and R ¹⁰ are each independently hydrogen; cyano, C _1-6 alkyl; C _1-6 alkylcarbonyl; amino; wherein each of the above C _1-6 alkyl groups may optionally be substituted with hydroxy;

where the substituents R1, Rb are each independently selected from the group including: 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 C _1-6 alkyl, BOC, COOH, C _3-6 aryl, possibly substituted with OH, or OCH ₂ C=CH, 4-6 membered heterocyclyl , containing 1-3 heteroatoms selected from N, S and O, O, N, halogen;

n can range from 1 to 3, or a pharmaceutically acceptable salt or isotope thereof.

In another embodiment, the present invention provides a compound according to claim 1, wherein

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; Rb 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 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, including:

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, wherein said heteroaryl is unsubstituted or substituted with C _1-6 alkyl, VOS; COOH; the remaining substituents are defined in the present invention.

In another embodiment, the present invention provides a compound of the present invention wherein R1 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 R1 is independently selected and is a 4-6 membered heterocyclyl containing 1-2 O heteroatoms.

In another embodiment, the present invention relates to a compound of the present invention in

- 25 045845 in which R1 is oxetane.

In another embodiment, the present invention provides a compound of the present invention wherein Y1 is -O-.

In another embodiment, the present invention relates to a compound of the present invention, in which Y 1 represents substituents of the form:

In another embodiment, the present invention relates to a compound of the present invention, in which Y 1 represents substituents of the form:

• * * 1

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

In another embodiment, the present invention provides a compound of the present invention wherein Rb is substituted or unsubstituted phenyl, wherein the substituents are as defined herein.

In another embodiment, the present invention provides a compound of the present invention wherein Rb is substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, isobenzofuranyl, benzimidazolyl, furan, where the substituents are as defined herein.

In another embodiment, the present invention provides a compound of the present invention wherein Rb is substituted or unsubstituted piperidine, azetidine, morpholine, tetrahydropyran.

In another embodiment, the present invention relates to a compound of the present invention, in which Y 1 represents substituents of the form:

Rb RbI ok /Rb IO

RbO=S=O

IIII/ ^N \a Rb is a substituted or unsubstituted -5-6-membered heteroaryl or heterocyclyl containing 1 to 2 heteroatoms independently selected from N, S and/or O, where the substituents are defined in the present invention.

In another embodiment, the present invention relates to a compound of the present invention, in which Y 1 represents substituents of the form:

Rb Rb. _o J _o

Y Rb /Ν^ a Rb is substituted or unsubstituted -C ₆ -aryl, 5-6 membered heteroaryl, where the substituents are defined in the present invention.

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

- 26 045845

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

4-(2,6-dimethylphenoxy)-M-(piperidin-4-yl)-6,7-dihydro-5H-cyclopenta[c1]pyrimidin2-amine;

4-(((6-benzyl-4-(4-cyano-2,6-dimethylphenoxy)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidin-2-yl)amino)methyl)benzoic ethyl ester acids;

4-(((6-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3c1]pyrimidin-2-yl)amino)methyl)benzoic acid ethyl ester;

4-(((7-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-c1]pyrimidin-2yl)amino)methyl)benzonitrile;

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

M-(1-benzylpiperidin-4-yl)-4-(2,6-dimethylphenoxy)-6,7-dihyde rho-5Hcyclopenta[c1]pyrimidin-2-amine;

4-((2-((4-cyanophenyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-c1]pyrimidin-4yl)oxy)-3,5-dimethylbenzonitrile;

4-((4-(4-formyl-2,6-dimethylphenoxy)-7-methyl-5,6,7,8-tetrahydro[3,4-c1]pyrimidin-2yl)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 -c1]azepine-7(6H)-carboxylate;

tert-butyl 2-((4-cyanophenyl)amino)-4-(4-formyl-2,6-dimethylphenioxy)-8,9-dihydro5H-pyrimido[4,5-c1]azepine-7(6H)-carboxylate ;

tert-butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidine-6(5H)-carboxylate;

4-((2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-c1]pyrimidin-4-yl)oxy)3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-6-(methylsulfonyl)-5,6,7,8-ropyrido[4,3c1]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitiryl tetrahydride ;

ethyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidine-6(5H)-carboxylate;

(E)-3-(4-((7-(tert-butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepine -4-yl)oxy)-3,5-dimethylphenyl)acrylic acid;

tert-butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5Hpyrimido[4,5-c1]azepine-7(6H)-carboxylate ;

4-((2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c1]azepin-4-yl)oxy)3,5-dimethylbenzonitrile;

tert-butyl 2-((4-cyanophenyl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8,9dihydro-5H-pyrimido[4,5-c1]azepine-7( 6H)-carboxylate;

4-((2-((4-cyanophenyl)amino)-7-picolinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5c1]azepin-4-yl)oxy)-3,5 -dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-isonicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5c1]azepin-4-yl)oxy)-3,5- dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-nicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5

- 27 045845 c1]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-(pyridin-3-ylmethyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-(pyridin-4-ylmethyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin-4-yl) hydroxy)-3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c1]azepin-4-yl)oxy)3,5-dimethylbenzonitrile;

tert-butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9tetrahydro-5H-pyrimido[4,5-c1] azein-7-carbonyl)piperidine-1-carboxylate;

4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-carbonyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile;

tert-butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro5H-pyrimido[4,5-c1]azepine-7(6H )-yl)piperidin-1-carboxylate;

4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5c1]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile;

4-((6-(2-aminoacetyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3c1]pyrimidin-4-yl)oxy)-3,5 -dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-6-(2-(3-hydroxyazetidin-1 -yl)acetyl)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidin-4 -yl)oxy)-3,5-dimethylbenzonitrile;

4-({2-[(4-cyanophenyl)amino]-6-[2-(morpholin-4-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3c1]pyrimidin-4-yl} hydroxy)-3,5-dimethylbenzonitrile;

4-({2-[(4-cyanophenyl)amino]-6-[2-(4,4-difluoropiperidin-1-yl)acetyl]-5H,6H,7H,8Hpyrido[4,3-c1]pyrimidin- 4-yl}oxy)-3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-(cyclopropanecarbonyl)-5,6,7,8-tetrahydro-[4,3c1]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile ;

4-({2-[(4-cyanophenyl)amino]-6-(morpholine-4-carbonyl)-5H,6H,7H,8H-pyrido[4,3c1]pyrimidin-4-yl}oxy)-3, 5-dimethylbenzonitrile;

4-({2-[(4-cyanophenyl)amino]-6-(4-methylpiperazin-1-carbonyl)-5H,6H,7H,8Hpyrido[4,3-c1]pyrimidin-4-yl}oxy)- 3,5-dimethylbenzonitrile;

tert-butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9

- 28 045845 tetrahyde rho-5H-pyrimido[4,5-c1]azepine-7-carbonyl)pyrrolidine-1-carboxylate;

(E)-tert-butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9tetrahydro-5H-pyrimido[4,5- c1]azepine-7-carbonyl)pyrrolidine-1-carboxylate;

(3)-tert-butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9tetrahydro-5H-pyrimido[4,5- c1]azepine-7-carbonyl)pyrrolidine-1-carboxylate;

4-((2-((4-cyanophenyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin- 4-yl)oxy)-3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-(5-methylfuran-2-yl)methyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]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-5Hpyrimido[4,5-c1 ]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-(4-hydroxybenzyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin-4-yl)oxy) -3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-(1-methoxypropan-2-yl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepine-4- yl)oxy)-3,5-dimethylbenzonitrile;

tert-butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidine-6- carbonyl)pyrrolidine-1-carboxylate;

4-((2-((4-cyanophenyl)amino)-6-(pyrrolidin-2-carbonyl)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidin-4-yl)oxy)-3 ,5-dimethylbenzonitrile;

4-((6-(azetidine-3-carbonyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3c1]pyrimidin-4-yl)oxy)-3 ,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-6-(pyrazin-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3c1]pyrimidin-4-yl)oxy)-3 ,5-dimethylbenzonitrile;

(3)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidine-6( 5H)-yl)-1-oxopropan-2-yl)carbamate;

(5)-4-((6-(2-aminopropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3с1]pyrimidin-4-yl)oxy)- 3,5-dimethylbenzonitrile;

(3)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidine-6( 5H)-yl)-1-oxo-3-phenylpropan-2-yl)carbamate;

(5)-4-((6-(2-amino-3-phenylpropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidine-4- yl)oxy)-3,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-7-(2-morpholinoethyl)-6,7,8,9-tetrahydro-5H

- 29 045845 pyrimido[4,5-c1]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile;

(^-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidine-6(5H )-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate;

tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidin-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-c1 ]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile;

4-((6-(2-amino-3-(1H-pyrazol-4-yl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-c1 ]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-c1]pyrimidin-6(5H)-yl)-3-oxopropyl)-1Hpyrazole-1-carboxylate;

(^-4-((6-(2-amino-3-hydroxypropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidin-4-yl )oxy)-3,5-dimethylbenzonitrile;

(3)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidine-6( 5H)-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2yl)carbamate;

(8)-4-((6-(2-amino-3-(4-hydroxyphenyl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-c1 ]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile;

(^-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidine-6(5H )-yl)-3-methyl-1-oxobutan-2-yl)carbamate;

(R)-4-((6-(2-amino-3-methylbytanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidine-4- yl)oxy)-3,5-dimethylbenzonitrile;

(3)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidine-6( 5H)-yl)-4-methyl-1-oxopentan-2-yl)carbamate;

(5)-4-((6-(2-amino-4-methylpentanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidine-4- yl)oxy)-3,5-dimethylbenzonitrile;

(5)-di-tert-butyl (6-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-c1]pyrimidin- 6(5H)-yl)-6-oxohexane-1,5-diyl)dicarbamate;

(5)-4-((2-((4-cyanophenyl)amino)-6-(2,6-diaminohexanoyl)-5,6,7,8tetrahydropyrido[4,3-c1]pyrimidin-4-yl) hydroxy)-3,5-dimethylbenzonitrile;

4-((7-(2-chloroacetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5- 30 045845 с1]azepine-4- yl)oxy)-3,5-dimethylbenzonitrile;

methyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-4-cyanophenyl)amino)-8,9-dihydro-5Hpyrimido[4,5-c1]azepine-7(6H)-carboxylate ;

4-((2-((4-cyanophenyl)amino)-7-(methylsulfonyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-c1]azepin-4-yl)oxy)-3, 5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-6-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3с1]pyrimidin-4-yl)oxy)-3 ,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-6-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3c1]pyrimidin-4-yl)oxy)-3 ,5-dimethylbenzonitrile;

4-((2-((4-cyanophenyl)amino)-6-(2-hydroxybenzyl)-5,6,7,8-tetrahydropyrido[4,3c1]pyrimidin-4-yl)oxy)-3,5 -dimethylbenzonitrile;

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

3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihyde rho-5Hpyrimido[4,5-c!]azepine-7(6H) -yl)propanoic acid;

4-((7-allyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c!]azepin-4yl)oxy)-3,5 -dimethylbenzonitrile;

4-((7-acetyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-c1]azepin-4yl)oxy)-3,5 -dimethylbenzonitrile

4-((7-(2-(1H-imidazol-1-yl)acetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5Hpyrimido[4,5- c!]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile;

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

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

methyl 2-{2-[(4-cyanophenyl)amino]-4-(4-formyl-2,6-dimethylphenoxy)5H,6H,7H,8H,9H-pyrimido[4,5-c1]azepine-7- yl}-2-oxoacetate;

4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-M-(oxan-4-yl)4aH,5H,6H,7H,8H,8aH-pyrido [4, 3-c1]pyrimidine-6-carboxamide.

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

In another embodiment, the present invention provides a compound of the present invention in the form of a pharmaceutically acceptable salt prepared using counterions such as halides, hydroxides, carboxylates, sulfates.

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

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

In another embodiment, the present invention provides 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 provides 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, additionally, at least one compound selected from the group consisting of HIV protease inhibitors, nucleoside reverse transcriptase inhibitors, 31 045845 ny transcriptase, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists and inhibitors of viral cell entry.

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 relative to wild-type HIV, comprising a compound of the present invention in a therapeutically effective amount.

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

In another embodiment, the present invention provides a pharmaceutical composition for the preparation of an agent 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 relates to a method of treating or preventing HIV, including the use of a composition of the present invention.

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

In another embodiment, the present invention relates to said method of treatment or prophylaxis, wherein said therapeutically effective amount of the compound means a daily dose that ranges from 0.1 to 500 mg/kg 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 provides a combination for the treatment or prevention of HIV-related diseases, comprising 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 inhibitors of viral entry into cells.

In another embodiment, the present invention provides a method for treating or preventing HIV-related diseases, 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 cell entry inhibitors.

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

In another embodiment, the present invention relates to a method for preparing a pharmaceutical composition of the present invention, comprising mixing a compound 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 the present description. In other embodiments presented below, each embodiment contains substituents that do not necessarily retain the most general scope set forth in the Summary of the Invention or in the present description.

Unless otherwise specified, technical and scientific terms used in the description of the present invention have the meanings known to one skilled in the art to which the invention relates. The description includes references to various techniques and materials known to one skilled in the art. The standard document that discusses the general principles of pharmacology is the monograph by Goodman and Gilman, The Pharmacological Basis of Therapeutics, 13th ed., McGraw Hill Companies Inc., New York (2017). Any suitable materials and/or methods known to one skilled in the art may be used in the practice of the present invention. However, preferred materials and methods are described in the specification of the present invention. The materials, reagents, etc. mentioned in the specification and examples are commercial preparations unless otherwise indicated.

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

In the description of the invention, for example, in any section of the application or in the claims, the terms include (include) and including have the generally accepted meaning. Those. the terms roughly correspond to the clauses containing at least or including at least. In relation to a method, the term comprising means that the method includes at least the steps mentioned. With respect to a compound or composition, the term including means that the compound or composition includes at least the specified features or components, but may also include additional features or components.

The term approximately, as used in the specification of the application, means about, about, approximately or approximately. The term approximately, when 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 approximate is used to indicate the permissible changes in a numerical value above and below a specified value by 20%.

When used in the specification, reference to 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. Likewise, a variable that is continuous in nature can 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 may mean 0, 1, or 2 if it is a discrete quantity, and may have values 0.0, 0.1, 0.01, 0.001, or any other actual value if it is a continuous variable.

If any group (eg, R1) is contained in a fragment or in any specified formula or in any described compound 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 permissible if the resulting compounds are stable compounds.

In one embodiment, the present invention provides a compound of formula I, wherein R1, X1, X ₂ , Y1 are as defined above. The terms above and as above mean the variables included by reference in the broadest definition of the variables specified in the Summary of the Invention or in the broadest claim.

In yet another embodiment, the present invention provides a compound that is a pharmaceutically acceptable salt of a compound of the present invention.

In another embodiment, the present invention provides a method of treating HIV infection or preventing HIV infection, which consists of administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, wherein R1, X1, _X2 , _Y1 are as defined higher.

In yet another embodiment, the present invention provides a method for treating or preventing HIV-related diseases, which comprises administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, wherein R1, X1, _X2 , Y1 are as 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 cell entry inhibitors.

In another embodiment, the present invention provides a method of inhibiting HIV reverse transcriptase in a subject infected with HIV, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula I, wherein R1, X1, _X2 , Y1 are: mentioned above.

In another embodiment, the present invention provides a method of inhibiting HIV reverse transcriptase in a subject infected with HIV, wherein the HIV reverse transcriptase contains at least one mutation compared to wild-type HIV, wherein the subject in need of treatment is administered therapeutically an effective amount of a compound of formula I, wherein R1, X1, _X2 , Y1 are as defined above.

In another embodiment, the present invention provides a method of inhibiting HIV reverse transcriptase in a subject infected with HIV, wherein the HIV reverse transcriptase has reduced sensitivity to the drugs efavirenz, nevirapine or delavirdine, which consists of administering a therapeutically effective amount to the subject in need of treatment. compounds of formula I, where R1, X1, X ₂ , Y1 have the meanings specified above.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of Formula I, wherein R1, X1, _X2 , Y1 are as defined above, and at least one carrier, excipient or diluent.

The following definitions apply throughout this document unless otherwise stated. Additionally, unless otherwise noted, all occurrences of functional groups are chosen independently, two occurrences

- 33 045845 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 specified number of carbon atoms (ie, C ₁ . ₆ αlkyl means 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, etc.

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 carbon atoms. 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 as 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, alone or in combinations, refer (unless otherwise specified) 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, tert-butoxy, pentoxy, isopentoxy, neopentoxy, tert-pentoxy, hexoxy -, isohexoxy, heptoxy, octoxy group, etc. Preferred alkoxy groups are methoxy and ethoxy.

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

Specific examples of monocyclic, bicyclic or tricyclic saturated carbocycles include 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 include 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, etc.

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

Specific examples of monocyclic, bicyclic or tricyclic saturated heterocycles include tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl, dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl, triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl, he scahydropyrimidinyl, hexahydropyrazinyl, dioxanil, morpholinyl, dithianyl, thioforfolinyl, piperazinyl, trithianyl, decahydroquinolinyl, oc-34 045845 tahydroindolyl, etc. Preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, imidazolidinyl, thiazolidinyl, dihydrooxazolyl, triazolidinyl, piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl. Particularly preferred are tetrahydrofuranyl, pyrrolidinyl, dioxolanyl, piperidinyl, dioxanyl, morpholinyl, thiomorpholinyl, piperazinyl.

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

Specific examples of monocyclic, bicyclic or tricyclic aromatic heterocycles are azetyl, oxetylidenyl, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuryl, isobenzofuryl, benzothienyl, isobenzothienyl, indolizinyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinil, naphthyridinyl, pteridinyl, benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazine yl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl, thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl, thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl, pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl, thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl, imidazothiazolyl, imidazoimidazolyl, isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl, oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl, oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl, carbazolyl, acridinyl, phenazine yl, phenothiazinyl, phenoxazinil, etc.

Preferred aromatic heterocycles are monocyclic or bicyclic aromatic heterocycles. Representing the interest of monocyclic, bicyclic or tricyclic aromatic heterocycles are pyrrolil, firil, thyenil, imidasolil, oxasolil, Izoxazole, thiazolil, isotiazolil, pyrazolil, triazolil, thiadiazolil, oxadiazolil, tetrazolil, pyridyl, pyrimidyl, pyramidyl, pyrasil, pyroimidinyl, pyramidinyl, pyramidinyl, pyramidinyl, pyroimidinyl, pyramidinyl, pyramidinyl, pyramidinyl, pyramidinyl, pyramidinyl, pyramidinyl, pyriminyl, pyramidyl, pyramidyl, pyramidyl, pyramidyl, pyroisinyl. Pyridazin, triazinyl, piranel, gasofilers, isobenzofuryl, benzothienyl, isobenzothienyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzo pyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl, isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl, oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl, thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl, pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furopyrimidinyl , isothiazolopyrimidinyl, thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl, pyrazolopyrimidinyl, imidazopyrimidinyl, oxadiazolopyridyl, thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl, thiadiazolopyrazinyl, triazopyrazinyl, oxadiazolopyrimidinyl, thiadiazolopyrimidinyl, triazolopyrimidinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, etc.

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 replaced.

The term heterocycle, heterocyclyl or heterocyclic means as used herein non-aromatic mono- or polycyclic systems (saturated or partially unsaturated) having from three to twelve atoms containing heteroatoms N, O or S. The heterocycle can be attached to the main moiety of the molecule through a nitrogen atom ( N-heterocyclyl) or through a carbon atom. Heterocycles may also be substituted. In particular, the heterocycle may be, without limitation, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morph olinyl, 1.1 -dioxothiomorpholin-4-yl, azepanil, diazepanil, homopiperazinil, 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-9azabicyclo[3.3.1]nonyl, or 3-thia-9-azabicyclo[3.3.1]nonyl. Specific examples of heterocycles also include dihydrofuryl, imidazolinyl, dihydro-oxazolyl, tetrahydropyridinyl, dihydropyryl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and 2-oxa-5-aza-bicyclo[2.2.1]heptyl. The term cycloalkenyl means, as used herein, a partially unsaturated cycloalkyl containing from 5 to 12 carbon atoms, containing from one to two carbon-carbon double bonds.

The term aryl as used herein means groups containing an aromatic ring having from 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. A heteroaryl group may be substituted or unsubstituted and may consist of one or more rings. Possible substituents include, but are not limited to, any of the previously mentioned substituents. Examples of typical 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 may be used equivalently with the terms heteroaryl ring or heteroaromatic.

An aryl group or a heteroaryl group (including the heteroaryl moiety of heteroaralkyl or heteroaralkoxy moieties and the like) may contain one or more substituents. Examples of suitable substituent on an unsaturated carbon atom of an aryl or heteroaryl group include, but are not limited to, halogen (F, Cl, Br or I), C ₁ . ₃ αlkyl, -CN, -OH, -C ₁ . ₃ alkyl and others as specified in the present invention.

The carbocycles or heterocycles referred to in the definition of R ⁷ may be attached to the remainder of the molecule of formula (I) via any suitable cyclic carbon atom or heteroatom unless specifically stated otherwise. So, 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-naphthalynyl, 2-naphthalenyl, etc. .d.

If any of the substituents (for example, R ⁷ ) occurs simultaneously in the same compound more than once, each of the definitions of such substituent is independent.

The term substituted shall mean that one or more hydrogen atoms of the atom or group referred to as substituted have been replaced by any of the listed groups, provided that the atom referred to is of normal valence, or that the valency of the corresponding group atom being replaced is not excessive, and that substitution results in a stable connection. The term substituted or unsubstituted means that the compound or substructure is either unsubstituted or substituted, as defined herein, 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 replaced by 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 via C or N atoms, -phenyl, -5-6-membered heteroaryl attached via C or N -atoms, -OR ^z , -N(R ^z )2, -NR ^z -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 h -SO2R ^z , in which each R ^z is independently selected and represents -H, -C1-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 a substituted or unsubstituted 4-9 membered heterocyclyl containing from 1 to 4 heteroatoms.

Another group from which substituents may be selected is: COO-isobutyl, NH2, 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 -OH, C ₁ . ₆ αlkyl, O or Rc; BOC, COOH, ^Rc , _C3 . ₆ aryl, possibly substituted with OH, O or OCH ₂ C=CH, 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 those combinations of substituents and derivatives that form a stable or chemically possible compound. 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 degrade at temperatures up to 40°C in the absence of chemically active conditions for at least one week.

Some of the 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 a state of dynamic equilibrium. Under normal conditions, their separation is impossible, therefore the pharmacological properties of the compounds of the present invention represent the totality of the effects of tautomers.

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

(1) ( ² ) (3)

Unless otherwise indicated, the structures depicted here also include all stereoisomers, that is, the 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 covers each diastereomer or enantiomer substantially free from other isomers (>90%, and preferably >95% molar purity), as well as mixtures of such isomers.

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

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

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 typically 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 ^PS , 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 ¹⁵ O, ¹⁷ O and ¹⁸ O, phosphorus such as ³² P, and sulfur such as ³⁵ S.

Certain isotopically labeled compounds of the present invention, for example those that include 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 administration and the availability of means of 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 decreased dosing rates, and may therefore be advantageous in some cases.

The isotopically labeled compounds of the invention can be prepared by conventional methods known to one skilled in the art or by methods similar to those described in the accompanying examples of synthetic methods, using 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 the distribution of a drug of the present invention or the determination of targets having affinity for the compounds of the present invention, in particular the 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 the reverse transcriptase expressed by the wild-type strain, which has been sequenced and is listed in the SwissProt database as P03366.

The term reduced sensitivity as used in the specification of the application means approximately a 10-fold or greater change in the sensitivity of an isolate of a particular viral strain compared to

- 37 045845 with the sensitivity that is observed in the wild-type virus under similar experimental conditions.

The compounds of the present invention are prepared using the methods shown in the following diagrams and described in the Carrying Out the Invention section. The starting materials and reagents that are used in the preparation of these compounds are commercial reagents supplied by companies, for example, Acros Organics, Alfa Aesar, Lancaster, Merck and Sigma-Aldrich and others, or they are obtained by known methods according to methods described in the literature, such , as Fieser and Fieser, Reagents for Organic Synthesis, Wiley & Sons: New York, vol. 1-21, R.C. LaRock, Comprehensive Organic Transformations, 2nd ed., Wiley-VCH, New York (1999), Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.), vol. 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, vol. 1-11 (1986) and Organic Reaction, Wiley & Sons: New York, vol. 140 (1991), as well as those found in databases such as, but not limited to, SciFinder and Reaxis. The following reaction schemes only illustrate 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 the indicated 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 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 general substituents, however, it will be clear to those skilled in the art that the nature of the R groups may 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. The sequence of reactions in the following examples is not intended to limit the scope of the invention as set forth in the claims.

Pharmaceutically acceptable solvates in accordance with the invention include solvates where the solvent may be isotopically substituted, for example, 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 solvents that form solvates 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 desired, in the form of a pharmaceutically acceptable salt or other derivative. As used herein, the term pharmaceutically acceptable salt refers to those salts which, to the best of medical judgment, are suitable for use in contact with human and animal tissue without undue toxicity, irritation, allergic reaction, etc., and meet a reasonable balance of benefit and risk. . Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in medicine. Salts may be prepared in situ during the isolation or purification of the compounds of the invention, or may be prepared separately by reacting the free acid or free base of a compound of the invention with a suitable base or acid, respectively. Examples of pharmaceutically acceptable, non-toxic acid salts include amino salts formed from 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 from other methods used in the art, 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-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalene sulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanate, valerate 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 prepared using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl

- 38 045845 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 is converted to an ester. 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 arylkyl ethers are examples of suitable esters. Specific esters are methyl, ethyl, propyl, butyl and benzyl esters. The term pharmaceutically acceptable esters further embraces compounds of the present invention in which the hydroxy groups are 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 reaction steps, appropriate protecting groups (as described, for example, in Protective Groups in Organic Chemistry by T. W. Greene and P. G. M. Wutts, 3rd Ed., 1999, Wiley, New York) can be administered before the critical stage 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 (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teos), carbobenzyloxy (Cbz) and p-methoxybenzyloxycarbonyl (Moz).

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

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

Another embodiment of the present invention relates to pharmaceutical compositions or drugs containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and drugs. In one example, the compounds of the present invention can be prepared by mixing at room temperature, the appropriate pH and at the desired degree of purity, with physiologically acceptable carriers, for example, carriers that are non-toxic to recipients at the doses and concentrations used, in a galenic administration form. The pH of the composition depends primarily on the specific use and concentration of the compound, but preferably can 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 prepared, dosed and administered in accordance with good medical practice. Factors considered in this context 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, the route of administration, the schedule of administration and other factors known to the practitioner.

The compounds of the invention can be administered by any suitable routes, including orally, topically (including buccally and sublingually), rectally, vaginally, transdermally, parenterally, subcutaneously, intraperitoneally, intrapulmonarily, intradermally, intrathecally and epidurally and intranasally. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention can be administered in any convenient form for administration, for example, tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches and the like. Such compositions may contain components conventional in pharmaceutical preparations, for example, 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, for example, in 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 S. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. Composition

- 39 045845 tions 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, flavoring agents , 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 assist in the manufacture of a pharmaceutical product (eg, a drug).

Thus the present invention also relates to the following:

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; a 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;

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 penetration into cells;

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 includes 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 give them higher solubility in water or other carrier is achieved using fairly simple techniques (preparation of salt, esterification, etc.), which are well known to a person skilled in the art. In addition, one skilled in the art may alter the route of administration and course of treatment for a particular compound to adjust the pharmacokinetics of the compound of the invention to achieve maximum therapeutic effect in the patient.

The term therapeutically effective amount as used herein means the amount necessary to reduce the severity of symptoms of a disease in a patient. The progression of HIV infection is recorded by measuring viral load (RNA) or T-cell levels. The dose is adjusted according to individual requirements in each case. The dosage 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 medications, 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 body weight in single-drug and/or combination therapy. A preferred daily dose is from about 0.1 to about 500 mg/kg body weight, more preferably from 0.1 to 100 mg/kg body weight, and most preferably from 1.0 to about 10 mg/kg body weight. Thus, for administration to a 70 kg patient, the dose ranges from about 7 mg to about 0.7 g per day. The daily dose can be administered as a single dose or in 1-5 divided doses. Typically, treatment begins with doses not exceeding the optimal dose. Then the dose is gradually increased until the optimal effect is achieved for a particular patient. A person skilled in these diseases, without much experimentation, based on his 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 can 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 administration as used herein includes administration of the agents simultaneously 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 one active agent may be administered substantially simultaneously.

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

The pharmaceutical preparations are preferably conventional drugs

- 40 045845 forms. In this form, the drug is divided into unit doses containing appropriate amounts of the active component. The unit dosage form may be a packaged preparation, the package containing discrete quantities 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 examples, which do not limit its scope. The following examples and preparations are provided to clarify the essence of the invention and facilitate its practical application.

Examples

General procedure for replacing a sulfo group with an activated amine

Reaction XIX

R _r NHCOH

NaH, DMF

To a solution of formamide (3.9 mmol, 1 eq.) in DMF (15 ml.) NaH (7 mmol, 1.8 eq.) is added at 0°C. The reaction mixture is stirred at room temperature. 20 minutes. Then the mixture is cooled again to 0°C and the sulfone (3.9 mmol, 1.0 eq.) is added to it. The reaction mixture is stirred for 8 hours, then the organic solvent is evaporated, and water (pH 9) is added to the residue. 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 the eluent.

General procedure for alkylation of substituted tetrahydropyrimidine derivatives

Reaction XX

n

R ₃ Hal

Base

R ₃

Place pyrimidine free base (1 mmol, 1 eq.) and alkyl bromide (1.1 mmol) into 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 hardens. Hydrobromide of the target product is formed. At the end of the reaction, cool the flask and add 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, and dried over anhydrous sodium sulfate. The organic solvent is removed under reduced pressure and the residue is purified by 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-c1]pyrimidin-2yl)amino)benzonitrile

II

ABOUT

_PhCH2Br

K ₂ CO ₃ (XX)

-41 045845

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

Hydrochloride 26 (59.6 g, 0.2 mol, 1 eq.) was dissolved in ethanol (400 ml) and triethylamine (27.8 ml, 0.2 mol, 1 eq.) was added and stirred for 5 min. Then 5% Pd/C (5 g) is added to the reaction mass. The reaction mixture is degassed and the debenzylation reaction is carried out under 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 layer of selitol, cold water (250 ml) and methylene chloride (500 ml) are added. The organic layer is separated, washed twice with water (2x150 ml), dried over anhydrous sodium sulfate, the drying agent is filtered off and the organic solvent is removed by rotary evaporation under reduced pressure. The residue was purified by column chromatography using Hex:EA (3:1) as eluent.

Rf = 0.6.

Weight = 20 g.

Yield = 52%.

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

To a solution of sodium ethoxide obtained by dissolving Na (1.95 g, 81 mmol, 3.0 eq.) in absolute ethanol (100 ml.) was added thiourea (3.22 g, 42 mmol, 1.5 eq.) 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 the addition of the alkylating reagent was completed, the mixture was stirred at room temperature for 1 hour. The reaction mixture was evaporated, and 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 and 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(bH)-carboxylate (29)

Pyrimidine 28 (5.68 g, 19.1 mmol, 1 eq.) is dissolved in 80 ml of DMF, then triethylamine (TEA) (2.66 ml, 19.1 mmol, 1 eq.) is added and after 5 min benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBor) is added. (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 is evaporated and purified by column chromatography using Hex:EA (3:1) as the eluent.

Weight = 4.6 g.

Yield = 68%.

tert-Butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine7(6H)-carboxylate (30)

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

Weight = 3.2 g.

Yield = 85%. LCMS (M+H) = 402.

- 42 045845 tert-Butyl

4-(4-cyano-2,6-dimethylphenoxy)-2-(methylsulfonyl)-5,8-dihydropyrido[3,4

d]pyrimidine-7(6H)-carboxylate (31)

To a solution of pyrimidine 30 (3.0 g, 7 mmol, 1 eq.) in methylene chloride (50 ml) at 0°C add m-chloroperbenzoic acid (mCPBA) (3.8 g, 21.1 mmol, 3 eq.). The reaction mixture is stirred for 24 hours. Then a saturated aqueous solution of NaHCO ₃ is added to the mixture to stop the reaction.

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%.

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

LCMS (M+H) = 434.

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

To a solution of formamide 32 (0.51 g, 3.9 mmol, 1 eq.) in DMF (15 ml.) NaH (0.28 g, 7 mmol, 1.8 eq.) was added at 0°C. The reaction mixture is stirred at room temperature. 20 minutes. Then the mixture is cooled again to 0°C and sulfone 31 (1.8 g, 3.9 mmol, 1.0 eq.) is added to it. The reaction mixture is stirred for 8 hours, then the organic solvent is evaporated, and water (pH 9) is added to the residue. 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 the eluent.

Weight = 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) is dissolved in methanol with saturated hydrogen chloride, stirred for an hour, the organic solvent is evaporated, and the resulting precipitate is recrystallized from ethanol.

Weight = 500 mg.

Yield = 96%.

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

Pyrimidine 20 free base (500 mg, 1 mmol, 1 eq.) 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 hardens. Hydrobromide of the target N-benzyl pyrimidine is formed. At the end of the reaction, cool the flask and add 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, and dried over anhydrous sodium sulfate. The organic solvent is removed under reduced pressure and the residue is purified using chromatography using

Neh:EA (1:3).

Weight = 300 mg.

Yield = 58%.

BB 0273459

1H NMR (400 MHz, DMSO-d ₆ , δ, ppm): 1.95-2.13 (m, 6H), 2.78 (br.s., 2H), 3.43 (br.s., 2H), 3.47- 3.57 (m, 2H), 3.64-3.79 (m, 2H), 7.19-7.46 (m, 12H). 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-4yl)oxy)-3,5-dimethylbenzonitrile

BB 0273774

BB 0273774

1H NMR (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.

- 44 045845

Example 3.

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

BB 0273775

BB 0273775

1H NMR (400 MHz, CDC13, δ, ppm): 1.26 (s, 3H), 2.18-2.20 (m, 2H), 2.23 (s, 6H), 3.14-3.18 (m, 2H), 3.743. 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.

- 45 045845

Example 4.

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

BB 0273892

1H NMR (400 MHz, CDCl ₃ , δ, ppm): 1.51 (s, 10H), 2.09 (s, 6H), 2.20-2.42 (m, 1H), 2.94-3.18 (m, 4H), 3.66 (b.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.

- 46 045845

Example 5.

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

VV 0273892 VV 0273943

BB 0273943

1H NMR (400 MHz, CDCl3, δ, ppm): 1.51 (s, 9H), 2.19 (s, 6H), 3.09 (br.s., 4H), 3.68 (br.s., 4H), 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)-7,8dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

BB 0273961

- 47 045845

BB 0273961 ^1H NMR (400 MHz, CDCI3, δ, ppm): 1.53 (s, 9H), 2.16 (s, 6H), 2.82-2.89 (m, 2H), 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)-3,5dimethylbenzonitrile

VV 0273961 ^VV0273963

BB 0273963 ^1H NMR (400 MHz, DMSO-06, δ, ppm): 2.11 (s, 6H), 3.02 (t, J=5.8 Hz, 2H), 3.50 (d, J=5.2 Hz, 2H ), 4.31 (br.s., 2H), 7.47 (br.s., 4 H), 7.79 (s, 2H).

Mass yield - 2.08 g.

(96%). LCMS m/z (M+H): 397.

- 48 045845

Example 8.

Synthesis

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

BB 0273964

1H NMR (400 MHz, CDCl3, 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.

- 49 045845

Example 9.

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

BB 0273965

1H NMR (400 MHz, CDCl3, δ, ppm): 1.33 (t, J=7.1 Hz, 3H), 2.17 (s, 6H), 2.89 (t, J=5.5 Hz, 2H), 3.86 (t , J=5.7 Hz, 2H), 4.24 (sq., 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.

- 50 045845

Example 10.

Synthesis of (E)-3-(4-((7-(tert-butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-d]azepine -4-yl)oxy)-3,5-dimethylphenyl)acrylic acid

BB 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., 4H). s., 4H), 6.56 (d, J=16.0 Hz, 1H), 7.27-7.39 (m, 2H), 7.40-7.52 (m, 2H), 7.53-7.67 (m, 2H), 9.95-10.09 (m , 1H).

- 51 045845

Example 11.

Synthesis of tert-butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5Hpyrimido[4,5-d]azepine-7 (bH)- carboxylate

BB 0273972 ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 1.51 (s, 9H), 2.14 (s, 6H), 3.06-3.10 (m, 4H), 3.65-3.68 (m, 4H ), 7.07 (b.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.

- 52 045845

Example 12.

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

BB 0273976 ^1H NMR (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 (b.s., 1H).

Mass yield - 0.237 g (92%).

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

- 53 045845

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

BB 0274009

1H NMR (400 MHz, CDCI3, δ, ppm): 1.51 (s, 9H), 2.10-2.17 (m, 6H), 3.08 (br.s., 4H), 3.67 (br.s., 4H ), 5.90-5.46 (m, 1H), 7.63-7.04 (m, 8H).

Mass yield - 0.06 g (8%).

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

- 54 045845

Example 13.

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

BB 0274010 ^1H NMR (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 (US, 1H).

Mass yield - 0.072 g (29%).

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

- 55 045845

Example 14.

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

N

BB 0274011 ^1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.05 (s, 3H), 2.12 (s, 3H), 3.05 (br.s., 2H), 3.12-3.24 (m , 2H), 3.51 (b.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, 2H), 10.10 (d, J=4.0 Hz, 1H).

Mass yield - 0.067 g (32%).

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

- 56 045845

Example 15.

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

N

BB 0274012 ^1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.04 (s, 3H), 2.12 (br.s., 3H), 3.06 (br.s., 2H), 3.19 (br.s. ., 2H), 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.

- 57 045845

Example 16.

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

BB 0274014 ^1H 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.

- 58 045845

Example 17.

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

BB 0274015 ^1H NMR (400 MHz, DMSO-d6, 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, J=1.5 Hz, 1H), 10.04 (s, 1H).

Mass yield - 0.090 g (64%).

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

- 59 045845

Example 18.

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

BB 0274016 ^1H NMR (400 MHz, DMSO-d6, 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.

- 60 045845

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

BB 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 (b.s., 2H), 9.99 (b.s., 1H),

Mass yield - 0.174 g (96%).

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

- 61 045845

Example 19.

Synthesis of tert-butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro5H-pyrimido[4,5-d] azein-7-carbonyl)piperidine-1-carboxylate.

Synthesis scheme 1.56.

BB 0274025 ^1H 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, 3H), 3.03-3.22 (m, 4H), 3.70-3.91 (m, 4H), 4.05-4.34 (m, 2H), 7.05-7.16 (m, 1H), 7.33 (t, J=8.4 Hz, 2H), 7.367.42 (m, 2H), 7.48 (d, J=4.5 Hz, 2H).

Mass yield - 0.230 g (55%).

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

- 62 045845

Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-carbonyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-d]azepin-4-yl) hydroxy)-3,5-dimethylbenzonitrile dihydrochloride

N

BB 0274026

1H NMR (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 (b.s., 2H), 3.62-3.90 (m, 4N), 7.41 (b.s., 4N), 7.78 (b.s., 2H), 8.86 (b.s., 1H), 9.27 (b.s., 1H), 10.08 (b.s., 1H).

Mass yield - 0.090 g (80%).

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

- 63 045845

Example 20.

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

BB 0274027 ^1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.26-1.46 (m, 11H), 1.68 (d, J=11.0 Hz, 2H), 2.08 (s, 6H), 2.582 .83 (m, 7H), 2.94 (b.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.

- 64 045845

Example 21.

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

N

BB 0274028 ^1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.97-2.19 (m, 8H), 2.35 (d, J=11.9 Hz, 2H), 2.94 (kv, J=11.1 Hz , 2H), 3.09 (dd, J=16.5, 6.54 Hz, 1H), 3.24-3.36 (m, 1H), 3.37-3.53 (m, 5H), 3.58-3.70 (m, 2H), 3.71-3.87 (m , 2H), 7.44 (s, 4H), 7.79 (s, 2H), 9.25 (d, J=10.2 Hz, 1H), 9.40 (d, J=9.1 Hz, 1H), 10.14 (br.s., 1H ), 12.13 (b.s., 1H).

Mass yield - 0.182 g (87%).

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

- 65 045845

Example 22.

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

VV 0273961 ^{VV 0273963}

BB 0274051 ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 2.18 (s, 6H), 2.82-3.11 (m, 2H), 3.56-3.88 (m, 2H), 3.90-4.27 (m , 2H), 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.

- 66 045845

Example 23.

Synthesis

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

RuVor (IX) Vos

N

BB 0274052 ^1H NMR (400 MHz, CDCl3, 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, 2H), 7.19 (d, J=7.1 Hz, 2H), 7.26 (s, 2H).

Mass yield - 0.005 g (12%).

LCMS m/z (M+H):510.

- 67 045845

Example 24.

Synthesis of tert-butyl 2-(4-(4-Cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro5H-pyrimido[4,5-d]azepine- 7-carbonyl)pyrrolidine-1-carboxylate

BB 0274063 ^1H NMR (400 MHz, DMSO-d ₆ , δ, ppm): 1.25 (br.s., 9H), 1.36 (s, 3H), 1.59-1.91 (m, 3H), 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 (b.s., 4H), 7.78 (b.s., 2H), 9.96-10.16 (m, 1H).

Mass yield - 0.128 g (57%).

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

- 68 045845

Example 25.

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

N

BB 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 (b.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.

- 69 045845

Example 26.

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

N

BB 0274065 ^1H NMR (400 MHz, DMSO-d ₆ , δ, ppm): 1.25 (br.s., 6H), 1.36 (s, 3H), 1.58-1.92 (m, 3H), 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 (b.s., 4H), 7.77 (b.s., 2H), 9.93-10.16 (m, 1H).

Mass yield - 0.098 g (50%).

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

- 70 045845

Example 27.

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

BB 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.

- 71 045845

Example 28.

Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(5-methylfuran-2-yl)methyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-d]azepine- 4-yl)oxy)-3,5-dimethylbenzonitrile

BB 0274073

1H NMR (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.

- 72 045845

Example 29.

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

BB 0274074 ^1H NMR (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.

- 73 045845

Example 30.

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

BB 0274075

1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.08 (s, 6H), 2.62 (br.s., 4H), 2.98 (br.s., 4H), 3.53 (br.s. ., 2H), 6.72 (d, J=8.3 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.40 (s, 4H), 7.77 (s, 2H), 9.30 (br.s., 1H), 10.03 (s, 1H).

Mass yield - 0.042 g (24%).

LCMS m/z (M+H):517.

- 74 045845

Example 31.

Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(1-methoxypropan-2-yl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-d]azepine-4- yl)oxy)-3,5-dimethylbenzonitrile.

Synthesis scheme 1.75.

BB 0274080 ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 1.06 (d, J=5.8 Hz, 3H), 2.04-2.27 (m, 6H), 2.81 (br.s., 4H) , 3.04 (br.s., 5Н), 3.32 (br.s., 1Н), 3.36 (br.s., 3H), 3.51 (d, J=6.7 Hz, 1Н), 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.

- 75 045845

Example 32.

Synthesis of 4-((7-(cyanomethyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin4-yl)oxy)-3 ,5-dimethylbenzonitrile

BB 0274095

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

Mass yield - 0.042 g (24%).

LCMS m/z (M+H): 450.

- 76 045845

Example 33.

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

BB 0274097 ^1H NMR (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-Voc).

- 77 045845

Example 34.

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

BB 0274098

1H NMR (400 MHz, DMSO-d6, 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 (b.s., 2H), 4.50-4.85 (m, 3H), 7.46 (b.s., 4H), 7.79 (s, 2H), 8.35-8.63 (m, 1H), 10.12 (b.s., 2H).

Mass yield - 0.032 g (88%).

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

- 78 045845

Example 35.

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

Pd/C, _H2

RuVor

Vos ₂ O (IX) Vos o o o o

N

CS2CO3 (XVII)

BB 0274099

1H NMR (400 MHz, DMSO-d6, 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.

- 79 045845

Example 36.

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

BB 0274100 ^1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.19 (s, 6H), 3.00-3.14 (m, 2H), 3.73-4.31 (m, 2H), 4.84-5.05 ( m, 2H), 7.32-7.60 (m, 9H). Mass yield - 0.012 g (20%). LCMS m/z (M+H): 503.

- 80 045845

Example 37.

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

BB 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 (b.s., 2H), 3.62-4.07 (m, 2H), 4.56 (s, 2H), 4.94-5.57 (m, 2H), 7.35 (b.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-Voc).

- 81 045845

Example 38.

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

BB 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 (b.s., 4H), 7.79 (s, 2H), 7.94 (s, 1H), 8.33 ( us.s., 2N).

Mass yield - 0.0233 g (88%).

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

- 82 045845

Example 39.

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

BB 0274103 ^1H NMR (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 (b.s., 6H), 7.50 (m, 3H).

Mass yield - 0.082 g (63%).

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

- 83 045845

Example 40.

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

BB 0274111 ^1H NMR (400 MHz, DMSO-d6, 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 (b.s., 2H), 7.26 (m, 5H), 7.43 (b.s. , 4Н), 7.79 (br.s., 2Н), 8.46 (br.s., 2Н), 10.10 (br.s., 1Н).

Mass yield - 0.078 g (86%).

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

- 84 045845

Example 41.

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

BB 0274118 ^1H NMR (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.

- 85 045845

Example 42.

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

BB 0274119

Ή NMR (400 MHz, CDCl ₃ , δ, ppm): 1.45 (s, 9H), 2.17 (s, 6H), 3.71-4.17 (m, 4H), 4.59-5.03 (m, 3H), 5.375 .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-Voc).

- 86 045845

Example 43.

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

Pd/C, n ₂

BocoO

BB 0274120 ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 1.43 (br.s., 10H), 2.07 (s, 3H), 2.11-2.23 (m, 6H), 2.45-2.68 ( m, 2H), 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).

- 87 045845

Example 44.

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

BB 0274121 ^1H NMR (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.

- 88 045845

Example 45.

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

N

BB 0274122 ^1H NMR (400 MHz, CDCl3, 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).

- 89 045845

Example 46.

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

0273963

BB 0274123 ^1H NMR (400 MHz, DMSO-06, 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 (b.s., 4H), 7.79 (s, 2H), 8.30 (b.s., 4H), 3H).

Mass yield - 0.008 g (85%).

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

- 90 045845

Example 47.

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

O

BB 0274124 ^1H NMR (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), 6.596.75 (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-Vos).

- 91 045845

Example 48.

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

VV 0274124 VV 0274125

BB 0274125 ^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 (b.s., 2H), 7.26 (m., 5H), 7.43 (b.s., 2H). s., 4N), 7.79 (br.s., 2H), 8.46 (b.s., 2H), 10.10 (br.s., 1H).

Mass yield - 0.048 g (90%).

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

- 92 045845

Example 49.

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

(IX) Vos

BB 0274126 ^1H NMR (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-Voc).

- 93 045845

Example 50.

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

BB 0274127 ^1H NMR (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.

- 94 045845

Example 51.

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

Pd/C, n.

BB 0274128 ^1H NMR (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-Vos).

- 95 045845

Example 52.

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

BB 0274129 ^1H NMR (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.

- 96 045845

Example 53.

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

BB 0274130 ^1H NMR (400 MHz, DMSO-d6, 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 (b.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-2Boc).

- 97 045845

Example 54.

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

BB 0274131 ^1H NMR (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, 2H), 2.85-3.09 (m, 2H), 3.77-4.04 (m, 2H), 4.53-4.59 (m, 2H), 7.46 (b.s., 4H), 7.79 (s, 2H), 8.01-8.14 (m, 3H), 8.36-8.40 (m, 3H).

Mass yield - 0.018 g (85%).

LCMS m/z (M+H): 525.

- 98 045845

Example 55.

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

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

Mass yield - 0.076 g (82%).

LCMS m/z (M+H): 528.

- 99 045845

Example 56.

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

N

BB 0274133 ^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 (b.s., 4H), 4.49 (b.s., 2H), 7.42 (b.s., 4N), 7.78 (b.s., 2H), 10.06 (b.s., 1H). Mass yield - 0.045 g (57%). LCMS m/z (M+H): 487.

- 100 045845

Example 57.

Synthesis of methyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-4-cyanophenyl)amino)-8,9-dihydro-5Hpyrimido[4,5-d]azepine-7 (bH)- carboxylate

N

BB 0274134 ^1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.09 (s, 6H), 3.03 (br.s., 4H), 3.64 (s, 7H), 7.41 (s, 4H ), 7.77 (s, 2H), 10.06 (s, 1H).

Mass yield - 0.095 g (82%). LCMS m/z (M+H): 469.

- 101 045845

Example 58.

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

N

BB 0274135 ^1H NMR (400 MHz, DMSO-d6, 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.

- 102 045845

Example 59.

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

BB 0274137 ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 2.12 (s, 6H), 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.

- 103 045845

Example 60.

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

N

BB 0274138 ^1H NMR (400 MHz, CDCl3, 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.

- 104 045845

Example 61.

Synthesis

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

BB 0274140 ^1H NMR (400 MHz, CDCla, δ, ppm): 2.14 (s, 6H), 3.00 (d, J=6.6 Hz, 4H), 3.83 (br.s., 2H), 4.01 (s, 2H), 6.83-6.92 (m, 2H), 7.02-7.11 (m, 2H), 7.33-7.38 (m, 2H), 7.39-7.44 (m, 2H), 7.47 (s, 2H).

Mass yield - 0.033 g (41%).

LCMS m/z (M+H): 503.

- 105 045845

Example 62.

Synthesis

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

BB 0274141 ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 2.13 (s, 6H), 2.51 (dt, J=10.6 Hz, 2.4 Hz, 2H), 2.90 (s, 4H), 3.78 (s, 2H), 3.87 (s, 2H), 4.75 (dd, J=8.3 Hz, 2.4 Hz, 2H), 6.95-7.07 (m, 2H), 7.25-7.33 (m, 4H), 7.33-7.38 ( m, 2H), 7.45 (s, 2H).

Mass yield - 0.062 g (70%).

LCMS m/z (M+H): 541.

- 106 045845

Example 63.

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

BB 0274143 ^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.

- 107 045845

Example 64.

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

BB 0274144 ^1H NMR (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.

- 108 045845

Example 65.

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

N

BB 0274145 ^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., 4H), 7.41 (b.s., 4H), 7.78 (b.s., 2H), 10.06 (b.s., 1H). Mass yield - 0.074 g (69%). LCMS m/z (M+H): 453.

- 109 045845

Example 66.

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

N

BB 0274227 ^1H NMR (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.

- 110 045845

Example 67.

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

N

BB 0274236 ^1H 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 (b.s., 1H).

M = 0.038 g (41%).

LCMS m/z (M+H): 533.

- 111 045845

Example 68.

Synthesis

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

BB 0275622 ^1H NMR (400 MHz, CDCl ₃ , δ, ppm): 2.42 (s, 5H), 2.51-2.68 (m, 1H), 2.73-2.92 (m, 1H), 3.01-3.30 (m , 2H), 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).

M = 0.006 g (33%).

LCMS m/z (M+H): 535.

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

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

The results of determining IC ₅₀ of compounds according to claim 1 are given in table. 1.

- 112 045845

Table 1

Results of a study of the activity of compounds according to claim 1 against _______human immunodeficiency virus HIV-1 subtype A

Activity in Activity in Compound regarding the strain HIV-1 strain 12RU 69831 (subtype A), μΜ Compound regarding the strain HIV-1 strain 12RU 69831 (subtype A), μΜ ВВ0273459 74.3452 ВВ0274138 0.00676 ВВ0274100 33.7972 ВВ0274140 27.8330 ВВ0274101 8.80281 ВВ0274141 173.752 ВВ0274102 0.00341 ВВ0274143 0.71014 ВВ0274103 228.260 ВВ0274144 1.62971 ВВ0274111 533.088 ВВ0274145 1.68874 ВВ0274118 0.32442 ВВ0274227 0.01252 ВВ0274119 102.739 ВВ0274236 0.04878 ВВ0274120 108.280 ВВ0273774 223.844 ВВ0274121 18.7265 ВВ0273775 295.399 ВВ0274122 18.9274 ВВ0273892 1223.77 ВВ0274123 2.06611 ВВ0273943 346.303 ВВ0274124 342.424 ВВ0273961 42.2535 ВВ0274125 82.1428 ВВ0273963 7.55667 ВВ0274126 45.3020 ВВ0273964 0.14526 ВВ0274127 12.0967 ВВ0273965 1.73077 ВВ0274128 113.114 ВВ0273969 10683.7 ВВ0274129 1.03921 ВВ0273972 117.416 ВВ0274130 240.000 ВВ0273976 0.00583 ВВ0274131 0.66666 ВВ0274009 290.502 ВВ0274132 0.90909 ВВ0274010 0.06201 ВВ0274133 10.4722 ВВ0274011 27.1318 ВВ0274134 0.09594 ВВ0274012 5.81395 ВВ0274135 6.13496 ВВ0274014 5.97609 ВВ0274137 0.00799 ВВ0274065 41.118 ВВ0274015 29.8805 ВВ0274072 4.065 ВВ0274016 4880.48 ВВ0274073 57.425 ВВ0274021 0.01022 ВВ0274074 83.333 ВВ0274025 3215.43 ВВ0274075 5.802 ВВ0274026 0.36398 ВВ0274080 0.414 ВВ0274027 37.037 ВВ0274095 11.333 ВВ0274028 16.194 ВВ0274097 663.967 ВВ0274051 0.00552 ВВ0274098 0.046 ВВ0274052 0.12745 ВВ0274099 0.152 ВВ0274063 230.263 ВВ0275622 0.032 ВВ0274064 493.421 ВВ0274239 359.0485 ВВ0274312 34.823 ВВ0274337 204.938

The features claimed in the description of the invention or in the claims, expressed in special forms and terms for carrying out the claimed function or method or method for achieving the claimed result, can be used separately or in any combination of such features to implement the invention in its various forms.

The present invention has been described with reference to illustrations and examples in order to explain and understand the invention. It will be apparent to one skilled in the art that various changes and modifications are possible within the scope and claimed claims. Therefore, it is intended that the specification of the application merely illustrates the invention and does not limit its scope. The scope of the invention is determined with reference to the claimed claims, including the entire scope of equivalents claimed by said claims.

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

Claims (36)

1. Compound of formula I where R1 is independently selected and represents 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; NHR ⁹ ; NR ⁹ R ¹⁰ ; substituted or unsubstituted C _2-6 alkenyl; substituted or unsubstituted C _2-6 alkynyl; X1, X ₂ represent (CH ₂ )n, and n is chosen independently for X1, X ₂ ; Y 1 is independently selected and represents -O- or substituents of the form: Rb is independently selected 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 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 4-9 membered heterocyclyl containing from 1 to 4 heteroatoms independently selected from N, S and/or O, R ⁷ , where Rb can be attached to the rest of the molecule through a linker (CH ₂ ) _n , R ⁷ represents C ₃ -cycloalkyl; R ⁹ and R ¹⁰ are each independently hydrogen; cyano, C _1-6 alkyl; C _1-6 alkylcarbonyl; amino; wherein each of the above C _1-6 alkyl groups may be optionally substituted with hydroxy; where the substituents R1, Rb are each independently selected from the group consisting of COO-isobutyl; HE; CN; _NH2 ; 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 C _1-6 alkyl; VOS; COOH; C ₆ -aryl, possibly substituted with OH or OCH ₂ C=CH; 4-6 membered heterocyclyl containing 1-3 heteroatoms selected from N, S and O; halogen; n can range from 1 to 3, or a pharmaceutically acceptable salt or isotope thereof. 2. The compound 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; Rb is chosen independently and is: -H, substituted or unsubstituted -C ₁ -C ₆ -alkyl, or unsubstituted -C ₂ -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 4-9 membered heterocyclyl containing from 1 to 2 heteroatoms independently selected from N and/or O, wherein said Rb substituents are each independently selected from the group, including: COO-tert-butyl; _NH2 ; C _1-4 alkoxy; 4-6-membered heteroaryl containing from 1 to 2 heteroatoms independently selected from the group N and O, wherein said heteroaryl is unsubstituted or substituted with C _1-6 alkyl; VOS; COOH; the remaining radicals are as defined in paragraph 1. 3. The compound of claim 1, wherein R1 is independently selected and is H, -CN, -CH=CHCN, -C=O or -CH=CH-COOH. 4. A compound according to claim 1, in which R1 is independently selected and is a 4-6-membered heterocyclyl containing 1-2 O heteroatoms. 5. A compound according to claim 3, wherein R1 is oxetane. 6. The compound according to claim 1, wherein Y1 is -O-. 7. A compound according to claim 1, in which Y1 represents substituents of the form: - 114 045845 8. A compound according to claim 1, in which Y1 represents substituents of the form: Rb Rb. I 9 O. ,J η Y Rb /N ₄ / ^N \ 9. A compound according to claim 1, 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 such as defined in clause 1. 10. A compound according to claim 1, wherein Rb is substituted or unsubstituted phenyl, wherein the substituents are as defined in claim 1. 11. A compound according to claim 1, wherein Rb is substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, isobenzofuranyl, benzimidazolyl, furan, wherein the substituents are as defined in claim 1. 12. A compound according to claim 1, wherein Rb is substituted or unsubstituted piperidine, azetidine, morpholine, tetrahydropyran. 13. A compound according to claim 1, in which Y1 represents substituents of the form: Rb RbI Dk O. ,Rb IO./O Rb Ύ O=S=OY IIII / ^N \ / ^N \/ a Rb is a substituted or unsubstituted -5-6-membered heteroaryl or heterocyclyl containing 1 to 2 heteroatoms independently selected from N, S and/or O, where the substituents are defined in paragraph. 1. 14. A compound according to claim 1, in which Y1 represents substituents of the form: Rb Rb. _o O. /J ₀ γ Rb ₀ ^<ί ^' a Rb represents a substituted or unsubstituted -C ₆ -aryl, 5-6-membered heteroaryl, where the substituents are defined in paragraph 1. 15. Connection 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[4,3d]pyrimidin-2-yl)amino)methyl)benzoic ethyl ester acids; 4-(((6-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2yl)amino)methyl)benzoic acid ethyl ester; 4-(((7-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2yl)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-2amine; 4-((2-((4-cyanophenyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3,5dimethylbenzonitrile; 4-((4-(4-formyl-2,6-dimethylphenoxy)-7-methyl-5,6,7,8-tetrahydro[3,4-d]pyrimidin-2yl)amino)benzonitrile; tert-butyl 4-(4-(1,3-dioxalan-2-yl)-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro5H-pyrimido [4,5- d] azepine-7(6H)-carboxylate; tert-butyl 2-((4-cyanophenyl)amino)-4-(4-formyl-2,6-dimethylphenioxy)-8,9-dihydro-5Hpyrimido[4,5-d]azepine-7(6H)-carboxylate ; tert-butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3d]pyrimidine-6(5H)-carboxylate; 4-((2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-6-(methylsulfonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4- 115 045845 yl)oxy)-3, 5-dimethylbenzonitiryl; ethyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3d]pyrimidine-6(5H)-carboxylate; (E)-3-(4-((7-(tert-butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5d]azepine- 4-yl)oxy)-3,5-dimethylphenyl)acrylic acid; tert-butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5Hpyrimido[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)-3,5dimethylbenzonitrile; tert-butyl 2-((4-cyanophenyl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8,9-dihydro-5Hpyrimido[4,5-d]azepine-7( 6H)-carboxylate; 4-((2-((4-cyanophenyl)amino)-7-picolinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4yl)oxy)-3,5- dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-isonicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4yl)oxy)-3,5- dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-nicotinoyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4yl)oxy)-3,5- dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin4-yl)oxy )-3,5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-(pyridin-3-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin4-yl)oxy )-3,5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-(pyridin-4-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin4-yl)oxy )-3,5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)oxy)-3,5dimethylbenzonitrile; tert-butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5Hpyrimido[4,5-d]azein -7-carbonyl)piperidine-1-carboxylate; 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-carbonyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5d]azepin-4-yl)oxy )-3,5-dimethylbenzonitrile; tert-butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5Hpyrimido[4,5-d]azepine-7(6H )-yl)piperidin-1-carboxylate; 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4yl)oxy )-3,5-dimethylbenzonitrile; 4-((6-(2-aminoacetyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4yl)oxy)-3,5- dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-6-(2-(3-hydroxyazetidin-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[4,3d]pyrimidin-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]pyrimidin4-yl} hydroxy)-3,5-dimethylbenzonitrile; 4-({2-[(4-cyanophenyl)amino]-6-[2-(4,4-difluoropiperidin-1-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3d]pyrimidin- 4-yl}oxy)-3,5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-(cyclopropanecarbonyl)-5,6,7,8-tetrahydro-[4,3-d]pyrimidin-4yl)oxy)-3,5-dimethylbenzonitrile ; 4-({2-[(4-cyanophenyl)amino]-6-(morpholine-4-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4yl}oxy)-3, 5-dimethylbenzonitrile; 4-({2-[(4-cyanophenyl)amino]-6-(4-methylpiperazin-1-carbonyl)-5H,6H,7H,8H-pyrido[4,3d]pyrimidin-4-yl}oxy)- 3,5-dimethylbenzonitrile; tert-butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5Hpyrimido[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-5Hpyrimido[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-5Hpyrimido[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[4,5d]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[4,5d]azepine- 4-yl)oxy)-3,5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-((1-methyl-III-pyrrol-2-yl)methyl)-6,7,8,9-tetrahydro-5Hpyrimido[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-4yl)oxy)- 3,5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-(1-methoxypropan-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5- 116 045845 d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile; tert-butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-d]pyrimidine-6-carbonyl )pyrrolidine-1-carboxylate; 4-((2-((4-cyanophenyl)amino)-6-(pyrrolidin-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3d]pyrimidin-4-yl)oxy)-3, 5-dimethylbenzonitrile; 4-((6-(azetidin-3-carbonyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin4-yl)oxy)-3, 5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-6-(pyrazin-2-carbonyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4yl)oxy)-3, 5-dimethylbenzonitrile; (R)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[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]pyrimidin4-yl)oxy)- 3,5-dimethylbenzonitrile; (S)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-d]pyrimidine-6( 5H)-yl)-1-oxo-3-phenylpropan-2-yl)carbamate; (S)-4-((6-(2-amino-3-phenylpropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3d]pyrimidin-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-4yl)oxy)- 3,5-dimethylbenzonitrile; (R)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-d]pyrimidine-6( 5H)-yl)-3-hydroxy-1-oxopropan-2-yl)carbamate; tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3d]pyrimidin-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,8Hpyrido[4,3-d] pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile; 4-((6-(2-amino-3-(1H-pyrazol-4-yl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[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-((4cyanophenyl)amino)-7,8-dihydropyrido[4 ,3-d]pyrimidin-6(5H)-yl)-3-oxopropyl)-1H-pyrazole-1carboxylate; (R)-4-((6-(2-amino-3-hydroxypropanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3d]pyrimidin-4-yl )oxy)-3,5-dimethylbenzonitrile; (S)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-d]pyrimidine-6( 5H)-yl)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl)carbamate; (S)-4-((6-(2-amino-3-(4-hydroxyphenyl)propanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8tetrahydropyrido[4,3-d] pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile; (R)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-d]pyrimidine-6( 5H)-yl)-3-methyl-1-oxobutan-2-yl)carbamate; (R)-4-((6-(2-amino-3-methylbutanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3d]pyrimidin-4-yl )oxy)-3,5-dimethylbenzonitrile; (S)-tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[4,3-d]pyrimidine-6( 5H)-yl)-4-methyl-1-oxopentan-2-yl)carbamate; (S)-4-((6-(2-amino-4-methylpentanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3d]pyrimidin-4-yl )oxy)-3,5-dimethylbenzonitrile; (S)-di-tert-butyl (6-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8dihydropyrido[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[4,3d]pyrimidin-4-yl)oxy )-3,5-dimethylbenzonitrile; 4-((7-(2-chloroacetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4yl)oxy)- 3,5-dimethylbenzonitrile; methyl 4-(4-cyano-2,6-dimethylphenoxy)-2-(4-(4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5d]azepine-7(6H)-carboxylate ; 4-((2-((4-cyanophenyl)amino)-7-(methylsulfonyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4yl)oxy)-3, 5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-6-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4yl)oxy)-3, 5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-6-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4yl)oxy)-3, 5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-6-(2-hydroxybenzyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4yl)oxy)-3,5- dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-6-(2-(prop-2-yn-1-yloxy)benzyl)-5,6,7,8-tetrahydropyrido[4,3d]pyrimidin- 4-yl)oxy)-3,5-dimethylbenzonitrile; - 117 045845 3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimido[4,5d]azepin-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, 5dimethylbenzonitrile; 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[4,5d] azepin-4-yl)oxy)-3,5-dimethylbenzonitrile; 4-((2-((4-cyanophenyl)amino)-7-(2-(methyl-III-imidazol-1-yl)acetyl)-6,7,8,9-tetrahydro-5Hpyrimido[4,5- d]azepin-4-yl)oxy)-3,5-dimethylbenzonitrile; 4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine6-sulfonamide; methyl 2-{2-[(4-cyanophenyl)amino]-4-(4-formyl-2,6-dimethylphenoxy)-5H,6H,7H,8H,9Hpyrimido[4,5-d]azepin-7-yl } -2-oxoacetate; 4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-K-(oxan-4-yl)-4aH,5H,6H,7H,8H,8aHpyrido [4,3 -d]pyrimidine-6-carboxamide. 16. A compound according to any one of claims 1 to 15, which includes at least one isotope. 17. A compound according to any one of claims 1 to 15 in the form of a pharmaceutically acceptable salt with counterions such as halides, hydroxides, carboxylates, sulfates. 18. Use of a compound according to any one of claims 1 to 17 as a reverse transcriptase inhibitor. 19. Use of a compound according to any one of claims 1 to 17 as a medicinal product having antiviral activity against HIV. 20. Use of a compound according to any one of claims 1 to 17 for the production of a medicinal product having antiviral activity against HIV. 21. A pharmaceutical composition having activity against reverse transcriptase, comprising a compound according to any one of claims 1 to 15 in a therapeutically effective amount and at least one carrier, excipient or diluent. 22. Pharmaceutical composition according to claim 21 for the treatment or prevention of HIV. 23. The pharmaceutical composition according to claim 21, having activity against HIV reverse transcriptase, further containing 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 into a cage. 24. The pharmaceutical composition according to claim 21, having activity against HIV reverse transcriptase, wherein the HIV reverse transcriptase contains at least one mutation compared to wild-type HIV. 25. The pharmaceutical composition according to claim 21, having activity against HIV reverse transcriptase, wherein HIV reverse transcriptase has reduced sensitivity to the drugs efavirenz, nevirapine, doravirine or delavirdine. 26. A pharmaceutical composition for the preparation of an agent for the treatment or prevention of HIV, comprising at least one compound according to any one of claims 1 to 15 in a therapeutically effective amount and a pharmaceutically acceptable carrier. 27. Use of a compound according to any one of claims 1 to 15 for the preparation of an agent for the treatment or prevention of HIV. 28. Use of the composition according to claim 22 to obtain an agent for the treatment or prevention of HIV. 29. A method of treating or preventing HIV, including the use of a composition according to any one of claims 21-26. 30. A method of treating or preventing HIV infection, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to any one of claims 115. 31. The method according to claim 30, wherein said therapeutically effective amount of the compound means a daily dose that ranges from 0.1 to 500 mg/kg body weight when administered parenterally. 32. The method according to claim 31, in which the daily dose is administered as a single dose or in 1-5 divided doses. 33. A combination for the treatment or prevention of HIV-related diseases, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 15 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 cells. 34. A method of treating or preventing HIV-related diseases, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 15 and at least one compound selected from the group consisting of inhibitors - 118 045845 HIV proteases, nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, CCR5 antagonists and inhibitors of viral cell entry. 35. Method of inhibiting HIV reverse transcriptase in the body of a subject infected HIV, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound according to any one of claims 1 to 15. 36. A method for preparing a pharmaceutical composition according to claim 21, comprising mixing a compound according to claims 1 to 15 with a pharmaceutically acceptable carrier, excipient or diluent.