Pyrimidine-based bicyclic compounds as antiviral agents for the treatment and prevention of HIV infection

Abstract

This invention relates to pyrimidine derivatives with HIV replication-inhibiting properties. The invention provides novel pyrimidine compounds designed for the treatment and prevention of HIV-mediated diseases. The invention also relates to pharmaceutical compositions and medicaments containing said compounds. Furthermore, the invention relates to the use of the above-described compounds for the treatment and / or prevention of HIV in subjects suffering from or at risk of HIV infection.

Description

Technical Field

[0001] This invention relates to pyrimidine derivatives with HIV replication-inhibiting properties. The invention provides novel pyrimidine compounds of formula I. These compounds can be used for the treatment and prevention of HIV-mediated diseases. The invention also relates to methods for obtaining said compounds and pharmaceutical compositions containing said compounds. Furthermore, the invention relates to the use of the above-described compounds for the treatment and prevention of HIV in subjects infected with or at risk of HIV infection. Background Technology

[0002] The prior art discloses compounds structurally related to the antiviral compound of this invention:

[0003] References:

[0004] J. Guillemont et al., filed WO 2006 / 035068, published on April 6, 2006.

[0005] J. Guillemont et al., filed WO 2006 / 035067, published on April 6, 2006.

[0006] J. Guillemont et al., filed WO 2006 / 045828, published on May 4, 2006.

[0007] J. Guillemont et al., filed WO 2006 / 035369, published on April 6, 2006.

[0008] HADe Koek and P. Wigerinck, filed WO 2006 / 094930, published on September 14, 2006.

[0009] HADe Koek and P. Wigerinck, filed WO 2006 / 087387, published on August 24, 2006.

[0010] PAJ Jansen et al., J. Med Chem., 48(6), 1901-1909 (2005).

[0011] K. Das et al., J. Med. Chem., 47(10), 2550-2660 (2004).

[0012] J. Guillemont et al., J. Med. Chem., 48(6), 2072-2079 (2005). Summary of the Invention

[0013] This invention relates to compounds of formula I.

[0014]

[0015] Where R 1 They are chosen independently and represent H-, -CN, CN-CH=CH-;

[0016] X 1 X 2 It is (CH2) n Substituents of type n, where n is chosen independently for X1 and X2 and can have values ​​from 1 to 3;

[0017] Y 1 It is independently selected and represents -O-, -S-, -S(=O)-, -S(=O)2-, or the following types of substituents:

[0018]

[0019] R b It is independently selected and represents -H, substituted or unsubstituted -C1-C6-alkyl, substituted or unsubstituted -C1-C6-alkenyl, substituted or unsubstituted -C6-aryl, substituted or unsubstituted -5-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and / or O, substituted or unsubstituted -C3-C9-cycloalkyl, or substituted or unsubstituted 4-9-membered heterocyclic group containing 1 to 4 heteroatoms independently selected from N, S and / or O; or a pharmaceutical salt thereof.

[0020] The compounds of Formula I inhibit HIV-1 reverse transcriptase and can be used in methods for treating and preventing HIV-mediated diseases.

[0021] The present invention also relates to compositions comprising compounds of formula I, which can be used for the treatment and prevention of HIV-mediated diseases. The present invention also relates to compounds of formula I, which can be used as a single therapeutic agent or in combination with other antiviral agents for treatment.

[0022] In one embodiment, the present invention relates to one of the following compounds:

[0023]

[0024]

[0025]

[0026]

[0027]

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044]

[0045]

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053] Detailed Implementation

[0054] In one embodiment, the present invention relates to a compound of formula I.

[0055]

[0056] Where R 1 They are chosen independently and represent H-, -CN, CN-CH=CH-;

[0057] X 1 X 2 It is (CH2) n Substituents of type n, where n is chosen independently for X1 and X2 and can have values ​​from 1 to 3;

[0058] Y 1 It is independently selected and represents -O-, -S-, -S(=O)-, -S(=O)2-, or the following types of substituents:

[0059]

[0060] R b It is independently selected and represents -H, substituted or unsubstituted -C1-C6-alkyl, substituted or unsubstituted -C1-C6-alkenyl, substituted or unsubstituted -C6-aryl, substituted or unsubstituted -5-6-membered heteroaryl (containing 1 to 4 heteroatoms independently selected from N, S and / or O), substituted or unsubstituted -C3-C9-cycloalkyl, or substituted or unsubstituted 4-9-membered heterocyclic (containing 1 to 4 heteroatoms independently selected from N, S and / or O); or a pharmaceutical salt thereof.

[0061] Where R b It can be done via (CH2) n A linker of type n is attached to the remainder of the molecule, where n is selected from 1 to 3.

[0062] In another embodiment, the present invention relates to a compound of formula I.

[0063]

[0064] Where R 1 It is independently selected and represents H, CN, CN-CH=CH, C=O, CH=CH-COOH, substituted or unsubstituted 4-6 membered heterocyclic groups containing 1-2 heteroatoms O; amino carbonyl group; NH2; substituted or unsubstituted C 1-6 Alkyl; halogen; substituted or unsubstituted C 1-6 Alkoxy; NHR 9 NR 9 R10 -C(=O)-NHR 9 -C(=O)-NR 9 R 10 ;-C(=O)-R 9 -CH=N-NH-C(=O)-R 9 ; substituted or unsubstituted C 1-6 Alkoxy C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl; substituted or unsubstituted C 2-6 Alkyne group; -C (=NOR) 8 )-C 1-4 Alkyl; R 7 and -Rb-R 7 ;

[0065] X 1 X 2 It is (CH2) n Substituents of type n, where n is chosen independently for X1 and X2;

[0066] Y 1 It is independently selected and represents -O-, -S-, -S(=O)-, -S(=O)2-, or the following types of substituents:

[0067]

[0068] R b Independently selected and representing -H, cyano, aminocarbonyl, substituted or unsubstituted -C1-C6-alkyl, substituted or unsubstituted -C2-C6-alkenyl, substituted or unsubstituted -C2-C6-ynyl, substituted or unsubstituted -C3-C6-aryl, substituted or unsubstituted 4-6-membered heteroaryl (containing 1 to 4 heteroatoms independently selected from N, S and / or O), substituted or unsubstituted -C3-C9-cycloalkyl, substituted or unsubstituted 4-9-membered heterocyclic (containing 1 to 4 heteroatoms independently selected from N, S and / or O), R 7 or R 9 ,

[0069] Where R b It can be done via (CH2) n The type of connector connects to the remaining part of the molecule.

[0070] R 7- It is a monocyclic, bicyclic, or tricyclic, saturated, partially saturated, or aromatic carbocyclic ring, or a monocyclic, bicyclic, or tricyclic, saturated, partially saturated, or aromatic 4-6 membered heterocycle (containing 1 to 4 heteroatoms independently selected from S, N, and O), wherein each of the carbocyclic or heterocyclic rings may optionally be substituted by one, two, three, four, or five substituents, each of which is independently selected from halogens, hydroxyl groups, mercapto groups, C... 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, mono- and di-(C) 1-6 alkyl)aminoC 1-6 Alkyl, formyl, C 1-6 alkyl carbonyl, C 3-7 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, polyhalogenated C 1-6 Alkyl, polyhalogenated C 1-6 Alkoxy, amino carbonyl, -C (=NOR) 8 ), R 7a -Rb-R 7a and R 7a -C 1-4 alkyl;

[0071] R 7a It is a monocyclic, bicyclic, or tricyclic, saturated, partially saturated, or aromatic carbocyclic ring, or a monocyclic, bicyclic, or tricyclic, saturated, partially saturated, or aromatic 4-6 membered heterocycle (containing 1 to 4 heteroatoms independently selected from S, N, and O), wherein each of the carbocyclic or heterocyclic rings may optionally be substituted by one, two, three, four, or five substituents, each of which is independently selected from halogens, hydroxyl groups, mercapto groups, C... 1-6 Alkyl, hydroxyl C 1-6 Alkyl, amino C 1-6 Alkyl, mono- or di-(C) 1-6 alkyl)aminoC 1-6 Alkyl, formyl, C 1-6 alkyl carbonyl, C 3-7 cycloalkyl, C 1-6 Alkoxy, C 1-6 alkoxycarbonyl, C 1-6 Alkylthio, cyano, nitro, polyhalogenated C 1-6 Alkyl, polyhalogenated C 1-6 Alkoxy, amino carbonyl and -CH (=NOR) 8 );

[0072] R 8 It is hydrogen, C 1-4 Alkyl, aryl or aryl C1-4 alkyl;

[0073] R 9 and R 10 Each of these groups is independently hydrogen; cyano, amino carbonyl, and hydroxyl groups; C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkyl carbonyl; C 1-6 alkoxycarbonyl; amino; one or two (C 1-6 alkyl)amino; mono- or di(C) 1-6 alkyl)aminocarbonyl; -CH (=NR) 11 ) or R 7 Wherein C 1-6 Each of the alkyl groups may optionally be independently substituted by one or two substituents, each of which is independently selected from hydroxyl, C, and D. 1-6 Alkoxy, hydroxy C 1-6 Alkoxy, carboxyl, C 1-6 alkoxycarbonyl, cyano, amino, aminocarbonyl, imino, and di(C) 1-4 Alkyl)amino, polyhalogenated methyl, polyhalogenated methoxy; polyhalogenated methylthio, -S (=O) p R 8 -NH-S (=O) p R 8 -C(=O)R 8 , -NHC(=O)H, -C(=O)NHNH2, NHC(=O)R 8 C(=NH)R 8 R 7 ,

[0074] Where R 1 R b The substituents are each independently selected from the group consisting of: COO-isobutyl, OH, CN, NH2, C1-4-alkoxy, C1-4 alkyl, 4-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from S, N and O (wherein the heteroaryl is unsubstituted or substituent by CN, NH2, OH, C1-6-alkyl, O or R). c (Substitute); BOC, COOH, R c C3-6-aryl groups optionally substituted with CN, NH2, OH, O, or OCH2C≡CH; 4-6-membered heterocyclic groups containing 1-3 heteroatoms selected from N, S, and O; O, N, S-C1-6-alkyl groups; halogens; NR 9 R 10 -C(=O)-NR 9 R 10 -C(=O)-C 1-6 alkyl;

[0075] R c It represents NHCOO-C1-6-alkyl.

[0076] n can have values ​​from 1 to 3.

[0077] In a further embodiment, the present invention relates to a compound as defined above.

[0078] R1 is independently selected and represents H, CN, CN-CH=CH, C=O, CH=CH-COOH, or a 4-6 membered heterocyclic group containing 1-2 heteroatoms O;

[0079] R b It is selected independently and represents

[0080] -H,

[0081] Substituted or unsubstituted -C1-C6-alkyl,

[0082] Substituted or unsubstituted -C1-C6-olefin,

[0083] Substituted or unsubstituted -C3-C6-aryl,

[0084] Substituted or unsubstituted 5-6 membered heteroaryl groups containing 1 to 4 heteroatoms independently selected from N, S, and / or O.

[0085] Substituted or unsubstituted -C3-C9-cycloalkyl, or

[0086] Substituted or unsubstituted 4-9 membered heterocyclic groups containing 1 to 4 heteroatoms independently selected from N, S, and / or O.

[0087] Among them, the substituent R mentioned above b Each is independently selected from a group that includes the following:

[0088] COO-isobutyl,

[0089] NH2,

[0090] CN

[0091] C1-4-alkoxy,

[0092] A 4-6 membered heteroaryl group containing 1 to 4 heteroatoms independently selected from S, N and O, wherein the heteroaryl group is unsubstituted or substituted with OH, C1-6-alkyl, O or Rc;

[0093] BOC;

[0094] COOH;

[0095] R c;

[0096] C3-6-aryl groups optionally substituted with OH, O, or OCH2C≡CH

[0097] 4-6 membered heterocyclic groups containing 1-2 heteroatoms selected from N and O.

[0098] O, N,

[0099] S-C1-6-alkyl,

[0100] halogen,

[0101] The remaining substituents are those defined in this invention.

[0102] In another embodiment, the present invention relates to a compound of the present invention, wherein R 1 It is chosen independently and represents H, -CN, -CH=CH-CN, -C=O, or -CH=CH-COOH.

[0103] In another embodiment, the present invention relates to a compound of the present invention, wherein R 1 It is an independently selected 4-6 membered heterocyclic group containing 1-2 heteroatoms O.

[0104] In another embodiment, the present invention relates to the compound of the invention, wherein R 1 It is oxacyclobutane, tetrahydrofuran, or tetrahydropyran.

[0105] In another embodiment, the present invention relates to a compound of the present invention, wherein Y 1 It is -O-, -S-, -S(=O)- or -S(=O)2-.

[0106] In another embodiment, the present invention relates to a compound of the present invention, wherein Y 1 It is a substituent of the following types:

[0107]

[0108] In another embodiment, the present invention relates to a compound of the present invention, wherein Y 1 It is a substituent of the following types:

[0109]

[0110] In another embodiment, the present invention relates to a compound of the present invention, wherein Rb is a substituted or unsubstituted methyl, ethyl, propyl, n-propyl, isopropyl, butyl, n-butyl, sec-butyl, tert-butyl, or pentyl group, wherein the substituent is as defined in the present invention.

[0111] In another embodiment, the present invention relates to a compound of the present invention, wherein Rb is a substituted or unsubstituted vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, wherein the substituent is as defined in the present invention.

[0112] In another embodiment, the present invention relates to a compound of the present invention, wherein Rb is a substituted or unsubstituted phenyl group, and wherein the substituents are as defined in the present invention.

[0113] In another embodiment, the present invention relates to a compound of the present invention, wherein Rb is a substituted or unsubstituted thiophene group, pyrrolo group, imidazolyl group, pyrazolyl group, pyridinyl group, pyrimidinyl group, pyridazinyl group, triazinyl group, tetrazolyl group, benzo[b]thiophene group, isobenzofuranyl group, isoindolile group, benzimidazolyl group, wherein the substituent is as defined in the present invention.

[0114] In another embodiment, the present invention relates to a compound of the present invention, wherein Rb is a substituted or unsubstituted cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, spiro[5.5]undecyl, wherein the substituent is as defined in the present invention.

[0115] In another embodiment, the present invention relates to a compound wherein Rb is a substituted or unsubstituted pyrimidine, piperidine, azacyclobutane, morpholine, piperazine, pyrrolidine, tetrahydropyran, furan, pyrrole, pyrazine, imidazole, or pyrazole.

[0116] In another embodiment, the present invention relates to a compound of the present invention, wherein Y 1 It is a substituent of the following types:

[0117] Furthermore, Rb is a substituted or unsubstituted 5-6 membered heteroaryl or heterocyclic group containing 1 to 4 heteroatoms independently selected from N, S and / or O, wherein the substituents are as defined in this invention.

[0118] In another embodiment, the present invention relates to a compound of the present invention, wherein Y 1 It is a substituent of the following types:

[0119] And Rb is a substituted or unsubstituted -C3-C6-aryl or a substituted or unsubstituted -C3-C9-cycloalkyl, wherein the substituent is as defined in this invention.

[0120] In another embodiment, the present invention relates to compounds selected from the following:

[0121] 4-((4-(2,6-dimethylphenoxy)-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-2-yl)amino)-benzonitrile

[0122] 4-(2,6-dimethylphenoxy)-N-(piperidin-4-yl)-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-2-amine

[0123] 4-(((6-benzyl-4-(4-cyano-2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)methyl)ethyl benzoate

[0124] 4-(((6-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)methyl)ethyl benzoate

[0125] 4-(((7-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile

[0126] N-(1-Benzylpiperidin-4-yl)-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydroquinazolin-2-amine

[0127] N-(1-Benzylpiperidin-4-yl)-4-(2,6-dimethylphenoxy)-6,7-dihydro-5H-cyclopentadien[d]pyrimidin-2-amine

[0128] 4-((2-((4-cyanophenyl)amino)-7-methyl-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0129] 4-((4-(4-formyl-2,6-dimethylphenoxy)-7-methyl-5,6,7,8-tetrahydro[3,4-d]pyrimidin-2-yl)amino)benzonitrile

[0130] 4-(4-(1,3-dioxolane-2-yl)-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylic acid tert-butyl ester

[0131] 2-((4-cyanophenyl)amino)-4-(4-formyl-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylic acid tert-butyl ester

[0132] 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-carboxylic acid tert-butyl ester

[0133] 4-((2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0134] 4-((2-((4-cyanophenyl)amino)-6-(methanesulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0135] ethyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0136] (E)-3-(4-((7-(tert-butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylphenyl)acrylic acid

[0137] 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylic acid tert-butyl ester

[0138] 4-((2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0139] 2-((4-cyanophenyl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylic acid tert-butyl ester

[0140] 4-((2-((4-cyanophenyl)amino)-7-pyridinoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0141] 4-((2-((4-cyanophenyl)amino)-7-isonicotinanoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0142] 4-((2-((4-cyanophenyl)amino)-7-nicotinanoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0143] 4-((2-((4-cyanophenyl)amino)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0144] 4-((2-((4-cyanophenyl)amino)-7-(pyridin-3-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0145] 4-((2-((4-cyanophenyl)amino)-7-(pyridin-4-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0146] 4-((2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0147] 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)piperidine-1-carboxylic acid tert-butyl ester

[0148] 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-carbonyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0149] 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptane-7(6H)-yl)piperidine-1-carboxylic acid tert-butyl ester

[0150] 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0151] 4-((6-(2-aminoacetyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0152] 4-((2-((4-cyanophenyl)amino)-6-(2-(3-hydroxyazacyclobutane-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0153] 4-({2-[(4-cyanophenyl)amino]-6-[2-(morpholin-4-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

[0154] 4-({2-[(4-cyanophenyl)amino]-6-[2-(4,4-difluoropiperidin-1-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

[0155] 4-((2-((4-cyanophenyl)amino)-7-(cyclopropanecarbonyl)-5,6,7,8-tetrahydro-[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0156] 4-({2-[(4-cyanophenyl)amino]-6-(morpholin-4-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

[0157] 4-({2-[(4-cyanophenyl)amino]-6-(4-methylpiperazin-1-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

[0158] 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-tert-butyl carboxylate

[0159] (R)-2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-tert-butyl carboxylate

[0160] (S)-2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-tert-butyl carboxylate

[0161] 4-((2-((4-cyanophenyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0162] 4-((2-((4-cyanophenyl)amino)-7-(5-methylfuran-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0163] 4-((2-((4-cyanophenyl)amino)-7-(1-methyl-1H-pyrrolo-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0164] 4-((2-((4-cyanophenyl)amino)-7-(4-hydroxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0165] 4-((2-((4-cyanophenyl)amino)-7-(1-methoxypropane-2-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0166] 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carbonyl)pyrrolidine-1-tert-butyl carboxylate

[0167] 4-((2-((4-cyanophenyl)amino)-6-(pyrrolidine-2-carbonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0168] 4-((6-(azacyclobutane-3-carbonyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0169] 4-((2-((4-cyanophenyl)amino)-6-(pyrazine-2-carbonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0170] (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyridino[4,3-d]pyrimidin-6(5H)-yl)-1-oxopropane-2-yl)tert-butyl carbamate

[0171] (S)-4-((6-(2-aminopropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0172] (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-oxo-3-phenylpropane-2-yl)carbamate tert-ester

[0173] (S)-4-((6-(2-amino-3-phenylpropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0174] 4-((2-((4-cyanophenyl)amino)-7-(2-morpholinoethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0175] (R)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-hydroxy-1-oxopropane-2-yl)tert-butyl carbamate

[0176] (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-(methylthio)-1-oxobutane-2-yl)tert-butyl carbamate

[0177] 4-({6-[2-amino-3-(1H-imidazol-5-yl)propionyl]-2-[(4-cyanophenyl)amino]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile

[0178] 4-((6-(2-amino-3-(1H-pyrazol-4-yl)propionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0179] 4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-oxopropyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester

[0180] (R)-4-((6-(2-amino-3-hydroxypropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0181] (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-(4-hydroxyphenyl)-1-oxopropane-2-yl)tert-butyl carbamate

[0182] (S)-4-((6-(2-amino-3-(4-hydroxyphenyl)propionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0183] (R)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate

[0184] (R)-4-((6-(2-amino-3-methylbutyryl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0185] (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methyl-1-oxopentane-2-yl)tert-butyl carbamate

[0186] (S)-4-((6-(2-amino-4-methylpentanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0187] (S)-(6-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-6-oxohexane-1,5-diyl)dicarbamate ditert-butyl ester

[0188] (S)-4-((2-((4-cyanophenyl)amino)-6-(2,6-diaminohexanoyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0189] 4-((7-(2-chloroacetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0190] 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-formate methyl ester

[0191] 4-((2-((4-cyanophenyl)amino)-7-(methanesulfonyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0192] 4-((2-((4-cyanophenyl)amino)-6-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0193] 4-((2-((4-cyanophenyl)amino)-6-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0194] 4-((2-((4-cyanophenyl)amino)-6-(2-hydroxybenzyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0195] 4-((2-((4-cyanophenyl)amino)-6-(2-(prop-2-yn-1-yloxy)benzyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0196] 3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptane-7(6H)-yl)propionic acid

[0197] 4-((7-allyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0198] 4-((7-acetyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0199] 4-((7-(2-(1H-imidazol-1-yl)acetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0200] 4-((2-((4-cyanophenyl)amino)-7-(2-(methyl-1H-imidazol-1-yl)acetyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0201] 4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-sulfonamide

[0202] 2-{2-[(4-cyanophenyl)amino]-4-(4-formyl-2,6-dimethylphenoxy)-5H,6H,7H,8H,9H-pyrimidino[4,5-d]azacycloheptane-7-yl}-2-oxoacetic acid methyl ester

[0203] 4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-N-(oxacyclohexane-4-yl)-4aH,5H,6H,7H,8H,8aH-pyrido[4,3-d]pyrimidine-6-carboxamide

[0204] In another embodiment, the present invention relates to a compound comprising at least one isotope.

[0205] In another embodiment, the present invention relates to a compound of the present invention, which is in the following form:

[0206] Free base,

[0207] Alternatively, it may be a pharmaceutical salt selected from the group consisting of salts containing an amino group, wherein the amino group is formed from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and chloric acid, or from organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, succinic acid, or malonic acid.

[0208] Or pharmaceutical salts: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucono-heptate, glycerophosphate, gluconate, hemisulfate, heptahydrate, hydroiodate, 2-hydroxyethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate.

[0209] Or medicinal salts containing alkali metals and / or alkaline earth metals, or containing non-toxic cations of ammonium, quaternary ammonium, and amines.

[0210] Or pharmaceutical salts, which are obtained using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfate and aryl sulfonate.

[0211] In another embodiment, the present invention relates to a compound that is used as a reverse transcriptase inhibitor.

[0212] In another embodiment, the present invention relates to a compound of the present invention, which is used as a pharmaceutical preparation having anti-HIV antiviral activity.

[0213] In another embodiment, the present invention relates to a compound of the present invention for obtaining a pharmaceutical formulation having anti-HIV antiviral activity.

[0214] In another embodiment, the present invention relates to a pharmaceutical composition for regulating reverse transcriptase activity, comprising a therapeutically effective amount of the compound of the present invention and at least one carrier, excipient or diluent.

[0215] In another embodiment, the present invention relates to a pharmaceutical composition for treating or preventing HIV, comprising a therapeutically effective amount of at least one compound of the present invention and at least one carrier, excipient or diluent.

[0216] In another embodiment, the present invention relates to a pharmaceutical composition for regulating HIV reverse transcriptase activity, comprising a therapeutically effective amount of the 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.

[0217] In another embodiment, the present invention relates to a pharmaceutical composition for regulating HIV reverse transcriptase activity, wherein the HIV reverse transcriptase has at least one mutation compared to wild-type HIV, and the pharmaceutical composition comprises a therapeutically effective amount of the compound of the present invention.

[0218] In another embodiment, the present invention relates to a pharmaceutical composition for regulating HIV reverse transcriptase activity, wherein the HIV reverse transcriptase has reduced sensitivity to drugs such as efavirenz, nevirapine, doravirine, or delavirdine, said pharmaceutical composition comprising a therapeutically effective amount of the compound of the present invention.

[0219] In another embodiment, the present invention relates to a pharmaceutical composition for obtaining an agent for treating or preventing HIV, comprising a therapeutically effective amount of at least one compound of the present invention, and a pharmaceutical carrier.

[0220] In another embodiment, the present invention relates to the use of the compounds of the present invention for obtaining a medicament for treating or preventing HIV.

[0221] In another embodiment, the present invention relates to the use of the compositions of the invention for obtaining a medicament for treating or preventing HIV.

[0222] In another embodiment, the present invention relates to a method for treating or preventing HIV, comprising using at least one compound of the present invention.

[0223] In another embodiment, the present invention relates to a method for treating or preventing HIV, which includes using the composition of the present invention.

[0224] In another embodiment, the present invention relates to a method for treating or preventing HIV infection, wherein a therapeutically effective amount of at least one compound of the present invention is administered to a subject in need of such treatment.

[0225] In another embodiment, the present invention relates to the above-described method for treatment or prevention, wherein the therapeutically effective amount of said compound refers to a daily dose of about 0.1 to about 500 mg / kg body weight when administered parenterally.

[0226] In another embodiment, the present invention relates to the above-described method for treatment or prevention, wherein the daily dose may be administered as a single dose or 1-5 separate doses.

[0227] In another embodiment, the present invention relates to a composition for treating or preventing HIV-mediated diseases, comprising a therapeutically effective amount of the 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.

[0228] In another embodiment, the present invention relates to a method for treating or preventing HIV-mediated disease, wherein a therapeutically effective amount of the 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 are administered to a subject requiring such treatment.

[0229] In another embodiment, the present invention relates to a method of reverse transcriptase inhibition in an HIV-infected subject, wherein a therapeutically effective amount of at least one compound of the present invention is administered to the subject requiring such treatment.

[0230] In another embodiment, the present invention relates to a method for obtaining the pharmaceutical composition of the present invention, which includes mixing the compound of the present invention with a pharmaceutical carrier.

[0231] The term "as described above" refers to the broadest definition of the respective groups specified in the Summary Section, the broadest claim of the invention, or this specification. In other embodiments provided below, substituents are present in each variant, optionally remaining within the most general scope specified in the Summary Section or this specification.

[0232] Unless otherwise stated, the technical and scientific terms used in the description of this invention have meanings known to experts in the prior art to which this invention pertains. This description includes references to various procedures and materials known to those skilled in the art. A standard document that takes into account common pharmacological factors is the monograph: Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, 13th edition, McGraw Hill Companies Inc., New York (2017). In the context of this invention, any suitable materials and / or methods known to those skilled in the art may be used. However, this specification contains descriptions of preferred materials and methods. Unless otherwise stated, the materials, reagents, etc., mentioned in the specification and examples are commercial products.

[0233] The term "compound of the present invention" or "compound of the present invention" as used herein refers to at least one compound mentioned in the present invention, and any combination thereof, including dual combinations, triple combinations, etc.

[0234] In the specification of this invention, for example, in any part of the application or in the claims of the invention, the terms "include" and "comprising" have their conventional meanings. That is, these terms generally correspond to the conditions of "containing at least" or "comprising at least". As for a method, the term "include" means that the method includes at least the mentioned stages. For a compound or composition, the term "include" means that the compound or composition includes at least the features or components described above; however, it may also include additional features or components.

[0235] The term "approximately" as used in this specification means about, roughly, around, or roughly. When used with respect to ranges of numbers, "approximately" means that the maximum and minimum values ​​within that range have the values ​​stated above. Generally, the term "approximately" is used to specify an acceptable variation of 20% higher or lower than a specified value.

[0236] This means that the numerical range used in the description refers to any value that the invention can use within the specified range. Therefore, a variable that is inherently discrete can have any integer value within the range, including the final value of the range. Similarly, a variable that is inherently continuous can have any actual value within the specified range, including the final value of the range. For example, if it is a discrete value, a variable that is specified to have a value between 0 and 2 can refer to 0, 1, or 2, and if it is a continuous variable, it can have values ​​of 0.0, 0.1, 0.01, 0.001, or any actual value.

[0237] If any group (e.g., R) 1If a compound is included in the fragment content or any formula mentioned or described more than twice, and the described compound is used or claimed in this invention, then its value is independent in each case. Furthermore, combinations of substituents and / or variables are permitted only in cases where the obtained compound is a stable compound.

[0238] In one embodiment of the invention, a compound of formula I is proposed, wherein R 1 X 1 X 2 Y 1 Having the above values. The terms "as described above," "as stated above," and "as described" refer to variables included in the broadest definition of a variable as mentioned in the summary portion of the invention or in the broadest claim of the specification of the invention.

[0239] In yet another embodiment of the invention, a compound is proposed that represents a free base or pharmaceutical salt compound according to the invention.

[0240] In another embodiment of the invention, a method for treating or preventing HIV infection is provided, the method comprising administering a therapeutically effective amount of a compound of formula I to a subject requiring treatment, wherein R 1 X 1 X 2 Y 1 It has the above values.

[0241] In yet another embodiment of the invention, a method for treating or preventing HIV-mediated diseases is proposed, comprising administering to a subject requiring treatment a therapeutically effective amount of a compound of formula I (wherein R...). 1 X 1 X 2 Y 1 Having the above values), 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.

[0242] In another embodiment of the invention, a method for inhibiting HIV reverse transcriptase in an HIV-infected subject is provided, the method comprising administering a therapeutically effective amount of a compound of formula I to a subject requiring treatment, wherein R 1 X 1 X 2 Y 1 It has the above values.

[0243] In another embodiment of the invention, a method for inhibiting HIV reverse transcriptase in an HIV-infected subject is provided, wherein the HIV reverse transcriptase contains at least one mutation compared to wild-type HIV, the method comprising administering a therapeutically effective amount of a compound of formula I to a subject requiring treatment, wherein R 1 X 1 X 2 Y 1 It has the above values.

[0244] In another embodiment of the invention, a method for inhibiting HIV reverse transcriptase in an HIV-infected subject is provided, wherein the HIV reverse transcriptase has reduced sensitivity to efavirenz, nevirapine, or deraviridine products, the method comprising administering to a subject requiring treatment a therapeutically effective amount of a compound of formula I, wherein R 1 X 1 X 2 Y 1 It has the above values.

[0245] In one embodiment of the invention, a pharmaceutical composition is provided comprising a compound of formula I (wherein R...). 1 X 1 X 2 Y 1 (having the above values), and at least one carrier, excipient or diluent.

[0246] Unless otherwise explicitly stated, the following definitions are used in this document. Furthermore, unless otherwise stated, all inclusions of functional groups are chosen independently, and two inclusions may be the same or different.

[0247] The term "alkyl" itself, or as part of another substituent, refers to a saturated hydrocarbon group having a straight or branched chain, including hydrocarbon groups having a specified number of carbon atoms (i.e., C16, C26, C36, C46, ​​C56, C6 ... 1-6 -alkyl group (assumed to have one to six carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, and isopropyl.

[0248] The term "alkynyl" itself, or as part of another substituent, refers to a hydrocarbon group in which at least one carbon-carbon bond is a triple bond, while the remaining bonds can be single, double, or other triple bonds. This includes hydrocarbon groups with 2 to 6 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, etc.

[0249] The term "alkenyl" itself, or as part of another substituent, refers to a hydrocarbon group in which at least one carbon-carbon bond is a double bond, while the remaining bonds can be single bonds or other double bonds. This includes hydrocarbon groups containing 2 to 6 carbon atoms. Examples of alkenyl groups include vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, and others.

[0250] The term "halogen" itself, or as part of another term, refers to an atom of fluorine, chlorine, bromine, or iodine.

[0251] The terms “carboxyl”, “carboxy”, or “hydroxycarbonyl” refer to the -COOH group.

[0252] The terms "alkoxy" and "alkoxy group" on their own or in combination refer (unless otherwise stated) to an aliphatic group of the alkyl-O- type, wherein the alkyl group is as defined above. Exemplary examples of alkoxy groups include (but are not limited to) methoxy-, ethoxy-, propoxy-, isopropoxy-, butoxy-, isobutoxy-, tert-butoxy-, pentooxy-, isopentoxy-, neopentoxy-, tert-pentoxy-, hexoxy-, isohexoxy-, heptoxy-, octoxy-, etc. Preferred alkoxy groups are methoxy- and ethoxy- groups.

[0253] Monocyclic, bicyclic, or tricyclic saturated carbon rings represent cyclic systems consisting of 1, 2, or 3 rings; wherein the specified cyclic system consists only of carbon atoms and contains only single bonds; monocyclic, bicyclic, or tricyclic partially saturated carbon rings represent cyclic systems consisting of 1, 2, or 3 rings; wherein the specified cyclic system consists only of carbon atoms and includes at least double bonds, provided that the cyclic system is not an aromatic cyclic system; monocyclic, bicyclic, or tricyclic aromatic carbon rings represent aromatic cyclic systems consisting of 1, 2, or 3 rings; wherein the specified cyclic system consists only of carbon atoms; the term "aromatic" is well known to those skilled in the art and refers to a cyclic conjugated system comprising 4n+2 electrons, i.e., 6, 10, 14, etc. π electrons (Huckel's rule). rule); Monocyclic, bicyclic, or tricyclic saturated heterocycles refer to cyclic systems consisting of 1, 2, or 3 rings and containing at least one heteroatom selected from O, N, or S; wherein the specified cyclic system contains only single bonds; Monocyclic, bicyclic, or tricyclic partially saturated heterocycles refer to cyclic systems consisting of 1, 2, or 3 rings and containing at least one heteroatom selected from O, N, or S and at least one double bond, provided that the cyclic system is not an aromatic cyclic system; Monocyclic, bicyclic, or tricyclic aromatic heterocycles refer to aromatic cyclic systems consisting of 1, 2, or 3 rings and containing at least one heteroatom selected from O, N, or S.

[0254] Specific examples of monocyclic, bicyclic, or tricyclic saturated carbocyclic rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[4,2,0]-octyl, cyclononyl, cyclodecyl, decahydronaphthyl, tetradecylhydroanthrayl, etc. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl are preferred, and cyclopentyl, cyclohexyl, and cycloheptyl are even more preferred.

[0255] Specific examples of monocyclic, bicyclic, or tricyclic partially saturated carbocyclic rings include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclic [4,2,0]octenyl, cyclononenyl, cyclodecenyl, octahydronaphthyl, 1,2,3,4-tetrahydronaphthyl, 1,2,3,4,4a,9,9a,10-octahydroanthracene, etc.

[0256] Specific examples of monocyclic, bicyclic, or tricyclic aromatic carbocyclic rings are phenyl, naphthyl, and anthracene. Phenyl is preferred.

[0257] Specific examples of monocyclic, bicyclic, or tricyclic saturated heterocycles include tetrahydrofuranyl, pyrrolylyl, dioxolanic, imidazoyl, thiazoylyl, tetrahydrothiophenyl, dihydrooxazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyrazolyl, piperidinyl, hexahydropyrimidinyl, hexahydropyrazinyl, dioxalyl, morpholinyl, dithiazoyl, thiomorpholinyl, piperazinyl, trithiazoyl, decahydroquinolinyl, octahydroindolyl, etc. Preferred are tetrahydrofuranyl, pyrrolylyl, dioxolanic, imidazoyl, thiazoylyl, dihydrooxazolyl, triazolyl, piperidinyl, dioxalyl, morpholinyl, thiomorpholinyl, and piperazinyl. Most preferred are tetrahydrofuranyl, pyrrolylyl, dioxolanic, piperidinyl, dioxalyl, morpholinyl, thiomorpholinyl, and piperazinyl.

[0258] Specific examples of monocyclic, bicyclic, and tricyclic partially saturated heterocycles include pyrrololinyl, imidazolinyl, pyrazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolane, 2,3-dihydro-1,4-benzodioxane-hexenyl, and dihydroindolyl. Preferred groups include pyrrololinyl, imidazolinyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolane, and indololinyl.

[0259] Specific examples of monocyclic, bicyclic, or tricyclic aromatic heterocycles include asetyl, oxetilidenyl, pyrroleyl, furanyl, thiopheneyl, imidazoleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuranyl, isobenzofuranyl, benzothiopheneyl, isobenzothiopheneyl, indolysinyl, indoleyl, isoindoleyl, benzooxazolyl, benzimidazoleyl, indoleyl, Benzo[a]isoxazolyl, benzo[a]isothiazolyl, benzo[a]pyrazolyl, benzo[a]oxadiazolyl, benzo[a]thiadiazolyl, benzo[a]triazolyl, purine, quinolinyl, isoquinolinyl, cinnolynyl, quinazinyl, phthalazinyl, quinoxolinyl, quinazolinyl, naphtyridinyl, pteridinyl, benzopyranyl, pyrrolopyridinyl, thienopyridinyl, furanopyridinyl, isothiazolpyridinyl, thiazopyridinyl, isoxazololopyridinyl, oxazololopyridinyl, pyrazololopyridinyl, imidazopyridinyl, pyrrolopyridinyl Pyrazinyl, thienopyrazinyl, furanopyrazinyl, isothiazolpyrazinyl, thiazopyrazinyl, isoxazolpyrazinyl, oxazolpyrazinyl, pyrazolpyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl, thienopyrimidinyl, furanopyrimidinyl, isothiazolpyrimidinyl, thiazopyrimidinyl, isoxazolpyrimidinyl, oxazolpyrimidinyl, pyrazolpyrimidinyl, imidazopyrimidinyl, pyrrolopyrazinyl, thienopyrazinyl, furanopyrazinyl, isothiazolpyrazinyl, thiazopyrazinyl, isoxazolpyrazinyl, oxazolpyrazinyl, pyrazolpyrazinyl, imidazopyrazinyl, oxadiazinyl Zolopyridyl, thiadiazolepyridyl, triazolepyridyl, oxadiazolepyrazinyl, thiadiazolepyrazinyl, triazolepyrazinyl, oxadiazolepyrimidinyl, thiadiazolepyrimidinyl, triazolepyrimidinyl, oxadiazolepyridazinyl, thiadiazolepyridazinyl, triazolepyridazinyl, imidazoxazinyl, imidazothiazolyl, imidazoxazinyl, isoxazinyl, isothiazinyl, pyrazoletriazinyl, oxazinyl, thiazolyl, imidazoxazinyl, oxadiazoletriazinyl, thiadiazoletriazinyl, triazoletriazinyl, carbazole, acridineyl, phenazinyl, phenthiazolyl, phenoxazinyl, etc.

[0260] The preferred aromatic heterocycles are monocyclic or bicyclic aromatic heterocycles. The monocyclic, bicyclic, or tricyclic aromatic heterocycles of interest are pyrroloyl, furanyl, thiophene, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, pyranyl, benzofuranyl, isobenzofuranyl, benzothiophene, isobenzothiophene, indoleyl, isoindoleyl, benzooxazolyl, benzoimidazolyl, indoleyl, benzoisooxazolyl, benzoisothiazolyl, benzopyrazolyl, benzooxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, xinolynyl, isoxinolynyl, phthalazinyl, quinoxolinyl, quinazolinyl, benzopyranyl, pyrrolopyridyl, thiophene-pyridine. Furanopyridyl, isothiazolylpyridyl, thiazopyridyl, isoxazolylpyridyl, oxazolylpyridyl, pyrazolylpyridyl, imidazopyridyl, pyrrolopyrazinyl, thienopyrazinyl, furanopyrazinyl, isothiazolylpyrazinyl, thiazopyrazinyl, isoxazolylpyrazinyl, oxazolylpyrazinyl, pyrazolylpyrazinyl, imidazopyrazinyl, pyrrolopyrimidineyl, thienopyrimidineyl, furanopyrazinyl The following are listed: anopyrimidinyl, isothiazolpyrimidinyl, thiazolpyrimidinyl, isoxazolpyrimidinyl, oxazolpyrimidinyl, pyrazolepyrimidinyl, imidazopyrimidinyl, oxadiazolepyridinyl, thiadiazolepyridinyl, triazolepyridinyl, oxadiazolepyrazinyl, thiadiazolepyrazinyl, triazolepyrazinyl, oxadiazolepyrimidinyl, thiadiazolepyrimidinyl, triazolepyrimidinyl, carbazole, acridinel, phenothiazinyl, phenotoxazinyl, etc.

[0261] The term "cycloalkyl" as used herein refers to a group having 3 to 12 carbon atoms in a monocyclic or polycyclic structure (including spirocyclic). For illustrative purposes, cycloalkyl includes, but is not limited to, the following groups: cyclopropyl, cyclopentyl, cyclohexyl, bicyclo[2.2.2]octyl, and spiro[5.5]undecyl, which can be substituted as in the case of other aliphatic or heteroaliphatic or heterocyclic substituents.

[0262] "Heterocycle," "heterocyclic group," or "heterocycle" herein refers to a non-aromatic monocyclic or polycyclic system (saturated or partially unsaturated) having three to twelve atoms containing heteroatoms N, O, or S. The heterocycle may be attached to the major moiety via a nitrogen atom (N-heterocyclic group) or via a carbon atom. The heterocycle may also be substituted. Specifically, a heterocycle may represent, but is not limited to, oxyranyl, oxyranyl, pyrrolyl, tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, 1,1-dioxo-thiomorpholin-4-yl, heptyl, diazolyl, homopiperazinyl, and oxazepyl. Anyl), 8-azabicyclo[3.2.1]octyl, quininecyclol, 8-oxa-3-azabicyclo[3.2.1]octyl, 9-azabicyclo[3.3.1]nonyl, 3-oxa-9-azabicyclo[3.3.1]nonyl, or 3-thia-9-azabicyclo[3.3.1]nonyl. Specific examples of heterocycles also include dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridyl, dihydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 2-oxa-5-azabicyclo[2.2.1]heptyl. The term "cycloalkenyl" herein refers to a partially unsaturated cycloalkyl group containing 5 to 12 carbon atoms and having one or two carbon-carbon double bonds.

[0263] In this document, the term "aryl" refers to a group containing an aromatic ring and having five to ten carbon atoms. Examples of aryl cyclic groups are phenyl and naphthyl.

[0264] As used herein, the terms "heteroaryl" and "heteroaryl ring" refer to stable heterocyclic and polycyclic aromatic segments having 5-10 atoms in the ring. Heteroaryl groups may or may not be substituted and may consist of one or more rings. Possible substituents include, in particular, any of the substituents mentioned above. Typical examples of heteroaryl rings are five- and six-membered monocyclic groups, such as thiophene, pyrrole, imidazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazolyl, etc.; and polycyclic heterocyclic groups, such as benzo[b]thiophene, isobenzofuranyl, isoindolyl, benzimidazolyl, etc. The term "heteroaryl" may be used equivalently to "heteroaryl ring" or "heteroaryl group".

[0265] Aryl or heteroaryl groups (including heteroaryl moieties such as heteroarylalkyl or heteroarylalkoxy moieties) may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of the aryl or heteroaryl group include, but are not limited to, halogens (F, Cl, Br, or I), C... 1-3 -alkyl, -CN, -OH, -C 1-3 -alkyl groups, as described in this invention.

[0266] Unless otherwise stated, in R 7 or R 7a The carbon ring or heterocycle mentioned in the definition can be attached to the rest of the molecule of formula (I) via any suitable cyclic carbon atom or heteroatom. Thus, for example, if the heterocycle represents an imidazole group, it can be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, etc., or if the carbon ring represents a naphthyl group, it can be 1-naphthyl, 2-naphthyl, etc.

[0267] If any of the substituents (e.g., R) 7 If a substance is encountered more than once in the same compound, then each of the substituents in the definition of such a substituent is independent.

[0268] The term "substituted" means that one or more hydrogen atoms at the atom or group mentioned as "substituted" are substituted by any of the listed groups, provided that the mentioned atom has a normal valence, or the valence of the substituted group atom is not excessive, and the substitution produces a stable compound. The term "substituted or unsubstituted" means that the compound or substructure is unsubstituted, or substituted by one or more substituents as mentioned or defined herein.

[0269] In this document, alkyl, alkenyl, alkynyl, alkylene, cycloalkyl, cycloalkenyl, heterocyclic, aryl, and heteroaryl groups, as well as other substructures containing at least one hydrogen atom in their composition, may be substituted with one or more substituents:

[0270] -F, -Cl, -Br, -CN, -OH, -NO2, -NH2, -CF3, -CHF2, -CH2F, -C1-C4-alkyl, -C2-C4-alkenyl, -C2-C4-ynyl, -C3-C9-cycloalkyl, -4-9-membered heterocyclic groups linked via C- or N- atoms, -phenyl, -5-6-membered heteroaryl groups linked 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 )2、-SO2-Rz , where each R z It is independently selected and represents -H, -C1-C6-alkyl, -C3-C9-cycloalkyl, -5-6-membered heteroaryl (containing 1 to 4 heteroatoms independently selected from group N, S and / or O), or substituted or unsubstituted 4-9-membered heterocyclic group (containing 1 to 4 heteroatoms);

[0271] Substituents can be represented from another set of those selected:

[0272] COO-isobutyl, NH2, CN, C 1-4 -alkoxy, 4-6-membered heteroaryl (containing 1 to 4 heteroatoms independently selected from the S, N, and O groups (17, 18, 67, 45, 60)), and the above heteroaryl groups are unsubstituted or converted to -OH, C 1-6 -alkyl, O or Rc substituted; BOC, COOH, R c C 3-6 -aryl (optionally substituted with OH, O, or OCH2C≡CH), 4-6 membered heterocyclic group (containing 1-2 heteroatoms selected from N and O), O, nitrogen atom, SC 1-6 -Alkyl, halogen. This invention contains only such combinations of substituents and derivatives, which form stable or chemically possible compounds. Stable or chemically possible compounds are those with sufficient stability for their synthesis and analytical detection. Preferred compounds of this invention are sufficiently stable and do not degrade for at least one week at temperatures up to 40°C in the absence of chemically active conditions.

[0273] Some of the compounds of this invention may exist in tautomeric forms, and unless otherwise stated, this invention includes such tautomeric forms of such compounds.

[0274] For example, the compounds of the present invention can exist in the form of tautomers 1-3 in a dynamic equilibrium state. Their separation is impossible under normal conditions; therefore, the pharmacological advantages of the compounds of the present invention represent the combined effects of the tautomers.

[0275] An example of the tautomer form of the compound according to the present invention is represented as follows:

[0276]

[0277] Unless otherwise stated, the structures shown herein also represent all stereoisomers, i.e., the R- and S-isomers of each asymmetric center. Furthermore, some stereochemical isomers, also mixtures of enantiomers and diastereomers of these compounds, are also the subject of this invention. Therefore, this invention covers each diastereomer or enantiomer (>90%, preferably >95% molar purity) that is significantly free of other isomers, as well as mixtures of such isomers.

[0278] Specific isomers can be obtained by following standard procedures, such as exposing the diastereomer salts to optically active acids or bases, followed by separation of the diastereomer mixture by crystallization and further separation of the optically active bases from these salts, to separate the racemic mixture. Examples of such acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, xylenetartaric acid, and camphorsulfonic acid. Another procedure for separating optically active isomers is the use of a chiral chromatographic column. Furthermore, another separation method involves synthesizing covalent diastereomer molecules by reacting the compounds of the present invention with an activated form of an optically pure acid or by using optically pure isocyanates. The obtained diastereomers can be separated using conventional methods, such as chromatography, distillation, crystallization, or sublimation, followed by hydrolysis to obtain enantiomerically pure compounds.

[0279] The optically active compounds of the present invention can be obtained using optically active starting materials. Such isomers can be in the form of free acids, free bases, esters, or salts.

[0280] This invention includes all pharmaceutically labeled compounds according to the invention, wherein one or more atoms are replaced by atoms having the same atomic number but different atomic weight or mass number from those commonly encountered in nature.

[0281] Examples of isotopes suitable for inclusion in compounds according to the invention include isotopes of hydrogen, such as... 2 H and 3 H, carbon, etc. 11 C 13 C and 14 C, chlorine 36 Cl, fluorine 18 F, iodine 123 I and 125 I, nitrogen 13 N and 15 N, oxygen 15 O、 17 O and 18 O, phosphorus 32 P and sulfur, etc. 35 S.

[0282] Some of the isotope-labeled compounds of the present invention, such as those comprising radioactive isotopes, are used to study the distribution of pharmaceutical formulations and / or substrates in tissues. In particular, for this purpose, radioactive isotopes such as tritium (i.e., 3 H) and carbon-14 (i.e. 14 C), which takes into account their ease of application and the availability of their detection tools.

[0283] Use heavier isotopes (e.g., deuterium, i.e.) 2 H) Alternatives can provide some therapeutic effects through metabolic stability regulation, for example, by increasing the in vivo half-life or reducing dose restrictions, and therefore may be preferred in some cases.

[0284] When using an appropriate isotopically labeled reagent instead of an unlabeled reagent used previously, the isotopically labeled compound according to the invention can be obtained using general methods known to those skilled in the art or by methods similar to those described in the appended synthetic method examples.

[0285] Therefore, the present invention also relates to the use of compounds according to the invention for diagnostic purposes, including the distribution of pharmaceutical formulations according to the invention or the identification of targets having affinity for compounds of the invention, particularly isotopically labeled compounds of the invention.

[0286] As used in this application, the term "wild-type" refers to an HIV strain that has a dominant genotype in the normal population and is resistant to reverse transcriptase inhibitors. The term "wild-type reverse transcriptase" as used in this application refers to a reverse transcriptase expressed by a wild-type strain, which is sequenced and available in the SwissProt database under the number P03366.

[0287] The term “reduced sensitivity” as used in this application means a change of approximately 10-fold or greater in the sensitivity of an isolate of a particular viral strain or compared to the sensitivity observed in wild-type viruses under similar experimental conditions.

[0288] The compound according to the invention is obtained using the method shown in the embodiments provided and described in the embodiments of the invention. The starting materials and reagents used to obtain the mentioned compounds were commercial reagents provided by companies such as Acros Organics, Alfa Aesar, Lancaster, Merck, and Sigma-Aldrich, or they were obtained using known methods according to procedures described in the literature and available in databases such as SciFinder and Reaxis (but not limited to them), such as Fieser and Fieser, Reagents for Organic Synthesis, Wiley & Sons: New York, TT1-21, RC LaRock, Comprehensive Organic Transformations, 2 ed., Wiley-VCH, New York (1999), Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.), TT1-9 Pergamon, Oxford (1991), Comprehensive Geterocyclic Chemistry, A.R. Katritzky and C.Wrees (Eds.), Pergamon, Oxford, TT.1-9 (1984), Comprehensive Geterocyclic Chemistry II, A.R. Katritzky and C.W. Rees (Eds), Pergamon, Oxford, TT1-11 (1986) and Organic Synthesis, Wiley & Sons: New York, TT1-40 (1991). The following reaction schemes are merely illustrative of some methods for synthesizing compounds according to the present invention, and those skilled in the art can formulate and propose different modifications to these reaction schemes by referring to the material of this application.

[0289] The starting materials and intermediate compounds in the mentioned reaction scheme can be obtained, and if necessary, can be purified using appropriate methods (including but not limited to filtration, distillation, crystallization, chromatography, etc.). Such materials can be characterized by appropriate methods (including physical constants and spectroscopic data).

[0290] Unless otherwise stated, the reactions described in this application are preferably carried out in an inert gas atmosphere at atmospheric pressure at a temperature of about -78°C to about 150°C, more preferably about 0°C to about 125°C, and most preferably at room temperature (e.g., at about 20°C).

[0291] Some compounds in the illustrated schemes are provided with the inclusion of broadly defined substituents; however, it will be apparent to a specialist that the nature of group R can vary depending on the structure of different compounds conforming to the present invention. Furthermore, the reaction conditions are typical, and alternative conditions are also well known. It is assumed that the reaction sequence in the following examples does not limit the scope of the invention as set forth above in the claims.

[0292] The pharmaceutical solvates according to the invention include solvates in which the solvent may be substituted with isotopes, such as D2O, d6-acetone, and d6-DMSO.

[0293] The term "solvent" refers to an association or complex of one or more molecules of solvent and a compound according to 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.

[0294] The term "hydrate" refers to a complex in which the solvent molecule is water.

[0295] The compounds of the present invention may exist in free form, or, if desired, in the form of pharmaceutical salts or other derivatives. As used herein, the term "pharmaceutical salt" refers to a salt suitable for use in contact with human and animal tissues, within the scope of the medical conclusions being reached, without excessive toxicity, irritation, allergic reactions, etc., and in accordance with a reasonable benefit / risk ratio. Pharmaceutical salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the pharmaceutical field. Salts may be obtained in situ during the isolation or purification of the compounds of the present invention, or may be obtained separately by the interaction of the compounds of the present invention, either as a free acid or a free base, with a suitable base or acid. Salts of amino groups formed from inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and chloric acid) or organic acids (such as acetic acid, oxalic acid, maleic acid, tartaric acid, succinic acid, or malonic acid), or salts of amino groups obtained by other methods used in the art (e.g., using ion exchange), may be examples of pharmaceutically acceptable, non-toxic acid salts. Other pharmaceutical salts include: adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, gluconate-heptyl sulfate, glycerol phosphate, gluconate, hemisulfate, heptaate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lacturonate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, neopentanoate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Typical salts of alkali metals and alkaline earth metals contain sodium, lithium, potassium, calcium, magnesium, etc. In addition, if desired, pharmaceutical salts may contain (if necessary) non-toxic cations of ammonium, quaternary ammonium, and amines obtained using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfate, and aryl sulfonate ions.

[0296] The compounds of the present invention can exist in the form of pharmaceutically acceptable esters. The term "pharmaceutically acceptable ester" refers to a derivative of the compounds of the present invention in which the carboxyl group is converted to an ester. Examples of suitable esters include lower alkyl, lower hydroxyalkyl, lower-alkoxy-lower-alkyl, amino-lower-alkyl, mono- or di-lower-alkyl-amino-lower-alkyl, morpholine-lower-alkyl, pyrrolidine-lower-alkyl, piperidine-lower-alkyl, piperazine-lower-alkyl, lower-alkyl-piperazine-lower-alkyl, and arylalkyl esters. Specific esters include methyl ester, ethyl ester, propyl ester, butyl ester, and benzyl ester. Furthermore, the term "pharmaceutically acceptable ester" encompasses compounds of the present invention in which the hydroxyl group is converted to the corresponding ester by an organic or inorganic acid 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, etc., which is non-toxic to organisms.

[0297] If one of the starting materials or compounds of the present invention contains one or more functional groups that are unstable or reactive under the reaction conditions of one or more reaction stages, the corresponding protecting group (such as those described, for example, in "Protective Groups in Organic Chemistry," TW Greene and PGM Utts, 3rd edition, 1999, Wiley, New York) can be introduced prior to the critical stage using methods well known in the art. Such protecting groups can be removed in a later stage of synthesis using standard methods described in the literature. Examples of protecting groups include: tert-butoxycarbonyl (Boc), 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl carbamate (Teoc), benzyloxycarbonyl (Cbz), and p-methoxybenzyloxycarbonyl (Moz).

[0298] The compounds of the present invention may contain several asymmetric centers and may exist in the form of optically pure enantiomers, enantiomer mixtures, such as racemates, diastereomer mixtures, diastereomer racemates, or mixtures of diastereomer racemates.

[0299] An "asymmetric carbon atom" is defined as a carbon atom with four different substituents. According to the Cahn-Ingold-Prelog rule, an asymmetric carbon atom can be either R- or S-configured.

[0300] Another embodiment of the invention relates to pharmaceutical compositions or pharmaceutical formulations containing the compounds of the invention and therapeutically inert carriers, diluents, or excipients, and methods for obtaining such compositions and pharmaceutical formulations using the compounds according to the invention. In one variant, the compounds of the invention can be prepared by stirring at room temperature, at the appropriate pH, and at the desired level with a physiologically acceptable carrier (e.g., a carrier in a galenine formulation that is non-toxic to the recipient at the dose and concentration used). The specific use and concentration of the compound primarily affect the pH of the composition, but preferably the pH can vary from about 3 to about 8. In another embodiment, the compounds of the invention are sterile. The compounds can be stored, for example, as solid or amorphous compositions, as lyophilized formulations, or as aqueous solutions.

[0301] The composition is prepared, administered, and applied according to good medical practice. Factors considered in this context include the specific disease to be managed, the specific mammal to be treated, the clinical condition of the specific patient, the cause of the disease, the site of delivery, the method of administration, the dosing regimen, and other factors familiar to the clinician.

[0302] The compounds according to the invention can be administered via any suitable route, including oral, local (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, epidural, and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

[0303] The compounds according to the invention can be administered in any suitable pharmaceutical form, such as tablets, powders, capsules, solutions, dispersants, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain ingredients commonly used in pharmaceutical formulations, such as diluents, carriers, pH adjusters, sweeteners, excipients, and other active ingredients.

[0304] Typical formulations are obtained by mixing the compounds of the present invention with a carrier or excipient. Acceptable carriers and excipients are well known to specialists in the field of the present invention and are described in detail in, for example, Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, by Ansel, Howard C. et al. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R. et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The composition may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing additives, colorants, sweeteners, flavorings, fragrances, diluents, and other known additives to provide an elegant presentation of the product (e.g., the compound or pharmaceutical composition according to the invention) or to aid in the manufacture of a pharmaceutical product (e.g., a pharmaceutical formulation).

[0305] Therefore, the present invention also relates to:

[0306] The compounds of the present invention are used as therapeutically active substances;

[0307] The compounds of the present invention are used as reverse transcriptase inhibitors;

[0308] The compounds of the present invention are used as pharmaceutical preparations having anti-HIV antiviral activity;

[0309] A pharmaceutical composition comprising the compound of the present invention and a therapeutically inert carrier;

[0310] The use of the compounds of this invention for the treatment or prevention of HIV;

[0311] The pharmaceutical composition having activity for HIV reverse transcriptase comprises a therapeutically effective amount of the compound according to the 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.

[0312] Use of the compounds according to the invention in obtaining pharmaceutical formulations for treating or preventing HIV;

[0313] The compounds of the present invention for the treatment or prevention of HIV; and

[0314] Methods for treating or preventing HIV include administering an effective amount of the compound of the present invention to a patient in need.

[0315] The compounds of the present invention can be modified to improve their solubility in water or other carriers by using sufficiently simple techniques well known to those skilled in the art (such as salting, etherification, etc.). Furthermore, specialists can alter the route of administration and treatment process of specific compounds to modulate the pharmacokinetics of the compounds of the present invention and achieve maximum therapeutic effect for patients.

[0316] The term "therapeuticly effective dose" as used in this application refers to the amount necessary to reduce the intensity of a patient's disease symptoms. The level of HIV infection development is established by measuring viral load (RNA) or T-cell levels. Dosage can be adjusted according to individual requirements in each specific case. Dosage can be adjusted within a wide range depending on many factors, such as the severity of the managed disease, the subject's age and relative health status, the patient's use of other pharmaceutical preparations, the route and dosage form of administration, and the physician's experience and qualifications. In the case of oral administration, when treated with a single pharmaceutical preparation and / or in combination therapy, a suitable daily dose is about 0.01 to about 100 mg / kg body weight. A preferred daily dose is about 0.1 to about 500 mg / kg body weight, more preferably 0.1 to 100 mg / kg body weight, and even more preferably 1.0 to about 10 mg / kg body weight. Therefore, for a patient weighing up to 70 kg, the dose is about 7 mg to about 0.7 g per day. The daily dose can be administered as a single dose or as 1-5 fractionated doses. Generally, treatment begins with the administered dose and does not exceed the optimal dose. The dosage is then gradually increased to achieve the best effect for the specific patient. A specialist physician of the mentioned disease, without any experiments, can determine the therapeutically effective amount of the compound according to the invention necessary to manage the disease in a specific patient based on his / her own experience and the description of the invention.

[0317] The active compound or its salt used in this invention can be administered in combination with other antiviral agents such as nucleoside reverse transcriptase inhibitors or HIV protease inhibitors. When the active compound or its derivative or salt is administered in combination with another antiviral agent, the activity of the combination may exceed that of the initial compound. In the case of combination therapy, such administration can be performed simultaneously or sequentially with the administration of the nucleoside derivative. Therefore, the term "simultaneous administration" as used in this application includes administration of the agents at the same time or at different times. Two or more agents can be administered simultaneously as part of a formulation containing two or more active ingredients; or two or more formulations each containing one active ingredient can be administered almost simultaneously.

[0318] The treatment mentioned includes prevention and treatment of the observed symptoms. Furthermore, the term "treatment of HIV infection" as used in this application also includes treatment or prevention of diseases or conditions related to or mediated by HIV infection, or their clinical symptoms.

[0319] Pharmaceutical formulations are preferably representative of standard pharmaceutical forms. In such forms, the product is divided into standard doses containing appropriate amounts of the active ingredient. Standard pharmaceutical forms can be packaged products, or packages containing discrete amounts of the product, such as packaged tablets, capsules, and powders in bottles or ampoules. Furthermore, standard doses can be capsules, tablets, starch capsules, or cakes, or can be packages containing specific amounts of any specified dosage form.

[0320] Best way to carry out the invention

[0321] The present invention is illustrated by the following embodiments, but not by limiting their scope. The purpose of providing the embodiments and products mentioned below is to explain the outline of the invention and support its practical application.

[0322] Example

[0323] A general procedure for replacing sulfonates with activated amines.

[0324] (Reaction XIX)

[0325]

[0326] At 0 °C, NaH (7 mmol, 1.8 eq.) was added to a formamide solution (3.9 mmol, 1 eq.) in dimethylformamide (15 mL). The reaction mixture was mixed at room temperature for 20 minutes. The mixture was then cooled to 0 °C again and sulfone (3.9 mmol, 1.0 eq.) was added. The reaction mixture was mixed for 8 hours, and the organic solvent was then evaporated. Water (pH = 9) was added to the residue. The resulting residue was filtered and washed with water. The residue was dissolved in dichloromethane and purified by chromatography using Hex:EA (1:1) as the eluent.

[0327] General procedure for alkylation of substituted tetrahydropyrimidine derivatives

[0328] (Reaction XX)

[0329]

[0330] Pyrimidine (1 mmol, 1 eq.) in its free base form and alkyl bromide (1.1 mmol) were transferred to a 50 mL round-bottom flask equipped with an effective reflux condenser (with a calcium chloride tube). The mixture was brought to a boil until all substances solidified. The hydrobromide of the target product was formed. At the end of the reaction, the flask was cooled, and 1 g of caustic soda was added in portions (while cooling to avoid significant heating) to 20 mL of aqueous solution. The extract in the separating funnel was identified, and chlorous acid was added. The organic phase was washed with water and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the residue was purified by chromatography using Hex:EA (1:3) as the eluent.

[0331] Example 1

[0332] Synthesis of 4-((7-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)benzonitrile

[0333]

[0334] 3-Oxoperidin-1,4-dicarboxylic acid 1-(tert-butyl) ester 4-ethyl ester (27)

[0335]

[0336] 26 hydrochloride (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 the mixture was stirred for 5 minutes. Then, 5% Pd / C (5 g) was added to the reactants. The reaction mixture was degassed and debenzylated in a hydrogen atmosphere. The reaction mixture was stirred for 3 days, and then Boc2O (43.6 g, 0.2 mol, 1 eq.) was added. The reaction mixture was stirred for 3 hours, and then passed through a silit layer, with the addition of cold water (250 mL) and dichloromethane (500 mL). The organic layer was separated, washed twice with water (2 x 150 mL), dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the organic solvent was removed by rotary evaporation under reduced pressure. The residue was purified by column chromatography using Hex:EA (3:1) as the eluent. Rf = 0.6.

[0337] Weight = 20g

[0338] Yield = 52%

[0339] 4-Hydroxy-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (28)

[0340]

[0341] Thiourea (3.22 g, 42 mmol, 1.5 eq.) and ketone ester (27) (7.67 g, 28.2 mmol, 1.0 eq.) were added to a sodium ethoxide solution obtained by dissolving Na (1.95 g, 81 mmol, 3.0 eq.) in anhydrous ethanol (100 mL). The reaction mixture was boiled for 8 hours, then cooled to room temperature and MeI (1.76 mL, 28.2 mmol, 1 eq.) was added dropwise from a dropping funnel while stirring. After the addition of the alkylating agent, the mixture was mixed at room temperature for 1 hour. The reaction mixture was boiled, and the residue was dissolved in water. A precipitate formed during acidification of the aqueous solution to pH 3–4 with citric acid. The precipitate was filtered and washed successively with water, hexane, and ethyl acetate.

[0342] Weight = 7.8g

[0343] Yield = 85%

[0344] 4-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-carboxylic acid tert-butyl ester (29)

[0345]

[0346] Pyrimidine 28 (5.68 g, 19.1 mmol, 1 eq.) was dissolved in 80 mL of dimethylformamide, followed by the addition of triethylamine (TEA) (2.66 mL, 19.1 mmol, 1 eq.), and then benzotriazol-1-yl-oxytripyrrolidinephosphonium hexafluorophosphate (PyBop) (9.9 g, 19.1 mmol, 1 eq.) over 5 minutes. The reaction mixture was stirred for 5 hours, then poured into ethyl acetate, and the organic phase was washed with a saturated sodium bicarbonate solution. The organic layer was distilled off and purified by column chromatography using Hex:EA (3:1) as the eluent.

[0347] Weight = 4.6g

[0348] Yield = 68%.

[0349] 4-(4-cyano-2,6-dimethylphenoxy)-2-(methylthio)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (30)

[0350]

[0351] Pyrimidine 29 (4.1 g, 8.5 mmol, 1 eq.) was dissolved in dimethylformamide (50 mL), followed by the addition of phenol 21 (1.24 g, 8.5 mmol, 1 eq.) and cesium carbonate (2.76 g, 8.5 mmol, 1 eq.). The reaction mixture was mixed for 8 hours, then poured into ethyl acetate and washed with water. The organic layer was distilled off and purified by column chromatography using Hex:EA (3:1) as the eluent.

[0352] Weight = 3.2g

[0353] Yield = 85%.

[0354] LCMS(M+H)=402

[0355] 4-(4-cyano-2,6-dimethylphenoxy)-2-(methanesulfonyl)-5,8-dihydro-pyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (31)

[0356]

[0357] To a solution of pyrimidine 30 (3.0 g, 7 mmol, 1 eq.) in dichloromethane (50 mL) at 0 °C, m-chloroperbenzoic acid (mCPBA) (3.8 g, 21.1 mmol, 3 eq.) was added. The reaction mixture was stirred for 24 hours. Then, to stop the reaction, a saturated aqueous solution of NaHCO3 was added to the mixture. The product was extracted with dichloromethane. The organic phase was distilled off on a rotary evaporator and purified by column chromatography using Hex:EA (1:1) as the eluent.

[0358] Weight = 2.2g

[0359] Yield = 54%

[0360] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.46 (s, 9H), 2.11 (s, 6H), 2.98 (t, J = 5.4Hz, 2H), 3.12 (s, 3H), 3.76 (t, J = 5.5Hz, 2H), 4.72 (broad singlet, 2H), 7.72–7.78 (m, 3H)

[0361] LCMS(M+H)=434

[0362] 2-((4-cyanophenyl)amino)-4-(2,6-dimethylphenoxy)-5,8-dihydropyrido[3,4-d]pyrimidine-7(6H)-carboxylic acid tert-butyl ester (32)

[0363]

[0364] At 0°C, NaH (0.28 g, 7 mmol, 1.8 eq.) was added to a solution of formamide 32 (0.51 g, 3.9 mmol, 1 eq.) in dimethylformamide (15 ml). The reaction mixture was stirred at room temperature for 20 minutes. The mixture was then cooled back to 0°C and sulfone 31 (1.8 g, 3.9 mmol, 1.0 eq.) was added. The reaction mixture was stirred for 8 hours, and the organic solvent was then evaporated. Water (pH = 9) was added to the residue. The resulting residue was filtered and washed with water. The residue was dissolved in dichloromethane and purified by column chromatography using Hex:EA (1:1) as the eluent.

[0365] Weight = 520mg

[0366] Yield = 42%

[0367] 4-(((4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)-benzonitrile hydrochloride (33)

[0368]

[0369] Pyrimidine 32 (500Mr) was dissolved in methanol saturated with hydrochloric acid and mixed for one hour. The organic solvent was then evaporated, and the resulting precipitate was recrystallized from ethanol.

[0370] Weight = 500mg

[0371] Yield = 96%

[0372] 4-(((7-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile (BB 0273459)

[0373]

[0374] Pyrimidine 20 in its free base form (500 mg, 1 mmol, 1 eq.) and benzyl bromide (205.5 mg, 1.1 mmol) were transferred to a 100 mL round-bottom flask equipped with an effective reflux condenser (with a calcium chloride tube). The mixture was brought to a boil until all substances solidified. Hydrobromide of the target N-benzylpyrimidine was formed. At the end of the reaction, the flask was cooled and 1 g of caustic soda was added in portions (while cooling to avoid significant heating) to a 20 mL aqueous solution. The product extracted in a separating funnel was separated, and the organic phase was washed with chlorinous acid and dried over anhydrous sodium sulfate. The organic solvent was removed under reduced pressure, and the residue was purified by chromatography using Hex:EA (1:3) as the eluent.

[0375] Weight = 300mg

[0376] Yield = 58%

[0377] BB 0273459

[0378] ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.95–2.13 (m, 6H), 2.78 (broad singlet, 2H), 3.43 (broad singlet, 2H), 3.47–3.57 (m, 2H), 3.64–3.79 (m, 2H), 7.19–7.46 (m, 12H)

[0379] LCMS m / z(M+H): 462.

[0380] Example 2

[0381] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-methyl-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0382]

[0383] BB 0273774

[0384] 1 H NMR (400MHz, CDCl3, 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=8.2Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.55 (s, 2H).

[0385] Weight yield -4.5 mg (8%)

[0386] LCMS m / z(M+H): 411.

[0387] Example 3

[0388] Synthesis of 4-((4-(4-formyl-2,6-dimethylphenoxy)-7-methyl-5,6,7,8-tetrahydro[3,4-d]pyrimidin-2-yl)amino)benzonitrile

[0389]

[0390] BB 0273775

[0391] 1 H NMR (400MHz, CDCl3, δ, ppm): 1.26 (s, 3H), 2.18-2.20 (m, 2H), 2.23 (s, 6H), 3.14-3.18 (m, 2H) , 3.74-3.78 (m, 2H), 7.20 (d, J=8.4Hz, 2H), 7.28 (d, J=8.4Hz, 2H), 7.76 (s, 2H), 10.07 (s, 1H).

[0392] Weight yield - 8.2 mg (12%)

[0393] LCMS m / z(M+H): 413

[0394] Example 4

[0395] Synthesis of tert-butyl 4-(4-(1,3-dioxolane-2-yl)-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylate

[0396]

[0397] BB 0273892

[0398] 1 H NMR (400MHz, CDCl3, δ, ppm): 1.51 (s, 10H), 2.09 (s, 6H), 2.20-2.42 (m, 1H), 2.94-3.18 (m, 4H), 3.66 (broad single peak, 4H), 4.06 (t, J=12.3Hz , 2H), 4.36 (dd., J=10.97Hz, 4.86Hz, 2H), 5.55 (s, 1H), 7.08 (s, 1H), 7.16 (d, J=8.56Hz, 2H), 7.30 (s, 2H), 7.41 (d, J=8.74Hz, 2H),

[0399] Weight yield: -0.0043g (12%)

[0400] LCMS m / z(M+H): 572.

[0401] Example 5

[0402] Synthesis of tert-butyl 2-((4-cyanophenyl)amino)-4-(4-formyl-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylate

[0403]

[0404] BB 0273943

[0405] 1 ¹H NMR (400MHz, CDCl₃, δ, ppm): 1.51 (s, 9H), 2.19 (s, 6H), 3.09 (broad singlet, 4H), 3.68 (broad singlet, 4H), 7.12 (broad singlet, 1H), 7.30 (s, 4H), 7.70 (s, 2H), 10.02 (s, 1H).

[0406] Weight yield: -0.056g (12%)

[0407] LCMS m / z(M+H): 514.

[0408] Example 6

[0409] Synthesis of tert-butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0410]

[0411] BB 0273961

[0412] 1 ¹H NMR (400MHz, CDCl₃, 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 (broad singlet, 2H), 7.39 (d, J = 8.8 Hz, 4H), 7.48 (s, 2H).

[0413] Weight yield -2.87g (46%)

[0414] LCMS m / z(M+H): 497.

[0415] Example 7

[0416] Synthesis of 4-((2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0417]

[0418] BB 0273963

[0419] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.11 (s, 6H), 3.02 (t, J = 5.8Hz, 2H), 3.50 (d, J = 5.2Hz, 2H), 4.31 (broad singlet, 2H), 7.47 (broad singlet, 4H), 7.79 (s, 2H).

[0420] Weight yield -2.08g (96%)

[0421] LCMS m / z(M+H): 397.

[0422] Example 8

[0423] Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(methanesulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0424]

[0425] BB 0273964

[0426] 1 H NMR (400MHz, CDCl3, δ, ppm): 2.16 (s, 6H), 2.98 (s, 3H), 3.04 (t, J=5.8Hz, 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)

[0427] Weight yield: -0.072g (84%)

[0428] LCMS m / z(M+H): 475.

[0429] Example 9

[0430] Synthesis of ethyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate

[0431]

[0432] BB 0273965

[0433] 1 H NMR (400MHz, CDCl3, δ, ppm): 1.33 (t, J=7.1Hz, 3H), 2.17 (s, 6H), 2.89 (t, J=5.5Hz, 2H), 3.8 6 (t, J=5.7Hz, 2H), 4.24 (kv, J=7.1Hz, 2H), 4.67 (s, 2H), 7.39 (d, J=8.9Hz, 4H), 7.49 (s, 2H)

[0434] Weight yield: -0.056g (56%)

[0435] LCMS m / z(M+H): 468.

[0436] Example 10

[0437] Synthesis of (E)-3-(4-((7-(tert-butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylphenyl)acrylic acid

[0438]

[0439] BB 0273969

[0440] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.40 (broad singlet, 9H), 2.07 (s, 6H), 3.02 (broad singlet, 4H), 3.59 (broad singlet, 4H), 6.56 (d, J = 16.0Hz, 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).

[0441] Example 11

[0442] Synthesis of tert-butyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylate

[0443]

[0444] BB 0273972

[0445] 1 ¹H NMR (400MHz, CDCl₃, δ, ppm): 1.51 (s, 9H), 2.14 (s, 6H), 3.06–3.10 (m, 4H), 3.65–3.68 (m, 4H), 7.07 (broad singlet, 1H), 7.29–7.35 (m, 2H), 7.36–7.42 (m, 2H), 7.48 (s, 2H).

[0446] Weight yield: -0.462g (24%)

[0447] LCMS m / z(M+H): 511.

[0448] Example 12

[0449] Synthesis of 4-((2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile dihydrochloride

[0450]

[0451] BB 0273976

[0452] 1¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.11 (s, 6H), 3.14–3.45 (m, 8H), 7.43 (s, 4H), 7.78 (s, 2H), 9.79 (broad singlet, 2H), 10.12 (broad singlet, 1H).

[0453] Weight yield: -0.237g (92%)

[0454] LCMS m / z(M+H): 411.

[0455] Synthesis of tert-butyl 2-((4-cyanophenyl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylate

[0456]

[0457] BB 0274009

[0458] 1 ¹H NMR (400MHz, CDCl₃, δ, ppm): 1.51 (s, 9H), 2.10–2.17 (m, 6H), 3.08 (broad singlet, 4H), 3.67 (broad singlet, 4H), 5.90–5.46 (m, 1H), 7.63–7.04 (m, 8H).

[0459] Weight yield: -0.06g (8%)

[0460] LCMS m / z(M+H): 537.

[0461] Example 13

[0462] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-pyridinoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0463]

[0464] BB 0274010

[0465] 1¹H NMR (400MHz, DMSO-d⁶, δ, ppm): 2.01–2.08 (m, 3H), 2.12 (s, 3H), 3.08 (d, J = 2.4Hz, 2H), 3.17 (d, J = 3.7Hz, 2H), 3.63 (broad singlet, 2H), 3.83–3.97 (m, 2H), 7.42 (d, J = 7.8Hz, 4H), 7.50 (t, J = 5.8Hz, 1H), 7.59 (d, J = 7.7Hz, 1H), 7.78 (d, J = 13.8Hz, 2H), 7.90–8.00 (m, 1H), 8.62 (d, J = 4.3Hz, 1H), 10.09 (broad singlet, 1H).

[0466] Weight yield: -0.072g (29%)

[0467] LCMS m / z(M+H): 516.

[0468] Example 14

[0469] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-isonicotinanoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0470]

[0471] BB 0274011

[0472] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.05 (s, 3H), 2.12 (s, 3H), 3.05 (broad singlet, 2H), 3.12–3.24 (m, 2H), 3.51 (broad singlet, 2H), 3.82–3.96 (m, 2H), 7.32–7.51 (m, 6H), 7.78 (d, J = 14.6Hz, 2H), 8.69 (d, J = 4.8Hz, 2H), 10.10 (d, J = 4.0Hz, 1H).

[0473] Weight yield: -0.067g (32%)

[0474] LCMS m / z(M+H): 516.

[0475] Example 15

[0476] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-nicotinanoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0477]

[0478] BB 0274012

[0479] 1 ¹H NMR (400MHz, DMSO-d⁶δ, ppm): 2.04 (s, 3H), 2.12 (broad singlet, 3H), 3.06 (broad singlet, 2H), 3.19 (broad singlet, 2H), 3.58 (broad singlet, 2H), 3.90 (broad singlet, 2H), 7.41 (d, J = 11.6Hz, 4H), 7.50 (dd, J = 7.5, 5.0Hz, 1H), 7.77 (d, J = 14.4Hz, 2H), 7.87 (d, J = 6.7Hz, 1H), 8.60–8.71 (m, 2H), 10.10 (broad singlet, 1H).

[0480] Weight yield: 0.055g (30%)

[0481] LCMS m / z(M+H): 516.

[0482] Example 16

[0483] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0484]

[0485] BB 0274014

[0486] 1 H NMR (400MHz, DMSO-d6, δ, ppm): 2.08 (s, 6H), 2.72 (d, J=7.5Hz, 4H), 3.01 (d, J=8.5Hz, 4H), 3.80 (s, 2H), 7.27 (dd , J=6.7, 5.2Hz, 1H), 7.40 (s, 4H), 7.54 (d, J=7.8Hz, 1H), 7.72-7.84 (m, 3H), 8.50 (d, J=4.2Hz, 1H), 10.04 (s, 1H).

[0487] Weight yield: -0.106g (78%)

[0488] LCMS m / z(M+H): 502.

[0489] Example 17

[0490] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(pyridin-3-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d1-azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0491]

[0492] BB 0274015

[0493] 1 H NMR (400MHz, DMSO-d6, δ, ppm): 2.08 (s, 6H), 2.67 (d, J=6.3Hz, 4H), 3.00 (dd, J=6.3, 2.6Hz, 4H), 3.71 (s, 2H ), 7.33-7.46 (m, 5H), 7.71-7.82 (m, 3H), 8.48 (dd, J=4.7, 1.5Hz, 1H), 8.56 (d, J=1.5Hz, 1H), 10.04 (s, 1H).

[0494] Weight yield: -0.090g (64%)

[0495] LCMS m / z(M+H): 502

[0496] Example 18

[0497] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(pyridin-4-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0498]

[0499] BB 0274016

[0500] 1 H NMR (400MHz, DMSO-d6, δ, ppm): 2.09 (s, 6H), 2.68 (d, J=5.8Hz, 4H), 3.02 (d, J=6.2Hz, 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).

[0501] Weight yield: -0.095g (66%)

[0502] LCMS m / z(M+H): 502.

[0503] Synthesis of 4-((2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0504]

[0505] BB 0274021

[0506] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.09 (broad singlet, 6H), 2.73–3.08 (m, 8H), 7.41 (broad singlet, 4H), 7.77 (broad singlet, 2H), 9.99 (broad singlet, 1H).

[0507] Weight yield: -0.174g (96%)

[0508] LCMS m / z(M+H): 411

[0509] Example 19

[0510] Synthesis of tert-butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)piperidine-1-carboxylate

[0511]

[0512] BB 0274025

[0513] 1 H NMR (400MHz, CDCl3, δ, ppm): 1.47 (s, 9H), 1.64-1.90 (m, 5H), 2.14 (d, J=1.6Hz, 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=8.4Hz, 2H), 7.36-7.42 (m, 2H), 7.48 (d, J=4.5Hz, 2H).

[0514] Weight yield: -0.230g (55%)

[0515] LCMS m / z(M+H): 622.

[0516] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-carbonyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile dihydrochloride

[0517]

[0518] BB 0274026

[0519] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.78 (broad singlet, 4H), 2.09 (broad singlet, 6H), 2.81–3.16 (m, 7H), 3.23 (broad singlet, 2H), 3.62–3.90 (m, 4H), 7.41 (broad singlet, 4H), 7.78 (broad singlet, 2H), 8.86 (broad singlet, 1H), 9.27 (broad singlet, 1H), 10.08 (broad singlet, 1H).

[0520] Weight yield -0.090g (80%)

[0521] LCMS m / z(M+H): 522.

[0522] Example 20

[0523] Synthesis of tert-butyl 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptane-7(6H)-yl)piperidine-1-carboxylate

[0524]

[0525] BB 0274027

[0526] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.26–1.46 (m, 11H), 1.68 (d, J = 11.0Hz, 2H), 2.08 (s, 6H), 2.58–2.83 (m, 7H), 2.94 (broad singlet, 4H), 3.91–4.08 (m, 2H), 7.41 (s, 4H), 7.78 (s, 2H), 10.01 (s, 1H).

[0527] Weight yield: -0.203g (82%)

[0528] LCMS m / z(M+H): 594.

[0529] Example 21

[0530] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile trihydrochloride

[0531]

[0532] BB 0274028

[0533] 1 H NMR (400MHz, DMSO-d6, δ, ppm): 1.97-2.19 (m, 8H), 2.35 (d, J=11.9Hz, 2H), 2.9 4 (kv, J=11.1Hz, 2H), 3.09 (dd, J=16.5, 6.54Hz, 1H), 3.24-3.36 (m, 1H), 3.37-3 0.53 (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 (broad single peak, 1H), 12.13 (broad single peak, 1H).

[0534] Weight yield: -0.182g (87%)

[0535] LCMS m / z(M+H): 494.

[0536] Example 22

[0537] Synthesis of 4-((6-(2-aminoacetyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0538]

[0539] BB 0274051

[0540] 1 H NMR (400MHz, CDCl3, 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).

[0541] Weight yield: -0.029g (26%)

[0542] LCMS m / z(M+H): 453

[0543] Example 23

[0544] Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(2-(3-hydroxyazacyclobutane-1-yl)acetyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0545]

[0546] BB 0274052

[0547] 1 ¹H NMR (400MHz, CDCl₃, δ, ppm): 1.90 (broad singlet, 1H), 2.34 (broad singlet, 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 = 7.5Hz, 2H), 7.19 (d, J = 7.1Hz, 2H), 7.26 (s, 2H).

[0548] Weight yield -0.005g (12%)

[0549] LCMS m / z(M+H): 510

[0550] Example 24

[0551] Synthesis of tert-butyl-2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-carboxylate

[0552]

[0553] BB 0274063

[0554] 1¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.25 (broad singlet, 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 (broad singlet, 4H), 7.78 (broad singlet, 2H), 9.96–10.16 (m, 1H).

[0555] Weight yield: -0.128g (57%)

[0556] LCMS m / z(M+H): 608

[0557] Example 25

[0558] Synthesis of (R)-2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0559]

[0560] BB 0274064

[0561] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.25 (broad singlet, 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 (broad singlet, 4H), 7.78 (d, J = 2.4Hz, 2H), 9.97–10.17 (m, 1H).

[0562] Weight yield: -0.103g (52%)

[0563] LCMS m / z(M+H): 608.

[0564] Example 26

[0565] Synthesis of tert-butyl (S)-2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-carboxylate

[0566]

[0567] BB 0274065

[0568] 1 ¹H NMR (400MHz, DMO-d6, δ, ppm): 1.25 (broad singlet, 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 (broad singlet, 4H), 7.77 (broad singlet, 2H), 9.93–10.16 (m, 1H).

[0569] Weight yield -0.098g (50%)

[0570] LCMS m / z(M+H): 608

[0571] Example 27

[0572] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0573]

[0574] BB 0274072

[0575] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.40–1.74 (m, 4H), 2.09 (s, 6H), 2.77 (broad singlet, 4H), 2.97 (broad singlet, 4H), 3.19–3.46 (m, 3H), 3.81–3.96 (m, 2H), 7.41 (s, 4H), 7.78 (s, 2H), 10.00 (broad singlet, 1H).

[0576] Weight yield: -0.096g (82%)

[0577] LCMS m / z(M+H): 495

[0578] Example 28

[0579] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(5-methylfuran-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0580]

[0581] BB 0274073

[0582] 1 ¹H NMR (400MHz, CDCl₃, 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 (broad singlet, 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).

[0583] Weight yield: -0.038g (44%)

[0584] LCMS m / z(M+H): 505

[0585] Example 29

[0586] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(1-methyl-1H-pyrrolo-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0587]

[0588] BB 0274074

[0589] 1 H NMR (400MHz, CDCl3, δ, ppm): 2.15 (s, 6H), 2.68 (dd, J=12.2Hz, 10.3Hz, 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=3.0Hz, 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).

[0590] Weight yield: -0.152g (38%)

[0591] LCMS m / z(M+H): 504

[0592] Example 30

[0593] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(4-hydroxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0594]

[0595] BB 0274075

[0596] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.08 (s, 6H), 2.62 (broad singlet, 4H), 2.98 (broad singlet, 4H), 3.53 (broad singlet, 2H), 6.72 (d, J = 8.3Hz, 2H), 7.14 (d, J = 8.0Hz, 2H), 7.40 (s, 4H), 7.77 (s, 2H), 9.30 (broad singlet, 1H), 10.03 (s, 1H).

[0597] Weight yield: -0.042g (24%)

[0598] LCMS m / z(M+H): 517

[0599] Example 31

[0600] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(1-methoxypropane-2-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0601]

[0602] BB 0274080

[0603] 1 ¹H NMR (400MHz, CDCl₃, δ, ppm): 1.06 (d, J = 5.8Hz, 3H), 2.04–2.27 (m, 6H), 2.81 (broad singlet, 4H), 3.04 (broad singlet, 5H), 3.32 (broad singlet, 1H), 3.36 (broad singlet, 3H), 3.51 (d, J = 6.7Hz, 1H), 7.14 (broad singlet, 1H), 7.24–7.33 (m, 2H), 7.36 (d, J = 7.90Hz, 2H), 7.47 (broad singlet, 2H).

[0604] Weight yield: -0.128g (48%)

[0605] LCMS m / z(M+H): 483

[0606] Example 32

[0607] Synthesis of 4-((7-(cyanomethyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0608]

[0609] BB 0274095

[0610] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.10 (s, 6H), 2.72 (broad singlet, 4H), 3.03 (broad singlet, 4H), 3.89 (s, 2H), 7.42 (broad singlet, 4H), 7.78 (s, 2H), 10.05 (broad singlet, 1H).

[0611] Weight yield: -0.042g (24%)

[0612] LCMS m / z(M+H): 450

[0613] Example 33

[0614] Synthesis of tert-butyl 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carbonyl)pyrrolidine-1-carboxylate

[0615]

[0616] BB 0274097

[0617] 1 H NMR (400MHz, CDCl3, 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).

[0618] Weight yield: -0.068g (67%)

[0619] LCMS m / z(M+H): 494(M-Boc).

[0620] Example 34

[0621] Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(pyrrolidine-2-carbonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0622]

[0623] BB 0274098

[0624] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.91 (broad singlet, 3H), 2.07–2.17 (m, 6H), 2.78–2.98 (m, 2H), 3.10–3.32 (m, 2H), 3.90 (broad singlet, 2H), 4.50–4.85 (m, 3H), 7.46 (broad singlet, 4H), 7.79 (s, 2H), 8.35–8.63 (m, 1H), 10.12 (broad singlet, 2H).

[0625] Weight yield: -0.032g (88%)

[0626] LCMS m / z(M+H): 494

[0627] Example 35

[0628] Synthesis of 4-((6-(azacyclobutane-3-carbonyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0629]

[0630] BB0274099

[0631] 1 ¹H NMR (400MHz, 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 (broad singlet, 4H), 7.79 (s, 2H).

[0632] Weight yield: -0.075g (52%)

[0633] LCMS m / z(M+H): 480

[0634] Example 36

[0635] Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(pyrazine-2-carbonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0636]

[0637] BB 0274100

[0638] 1 H NMR (400MHz, 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).

[0639] Weight yield -0.012g (20%)

[0640] LCMS m / z(M+H): 503

[0641] Example 37

[0642] Synthesis of (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-oxopropane-2-yl)tert-butyl carbamate

[0643]

[0644] BB 0274101

[0645] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 1.35–1.49 (m, 9H), 1.61 (s, 3H), 2.17 (s, 6H), 2.55–2.86 (m, 1H), 3.07 (broad singlet, 2H), 3.62–4.07 (m, 2H), 4.56 (s, 2H), 4.94–5.57 (m, 2H), 7.35 (broad singlet, 2H), 7.39–7.44 (m, 2H), 7.48 (s, 2H).

[0646] Weight yield: -0.075g (52%)

[0647] LCMS m / z(M+H): 468(M-Boc).

[0648] Example 38

[0649] Synthesis of (S)-4-((6-(2-aminopropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d1pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0650]

[0651] BB 0274102

[0652] 1 ¹H NMR (400MHz, DMSO-d6, 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 (broad singlet, 4H), 7.79 (s, 2H), 7.94 (s, 1H), 8.33 (broad singlet, 2H).

[0653] Weight yield: -0.0233g (88%)

[0654] LCMS m / z(M+H): 468

[0655] Example 39

[0656] Synthesis of (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-oxo-3-phenylpropane-2-yl)carbamate tert-butyl

[0657]

[0658] BB 0274103

[0659] 1 ¹H NMR (400MHz, DMSO-d6, 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 (broad singlet, 6H), 7.50 (m, 3H).

[0660] Weight yield: -0.082g (63%)

[0661] LCMS m / z(M+H): 544(M-Boc).

[0662] Example 40

[0663] Synthesis of (S)-4-((6-(2-amino-3-phenylpropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0664]

[0665] BB 0274111

[0666] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.09 (broad singlet, 6H), 2.59–2.82 (m, 1H), 3.15 (broad singlet, 2H), 3.33–3.60 (m, 1H), 3.67–4.08 (m, 1H), 4.40–4.56 (m, 2H), 4.79 (broad singlet, 2H), 7.26 (m, 5H), 7.43 (broad singlet, 4H), 7.79 (broad singlet, 2H), 8.46 (broad singlet, 2H), 10.10 (broad singlet, 1H).

[0667] Weight yield: -0.078g (86%)

[0668] LCMS m / z(M+H): 544

[0669] Example 41

[0670] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(2-morpholinoethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0671]

[0672] BB 0274118

[0673] 1 ¹H NMR (400MHz, CDCl₃, δ, ppm): 2.14 (s, 6H), 2.52 (broad singlet, 4H), 2.58 (t, J = 6.90Hz, 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).

[0674] Weight yield: -0.014g (24%)

[0675] LCMS m / z(M+H): 524

[0676] Example 42

[0677] Synthesis of (R)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-hydroxy-1-oxopropane-2-yl)carbamate tert-butyl

[0678]

[0679] BB 0274119

[0680] 1 H NMR (400MHz, CDCl3, δ, ppm): 1.45 (s, 9H), 2.17 (s, 6H), 3.71-4.17 (m, 4H), 4.59-5.03 (m, 3H), 5.37-5.77 (m, 1H), 7.31-7.45 (m, 4H), 7.49 (s, 2H).

[0681] Weight yield: -0.011g (42%)

[0682] LCMS m / z(M+H): 484(M-Boc).

[0683] Example 43

[0684] Synthesis of tert-butyl (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-(methylthio)-1-oxobutane-2-yl)carbamate

[0685]

[0686] BB 0274120

[0687] 1 ¹H NMR (400MHz, CDCl₃, δ, ppm): 1.43 (broad singlet, 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 = 4.6Hz, 4H), 7.48 (broad singlet, 2H), 8.01 (s, 2H).

[0688] Weight yield: -0.089g (55%)

[0689] LCMS m / z(M+H): 528(M-Boc)

[0690] Example 44

[0691] Synthesis of 4-((6-(2-amino-3-(1H-pyrazol-4-yl)propionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0692]

[0693] BB 0274121

[0694] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.11 (broad singlet, 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 (broad singlet, 2H), 9.13 (s, 1H), 10.05 (broad singlet, 1H).

[0695] Weight yield -0.005g (8%)

[0696] LCMS m / z(M+H): 534

[0697] Example 45

[0698] Synthesis of tert-butyl 4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-oxopropyl)-1H-pyrazole-1-carboxylic acid

[0699]

[0700] BB 0274122

[0701] 1H NMR (400MHz, 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).

[0702] Weight yield: -0.032g (33%)

[0703] LCMS m / z(M+H): 534(M-2Boc)

[0704] Example 46

[0705] Synthesis of (R)-4-((6-(2-amino-3-hydroxypropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0706]

[0707] BB 0274123

[0708] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.13 (s, 6H), 2.71–3.01 (m, 2H), 3.74 (broad singlet, 2H), 3.95 (broad singlet, 2H), 4.52–4.68 (m, 2H), 4.80 (broad singlet, 2H), 7.46 (broad singlet, 4H), 7.79 (s, 2H), 8.30 (broad singlet, 3H).

[0709] Weight yield: -0.008g (85%)

[0710] LCMS m / z(M+H): 484

[0711] Example 47

[0712] Synthesis of tert-butyl (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-(4-hydroxyphenyl)-1-oxopropane-2-yl)carbamate

[0713]

[0714] BB 0274124

[0715] 1 H NMR (400MHz, CDCl3, δ, ppm): 1.43 (d, J=6.9Hz, 9H), 2.17 (broad single peak, 6H), 2.61-2.85 (m, 2H), 3.03-3.45 (m, 1H), 3.56-3.80 (m, 1H), 3.92-4.22 (m , 1H), 4.37-4.64(m, 1H), 4.69-5.02(m, 2H), 5.36-5.53(m, 1H), 6.59-6.75(m, 2H), 6.97-7.10(m, 2H), 7.35(d, J=15.5Hz, 4H), 7.48(s, 2H).

[0716] Weight yield: 0.055g (40%)

[0717] LCMS m / z(M+H): 560(M-Boc).

[0718] Example 48

[0719] Synthesis of (S)-4-((6-(2-amino-3-(4-hydroxyphenyl)propionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0720]

[0721] BB 0274125

[0722] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.09 (broad singlet, 6H), 2.59–2.82 (m, 1H), 3.15 (broad singlet, 2H), 3.33–3.60 (m, 1H), 3.67–4.08 (m, 1H), 4.40–4.56 (m, 2H), 4.79 (broad singlet, 2H), 7.26 (m, 5H), 7.43 (broad singlet, 4H), 7.79 (broad singlet, 2H), 8.46 (broad singlet, 2H), 10.10 (broad singlet, 1H).

[0723] Weight yield: -0.048g (90%)

[0724] LCMS m / z(M+H): 560

[0725] Example 49

[0726] Synthesis of (R)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d1pyrimidin-6(5H)-yl)-3-methyl-1-oxobutane-2-yl)carbamate tert-butyl

[0727]

[0728] BB 0274126

[0729] 1 H NMR (400MHz, DMSO-d6, 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).

[0730] Weight yield: -0.042g (52%)

[0731] LCMS m / z(M+H): 496(M-Boc).

[0732] Example 50

[0733] Synthesis of (R)-4-((6-(2-amino-3-methylbutyryl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0734]

[0735] BB 0274127

[0736] 1 H NMR (400MHz, CDCl3, 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).

[0737] Weight yield: -0.038g (92%)

[0738] LCMS m / z(M+H): 496

[0739] Example 51

[0740] Synthesis of (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methyl-1-oxopentane-2-yl)carbamate tert-butyl

[0741]

[0742] BB 0274128

[0743] 1 H NMR (400MHz, CDCl3, δ, ppm): 0.88-1.13 (m, 6H), 1.35-1.48 (m, 9H), 1.58 (d, J==1.4Hz, 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).

[0744] Weight yield: -0.064g (56%)

[0745] LCMS m / z(M+H): 510(M-Boc)

[0746] Example 52

[0747] Synthesis of (S)-4-((6-(2-amino-4-methylpentanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0748]

[0749] BB 0274129

[0750] 1 ¹H NMR (400MHz, DMSO-d6, 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 (broad singlet, 4H), 7.79 (s, 2H), 8.28 (broad singlet, 2H)

[0751] Weight yield -0.060g (90%)

[0752] LCMS m / z (M+H): 510

[0753] Example 53

[0754] Synthesis of (S)-(6-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-6-oxohexane-1,5-diyl)dicarbamate di-tert-butyl

[0755]

[0756] BB 0274130

[0757] 1 ¹H NMR (400MHz, 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 (broad singlet, 4H), 7.80 (s, 2H), 8.02–8.14 (m, 2H), 8.34–8.38 (m, 3H).

[0758] Weight yield: -0.022g (18%)

[0759] LCMS m / z(M+H): 525(M-2Boc)

[0760] Example 54

[0761] Synthesis of (S)-4-((2-((4-cyanophenyl)amino)-6-(2,6-diaminohexanoyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0762]

[0763] BB 0274131

[0764] 1¹H NMR (400MHz, DMSO-d6, 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 (broad singlet, 4H), 7.79 (s, 2H), 8.01–8.14 (m, 3H), 8.36–8.40 (m, 3H)

[0765] Weight yield: -0.018g (85%)

[0766] LCMS m / z(M+H): 525

[0767] Example 55

[0768] Synthesis of (S)-4-((6-(2-amino-4-(methylthio)butyryl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0769]

[0770] BB 0274132

[0771] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.08 (s, 3H), 2.15 (broad singlet, 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 (broad singlet, 4H), 7.79 (s, 2H), 8.40 (broad singlet, 2H)

[0772] Weight yield: -0.076g (82%)

[0773] LCMS m / z(M+H): 528

[0774] Example 56

[0775] Synthesis of 4-((7-(2-chloroacetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0776]

[0777] BB 0274133

[0778] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.10 (s, 6H), 3.02 (broad singlet, 2H), 3.13 (broad singlet, 2H), 3.75 (broad singlet, 4H), 4.49 (broad singlet, 2H), 7.42 (broad singlet, 4H), 7.78 (broad singlet, 2H), 10.06 (broad singlet, 1H).

[0779] Weight yield: -0.045g (57%)

[0780] LCMS m / z(M+H): 487

[0781] Example 57

[0782] Synthesis of methyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylate

[0783]

[0784] BB 0274134

[0785] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.09 (s, 6H), 3.03 (broad singlet, 4H), 3.64 (s, 7H), 7.41 (s, 4H), 7.77 (s, 2H), 10.06 (s, 1H).

[0786] Weight yield: -0.095g (82%)

[0787] LCMS m / z(M+H): 469

[0788] Example 58

[0789] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(methanesulfonyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d1-azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0790]

[0791] BB 0274135

[0792] 1¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.10 (broad singlet, 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).

[0793] Weight yield -0.08g (75%)

[0794] LCMS m / z(M+H): 489

[0795] Example 59

[0796] Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0797]

[0798] BB 0274137

[0799] 1 H NMR (400MHz, CDCl3, δ, ppm): 2.12 (s, 6H), 2.90 (dd, J=15.1Hz, 4.8Hz, 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).

[0800] Weight yield: -0.026g (38%)

[0801] LCMS m / z(M+H): 488

[0802] Example 60

[0803] Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0804]

[0805] BB 0274138

[0806] 1H NMR (400MHz, 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=7.9Hz, 4.8Hz, 1H), 7.77 (d, J=7.8Hz, 1H), 8.19 (dt, J=7.9Hz, 1.9Hz, 1H), 8.53-8.68 (m, 1H).

[0807] Weight yield -0.030g (40%)

[0808] LCMS m / z(M+H): 488

[0809] Example 61

[0810] Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(2-hydroxybenzyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0811]

[0812] BB 0274140

[0813] 1 ¹H NMR (400MHz, CDCl₃, δ, ppm): 2.14 (s, 6H), 3.00 (d, J = 6.6Hz, 4H), 3.83 (broad singlet, 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).

[0814] Weight yield: -0.033g (41%)

[0815] LCMS m / z(M+H): 503

[0816] Example 62

[0817] Synthesis of 4-((2-((4-cyanophenyl)amino)-6-(2-(prop-2-yn-1-yloxy)benzyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0818]

[0819] BB 0274141

[0820] 1 H NMR (400MHz, CDCl3, δ, ppm): 2.13 (s, 6H), 2.51 (dt, J=10.6Hz, 2.4Hz, 2H), 2.90 (s, 4H), 3.78 (s, 2H), 3.87 (s , 2H), 4.75 (dd, J=8.3Hz, 2.4Hz, 2H), 6.95-7.07 (m, 2H), 7.25-7.33 (m, 4H), 7.33-7.38 (m, 2H), 7.45 (s, 2H).

[0821] Weight yield: -0.062g (70%)

[0822] LCMS m / z(M+H): 541

[0823] Example 63

[0824] Synthesis of 3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptane-7(6H)-yl)propionic acid

[0825]

[0826] BB 0274143

[0827] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.01–2.22 (m, 6H), 2.60–2.82 (m, 2H), 3.16 (broad singlet, 10H), 7.43 (broad singlet, 4H), 7.79 (s, 2H), 10.09 (broad singlet, 1H).

[0828] Weight yield: -0.09g (33%)

[0829] LCMS m / z(M+H): 483

[0830] Example 64

[0831] Synthesis of 4-((7-allyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0832]

[0833] BB 0274144

[0834] 1¹H NMR (400MHz, CDCl₃, δ, ppm): 2.15 (s, 6H), 2.61–2.81 (m, 4H), 3.07 (broad singlet, 4H), 3.19 (d, J = 6.2Hz, 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).

[0835] Weight yield: -0.011g (17%)

[0836] LCMS m / z (M+H): 451

[0837] Example 65

[0838] Synthesis of 4-((7-acetyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0839]

[0840] BB 0274145

[0841] 1 ¹H NMR (400MHz, DMSO-d6, δ, ppm): 2.10 (broad singlet, 9H), 2.98 (broad singlet, 2H), 3.09 (broad singlet, 2H), 3.70 (broad singlet, 4H), 7.41 (broad singlet, 4H), 7.78 (broad singlet, 2H), 10.06 (broad singlet, 1H).

[0842] Weight yield: -0.074g (69%)

[0843] LCMS m / z(M+H): 453

[0844] Example 66

[0845] Synthesis of 4-((7-(2-(1H-imidazol-1-yl)acetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0846]

[0847] BB 0274227

[0848] 1¹H NMR (400MHz, DMSO-d⁶, δ, ppm): 2.11 (d, J = 10.2Hz, 6H), 3.03 (broad singlet, 2H), 3.17 (broad singlet, 2H), 3.76 (broad singlet, 4H), 5.13 (d, J = 6.1Hz, 2H), 6.90 (broad singlet, 1H), 7.10 (d, J = 7.40Hz, 1H), 7.43 (d, J = 5.8Hz, 4H), 7.61 (d, J = 6.7Hz, 1H), 7.79 (d, J = 6.7Hz, 2H), 10.08 (broad singlet, 1H).

[0849] Weight yield: -0.011g (21%)

[0850] LCMS m / z(M+H): 519

[0851] Example 67

[0852] Synthesis of 4-((2-((4-cyanophenyl)amino)-7-(2-(methyl-1H-imidazol-1-yl)acetyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile

[0853]

[0854] BB 0274236

[0855] 1 ¹H NMR (400MHz, DMSO-d⁶, δ, ppm): 2.00–2.23 (m, 9H), 2.92–3.25 (m, 4H), 3.77 (broad singlet, 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 (broad singlet, 1H).

[0856] M = 0.038g (41%)

[0857] LCMS m / z(M+H): 533

[0858] Example 68

[0859] Synthesis of 4-((6-(2-amino-3-(IH-imidazol-5-yl)propionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile

[0860]

[0861] BB 0275622

[0862] 1 H NMR (400MHz, CDCl3, 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=0.9Hz, 1H), 7.37 (s, 2H), 7.47 (dd, J=4.9, 1.0Hz, 1H), 7.63 (d, J=8.7Hz, 2H), 7.83 (d, 2H)

[0863] M = 0.006g (33%)

[0864] LCMS m / z(M+H): 535

[0865] The evaluation of the HIV replication inhibition / protection of the anti-HIV product of the present invention on human cells was carried out by measuring the change in the concentration of live cells in experimental wells containing MT-4 cells infected with HIV-1 and by measuring the production of viral protein p24 in the presence of different concentrations of the compound according to the present invention.

[0866] The antiviral activity of the product against HIV-1 subtype A strain 12RU 69831 was determined when cell cultures were infected with a constant dose of virus (corresponding to 300 CCID50).

[0867] The results of IC50 determination of the compounds according to the present invention are provided in Table 1.

[0868] Table 1. Activity of the compounds according to the present invention against human immunodeficiency virus HIV-1 subtype A

[0869]

[0870]

[0871] The features mentioned in the specification or claims, expressed in a particular form and terminology for implementing the claimed function or achieving the claimed result, may be used alone or in any combination of such features to implement the invention in its different forms.

[0872] The invention has been described with reference to examples and embodiments, the purpose of which is to elucidate and understand the nature of the invention. It will be apparent to those skilled in the art that various changes and modifications are possible within the scope of the invention and the claims. Therefore, we consider the specification to be merely illustrative and not to limit its scope. The scope of the invention is determined by reference to the claims of the invention (including the entire scope of equivalent substitutions covered by the claims).

[0873] All patents, patent applications and publications cited in the specification are included in the specification as references in their entirety, as if they were cited individually.

Claims

1. A compound of formula I Equation I, Where R 1 Independently select and represent H, -CN, -CH=CH-CN, -CH=CH-COOH, and 4-6 membered heterocyclic groups containing 1-2 heteroatoms O; X 1 X 2 (CH2) n Substituents of type n, where n is chosen independently for X1 and X2; Y 1 The following types of groups are selected and represented independently: , , or ; When Y 1 yes hour, R b Indicates: unsubstituted -C1-C6-alkyl, with C 1-4 -alkoxy or COOH-substituted -C1-C6-alkyl, unsubstituted -C2-C6-alkenyl, unsubstituted 4-9-membered heterocyclic groups containing 1 to 4 heteroatoms independently selected from N and / or O, or Boc-substituted 4-9-membered heterocyclic groups containing 1 to 4 heteroatoms independently selected from N and / or O. When Y 1 yes hour, R b Indicates: unsubstituted -C1-C6-alkyl, -C1-C6-alkyl substituted with NH2, unsubstituted -5-6-membered heteroaryl containing 1 to 4 heteroatoms independently selected from N, S and / or O, unsubstituted 4-9-membered heterocyclic group containing 1 to 4 heteroatoms independently selected from N and / or O, or 4-9-membered heterocyclic group substituted with Boc or COO-isobutyl containing 1 to 4 heteroatoms independently selected from N and / or O. When Y 1 yes hour, R b Indicates: unsubstituted -C1-C6-alkyl, When Y 1 yes hour, R b Indicates: unsubstituted -C1-C6-alkyl, n has values ​​from 1 to 3.

2. The compound according to claim 1, wherein R 1 H, -CN, -CH=CH-CN, or -CH=CH-COOH can be selected and represented independently.

3. The compound according to claim 1, wherein R 1 Independently select and represent 4-6 membered heterocyclic groups containing 1-2 heteroatoms O.

4. The compound according to claim 3, wherein R 1 This indicates oxobutane.

5. The compound according to claim 1, wherein the -C1-C6-alkyl group is methyl, ethyl, propyl, butyl, or pentyl.

6. The compound according to claim 1, wherein the -5-6 heteroaryl group is pyrrole, imidazolyl, pyrazolyl, pyridinyl, or pyrimidinyl.

7. The compound according to claim 1, wherein the 4-9 membered heterocyclic group is piperidinyl, aziridine, morpholinyl, or tetrahydropyranyl.

8. Compounds selected from: 4-(((6-benzyl-4-(4-cyano-2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)methyl)benzoic acid ethyl ether 4-(((6-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)amino)methyl)benzoic acid ethyl ether 4-(((7-benzyl-4-(2,6-dimethylphenoxy)-5,6,7,8-tetrahydropyridino[3,4-d]pyrimidin-2-yl)amino)methyl)benzonitrile 4-((2-((4-cyanophenyl)amino)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((4-(4-formyl-2,6-dimethylphenoxy)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)amino)benzonitrile 4-(4-(1,3-dioxolane-2-yl)-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylic acid tert-butyl ester 2-((4-cyanophenyl)amino)-4-(4-formyl-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylic acid tert-butyl ester 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylic acid tert-butyl ester 4-((2-((4-cyanophenyl)amino)-6-(methanesulfonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile ethyl 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-formate (E)-3-(4-((7-(tert-butoxycarbonyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylphenyl)acrylic acid 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylic acid tert-butyl ester 2-((4-cyanophenyl)amino)-4-(4-(2-cyanovinyl)-2,6-dimethylphenoxy)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-carboxylic acid tert-butyl ester 4-((2-((4-cyanophenyl)amino)-7-pyridinoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-isonicotinanoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-nicotinanoyl-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(pyridin-2-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(pyridin-3-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(pyridin-4-ylmethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)piperidine-1-carboxylic acid tert-butyl ester 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-carbonyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptane-7(6H)-yl)piperidine-1-carboxylic acid tert-butyl ester 4-((2-((4-cyanophenyl)amino)-7-(piperidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((6-(2-aminoacetyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-6-(2-(3-hydroxyazacyclobutane-1-yl)acetyl)-5,6,7,8-tetrahydropyridino[4,3-d]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]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile 4-({2-[(4-cyanophenyl)amino]-6-[2-(4,4-difluoropiperidin-1-yl)acetyl]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(cyclopropanecarbonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-({2-[(4-cyanophenyl)amino]-6-(morpholin-4-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile 4-({2-[(4-cyanophenyl)amino]-6-(4-methylpiperazin-1-carbonyl)-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester (R)-2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-tert-butyl carboxylate (S)-2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-7-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester 4-((2-((4-cyanophenyl)amino)-7-(tetrahydro-2H-pyran-4-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(5-methylfuran-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(1-methyl-1H-pyrrolo-2-yl)methyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(4-hydroxybenzyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(1-methoxypropane-2-yl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 2-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-carbonyl)pyrrolidine-1-carboxylic acid tert-butyl ester 4-((2-((4-cyanophenyl)amino)-6-(pyrrolidine-2-carbonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((6-(azacyclobutane-3-carbonyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-6-(pyrazine-2-carbonyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-oxopropane-2-yl)tert-butyl carbamate (S)-4-((6-(2-aminopropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-1-oxo-3-phenylpropane-2-yl)tert-butyl carbamate (S)-4-((6-(2-amino-3-phenylpropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(2-morpholinoethyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile (R)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-hydroxy-1-oxopropane-2-yl)tert-butyl carbamate (1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-(methylthio)-1-oxobutane-2-yl)tert-butyl carbamate 4-({6-[2-amino-3-(1H-imidazol-5-yl)propionyl]-2-[(4-cyanophenyl)amino]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidin-4-yl}oxy)-3,5-dimethylbenzonitrile 4-((6-(2-amino-3-(1H-pyrazol-4-yl)propionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-(2-((tert-butoxycarbonyl)amino)-3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-oxopropyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (R)-4-((6-(2-amino-3-hydroxypropionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-(4-hydroxyphenyl)-1-oxopropane-2-yl)tert-butyl carbamate (S)-4-((6-(2-amino-3-(4-hydroxyphenyl)propionyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (R)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-3-methyl-1-oxobutane-2-yl)tert-butyl carbamate (R)-4-((6-(2-amino-3-methylbutyryl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (S)-(1-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-4-methyl-1-oxopentane-2-yl)tert-butyl carbamate (S)-4-((6-(2-amino-4-methylpentanoyl)-2-((4-cyanophenyl)amino)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile (S)-(6-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-6-oxohexane-1,5-diyl)tert-butyl dicarboxylate (S)-4-((2-((4-cyanophenyl)amino)-6-(2,6-diaminohexanoyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((7-(2-chloroacetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-(4-cyano-2,6-dimethylphenoxy)-2-((4-4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptan-7(6H)-formate methyl ester 4-((2-((4-cyanophenyl)amino)-7-(methanesulfonyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-6-(pyridin-4-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-6-(pyridin-3-ylmethyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-6-(2-hydroxybenzyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-6-(2-(prop-2-yn-1-yloxy)benzyl)-5,6,7,8-tetrahydropyridino[4,3-d]pyrimidin-4-yl)oxy)-3,5-dimethylbenzonitrile 3-(4-(4-cyano-2,6-dimethylphenoxy)-2-((4-cyanophenyl)amino)-8,9-dihydro-5H-pyrimidino[4,5-d]azacycloheptane-7(6H)-yl)propionic acid 4-((7-allyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((7-acetyl-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((7-(2-(1H-imidazol-1-yl)acetyl)-2-((4-cyanophenyl)amino)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-((2-((4-cyanophenyl)amino)-7-(2-(methyl-1N-imidazol-1-yl)acetyl)-6,7,8,9-tetrahydro-5H-pyrimidino[4,5-d]azacycloheptane-4-yl)oxy)-3,5-dimethylbenzonitrile 4-(4-cyano-2,6-dimethylphenoxy)-2-[(4-cyanophenyl)amino]-5H,6H,7H,8H-pyrido[4,3-d]pyrimidine-6-sulfonamide 2-{2-[(4-cyanophenyl)amino]-4-(4-formyl-2,6-dimethylphenoxy)-5H,6H,7H,8H,9H-pyrimidino[4,5-d]azacycloheptane-7-yl}-2-oxoacetic acid methyl ester.

9. The compound according to claim 1, wherein it is in the form of a free base or a pharmaceutical salt.

10. Use of the compound according to claim 1 in the preparation of a medicament used as an inhibitor of HIV reverse transcriptase.

11. Use of the compound according to claim 1 in the preparation of a pharmaceutical formulation having anti-HIV antiviral activity.

12. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and at least one carrier.

13. Use of the pharmaceutical composition according to claim 12 in the preparation of a medicament, wherein the medicament has antireverse transcriptase activity.

14. Use of the pharmaceutical composition according to claim 12 in the preparation of a medicament for the treatment or prevention of HIV.

15. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition has anti-HIV reverse transcriptase activity, and the pharmaceutical composition further comprises 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.

16. The use according to claim 13, wherein the drug has anti-HIV reverse transcriptase activity, wherein the HIV reverse transcriptase contains at least one mutation compared to wild-type HIV.

17. The use according to claim 13, wherein the drug has anti-HIV reverse transcriptase activity, wherein HIV reverse transcriptase has reduced sensitivity to efavirenz, nevirapine, doravirine or deraviridine.

18. A pharmaceutical composition for treating or preventing HIV-mediated diseases, said composition comprising a therapeutically effective amount of the compound according to claim 1 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.

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