PYRIMIDO[5,4-D]PYRIMIDINE-BASED COMPOUNDS, METHODS AND USES THEREOF

Title:

PYRIMIDO[5,4-D]PYRIMIDINE-BASED COMPOUNDS, METHODS AND USES THEREOF

Document Type and Number:

WIPO Patent Application WO/2023/209250

Kind Code:

Abstract:

The present disclosure relates to a compound of the formula (6) or (7); or a pharmaceutically acceptable salt, ester, solvate thereof, for use in medicine, in particular for the use in treatment and therapy of malaria and leishmaniasis. Furthermore, the present disclosure also relates to methods to obtain pyrimido[5,4-d]pyrimidine-based compounds, in particular the compound of formula (6) or (7).

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Inventors:

GONÇALVES CARVALHO MARIA ALICE (PT)
MENDES FERREIRA PEDRO EDUARDO (PT)
MEIRINHO SOFIA GABRIEL (PT)
CORDEIRO DA SILVA ANABELA (PT)
PINTO DA COSTA TAVARES JOANA ALEXANDRA (PT)
GOMES LOPES ANDRÉ MANUEL (PT)

Application Number:

PCT/EP2023/061576

Publication Date:

November 02, 2023

Filing Date:

May 02, 2023

Export Citation:

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Assignee:

UNIV DO MINHO (PT)
UNIV DO PORTO (PT)
I3S INSTITUTO DE INVESTIGACAO E INOVACAO EM SAUDE DA UNIV DO PORTO ASSOCIACAO (PT)

International Classes:

C07D487/04; A61K31/519; A61P33/00; A61P33/06

Foreign References:

FR2992316A1

2013-12-27

Other References:

LOPES ANDRÉ ET AL: "Pyrimido[5,4- d ]pyrimidine-Based Compounds as a Novel Class of Antitrypanosomal and Antileishmanial Agents", ACS MEDICINAL CHEMISTRY LETTERS, vol. 13, no. 9, 9 August 2022 (2022-08-09), US, pages 1427 - 1433, XP093057251, ISSN: 1948-5875, Retrieved from the Internet DOI: 10.1021/acsmedchemlett.2c00170
ROCHA ASHLY ET AL: "6-Carbohydrazonamidepurines: Convenient Precursors for 4,8-Disubstituted Pyrimido[5,4-d]pyrimidines", SYNLETT, vol. 25, no. 03, 19 December 2013 (2013-12-19), DE, pages 343 - 348, XP093057326, ISSN: 0936-5214, DOI: 10.1055/s-0033-1340344
ALICE CARVALHO M ET AL: "An Efficient Synthesis of 7,8-Dihydropyrimido[5,4-d]pyrimidines", EUROPEAN JOURNAL OF ORGANIC CHEMISTRY, WILEY-VCH, DE, vol. 2007, no. 8, 12 January 2007 (2007-01-12), pages 1324 - 1331, XP072109285, ISSN: 1434-193X, DOI: 10.1002/EJOC.200600883
M.F.J.R.P.: "Facile Synthesis of 6-Cyano-9-Substituted-9H-Purines and Their Ring Expansion to 8-(Arylamino)-4-lmino-3-Methylpyrimidino[5,4-d]Pyrimidines", J. CHEM. SOC. PERKIN TRANS., vol. 1, 2001, pages 2532 - 2537, Retrieved from the Internet
CARVALHO, M. A.ESPERANCA, S.ESTEVES, T.PROENGA, M. F.: "An Efficient Synthesis of 7,8-Dihydropyrimido[5,4-d]pyrimidines", EUR. J. ORG. CHEM., 2007, pages 1324 - 1331

Attorney, Agent or Firm:

PATENTREE (PT)

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Claims:

C L A I M S 1. A compound of the formula (6) or (7) or a pharmaceutically acceptable salt, solvate, N- oxide, stereoisomer, diastereoisomer, enantiomer, atropisomer or polymorph Formula (6) Formula (7) wherein R1, R2 and R3 are independently selected from each other; R1 is selected from a list consisting of: unsubstituted or substituted aryl; heteroaryl; R2 is selected from a list consisting of: H, halogen, alkyl, alkoxy; haloalkyl, substituted amine; R3 is selected from a list consisting of: H, halogen, haloalcoxy, alkoxy; wherein R2 and R3 are not simultaneously H. 2. The compounds according to the previous claim, wherein halogen is Br, F or Cl. 3. The compounds according to the previous claim, wherein the alkoxy is a C1-C6 alkoxy; preferably C1-C3 alkoxy. 4. The compounds according to the previous claim, wherein the alkyl is a C1-C6 alkyl; preferably C1-C3 alkyl. 5. The compounds according to any of the previous claims, wherein the substituted group of R1 aryl is selected from a halogen, an alcohol or alkoxy. 6. The compounds according to any of the previous claims, wherein the substituted aryl comprises 6 carbons. 7. The compounds according to any of the previous claims, wherein R1 is a substituted aryl selected from: phenyl, 2-HOC6H4; 2-HO-4-MeOC6H3; 2-HO-5-ClC6H3; 3,4-(HO)2C6H3; 3,4,5-(HO)3C6H2; 3,4-(MeO)2C6H3; 3-MeO-4-HOC6H3; 3-HO-4-MeOC6H3; 3-Cl-C6H4; 4-ClC6H4; 3-FC6H4; 4- FC6H4; or 4-BrC6H4. 8. The compounds according to any of the previous claims, wherein the heteroaryl of R1 is an pyridine; preferably an unsubstituted pyridine. 9. The compounds according to the previous claim, wherein the unsubstituted pyridine is selected from a list consisting of : 3-pyridinyl, or 4-pyridinyl. 10. The compounds according to any of the previous claims wherein R1 is selected from a list consisting of: Ph, 2-HOC6H4, 2-HO-4-MeOC6H3, 2-HO-5-ClC6H3, 3,4-(HO)2C6H3, 3,4,5- (HO)3C6H2, 3,4-(MeO)2C6H3, 3-MeO-4-HOC6H3, 3-HO-4-MeOC6H3, 3-Cl-C6H4, 4-ClC6H4, 3- FC6H4, 4-FC6H4, 3-pyridinyl, 4-pyridinyl, 4-BrC6H4. 11. The compounds according to any of the previous claims wherein R3 is selected from a list consisting of: H, F, Cl, OCF3, OMe. 12. The compounds according to any of the previous claims wherein R2 is selected from ^{a list} , , . 13. The compounds according to any of the previous claims wherein the compound is one of the following :

. 14. The compounds according to any of the previous claims wherein the compound is one of the following:

. 15. The compounds according to any of the previous claims wherein the compound is a salt. 16. The compounds according to any of the previous claims for use in medicine or veterinary. 17. The compounds according to any of the previous claims for use in the prevention or treatment of infections. 18. The compounds according to any of any one of the previous claims for use in the prevention or treatment of malaria or leishmaniasis. 19. The compounds according to any of the previous claims for use in the prevention or treatment of parasite infection, preferably P. falciparum infection. 20. The compounds according to any of the previous claims for use in the prevention, therapy, or treatment of parasite infection, preferably from P. falciparum strains 3D7 or/and Dd2. 21. The compounds according to any of the previous claims for use in the prevention, therapy, or treatment of parasite infection, preferably Leishmania infection. 22. The compounds according to any of the previous claims for use in the prevention or treatment of parasite infection, preferably from L. infantum promastigote and amastigote forms or L. infantum promastigote multi-resistant M 200.5 strain.

23. Pharmaceutical composition comprising a compound as defined in any one of claims 1-22 in a therapeutically effectively amount and a pharmaceutically acceptable excipient. 24. Pharmaceutical composition according to the previous claim wherein the pharmaceutically acceptable excipient is a carrier, adjuvant, excipient or mixtures thereof. 25. Pharmaceutical composition according to any of the previous claims 23-24 comprising a further anti-viral agent, preferably an anti-HIV agent or anti- tuberculosis agent.

Description:

D E S C R I P T I O N PYRIMIDO[5,4-D]PYRIMIDINE-BASED COMPOUNDS, METHODS AND USES THEREOF TECHNICAL FIELD [0001] The present disclosure relates to a compound of formula 6 and formula 7; or a pharmaceutically acceptable salt, ester, solvate thereof, for use in medicine, in particular for the use in treatment and therapy of malaria and leishmaniasis. [0002] Furthermore, the present disclosure also relates to methods to obtain pyrimido [5,4- d]pyrimidine-based compounds, in particular the compounds of formula 6 and 7. TECHNICAL BACKGROUND [0003] Malaria affects the whole world, with half of the global population at risk of infection. [0004] Malaria is caused by Plasmodium parasites. Five species are capable of infecting humans: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae and Plasmodium knowlesi. P. falciparum is the most virulent form and is responsible for majority of the death toll. [0005] Most of the drugs currently used for treating malaria patients include artemisinins, aminoquinolines, arylaminoalcohols and anti-folate drugs. [0006] Presently, there is a growing need for antimalarial agents, either for monotherapy or as multi- drug therapies as drug-resistant strains are emerging worldwide, in particular mefloquine and chloroquine resistant strains. Therefore, new agents able to kill the resistant malaria parasites are warranted. [0007] Leishmaniasis is a tropical and subtropical disease caused by an intracellular parasite transmitted to humans by the bite of a sand fly. It is endemic in several countries and causes 70,000 deaths per year worldwide. Clinical features depend on the species of Leishmania involved and the immune response of the host. Manifestations range from the localized cutaneous to the visceral form with potentially fatal outcomes. [0008] Despite its great epidemiological importance, leishmaniasis is considered to be a disease that has been neglected by different public and private organizations financing health improvement and research. Therefore, the development of new effective agents against leishmaniasis are needed. [0009] These facts are disclosed in order to illustrate the technical problem addressed by the present disclosure. GENERAL DESCRIPTION [0010] An aspect of the present disclosure is related to compounds of the formula (6) or (7) or a pharmaceutically acceptable salt, solvate, N-oxide, stereoisomer, diastereoisomer, enantiomer, atropisomer or polymorph Formula (6) Formula (7) wherein R1, R2 and R3 are independently selected from each other; R1 is selected from a list consisting of: unsubstituted or substituted aryl, heteroaryl; R2 is selected from a list consisting of: H, halogen, alkyl, alkoxy; haloalkyl, substituted amine; R3 is selected from a list consisting of: H, halogen, alkoxy, haloalcoxy; wherein R2 and R3 are not simultaneously H. [0011] The new compound of the present disclosure may be use in medicine, in particular for the use in treatment and therapy of malaria and leishmaniasis. [0012] In an embodiment, halogen is Br, F or Cl. [0013] In an embodiment, the alkoxy is a C1-C6 alkoxy; preferably C1-C3 alkoxy. [0014] In an embodiment, the alkyl is a C1-C6 alkyl; preferably C1-C3 alkyl. [0015] In an embodiment, R1 is a substituted aryl. Preferably, R1 group is selected from an aryl with a halogen, an alcohol or alkoxy. [0016] In an embodiment, wherein halogen is Br, F or Cl. [0017] Method of production of compound described in any of the claims 1-17. [0018] In an embodiment, the R1 aryl comprises 6 carbons. [0019] In an embodiment, the substituted aryl of formula (6/7) may be selected from a list consisting of: 2-HOC6H4, 2-HO-4-MeOC6H3, 2-HO-5-ClC6H3, 3,4-(HO)2C6H3, 3,4,5-(HO)3C6H2, 3,4-(MeO)2C6H3, 3-MeO-4- HOC ₆H ₃, 3-HO-4-MeOC ₆H ₃, 3-Cl-C ₆H ₄, 4-ClC ₆H ₄, 3-FC ₆H ₄, 4-FC ₆H ₄, 4-BrC ₆H ₄. [0020] In an embodiment, the heteroaryl preferably may be a pyridine; more preferably an unsubstituted pyridine, even more preferably a pyridine selected from a list consisting of: 3-pyridinyl, 4-pyridinyl. [0021] In an embodiment, R3 of formula (6) and formula (7) is selected from a list consisting of: H, F, Cl, OCF3, OMe . [0022] In an embodiment, R2 of formula (6/7) is selected from a list consisting of: H, Cl, CF3, OMe,

. [0025] In an embodiment, the compound may be one of the following

. [0026] In an embodiment, the compound is a salt. [0027] Another aspect of the present disclosure it is related to the use of the compounds of the present disclosure in medicine or veterinary. Preferably for use in the prevention, therapy, or treatment of infection. More preferably, in the prevention, therapy or treatment of malaria and leishmaniasis. [0028] In an embodiment, the disclosed compounds, or related ones, may be used for the prevention, treatment of parasite infection, preferably P. falciparum infection. [0029] In an embodiment, the disclosed compounds, or related ones, may be used for the prevention, treatment of parasite infection, preferably from P. falciparum strains 3D7 and Dd2. [0030] In an embodiment, the disclosed compounds, or related ones, may be used for the prevention, or treatment of parasite infection, preferably from L. infantum promastigote and amastigote forms and L. infantum promastigote multi-resistant M200.5 strain. [0031] This disclosure also relates to a pharmaceutical composition comprising any of the disclosed compounds, or related ones, in a therapeutically effective amount and a pharmaceutically acceptable excipient. [0032] In an embodiment, the pharmaceutically acceptable excipient is a carrier, adjuvant, excipient or mixtures thereof. [0033] The subject matter of the invention also provides advantageous properties. In particular, the compounds of the invention are highly active in vitro against L. infantum promastigote and intracellular amastigote forms, and P. falciparum strains 3D7 and Dd2. Compounds are new and represent a new scaffold with activity against L. infantum promastigote and amastigote forms, and P. falciparum strains 3D7 and Dd2. [0034] In an embodiment, the present disclosure represents new therapeutic options for the treatment of leishmaniasis and malaria. [0035] Another aspect of the present disclosure relates to the production of the compound of present disclosure, namely by the synthesis pathway described in the following schemes 1, 2 and 3. DETAILED DESCRIPTION [0036] The present disclosure relates to a compound of the formula 6 or formula 7; or a pharmaceutically acceptable salt, ester, solvate thereof, for use in medicine, in particular for the use in treatment and therapy of malaria and leishmaniasis. Furthermore, the present disclosure also relates to methods to obtain pyrimido[5,4-d]pyrimidine-based compounds, in particular the compounds of formula 6 and formula 7. Formula (6) Formula (7) wherein R1, R2 and R3 are independently selected from each other; R1 is selected from a list consisting of: unsubstituted or substituted aryl, heteroaryl; R2 is selected from a list consisting of: H, halogen, alkyl, alkoxy; haloalkyl, substituted amine; R3 is selected from a list consisting of: H, halogen, alkoxy, haloalcoxy; wherein R2 and R3 are not simultaneously H. [0037] The new compound disclosed in the present disclosure may be use in medicine, in particular for the use in treatment and therapy of malaria and leishmaniasis. -1P ^H _T _eh ^t d ₎ 01 01 01 0 0 5 0 5 5 n ^M > > 1 _{> >} 2 1 0 0 0 0 >0 >0 0 0 0 0 0 0 ⁰ ₅ ⁰ ₅ >0 0 ^. ^m _i ^r _yp 3 3 o 2 ^d _i H 3 H6 H 2 2 6 H 3 H 3 3 ₆ H H ₆ 3 C C 3 ₆ H ₆ 3 ₆ H ₆ ^m _{i 6} C 3 ^r ₎ C H _i 1 ) ² ₆ O ^O _e H ₆ C 3 ₎ C H C C ) ² ₆ ³ ₎ ² R C p ) ² O C o O H ^O 4 ) ^{2 H}- C ) ² O C ) ² ) O 4 4 4 4 ( _e H ₆ O ⁴- ^M- 4 O H ^O _e O H ^O _e H 4 6 H ₆ H6 H ₆n H ⁽ - ^o - _z ⁵ ⁴ _, M ⁽- ^C _l H O ( e - O H ⁽ ⁽ - M ⁽ ⁽ H ⁽ - M H ( ^C ₆ ^C 5 C - M ^H - ⁵ _{, - -} ⁵ _{, - l} ^C ^C _l C C F _r ^C ^B H _l ^a _, ⁴ _, ⁴ _{, -} ⁴ _{, - -} ⁴ _, ⁴ _, ⁴ _, ⁴ _, ⁴ _, ⁴ _{, - - - - 6} ^C- _r 3 3 3 3 3 3 3 3 3 3 3 3 3 3 4 3 4 C 3 ^d _y ^H-8 _fo H _y 2 H H H _i ^t R O ₂ O ₂ O ₂ O ₂ _i ^v H ^t C H H H _{c 2} C ₂ C ₂ C e ^O _e ^O _e ^O ₂ _e H _l C H H H A ^{a n} C C C i H H H H H H H H H H M M M O O O O _{c l} ⁱ l _{g l}e _l ^{o c} 3 R O F ³ O F ³ O F ^{3 O} _e ^O _e ^O _e _i ^{o d} B _{e F F F F} C C C M M M H H H H H H H H H _. ^v _i ^{1 r} _e ^e _l ^d _a b _c d e _g h mn o _r ^q _a ^r _a ^s _a ^t _a ^v _a ^x _ab A 7 7 7 7 7 7 7 7 7 7 p 7 q 7 7 7 7 7 7 7 7 ^a _T M P n i ^o _i ^t _s 8 4 6 a ⁰ ₅ ^{M5 6} _{. a} m ^C _{I .} 4 ⁰ _. 3 1 ^N ^{A µ} ₍ 1 _. e ^x ^p _e _y d ^t ^d ₎ ⁿ i l _i ^{M y} _t W ^D _S ^µ 4 9 8 ⁱ _v 0 6 7 3 ⁱ _t 1 ₍ ^c _e ^l _e ^s ^– 2 ^I _S 1 _; I _S ^> 1 _I 0 n 2 ^S _> ¹ _{> i} ^ot _s 6 _a _t ^r ^e 2 _tn ^o _g ^e ⁱ _c _t n ^s _a o ) ^c 8m 5 5 ^o _r ⁰ ₅ ^M5 1 ² _. ^y _r ^{P C} _I ³ _. ⁹ _. 0 o ^t e ^µ ₍ 2 3 1 _i ^p _i _y ^bh ^{t n} ^d i ^l _i ^l _a W ₎ M ^m _i D ^x S ^µ 6 _a 0 9 99 34 m 1 _{( f} ^l _a h ^– ⁰ ₅ C _I; 1 R 4 4 M H ₆ H ^µ ^C _l ^C ₆ ⁰ ₁ C _l _- ^C _{- f} o _. 4 3 ^e _s ^d _e od _i ⁿ e m l _g ^r _e n ^t _e 2 ⁱ _s d R _{a t} _t o a N- _l n C _i ^o d i ^{t N} ^b _i ^; ₎ 3 h ^% ₀ R ⁿ i ² H H H ^h _t ^< ^z w n a b ^{o o} _i ^t 7 b 7 _x 7 _{r i} G _{- i} ^bh D _S n ^I ₍ [0038] According to Table 1, 22 compounds presented IC50 below 10 µM against L. infantum promastigotes and were selected for activity testing against intracellular amastigotes. [0039] According to Table 1, compounds 7a, 7b, 7c, 7m, 7o, 7aq, 7ar, 7av, 7ax show an activity below 10 µM against intracellular amastigotes and a selectivity index above 20. [0040] Table 2. Biological Activity of 8-Hydrazonopirimidopyrimidines of structure 7 against L. infantum promastigote multi-resistant M200.5 strain. [0041] According to Table 2, compounds 7a, 7b and 7ar were equally active against the chemo-resistant L. infantum promastigotes M200.5.

_.- _e ⁿ _i ^l _l ^l _e ^c1P H ^Tt _s ⁿ _i ^a _g ^adn ^a2d ^Ddn ^a7 D3 _sn ⁱ _a ^r _t ^s m ^u _ra ^p _i _l ^ca ^f _. ^Pt _s _i ⁿ ^a _g ^a ⁶dn ^a ⁷ ^e _ru ^t _c ^u _r ^t _sf ^os _e _i ⁿ 3 3 ^d _i 2 H 3 H H 2 2 _i ^m 3 6 H ₆ H ₆ 6 3 C ^C- 3 3 3 H 3 H6 H 3 H6 H ^r C ₆ C e 6 C ₆ C ₆ _y 1 H ₆ C ² H ₆ O ^O C H ₆ C H ₆ C p R C ^{2 3} ₎ ) _e 4 M O C ^{2 H}- H - _l C ^{2 3} ₎ ) ^{2 3} ₎ ) ² O C ² O ^l _yo ) O H ^O _e 4 ) O ⁴- ^M- 6 ^O- ^C- ) O H ^O _e ) H ^O _e 4 4 4 4 H _i ⁿ 4 ^d _i H ⁽ _i ^{m (} - _- ⁵ MH ( ₆ _{- l} ^C H O ⁴ ⁽ - ^C- ⁴- ⁵- _- e O H H H H ⁽ ⁽ - O - ⁵ M ⁽- H ⁽ ⁽ - H 5 M ⁽ ₆ H ₆ H l ^C _l ^C ₆ ^C ₆ _{r i} ^d H r ₆ _i 5 _l ^C ^r _i ⁴ _, _, 3 ⁴ _, 3 ⁴ _, 3 ^C- 3 ⁴ _, 3 ^M- 3 ^H- 3 ^O- 2 ^O- 2 ^O- 2 ⁴ _, _, 3 ⁴ _, 3 ⁴ - _, 3 ⁴ _, _, 3 ⁴ - _, 3 ⁴ _, 3 ^C- 3 ^C C - 4 ^F- 3 ^B- 4 ^p- H 3 C ₆ ^C- 3p _fo _y ^t _i H H H H H _i ^v O ^{t O O O} ₂ O ₂ O ₂ O ₂ O ₂ _c 2 _l H H H H H H H H _{e e e} H H H H H ^A R H H H H H C C C C M M M _{2 2 2 2} C ₂ ^a H H H H H _c ⁱ C C C C C _g O O O O O _l ^o _i ^o ^B _. ³ 3 O O O O O O ^O ^e _l R _{F F F F} F ^{3 3 3 3 3 3} _e ^O _e ^O _e H H H H H H H H H H C F C F C F C F C F C M M M b ^a _T ^] _a b _c d _{g j k l r} ^q _a ^r _a ^s _a ^t _a ^u _a ^v _a ^x _a ₂ 7 7 7 7 e 7 7 h 7 7 7 7 m 7 n 7 o 7 p 7 q 7 7 7 7 7 7 7 7 7 ⁴ ₀ ⁰ _[ 1P ^H _T ^I _S ₎ M ⁿ ₍ ⁰ ^C ₅ _I ₎ Mµ 1 d 2 ⁽ D 1 8 1 4 6 5 3 1 3 2 2 4 6 4 ^y _t ^il _i ^b _a ⁱ _v 7 D 3 9 9 8 6 7 2 5 0 5 5 9 3 6 5 % 3 1 1 1 2 2 2 2 ^x _ed n i 2 3 2 ^e _v 3 H6 H 3 H6 3 ⁱ _t 1 H ₆ C C ₆ H ₆ C H ^c _e R C 4 4 ) ^{2 3} ₎ ) ² 4 ³ _{) 6} ^l O H C ² C ² _e ^s H H 4 4 O H ^O _e 4 H 6 ) O ) O H O _I _{6 6} H H l ⁽ ₆ ^C- ^{( S} ^C _{6 6} H - M O H - H _; C _l ^C C C ⁽- _- ⁵ ^C _, ⁽ _{- l} ^{C (}- _- ⁵ ^F _, ⁽- _- ^F- ⁴ _, ⁴ _, ⁴ _, ^C- ^{H 4 4 4 e} _v 4 3 4 3 3 3 3 4 - 2 _, 3 _, 3 _, 3 ⁱ _t c _ato n- _a 2 _l R C _l C _l C _l C _l C _l C _l C _l C F ³ C F ³ _l ⁿ C C _; d _e _i ⁿ m ^r _e ^t _e R H H H H H H H H H H _l C _l d 3 C _F H H _to n ^– ^z _a b _{x s t v z} ^b _a ^c _a ^d d a ^{j o} n 7 b 7 e 6 7 7 7 u 7 7 7 7 7 7 _a 7 _a 7 _j 6 [0043] _{According to table 3, compounds of formula 6 and 7 may be active simultaneously against both P.} _{falciparum strains 3D7 and Dd2 or only one.} [0044] Compounds 7b, 7d, 7j, 7k, 7at, 7az, 7t, 7u, 7v, 7z, 7ab, 7ao present high activity against P. falciparum strains 3D7 and Dd2, compounds 7a, 7aq, 7as, 7bb, 7s, 7ac and 7ad present high activity against strain 3D7 and compounds 7e, 7l, 7au, 6e, 7ab, 7aj and 6j present high activity against strain Dd2. [0045] Compounds 7b, 7at, 7u, 7v and 7z were active against both P. falciparum 3D7 and Dd2 strains with an IC ₅₀ below 500 nM and a selectivity index above 100. [0046] Compounds 7a, 7aq, 7as and 7bb, active against P. falciparum 3D7 strain, present an IC ₅₀ between 77 nM and 346 nM and a selectivity index between 1298 and 72. [0047] Compounds 7e, 7au, 6e, 7ab and 7aj, active against P. falciparum Dd2 strain, present IC50 between 48.42 nM and 557.4 nM and a selectivity index between 1843 and 17. Compound 7au should be highlighted as highly potent, with an IC50 of 54.24 nM, and as the most selective, with a selectivity index of 1843. [0048] In an embodiment, L. infantum promastigotes were prepared. Promastigotes from the L. infantum strain (MHOM/MA/67/ITMAP-263) were grown in 5 ml on a T25 flasks in Schneider's insect medium supplemented with 10% heat inactivated Fetal Bovine Serum (FBS), 200U/ml penicillin/streptomycin, 6 μg/ml Phenol Red and 5 mM HEPES. The cultures were maintained in an incubator at 27 ºC and diluted to 2x10 ⁵/ml every 5 days. For the assays the parasites used were equivalent to late/log with two or three days of culture. [0049] In an embodiment, L. infantum luciferase expressing axenic amastigotes were prepared. Luciferase-expressing L. infantum (MHOM/MA/67/ITMAP-263) axenic amastigotes expressing episomal luciferase were maintained in MAA/20 (axenic amastigote medium) at 37ºC, 5% CO2 environment with subculture every 7 days at 1x10 ⁶/ml in 5 ml on T25 ventilated flasks. [0050] In an embodiment, THP-1 Cell culture was prepared. Human leukemia cell line, THP-1 (ATCC. TIB- 202™) were cultured in RPMI-1640 medium supplemented with 10% heat-inactivated Fetal Bovine Serum (FBS), 2 mM L-glutamine, 100 UI/mL penicillin/streptomycin, 20 mM HEPES. Cell line was maintained in a humidified incubator at 37 ºC and 5% CO2 by subculture every three days in 20 ml of media at a concentration of 2x10 ⁵/ml in a T75 flask. All cell culture reagents were purchased from Lonza-Bioscience (Morrisville, NC). [0051] In an embodiment, in vitro evaluation of compounds activity against L. infantum promastigotes was carried out. The compounds efficacy was evaluated using a resazurin-based assay. Parasites were added to 100 μl of serial dilutions of compounds in supplemented complete medium at a cell density of 1x10 ⁶/ml. As positive controls, the antileishmanial miltefosine drugs, were included. The final volume of the assay is 200 μl/well. Each condition was carried out in duplicate. Following 72h incubation 20 μl of a 0.5 mM resazurin solution was added and plates were incubated for a further 4 h. Fluorescence was measured at 544 nm and 590 nm excitation and emission wavelength, respectively, using a Synergy 2 Multi-Mode Reader (Biotek, Winooski, VT, USA). Results were shown as % of parasite growth inhibition compared to control (untreated parasites) and represent the average of at least three independent experiments. The effect was evaluated by the determination of the IC50 value (concentration required to inhibit growth in 50%) and calculated by non-linear regression curves using GraphPad Prism version 8.1.1 for Windows (GraphPad Software, San Diego CA, USA). [0052] In an embodiment, in vitro cytotoxicity assay was performed. The cytotoxicity effect of compounds on THP-1-derived macrophages was assessed by the colorimetric MTT assay (3-(4,5- dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) as already described, with some modifications. Briefly, THP-1 cells were suspended in RPMI complete medium at a density of 1 x 10 ⁶ cells/ml and 100 μl/well were seeded in a 96-well plate and were differentiated into macrophages by addition of 40 ng/mL of phorbol myristate 13-acetate (PMA, Sigma, Saint Louis, MI, USA) for 24 h followed by replacement with fresh medium for more 24 h. Subsequently, cells were incubated with 100 μl of compounds ranging from 100 to 12.5 μM after dilution in the RPMI complete medium. Each condition was carried out in quadruplicate. After 72 h of incubation at 37 ºC 5% CO2, the medium was removed and 200 μl of 0.5 mg/mL MTT solution diluted in RPMI was added. Plates were incubated for an additional 4 h. Then 160 μl of media was removed and the same volume of 2-propanol was added. Absorbance was read at 570 nm using a Synergy 2 Multi-Mode Reader (Biotek, Winooski, VT, USA). Cytotoxicity was evaluated by the determination of the CC50 value (drug concentration that reduced the percentage of viable cells in 50%) and calculated by non-linear regression analysis using GraphPad Prism version 8.1.1 for Windows (GraphPad Software, San Diego, CA, USA). The results represent the average of at least three independent experiments. For each compound, the Selectivity Index (SI) was calculated as the ratio between cytotoxicity in THP-1 (CC50, 72 h) and activity against parasites (IC50, 72 h). [0053] In an embodiment, in vitro evaluation of anti-amastigotes activity on infected cells was performed. The activity against L. infantum intracellular amastigotes was evaluated as described previously, with some modifications. Briefly, THP-1 cells were resuspended in RPMI complete medium at a density of 1 x10 ⁶ cells/ml and 100 μl/well were seeded in a 96-well plate and were differentiated into macrophages by addition of 40 ng/mL of phorbol-myristate 13-acetate (PMA, Sigma, Saint Louis, MI, USA) for 24 h followed by replacement with fresh medium for more 24 h. After that, cells were infected for 4 h with L. infantum axenic amastigotes expressing episomal luciferase in a macrophage: amastigotes ratio of 1:10 at 37 ºC, 5% CO2. Non-internalized parasites were washed, and compounds were added at different concentrations in a final volume of 100 μL. As quality control a dose response curve to miltefosine was included in all assays. Each condition was carried out in quadruplicate. After 72 h of incubation, the media was substituted by 100 μL of PBS and 25 μL of Glo-lysis buffer from the Steady-Glo Luciferase Assay System (Promega, Madison, WI, USA) was added. The plates have been placed in an agitator at 100 rpm for 10 minutes at room temperature. Finally, 30 μL of the Steady-Glo reagent (Promega, Madison, WI, USA) was added to the plate and was incubated for 15 min in the dark at the same conditions.140 μL of the well content was transferred to white-bottom 96-well plates. The luminescence intensity was read using a Synergy 2 Multi-Mode Reader (Biotek, Winooski, VT, USA). The antileishmanial effect was evaluated by the determination of the IC50 value and calculated by the non-linear regression analysis using GraphPad Prism version 8.1.1 for Windows (GraphPad Software, San Diego CA, USA). [0054] In an embodiment, in vitro evaluation of anti-malarial activity was carried out. [0055] In an embodiment, P. falciparum lines were obtained from MR4-Malaria Resources and maintained at ~ 4% haematocrit with human red blood cells in RPMI-1640, supplemented with 2mM L- glutamine, 200μM hypoxanthine, 0.25μg/mL gentamycin, 25mM HEPES, 0.2% NaHCO3, and 0.25% Albumax II. Parasite cultures were maintained at 37°C under a humidified controlled atmosphere of 5% O2/5% CO2/90% N2. Parasite growth was monitored through Giemsa-stained blood smears. Parasite synchronization was performed with 5% sorbitol for 15 minutes at 37 °C. To obtain highly synchronous cultures, sorbitol treatment was applied after 6 – 8 hours. [0056] In an embodiment, in order to determine antimalarial activities, synchronized ring-stage parasite was incubated at 37°C with 0.2% starting parasitemia and 1% haematocrit. After 72h, to determine the parasite growth, the parasites were stained with SYBR Green (Thermofisher) in PBS 1x for 30 minutes and then fluorescence analysed and growth normalized to the controls with no drugs. The IC50 values were calculated using nonlinear regression analysis with GraphPad prism 6 software. [0057] In an embodiment, compounds 7 were synthesized following the synthesis pathway described in the following schemes 1, 2 and 3 Scheme 2 a R3 = F, R2 = H b R3 = OCF ₃, R2 = H c R3 = OMe, R2 = H d R3 = H, R2 = OMe e R3 = H, R2 = Cl f R3 = Cl, R2 = CF ₃ g R3 = F, R2 = Cl j R3 = H, R2 = OCH ₂(4'-pyridinyl)

m R3= OMe, R2 = H, R1 = 3,4-(HO)2C6H3 n R3= OMe, R2 = H, R1 = 3,4,5-(HO)3C6H2 o R3= OMe, R2 0 H, R1 = 3,4-(MeO)2C6H3 p R3= H, R2= OMe, R1 = 3,4-(HO)2CeH3 q R3= H, R2= OMe, R1 = 3,4,5-(HO)3C6H2 r R3= H, R2= OMe, R1 = 3,4-(MeO)2CeH3 s R3=H, R2= Cl, R1 = 4-FC6H4 t R3= H, R2= Cl, R1 = 3-FC6H4 u R3= H, R2= Cl, R1 = 3,4-(HO)2CeH3 v R3= H, R2= Cl, R1 = 3,4,5-(HO)3CeH2 x R3= H, R2= Cl, R1 = 4-pyridinyl z R3= H, R2= Cl, R1 = 3,4-(MeO)2CeH3 ab R3= H, R2= Cl, R1 = 4-CICeH4 ac R3= Cl, R2= CF3, R1 = 2-HOC6H4 ad R3= Cl, R2= CF3, R1 = 3,4-(HO)2CeH3 aj R3= F, R2= Cl, R1 = 3,4,5-(HO)3C6H2 ao R3= H, R2= NHCO(4’-Pyridinyl), R1 = 3,4-(HO)2C6H3 aq R3= H, R2= OCH2CH2OH, R1 = 3-CICeH4 ar R3 = H, R2= OCH2CH2OH, R1 = 4-CICeH4 as R3= H, R2= OCH2CH2OH, R1 = 3-FCeH4 at R3= H, R2= OCH2CH2OH, R1 = 4-BrCeH4 au R3= H, R2= OCH2CH2OH, R1 = 3-pyridinyl av R3= H, R2= OCH2CH2-morpholinyl, R1 = Ph ax R3= H, R2= OCH2CH2-morpholinyl, R1 = 3-CICeH4 az R3= H, R2= OCH2CH2-morpholinyl, R1 = 4-CICeH4 ba R3= H, R2= OCH2CH2-thiomorpholinyl, R1 = 3-CICeH4 bb R3= H, R2= OCH2CH2-piperazinyl-CO2Et, R1 = 3-CIC6H4 [0058] In an embodiment, compounds 4a-h and 4l (Scheme 1) were synthesized according to procedures reported in [1]. The synthesis of compounds 4m-r (Scheme 1) are described here for the first time. These compounds were obtained from the corresponding compounds 4a and 4b by reaction with an alkyl or acyl halide in acetonitrile, under a basic medium, at 80 °C, and a nitrogen atmosphere, according to procedures described below. [0059] In an embodiment, compounds 5 (Scheme 2) were obtained from compounds 4 following the procedure reported in [2]. [0060] In an embodiment, compounds 6a-g and 6j (Scheme 2) were obtained from the reaction of the corresponding compounds 5 with piperidine (4 – 6 mol equiv.) at 80 °C. Compounds 6 were isolated after the elimination of piperidine in the rotary evaporator and the addition of acetonitrile, ethanol or water as described below. [0061] In an embodiment, compounds 7 were obtained by two synthetic methods, as described in scheme 3. When compounds 7 were obtained through method A, to a suspension of 6 in DMSO or ethanol, at 30 ^oC and under magnetic stirring, an aldehyde was added, followed by a catalytic amount of H ₂SO ₄. The reaction was monitored by TLC and when it showed the absence of the limiting reagent, the product was precipitated by adding distilled water when DMSO was used as the solvent. The product precipitated from the reaction mixture when the solvent used was ethanol. The solid in suspension was filtered off, washed with distilled water or ethanol in the funnel and dried at ~80 ^oC. The solids were identified as 7. [0062] In an embodiment, when compounds 7 were obtained through method B, to a suspension of 5 in DMSO, at r.t. and under stirring, an aldehyde and an excess of piperidine (2 eq.) were added. The reaction continued under stirring, in a closed flask, at 80 ^oC until TLC showed the absence of 5 (between 30 to 120 minutes). Then piperidine was removed in a rotary evaporator, under vacuum. To the resulting solution was added acetic acid (2 equiv.) followed by distilled water or acetonitrile. The solid in suspension was filtered off, washed in the funnel with water and dried at ~80 ^oC. The solids were identified as 7. [0063] The reactions of all the chemical compounds were monitored by thin layer chromatography (TLC) using silica gel 60 plates (Macherey-Nagel), with 0.2 mm and a fluorescent indicator. A UV chamber (CN- 6 Vilber Lourmat) with a 254 nm lamp was used for their revelation. Flash chromatography was performed using silica gel (particle size < 0.063 mm) from MN KIieselgel 60 (230 ASTM). For reactions using temperature, a hot plate stirrer SELECTA with temperature control was used with appropriate magnetic stirring and temperature according to the specific procedure. Solvents were evaporated in a Buchi RE 210 rotary evaporator with vacuum and variable bath temperature. NMR spectra were obtained in Bruker Avance III (at 400 MHz for ¹H NMR and 100 MHz for ¹³C NMR), at 25 ^oC and using deuterated dimethylsulfoxide (DMSO-d6) as solvent. Chemical shifts were recorded in parts per million (ppm) using the residual solvent peak as an internal standard. IR spectra were recorded in FT-IR Bomem MB 104 using nujol mulls and NaCl cells. Melting points were determined in a Stuart SMP3 apparatus and were not corrected. Elemental analysis was performed on a LECO CHNS-932 instrument. [0064] In an embodiment, synthesis of 9-(3-(2-hydroxyethoxy)phenyl)-9H-purine-6-carbonitrile (compound 4m) was performed. In a vial, compound 4a (1.00g, 4.23 mmol), acetonitrile (10 mL) and Cs2CO3 (1.4 mol equiv.) were added. The vial was closed and the reaction mixture was placed, under efficient magnetic stirring, at 80 ^oC, for 10 minutes. The mixture was cooled and 2-bromoethanol (10 mol equiv.) was added. The vial was closed and the reaction continued, at 80 ^oC, until the TLC showed absence of starting reagent (2 days). The reaction mixture was cooled and then diluted with acetonitrile (20 mL). The resulting suspension was filtered through a silica column (0.5 cm high) and the resulting solution was concentrated in the rotary evaporator. Cold diethyl ether (5 mL) was added to the residue and the resulting yellow solid was filtered off and washed in the funnel with diethyl ether. The solid was identified as 4m(1.10 g, 4.04 mmol, 96%). Mp: 132 - 133 °C; IR (nujol mull) ʋ/cm ^-1: 3541, 3433, 3097, 3096, 2250 (CN), 1612, 1683, 1508; ¹H NMR (400 MHz, DMSO-d ₆) ^: 9.37 (s, 1H, H8), 9.17 (s, 1H, H2), 7.54 (t, 1H, J = 8,0 Hz, Hm), 7.51 (t, 1H, J = 2.0 Hz, Ho’), 7.46 (dd, 1H, J = 2.0, 8.0 Hz, Ho), 7.11 (dd, 1H, J = 2,0; 8.0 Hz, Hp), 4.92 (br. s, 1H, OH exchangeable by D2O), 4.07 (t, 2H, J = 4.8 Hz, H10), 3.74 (t, 2H, J = 4.8 Hz, H11); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 159.5, 152.9, 152.6, 149.5, 135.6, 134.6, 130.7, 129.3, 115.6, 114.7, 114.3, 110.2, 70.0, 59.5. [0065] In an embodiment, synthesis of 9-(3-(2-morpholinoethoxy)phenyl)-9H-purine-6-carbonitrile (compound 4n) was performed. In a vial, compound 4a (0.43 g, 1.81 mmol), acetonitrile (5 mL) and Cs2CO3 (1.0 mol equiv.) were added. The vial was closed and the reaction mixture was placed, under efficient magnetic stirring, at 80 ^oC, for 10 minutes. The mixture was cooled and 4-(2-bromoethyl)morfoline (1.5 mol equiv.) was added. The vial was closed and the reaction continued, at 80 ^oC, until the TLC showed absence of starting reagent (1 h). The reaction mixture was cooled and then diluted with acetonitrile (20 mL). The resulting suspension was filtered through a silica column (0.5 cm high) and the resulting solution was concentrated in the rotary evaporator. Cold diethyl ether (5 mL) was added to the residue and the resulting green solid was filtered off and washed in the funnel with diethyl ether. The solid was identified as 4n (0.45 g, 1.32 mmol, 73 %). Mp: 153 - 155°C; IR (nujol mull) ʋ/cm ^-1: 3099, 2245 (CN), 1807, 1778, 1583, 1520; ¹H NMR (400 MHz, DMSO-d6) ^: 9.34 (s, 1H, H8), 9.18 (s, 1H, H2), 7.54 (t, 1H, J = 8.0 Hz, Hm), 7.52 (t, 1H, J = 2.0 Hz, Ho’), 7.50 (dd, J = 2.0, 8.0 Hz, 1H, Ho), 7.12 (dd, J = 2.0, 8.0 Hz, 1H, Hp), 4.18 (t, J = 6.0 Hz, 2H, H10), 3.57 (t, J = 4.8 Hz, 4H, H13), 2.73 (t, J = 6.0 Hz, 2H, H11), 2.49 (t, J = 4.8 Hz, 4H, H12); ¹³C NMR (100 MHz, DMSO-d6) ^: 159.2, 152.8, 152.6, 149.5, 135.6, 134.6, 130.6, 129.3, 115.7, 114.6, 114.3, 110.2, 66.1, 65.7, 56.8, 53.6. [0066] In an embodiment, synthesis of 9-(3-(2-thiomorpholinoethoxy)phenyl)-9H-purine-6-carbonitril e (compound 4o) was performed. In a vial, compound 4a (0.51 g, 2.13 mmol), acetonitrile (10 mL) and Cs ₂CO ₃ (1.0 mol equiv.) were added. The vial was closed and the reaction mixture was placed, under efficient magnetic stirring, at 80 ^oC, for 10 minutes. The mixture was cooled and 4-(2- bromoethyl)thiomorfoline (2.4 mol equiv.) was added. The vial was closed and the reaction continued, at 80 ^oC, until the TLC showed absence of starting reagent (2 h and 20 minutes). The reaction mixture was cooled and then diluted with acetonitrile (20 mL). The resulting suspension was filtered through a silica column (0.5 cm high) and the resulting solution was concentrated in the rotary evaporator. Cold diethyl ether (5 mL) was added to the residue and the resulting brown solid was filtered off and washed in the funnel with diethyl ether. The solid was identified as 4o (0.31 g, 0.86 mmol, 40 %). Mp: 115 - 117°C; IR (nujol mull) ʋ/cm ^-1: 3127, 3097, 3008, 2239 (CN), 1612, 1595, 1504; ¹H NMR (400 MHz, DMSO-d6) ^: 9.33 (s, 1H, H8), 9.17 (s, 1H, H2), 7.6 - 7.4 (m, 3H, Hm, Ho’, Ho), 7.01 (dd, J = 2.0, 8.0 Hz, 1H, Hp), 4.15 (t, J = 5.8 Hz, 2H, H10), 2.77 (m, 6H, H11, H12), 2.59 (t, J = 4.8 Hz, 4H, H13); ¹³C NMR (100 MHz, DMSO-d6) ^: 159.2, 152.8, 152.5, 149.4, 135.5, 134.6, 130.6, 129.3, 115.6, 114.7, 114.2, 110.1, 66.79, 57.06, 54.77, 27.12; MS (ESI) 367 [M + 1] ⁺. [0067] In an embodiment, synthesis of ethyl 4-(2-(3-(6-cyano-9H-purin-9-yl)phenoxy)ethyl)piperazine-1- carboxylate (compound 4p) was performed. In a vial, compound 4a (0.32 g, 1.36 mmol), acetonitrile (5 mL) and Cs ₂CO ₃ (1.5 mol equiv.) were added. The vial was closed and the reaction mixture was placed, under efficient magnetic stirring, at 80 ^oC, for 10 minutes. The mixture was cooled and ethyl 4-(2- bromoethyl)piperazine-1-carboxylatene (1.5 mol equiv.) was added. The vial was closed and the reaction continued, at 80 ^oC, until the TLC showed absence of starting reagent (2 h). The reaction mixture was cooled and then diluted with acetonitrile (15 mL). The resulting suspension was filtered through a silica column (0.5 cm high) and the resulting solution was concentrated in the rotary evaporator. Cold diethyl ether (5 mL) was added to the residue and the resulting beige solid was filtered off and washed in the funnel with diethyl ether. The solid was identified as 4p (0.40 g, 0.96 mmol, 71 %). Mp: 107 - 109°C; IR (nujol mull) ʋ/cm ^-1: 3101, 3062, 2243 (CN), 1672, 1616, 1590, 1508; ¹H NMR (400 MHz, DMSO-d ₆) ^: 9.34 (s, 1H, H8), 9.18 (s, 1H, H2), 7.65 - 7.45 (m, 3H, Hm, Ho’, Ho), 7.11 (dd, J = 2.0, 8.0 Hz, 1H, Hp), 4.18 (t, J = 5.6 Hz, 2H, H10), 4.02 (q, J = 7.2 Hz, 2H, OEt), 3.35 (t, J = 4.8 Hz, 4H, H13), 2.76 (t, J = 6.0 Hz, 2H, H11), 2.46 (t, J = 4.8 Hz, 4H, H12), 1.14 (t, J = 7.2 Hz, 3H,OEt); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 159.2, 154.5, 152.8, 152.5, 149.4, 135.5, 134.6, 130.6, 129.2, 115.6, 114.6, 114.2, 110.1, 65.81, 60.6, 56.3, 52.7, 43.3, 14.5; MS (ESI) 422 [M + 1] ⁺. [0068] In an embodiment, synthesis of 9-(3-(pyridin-4-ylmethoxy)phenyl)-9H-purine-6-carbonitrile (compound 4q) was performed. A suspension of 4a (1.98 g, 8.34 mmol) and Cs2CO3 (2.0 mol equiv.) in acetonitrile (190 mL) was submitted to reflux for 10 min. To this reaction mixture was added cautiously a suspension of 4-(chloromethyl)pyridinium chloride (2.0 mol equiv.) and Cs2CO3 (2 mol equiv.) in acetonitrile (130 mL) and the mixture was refluxed for 2 hours, when the TLC showed absence of 4a. The reaction mixture was cooled to room temperature and filtered through a silica gel column (0.5 cm high). The resulting solution was concentrated in the rotary evaporator, the solid in suspension was filtered and washed with a mixture of acetonitrile/diethyl ether (1:2) and was identified as compound 4q (1.96 g, 5.93 mmol, 71%). Mp 210 - 212 °C; IR (nujol mull) ʋ/cm ^-1: 3062, 1597, 1579, 1500; ¹H NMR (400 MHz, DMSO- d ₆) ^: 9.34 (s, 1H, H2), 9.18 (s, 1H, H8), 8.59 (d, J = 6.0 Hz, H2, Hm’’), 7.65 (t, J = 2.4 Hz, 1H, Ho’), 7.58 (t, 1H, J = 8.0 Hz, Hm), 7.54 (dt, 1H, J = 1.6, 8.0 Hz, Ho), 7.47 (d, J = 6.0 Hz, 2H, Ho’’), 7.20 (ddd, J = 8.0, 2.4, 1.6 Hz, 1H, Hp), 5.29 (s, 2H, H10); ¹³C NMR (100 MHz, DMSO-d6) ^: 158.7, 152.9, 152.6, 149.8, 149.4, 145.7, 135.6, 134.7, 130.8, 129.3, 122.0, 116.3, 114.8, 114.3, 110.7, 68.0. Anal. Calcd. for C ₁₈H ₁₂N ₆O: C, 65.85; H, 3.68; N, 25.60. Found: C, 65.74; H, 3.67; N, 25.55. [0069] In an embodiment, synthesis of N-(3-(6-cyano-9H-purin-9-yl)phenyl)isonicotinamide (compound 4r) was performed. In a vial, the compound 4b (0.61 g, 2.57 mmol), dried acetonitrile (5 mL), Isonicotinoyl chloride hydrochloride (1.5 mol equiv.) and triethyl amine (4 mol equiv.) were added. The vial was closed under nitrogen atmosphere and the reaction mixture was placed, under efficient magnetic stirring, at 80 ^oC, until the TLC showed absence of 4b (1 h and 35 minutes). The reaction mixture was cooled and cold water (20 mL) was added. The resulting suspension was filtered off and the solid was washed in the funnel abundantly with water, followed by acetonitrile and diethyl ether. The beige solid was identified as 4r (0.78 g, 2.28 mmol, 89 %). Mp > 300°C; IR (nujol mull) ʋ/cm ^-1: 3377, 3078, 3034, 2251 (CN), 1698, 1609, 1590, 1549, 1504; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.8 (br. s, 1H, NH) exchangeable by D ₂O, 9.30 (s, 1H, H8) 9.18 (s, 1H, H2), 8.80 (d, J = 4.8 Hz, 2H, Hm’’), 8.41 (t, J = 2.0 Hz, 1H, Ho’), 7.89 (m, 3H, Ho, Ho’’), 7.65 (t, J = 8.0 Hz, 1H, Hm), 7.61 (dd, J = 2.0, 8.0 Hz, 1H, Hp); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 164.4, 152.9, 152.7, 150.4, 149.4, 141.6, 139.8, 135.6, 133.8, 130,1, 129.4, 121,7, 120,6, 119,6, 115,8, 114.3. [0070] In an embodiment, synthesis of aromatic pyrimidipyrimidines (compounds 6a-6j) were performed by the following general procedure. To a suspension of 5, in EtOH or DMSO, in a vial, under magnetic stirring, was added piperidine (4 - 6 mol equiv.) and the mixture was kept under stirring at 80 ^oC until TLC showed absence of starting reagent. The resulting reaction mixture was concentrated in a rotary evaporator and the product was precipitated by addition of acetonitrile, ethanol or water. The solid in suspension was then filtered off, washed with ethanol followed by diethyl ether, and identified as compound 6. [0071] In an embodiment, synthesis of N-(4-fluorophenyl)-8-hydrazineylpyrimido[5,4-d]pyrimidin-4- amine (compound 6a) was performed. Compound 6a (0.20 g, 0.72 mmol, 67 %) was obtained as a light orange solid from 5a (0.29 g, 1.07 mmol), piperidine (6 mol equiv.), after 17 h of reaction. The reaction was performed in DMSO (1.0 mL) and the product was precipitated with water (10 mL). Mp 286 – 288; IR (nujol mull) ʋ/cm ^-1: 3345, 3307, 3253, 3165, 1624, 1601, 1576, 1546, 1510; ¹H NMR (400 MHz, DMSO-d ₆) ^: 9.99 (s, 1H, NH exchangeable by D2O), 9.72 (s, 1H, NH exchangeable by D2O), 8.53 (s, 1H, H6), 8.50 (s, 1H, H2), 8.00 (dd, J= 8.8, 4.8 HZ, 2H, Ho), 7.20 (t, J= 8.8 Hz, 2H, Hm), 4.92 (s, 2H, NH2 exchangeable by D2O); ¹³C NMR (100 MHz, DMSO-d6) ^: 158.3 (d, J = 239 Hz), 154.8, 153.5, 135.0 (d, J = 3 Hz), 131.5, 130.8, 123.4 (d, J = 8 Hz), 115.0 (d, J = 22 Hz). [0072] In an embodiment, synthesis of 8-hydrazineyl-N-(4-(trifluoromethoxy)phenyl)pyrimido[5,4- d]pyrimidin-4-amine (compound 6b) was performed. Compound 6b (0.67 g, 2.00 mmol, 84 %) was obtained as an yellow solid from 5b (0.81 g, 2.39 mmol), piperidine (4 mol equiv.), after 1 h of reaction, in ethanol (5 mL). The reaction was performed in ethanol (5 mL) and the product was isolated by filtration from the reaction mixture. Mp 215 – 216 °C; IR (nujol mull) ʋ/cm ^-1: 3361, 3288, 3249, 3171, 3054, 1634, 1610, 1582, 1557, 1528, 1507; ¹H NMR (400 MHz, DMSO-d6) ^: 10.41 (s, 1H, NH exchangeable by D2O), 10.10 (br. s, 1H, NH exchangeable by D2O), 8.72 (s, 1H, H2), 8.63 (s, 1H, H6), 8.04 (d, J = 8.4 Hz, 2H, Ho), 7.39 (d, J = 8.4 Hz, 2H, Hm), 6.52 (s, 2H, NH exchangeable by D ₂O); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 157.06, 156.23, 154.90, 153.36, 143.79, 137.87, 131.68, 130.86, 122.87, 121.30, 120.16 (q, J = 255 Hz); [0073] In an embodiment, synthesis of 8-hydrazineyl-N-(4-methoxyphenyl)pyrimido[5,4-d]pyrimidin-4- amine (compound 6c) was performed. Compound 6c (0.34 g, 0.97 mmol, 67 %) was obtained as a yellow solid from 5d (0.40 g, 1.41 mmol), piperidine (6 mol equiv.), after 19 h of reaction in DMSO (2 mL). M.p 215 – 217 °C; ¹H NMR (400 MHz, DMSO-d6) ^: 9,78 (s, 1H, NH exchangeable by D2O), 9,67 (s, 1H, NH exchangeable by D2O), 8,53 (s, 1H, H6), 8,50 (s, 1H, H2), 7,86 (d, 2H, J= 8,4 Hz, Ho), 7,18 (d, 2H, J= 8,4Hz, Hm), 4,85 (s, 2H, NH ₂ exchangeable by D ₂O), 2,28 (s, 3H, OMe) ppm. [0074] In an embodiment, synthesis of 8-hydrazineyl-N-(3-methoxyphenyl)pyrimido[5,4-d]pyrimidin-4- amine (compound 6d) was performed. Compound 6d (0.28 g, 0.97 mmol, 67 %) was obtained as an yellow solid from 5d (0.42 g, 1.46 mmol), piperidine (6 mol equiv.), after 22 h of reaction. The reaction was performed in DMSO (2 mL) and the product was precipitated with water (10 mL). Mp 248 – 250; IR (nujol mull) ʋ/cm ^-1: 3350, 3247, 1602, 1558, 1531; ¹H NMR (400 MHz, DMSO-d ₆) ^: 9.77 (br. s, 2H, NH exchangeable by D2O), 8.57 (s, 1H), 8.50 (s,1H), 7.69 (t, 2.4 Hz, 1H, Ho´), 7.60 (dd, J= 2.4, 8.4 Hz, 1H, Ho´), 7.38 (t, J= 8.4 Hz, 1H, Hm), 6.68 (d, J= 3.2, 8.4 Hz, 2H,Hp), 5.04 (br. s, 2H, NH2 exchangeable by D2O), 3.75 (s, 3H, OMe); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 159.5, 154.9, 157.2, 153.6, 156.3, 139.8, 131.5, 130.9, 129.4, 113.5, 109.1, 107.2, 55.2. [0075] In an embodiment, synthesis of N-(3-chlorophenyl)-8-hydrazineylpyrimido[5,4-d]pyrimidin-4- amine (compound 6e) was performed. Compound 6e (0.45 g, 1.56 mmol, 83 %) was obtained as an orange solid from 5e (0.54 g, 1.87 mmol), piperidine (4 mol equiv.) after 5 h of reaction. The reaction was performed in DMSO (2 mL) and the product was precipitated with acetonitrile (10 mL) and acetic acid (0,27 mL, 4.68 mmol, 2.5 eq.). The solid was washed with acetonitrile and diethyl ether. Mp 260 - 262°C; IR (nujol mull) ʋ/cm ^-1: 3275, 1617, 1604, 1584, 1563, 1543 ; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.07 (br s, 1H, NH exchangeable by D ₂O), 9.74 (br s, 1H, NH exchangeable by D ₂O), 8.62 (s, 1H, H2), 8.51 (s, 1H, H6), 8.28 (t, J = 2.0 Hz, 1H, Ho´), 7.94 (dd, J = 8.0, 2.0 Hz, 1H, Ho), 7.37 (t, J = 8.0 HZ, 1H, Hm), 7.14 (dd, J = 8.0, 2.0 Hz, 1H, Hp), 4.88 br s, 2H, NH2 exchangeable by D ₂O); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 157.2, 156.3, 155.0, 153.4, 140.3, 132.9, 131.8, 130.9, 130.2, 123.2, 120.6, 119.8; MS (ESI) 286 [M – 1]-. [0076] In an embodiment, synthesis of N-(4-chloro-3-(trifluoromethyl)phenyl)-8- hydrazineylpyrimido[5,4-d]pyrimidin-4-amine (compound 6f) was performed. Compound 6f (0.823 g, 2.31 mmol, 82%) was obtained as a yellow solid from 5f (1.00 g, 2.81 mmol), piperidine (4 mol equiv.), after 17 h of reaction in ethanol. Mp 238 – 240; IR (nujol mull) ʋ/cm ^-1: 3354, 3314, 3280, 3125, 1602, 1561, 1532; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.36 (s, 1H, NH exchangeable by D ₂O), 9.84 (s, 1H, NH exchangeable by D ₂O), 8.68 (d, J = 2.4 Hz, 1H, Ho´), 8.63 (s, 1H, H6), 8.52 (s,1H, H2), 8.37 (dd, J = 8.8, 2.4 Hz, 1H, Ho), 7.69 (d, J= 8.8 Hz, 1H, Hm); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 157.0, 156.2, 155.1, 153.1, 138.4, 131.7, 130.9 (2C), 126.49 (q, J = 30 Hz), 125.9, 123.95 (q, J = 2 Hz), 122.8 (q, J = 272 Hz), 120.02 (q, J = 6 Hz). MS (ESI) 354 [M – 1]-. [0077] In an embodiment, synthesis of N-(3-chloro-4-fluorophenyl)-8-hydrazineylpyrimido[5,4- d]pyrimidin-4-amine (compound 6g) was performed. Compound 6g (0.09 g, 0.29 mmol, 35 %) was obtained as a grey solid from 5g (0.16 g, 0.54 mmol) and piperidine (4 mol equiv.), after 17 h of reaction. The reaction was performed in ethanol (25 mL) and the product was precipitated with ethanol (10 mL). Mp 257 – 259 °C; IR (nujol mull) ʋ/cm ^-1: 3359, 3319, 3271, 3121, 3070, 1647, 1609, 1584, 1561, 1534; ¹H NMR (400 MHz, DMSO-d6) ^: 9.83 (br. S, 1H, NH exchangeable by D2O), 8.59 (s, 1H, H6), 8.51 (s, 1H, H2), 8.31 (dd, J = 4.4, 2.8 Hz, 1H, Ho´), 7.94 (ddd, J = 9.2, 4.4, 2.8 Hz, 1H, Ho), 7.36 (t, J = 9.2 Hz, 1H, Hm), 4.89 br. S, 2H, NH exchangeable by D2O); ¹³C NMR (100 MHz, DMSO-d6) ^: 156.7, 155.9, 154.5, 153.2 (d, J = 242 Hz), 152.9, 135.6 (d, J = 3Hz), 131.3, 130.5, 122.6, 121.4 (d, J = 7Hz, CH), 118.6 (d, J = 18Hz), 116.1 (d, J = 21Hz). MS (ESI) 304 [M – 1]-. [0078] In an embodiment, synthesis of 8-hydrazineyl-N-(3-(pyridin-4-ylmethoxy)phenyl)pyrimido[5,4- d]pyrimidin-4-amine (compound 6j) was performed. Compound 6j (0.15 g, 0.41 mmol, 45 %) was obtained as an orange solid from 5o (0.33 g, 0.91 mmol) and piperidine (4 mol equiv.), after 8 h of reaction. The reaction was performed in ethanol and the product was precipitated with acetonitrile. Mp 205 - 208 °C; IR (nujol mull) ʋ/cm ^-1: 3346, 3291, 3033, 1603, 1584, 1558, 1537 ; ¹H NMR (400 MHz, DMSO-d ₆) ^: 9.76 (br. s, 1H, NH exchangeable by D2O), 9.82 (s, 1H, NH exchangeable by D2O), 8.57 (m, 3H, H2; H6; Hm’’), 8.50 (s, 1H, H2; H6), 7.94 (s, 1H, NH exchangeable by D2O), 7.84 (t, J = 2.0 Hz, 1H, Ho’), 7.61 (dd, J = 8.4, 2.0 Hz, 1H, Ho), 7.45 (d, J = 6.0 Hz, 2H, Ho’’), 7.27 (t, J = 8.4 Hz, 1H, Hm), 6.76 (dd, J = 8.4, 2.0 Hz, 1H, Hp), 5.19 (s, 2H, H10), 4.82 (br. s, 2H, NH2 exchangeable by D2O); ¹³C NMR (100 MHz, DMSO-d6) ^: 158.09, 157.14, 156.18, 154.91, 153.47, 149.75, 146.27, 139.87, 131.51, 130.91, 129.44, 121.93, 114.02, 109.79, 107.96, 67.62. MS (ESI) 361 [M+1] ⁺; Anal. Calcd. for C18H16N8O: C, 59.99; H, 4.48; N, 31.09. Found: C, 59.96; H, 4.47; N, 31.15. [0079] In an embodiment, synthesis of 4,8-disubstitued-pyrimido[5,4-d]pyrimidines (compounds 7) were performed using method A. To a suspension of 6 in DMSO or ethanol, at 30 ^oC and under stirring, an aldehyde was added, followed by a catalytic amount of H ₂SO ₄. The reaction was monitored by TLC and when it showed the absence of limiting reagent, the product was precipitated by adding distilled water when DMSO was used as the solvent. The product precipitated from the reaction mixture when the solvent used was ethanol. The solid in suspension was filtered off, washed with distilled water or ethanol in the funnel and dried at ~80 ^oC. [0080] In an embodiment, synthesis of 4,8-disubstitued-pyrimido[5,4-d]pyrimidines (compounds 7) were performed using method B. To a suspension of 5 in DMSO, at r.t. and under stirring, an aldehyde and an excess of piperidine (2 eq.) were added. The reaction continued under stirring, in a closed flask, at 80 ^oC until TLC showed absence of 5 (between 30 to 120 minutes). Then piperidine was removed in a rotary evaporator, under vacuum. To the resulting solution was added acetic acid (2 equiv.) followed by distilled water or acetonitrile. The solid in suspension was filtered off, washed in the funnel with water and dried at ~80 ^oC. [0081] In an embodiment, synthesis of 4-((2-(8-((4-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-4- yl)hydrazineylidene)methyl)benzene-1,2-diol (compound 7a) was performed. Compound 7a (0.28 g, 0.74 mmol, 98%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6a) (0.20 g, 0.75 mmol) with 1.1 equiv. of 3,4-dihydroxibenzaldehyde, after 1h of reaction in DMSO. Mp 274 °C (Dec.); IR (nujol mull) ʋ/cm ^-1: 3358, 3314, 3068, 1620,1605, 1583, 1568, 1549, 1534, 1504 ; ¹H NMR (400 MHz, DMSO-d6) ^: 10.2 (s, 1H, NH exchangeable by D2O), 10.0–9.00 (bs, 2H, m,p-OH exchangeable by D2O), 8.63 (s, 1H, H6), 8.58 (s, 1H, H2), 8.49 (s, 1H, H9), 7.97 (dd, 2H, J= 5.2, 9.2 Hz, Ho), 7.32 (d, 1H, J= 2.0 Hz, Ho’’), 7.22 (t, 2H, J= 9.2 Hz, Hm), 7.01 (dd, 1H, J= 2.0, 8.4 Hz, Ho’), 6.79 (d, 1H, J= 8.4 Hz, Hm’); ¹³C NMR (100 MHz, DMSO-d6) ^: 159.9 (d, J = 240 Hz), 156.5, 154.2, 153.5, 152.9, 150.9, 148.5, 145.8, 134.7 (d, J = 2.0 Hz), 131.9, 131.8, 125.5, 124.0 (d, J = 8.0 Hz), 121.1, 115.7, 115.3 (d, J = 23 Hz), 113.3. MS (ESI) 392 [M+1] ^+. Anal. Calcd. for C ₁₉H ₁₄FN ₇O ₂: C, 58.31; H, 3.61; N, 25.05. Found: C, 58.33; H, 3.60; N, 25.08. [0082] In an embodiment, synthesis of 5-((2-(8-((4-fluorophenyl)amino)pyrimido[5,4-d]pyrimidin-4- yl)hydrazineylidene)methyl)benzene-1,2,3-triol (compound 7b) was performed. Compound 7b (0.22 g, 0.53 mmol, 99%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6a) (0.15 g, 0.54 mmol) with 1.2 equiv. of 3,4,5-trihydroxibenzaldehyde, after 1h of reaction in DMSO. Mp 283 °C (Dec.); IR (nujol mull) ʋ/cm ^-1: 3358, 3273, 3052, 1653, 1609, 1571, 1534, 1504; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.2 (s, 1H, NH exchangeable by D ₂O), 10.0-9.00 (br s, 3H, OH exchangeable by D2O), 8.64 (s, 1H, H6), 8.57 (s, 1H, H2), 8.42 (s, 1H, H9), 7.95 (dd, 2H, J= 5.2, 9.2 Hz, Ho), 7.22 (t, 2H, J= 9.2 Hz, Hm), 6.79 (s, 2H, Ho’); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 160.0 (d, J = 240 Hz), 156.5, 154.4, 152.9, 152.2, 151.8, 146.3, 136.6, 134.7 (d, J = 3.0 Hz), 131.9, 131.6, 124.4, 124.2 (d, J = 8.0 Hz), 115.4 (d, J = 23 Hz), 107.1. MS (ESI) 406 [M-1]-. Anal. Calcd. for C ₁₉H ₁₄FN ₇O ₃: C, 56.02; H, 3.46; N, 24.07. Found: C, 56.00; H, 3.45; N, 24.04 [0083] In an embodiment, synthesis of 8-(2-(3,4-dimethoxybenzylidene)hydrazineyl)-N-(4- fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7c) was performed. Compound 7c (0.09 g, 0.21 mmol, 96%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6a) (0.06 g, 0.22 mmol) with 1.2 equiv. of 3,4-dimethoxybenzaldehyde, after 1h of reaction in DMSO. Mp 255-258 °C; IR (nujol mull) ʋ/cm ^-1: 3366, 3306, 3026, 1597, 1564, 1534, 1508; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.5-9.00 (bs, 1H, NH exchangeable by D ₂O), 8.59 (s, 1H, H6), 8.56 (s, 1H, H2), 8.52 (s, 1H, H9), 7.92 (dd, 2H, J= 5.2, 9.2 Hz, Ho), 7.51 (d, 1H, J= 2.0 Hz, Ho’’), 7.26 (dd, 1H, J= 2.0, 8.4 Hz, Ho’), 7.18 (t, 2H, J= 9.2 Hz, Hm), 7.01 (d, 1H, J= 8.4 Hz, Hm’), 3.84 (s, 3H, p-OCH ₃), 3.79 (s, 3H, m-OCH ₃); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 159.9 (d, J = 240 Hz), 156.6, 154.1, 153.9, 153.5, 151.3, 150.3, 149.3, 134.6 (d, J = 3.0 Hz), 131.9, 131.7, 127.2, 123.8 (d, J = 8.0 Hz), 122.4, 119.7, 115.3 (d, J = 22 Hz), 112.0, 55.9, 55.8; MS (ESI) 420 [M+1] ⁺. Anal. Calcd. for C ₂₁H ₁₈FN ₇O ₂: C, 60.14; H, 4.33; N, 23.38. Found: C, 60.17; H, 4.34; N, 23.35. [0084] In an embodiment, synthesis of 8-(2-(3-chlorobenzylidene)hydrazineyl)-N-(4- fluorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7d) was performed. Compound 7d (0.10 g, 0.25 mmol, 96%) was obtained, through method A, as a light-yellow solid by reaction of pyrimidopyrimidine (compound 6a) (0.07 g, 0.26 mmol) with 1.5 equiv. of 3-chlorobenzaldehyde, after 20 min of reaction in DMSO. Mp 243-245 °C; IR (nujol mull) ʋ/cm ^-1: 3559, 3347, 3252, 3074, 1611, 1583, 1544, 1511; ¹H NMR (400 MHz, DMSO-d6) ^: 13.0-11.0 (bs, 1H, NH exchangeable by D2O), 10.2 (s, 1H, NH exchangeable by D2O), 8.67 (s, 1H, H2), 8.64 (s, 2H, H6; H9), 8.00 (dd, 2H, J= 5.2, 9.2 Hz, Ho), 7.82 (s, 1H, Ho’’), 7.68 (d, 1H, J= 2.0, 8.0 Hz, Ho’), 7.48 (m, 2H, Hp’; Hm’), 7.22 (t, 2H, J= 9.2 Hz, Hm); ¹³C NMR (100 MHz, DMSO-d6) ^: 159.7 (d, J = 240 Hz), 156.4, 154.7 (2C), 154.1, 146.9, 136.7, 134.8 (d, J = 3,0 Hz), 133.7, 132.4, 131.4, 130.8, 129.7, 126.2 (2C) 123.8 (d, J = 8,0 Hz), 115.2 (d, J = 22 Hz); MS (ESI) 394 [M+1] ⁺. Anal. Calcd. for C ₁₉H ₁₃ClFN ₇: C, 57.95; H, 3.33; N, 24.90. Found: C, 57.93; H, 3.34; N, 24.94. [0085] In an embodiment, synthesis of 4-((2-(8-((4-(trifluoromethoxy)phenyl)amino)pyrimido[5,4- d]pyrimidin-4-yl)hydrazineylidene)methyl)benzene-1,2-diol (compound 7e) was performed. Compound 7e (0.26 g, 0.57 mmol, 94%) was obtained, through method A, as an orange solid by reaction of pyrimidopyrimidine (compound 6b) (0.20 g, 0.59 mol) with 1.1 equiv. 3,4-dihydroxybenzaldehyde, after 30 minutes of reaction in DMSO. Mp 264-274 ºC; IR (nujol mull) ʋ/cm ^-1: 2855 -1624.8 (br), 1580, 1529, 1510. ¹H RMN (400 MHz, DMSO-d ₆); δ: 10.36 (s, 1H, NH), 9.56 (br s, 1H, OH exchangeable by D ₂O), 9.26 (br s, 1H, OH exchangeable by D ₂O), 8.69 (s, 1H, CH, H6), 8.61 (s, 1H, CH, H2), 8.52 (s, 1H, CH, H9), 8.10 (d, J = 8,4 Hz, 2H, CH, Ho), 7.39 (d, J = 8,4 Hz, 2H, CH, Hm), 7.33 (d, J = 2,0 Hz, 1H, CH, Ho’’), 7.01 (dd, J = 8,4 Hz, J = 2,0 Hz, 1H, CH, Ho´), 6.81 (d, J= 8,4 Hz, 1H, CH, Hm’), 3.83 (s, 3H, CH3, OMe); ¹³C RMN (100 MHz, DMSO-d6); δ: 156.4, 154.1, 153.3, 152.6, 151.2, 148.5, 145.8, 144.2, 137.6, 132.1, 131.7, 125.5, 123.4, 121.4, 121.2, 120.16 (q, J = 254 Hz); 115.6, 113.3; Anal. Calcd. for C ₂₀H ₁₄F ₃N ₇O ₃: C, 52.52; H, 3.09; N, 21.44. Found: C, 52.55; H, 3.10; N, 21.40. [0086] In an embodiment, synthesis of 2-methoxy-4-((2-(8-((4- (trifluoromethoxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-4-yl )hydrazineylidene)methyl)phenol (compound 7g) was performed. Compound 7g (0.26 g, 0.58 mmol, 97%) was obtained, through method A, as an orange solid by reaction of pyrimidopyrimidine (compound 6b) (0.20 g, 0.59 mol) with 4-hydroxy- 3-methoxybenzaldehyde (0.11 g, 0.66 mmol), after 20 minutes of reaction in DMSO. Mp 170-175 ºC; IR (nujol mull) ʋ/cm ^-1: 2926, 2855, 2254, 2128, 1654, 1610, 1576.7, 1533.3, 1510. ¹H NMR (400 MHz, DMSO- d6); δ: 10.37 (s, 1H, NH), 9.68 (br s, 1H, OH exchangeable by D2O), 8.70 (s, 1H, CH, H6), 8.62 (s, 1H, CH, H2), 8.59 (s, 1H, CH, H9), 8.11 (d, J = 8.8 Hz, 2H, CH, Ho), 7.41 (d, J = 2,0 Hz, 1H, CH, Ho’’), 7.40 (d, J = 8,8 Hz, 2H, CH, Hm), 7.17 (dd, J = 8 Hz, J = 2Hz, 1H, CH, Ho’) 6.86 (d, J = 8 Hz, 1H, CH, Hm), 3.83 (s, 3H, CH3, OMe); ¹³C NMR (100 MHz, DMSO-d ₆); δ: 156.4, 154.1, 153.1, 152.4, 151.2, 149.6, 148.1, 144.2, 137.6, 131.6, 132.5, 125.5, 123.4, 122.8, 121.4, 120.12 (q, J = 246 Hz), 115.5, 109.6, 55. 7; Anal. Calcd. for C ₂₁H ₁₆F ₃N ₇O ₃: C, 53.51; H, 3.42; N, 20.80. Found: C, 53.55; H, 3.41; N, 20.84. [0087] In an embodiment, synthesis of 2-methoxy-5-((2-(8-((4- (trifluoromethoxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-4-yl )hydrazineylidene)methyl)phenol (compound 7h) was performed. Compound 7h (0.20 g, 0.43 mmol, 94%) was obtained, through method A, as an orange solid by reaction of pyrimidopyrimidine (compound 6b) (0.15 g, 0.46 mmol) with 3- hydroxy-4-methoxybenzaldehyde (0.08 g, 0.50 mmol), after 30 minutes of reaction in DMSO. Mp 262 °C, dec; IR (nujol mull) ʋ/cm ^-1: 3340, 3262, 1609, 1563, 1536, 1503; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.32 (s, 1H, NH-8 exchangeable by D ₂O), 9.30 (s, <1H, OH exchangeable by D ₂O), 8.68 (s, 1H, H ₆), 8.62 (s, 1H, H ₂), 8.54 (s, 1H, H9), 8.10 (d, J = 8.8 Hz, 2H, Ho), 7.38 (d, J = 8.8 Hz, 2H, Hm), 7.36 (d, J = 2.0 Hz, 1H, Ho’’), 7.11 (dd, J = 8.4, 2.0 Hz, 1H, Ho’), 6.98 (d, J = 8.4 Hz, 1H, Hm’), 3.81 (s, 3H, OCH3); ¹³C NMR (100 MHz, DMSO-d6) ^: 156.4, 154.1, 153.6, 152.9, 150.5, 150.2, 146.9, 144.2, 137.6, 132.0, 131.8, 127.0, 120.20 (q, J = 254 Hz), 123.3, 121.4, 120.9, 112.8, 111.9, 55.6; MS (ESI) 472 [M+H] ⁺; Anal. Calcd. for C ₂₁H ₁₆F ₃N ₇O ₃: C, 53.51; H, 3.42; N, 20.80. Found: C, 53.54; H, 3.40; N, 20.77. [0088] In an embodiment, synthesis of 2-((2-(8-((4-(trifluoromethoxy)phenyl)amino)pyrimido[5,4- d]pyrimidin-4-yl)hydrazineylidene)methyl)phenol (compound 7j) was performed. Compound 7j (0.172 g, 0.389 mmol, 86%) was obtained, through method A, as a light orange solid by reaction of pyrimidopyrimidine (compound 6b) (0.15 g, 0.45 mmol) with salicylaldehyde (0.05 mL, 0.50 mmol), after 25 minutes of reaction in DMSO. Mp 208-210 °C; IR (nujol mull) ʋ/cm ^-1: 3339, 3230, 3100, 3073, 1609, 1576, 1540, 1511; ¹H NMR (400 MHz, DMSO-d6) ^: 12.3-12.0 (br s, <1H, OH exchangeable by D2O), 11.55 (s, 1H, NH-8 exchangeable by D2O), 11.32 (s, 1H, NH-4 exchangeable by D2O), 8.81 (s, 1H, H9), 8.73 (s, 1H, H ₂), 8.68 (s, 1H, H ₆), 8.12 (d, J = 9.2 Hz, 2H, H _o), 7.45 (d, J = 7.2 Hz, 1H, H _o’), 7.36 (d, J = 8.4 Hz, 2H, H _m), 7.31 (td, J = 8.4, 1.6 Hz, 1H, H _p’), 6.92 (ddd, J = 8.0, 1.6, 0.8 Hz, 1H, H _m’’), 6.90 (ta, J = 8.4, 7.2 Hz, 1H, H _m’); ¹³C NMR (100 MHz, DMSO-d6) ^: 157.7, 156.4, 154.8, 154.7, 154.0, 149.4, 144.1, 137.7, 131.4, 130.1, 120.21 (q, J = 254 Hz), 123.2, 121.3, 119.4, 118.7, 116.6; MS (ESI) 440 [M-H]-. Anal. Calcd. for C ₂₀H ₁₄F ₃N ₇O ₂: C, 54.43; H, 3.20; N, 22.21. Found: C, 54.40; H, 3.21; N, 22.25. [0089] In an embodiment, synthesis of 5-methoxy-2-((2-(8-((4- (trifluoromethoxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-4-yl )hydrazineylidene)methyl)phenol (compound 7k) was performed. Compound 7k (0.19 g, 0.40 mmol, 85%) was obtained, through method A, as an orange solid by reaction of pyrimidopyrimidine (compound 6b) (0.16 g, 0.47 mmol) with 2- hydroxy-4-methoxybenzaldehyde (0.08 g, 0.52 mmol), after 29 minutes of reaction in DMSO. Mp 225-228 °C; IR (nujol mull) ʋ/cm ^-1: 3361, 3296, 3237, 1630, 1606, 1569, 1538, 1509; ¹H NMR (400 MHz, DMSO-d6) ^: 12.2-11.8 (br s, <1H, OH exchangeable by D ₂O), 11.38 (s, 1H, NH-4 exchangeable by D ₂O), 10.28 (s, 1H, NH-8 exchangeable by D2O), 8.72 (s, 1H, H9), 8.70 (s, 1H, H2), 8.66 (s, 1H, H6), 8.11 (d, J = 9.2 Hz, 2H, Ho), 7.36 (d, J = 8.4 Hz, 2H, Hm), 7.36 (s, 1H, Hm’’), 6.50 (dd, J = 8.4, 2.4 Hz, 1H, Hm’), 6.46 (d, J = 8.4 Hz, 1H, Ho’), 3.76 (s, 3H, OCH ₃); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 162.1, 159.6, 156.4, 154.7, 153.9, 153.6, 149.8, 144.0, 137.7, 132.4, 131.6, 120.20 (q, J = 254 Hz), 123.1, 121.3, 111.9, 106.5, 101.3, 55.3. Anal. Calcd. for C ₂₁H ₁₆F ₃N ₇O ₃: C, 53.51; H, 3.42; N, 20.80. Found: C, 53.54; H, 3.40; N, 20.82. [0090] In an embodiment, synthesis of 4-chloro-2-((2-(8-((4- (trifluoromethoxy)phenyl)amino)pyrimido[5,4-d]pyrimidin-4-yl )hydrazineylidene)methyl)phenol (compound 7l) was performed. Compound 7l (0.19 g, 0.40 mmol, 88%) was obtained, through method A, as an orange solid by reaction of pyrimidopyrimidine (compound 6b) (0.15 g, 0.46 mmol) with 5-chloro-2- hydroxybenzaldehyde (0.08 g, 0.50 mmol), after 15 minutes of reaction in DMSO. Mp 203-204 °C; IR (nujol mull) ʋ/cm ^-1: 3354, 3255, 1624, 1606, 1576, 1538, 1510; ¹H NMR (400 MHz, DMSO-d6) ^: 13.0-12.0 (br s, <1H, OH exchangeable by D2O), 11.55 (s, 1H, NH-4 exchangeable by D2O), 10.35 (s, 1H, NH-8 exchangeable by D2O), 8.80 (s, 1H, H9), 8.74 (s, 1H, H2), 8.69 (s, 1H, H6), 8.14 (d, J = 9.2 Hz, 2H, Ho), 7.62 (s, 1H, Ho’’), 7.38 (d, J = 8.8 Hz, 2H, H _m), 7.30 (dd, J = 8.8, 2.8 Hz, 1H, H _p’), 6.94 (d, J = 8.8 Hz, 1H, H _m’); ¹³C NMR (100 MHz, DMSO-d6) ^: 156.5, 156.2, 154.7, 154.1, 147.0, 144.2, 137.7, 132.6, 131.4, 130.8, 128.0, 120.17 (q, J = 254 Hz), 123.2, 123.0, 121.3, 120.7, 111.4; MS (ESI) 474 [M-1]-. Anal. Calcd. for C ₂₀H ₁₃ClF ₃N ₇O ₂: C, 50.49; H, 2.75; N, 20.61. Found: C, 50.46; H, 2.74; N, 20.65. [0091] In an embodiment, synthesis of 4-((2-(8-((4-methoxyphenyl)amino)pyrimido[5,4-d]pyrimidin-4- yl)hydrazineylidene)methyl)benzene-1,2-diol (compound 7m) was performed. Compound 7m (0.27 g, 0.67 mmol, 99%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6c) (0.20 g, 0.67 mmol) with 1.1 equiv. of 3,4-dihydroxybenzaldehyde after 1h of reaction in DMSO. Mp 273-276 °C; IR (nujol mull) ʋ/cm ^-1: 3306, 3172, 1605, 1564, 1527, 1504; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.0 (s, 1H, NH exchangeable by D ₂O), 10.0-9.00 (bs, 2H, m,p-OH exchangeable by D ₂O), 8.58 (s, 1H, H6), 8.55 (s, 1H, H2), 8.39 (s, 1H, H9), 7.79 (d, 2H, J= 8.8 Hz, Ho), 6.94 (d, 2H, J= 8.8 Hz, Hm), 6.78 (s, 2H, Ho’), 3.76 (s, 3H, p-OCH3); ¹³C NMR (100 MHz, DMSO-d6) ^: 156.4, 156.2, 154.4, 153.1, 152.5, 151.2, 148.6, 145.9, 131.7 (2C), 131.2, 125.7, 123.7, 121.3, 115.7, 113.8, 113.5, 55.4. MS (ESI) 404 [M+1] ⁺. Anal. Calcd. for C ₂₀H ₁₇N ₇O ₃: C, 59.55; H, 4.25; N, 24.31. Found: C, 59.57; H, 4.26; N, 24.28. [0092] In an embodiment, synthesis of 5-((2-(8-((4-methoxyphenyl)amino)pyrimido[5,4-d]pyrimidin-4- yl)hydrazineylidene)methyl)benzene-1,2,3-triol (compound 7n) was performed. Compound 7n (0.32 g, 0.75 mmol, 99%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6c) (0.22 g, 0.75 mmol) with 1.1 equiv. of 3,4,5-trihydroxybenzaldehyde after 1h of reaction in DMSO. Mp 284-287 °C; IR (nujol mull) ʋ/cm ^-1: 3358, 3273, 3052, 1653, 1609, 1571, 1534, 1504; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.0 (s, 1H, NH exchangeable by D ₂O), 10.0-9.00 (bs, 3H, m,p- OH exchangeable by D2O), 8.58 (s, 1H, H6), 8.55 (s, 1H, H2), 8.39 (s, 1H, H9), 7.79 (d, 2H, J= 8.8 Hz, Ho), 6.94 (d, 2H, J= 8.8 Hz, Hm), 6.78 (s, 2H, Ho’), 3.76 (s, 3H, p-OCH ₃); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 156.5, 156.2, 154.4, 153.1, 152.5, 151.5, 146.3, 136.5, 131.7, 131.7, 124.5, 123.8, 113.9, 107.1, 55.4; MS (ESI) 420 [M+1] ⁺. Anal. Calcd. for C ₂₀H ₁₇N ₇O ₄: C, 57.28; H, 4.09; N, 23.38. Found: C, 57.31; H, 4.08; N, 23.42. [0093] In an embodiment, synthesis of 8-(2-(3,4-dimethoxybenzylidene)hydrazineyl)-N-(4- methoxyphenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7o) was performed. Compound 7o (0.27 g, 0.63 mmol, 99%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6c) (0.18 g, 0.64 mmol) with 1.2 equiv. of 3,4-dimethoxybenzaldehyde after 1h of reaction in DMSO. Mp 248-250 °C; IR (nujol mull) ʋ/cm ^-1: 3381, 3351, 3291, 3067, 1598, 1564, 1537, 1504; ¹H NMR (400 MHz, DMSO-d6) ^: 10.1 (s, 1H, NH exchangeable by D2O), 8.60 (s, 1H, H6), 8.60 (s, 1H, H2), 8.59 (s, 1H, H9), 7.82 (d, 2H, J= 8.8 Hz, Ho), 7.51 (d, 1H, J= 2.0 Hz, Ho’’), 7.26 (dd, 1H, J= 2.0, 8.4 Hz, Ho’), 7.03 (d, 2H, J= 8.8 Hz, Hm), 7.01 (d, 1H, J= 8.4 Hz, Hm’), 3.84 (s, 3H, p-OCH3), 3.79 (s, 3H, m- OCH3), 3.76 (s, 3H, p-OCH3); ¹³C NMR (100 MHz, DMSO-d6) ^: 156.3, 156.0, 154.2, 153.2, 152,6, 151.1, 150.4, 149.1, 131,7, 131.6, 131.1, 126.9, 123.6, 122.4, 113.7, 111.5, 108.7, 55.6, 55.6, 55.3; MS (ESI) 432 [M+1] ⁺. Anal. Calcd. for C ₂₂H ₂₁N ₇O ₃: C, 61.24; H, 4.91; N, 22.73. Found: C, 61.27; H, 4.90; N, 22.76. [0094] In an embodiment, synthesis of 4-((2-(8-((3-methoxyphenyl)amino)pyrimido[5,4-d]pyrimidin-4- yl)hydrazineylidene)methyl)benzene-1,2-diol (compound 7p) was performed. Compound 7p (0.28 g, 0.67 mmol, 99%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6d) (0.20 g, 0.68 mmol) with 1.02 equiv. of 3,4-dihydroxybenzaldehyde after 1h and 20 minutes of reaction in DMSO. Mp 280 (Dec.) °C; IR (nujol mull) ʋ/cm ^-1: 3314, 3045, 1605, 1568, 1534; ¹H NMR (400 MHz, DMSO-d6) ^: 10.1 (s, 1H, NH exchangeable by D2O), 10.0-9.00 (br s, 2H, m,p-OH exchangeable by D ₂O), 8.71 (s, 1H, H2), 8.58 (s, 1H, H6), 8.54 (s, 1H, H9), 7.68 (t, 1H, J= 2.4 Hz, Ho’), 7.60 (dd, 1H, J= 2.4, 8.0 Hz, Ho), 7.35 (d, 1H, J= 2.0, Ho’’’), 7.29 (t, 1H, J= 8.0 Hz, Hm), 7.04 (dd, 1H, J= 2.0, 8.4 Hz, Ho’’), 6.81 (d, 1H, J= 8.4 Hz, Hm’’), 6.73 (dd, 1H, J= 2.4, 8.0 Hz, Hp), 3.77 (s, 3H, m-OCH ₃); ¹³C NMR (100 MHz, DMSO-d6) ^: 159.4, 156.3, 154.3, 152.5, 151.8, 151.4, 145.8, 148.7, 139.3, 132.0, 131.4, 129.3, 129.3, 115.6, 114.0, 113.5, 109.5, 107.7, 55.1; MS (ESI) 404 [M+1] ⁺. Anal. Calcd. for C ₂₀H ₁₇N ₇O ₃: C, 59.55; H, 4.25; N, 24.31. Found: C, 59.58; H, 4.24; N, 24.35. [0095] In an embodiment, synthesis of 5-((2-(8-((3-methoxyphenyl)amino)pyrimido[5,4-d]pyrimidin-4- yl)hydrazineylidene)methyl)benzene-1,2,3-triol (compound 7q) was performed. Compound 7q (0.20 g, 0.48 mmol, 99%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6d) (0.14 g, 0.48 mmol) with 1.1 equiv. of 3,4,5-trihydroxybenzaldehyde after 1h of reaction in DMSO. Mp 270-272 °C; IR (nujol mull) ʋ/cm ^-1: 3336, 3052, 1653, 1598, 1568, 1530; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.1 (s, 1H, NH exchangeable by D ₂O), 10.0-9.00 (bs, 3H, m,p-OH exchangeable by D ₂O), 8.71 (s, 1H, H2), 8.57 (s, 1H, H6), 8.46 (s, 1H, H9), 7.67 (t, 1H, J= 2.4 Hz, Ho’), 7.59 (dd, 1H, J= 2.4, 8.0 Hz, Ho), 7.29 (t, 1H, J= 8.0 Hz, Hm), 6.82 (s, 2H, Ho’’), 6.73 (dd, 1H, J= 2.4, 8.0 Hz, Hp), 3.77 (s, 3H, m-OCH ₃); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 159.5, 156.4, 154.5, 152.4 (2C), 151.2, 146.3, 139.8, 139.4, 132.0, 131.5, 129.4, 124.1, 114.0, 109.6, 107.8, 107.2, 55.2 ; MS (ESI) 420 [M+1] ⁺. Anal. Calcd. for C ₂₀H ₁₇N ₇O ₄: C, 57.28; H, 4.09; N, 23.38. Found: C, 57.32; H, 4.08; N, 23.34. [0096] In an embodiment, synthesis of 8-(2-(3,4-dimethoxybenzylidene)hydrazineyl)-N-(3- methoxyphenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7r) was performed. Compound 7r (0.15 g, 0.35 mmol, 61%) was obtained, through method B, after addition of acetonitrile to the reaction mixture, as a yellow solid, by reaction of pyrimidopyrimidine (compound 5d) (0.16 g, 0.57 mmol) with 1.02 equiv. of 3,4-dimethoxybenzaldehyde after 35 minutes of reaction in DMSO. Mp 221 - 223 °C; IR (nujol mull) ʋ/cm ^-1: 3351, 3306, 3097, 1601, 1568, 1538, 1512; ¹H NMR (400 MHz, DMSO-d6) ^: 11.8 (br s, 1H, NH exchangeable by D2O), 9,99 (s, 1H, NH exchangeable by D2O), 8,70 (s, 1H, H2), 8,58 (s, 1H, H6), 8,54 (s, 1H, H9), 7,73 (s, 1H, Ho’), 7,64 (d, 1H, J= 8,0 Hz, Ho), 7,39 (s, 1H, Ho’’’), 7,28 (t, 1H, J= 8,0 Hz, Hm), 7,20 (d, 1H, 8,4 Hz, Ho’’), 7,03 (d, 1H, J= 8,4 Hz, Hm’’), 6,69 (dd, 1H, J= 2,4; 8,0 Hz, Hp), 3,84 (s, 3H, p-OCH ₃), 3,80 (s, 3H, m-OCH ₃), 3,77 (s, 3H, m-OCH ₃); ¹³C NMR (100 MHz, DMSO-d6) ^: 159.5, 156.4, 155.1, 154.9, 153.9, 150.0, 139.6, 149.1, 148.9, 132.0, 129.3, 113.7, 127.1, 122.0, 109.2, 111.5, 107.5 (2C), 55.1, 13.5, 55.61, 55.55. MS (ESI) 432 [M+1] ⁺. Anal. Calcd. for C ₂₂H ₂₁N ₇O ₃: C, 61.24; H, 4.91; N, 22.73. Found: C, 61.30; H, 4291; N, 22.81. [0097] In an embodiment, synthesis of N-(3-chlorophenyl)-8-(2-(4- fluorobenzylidene)hydrazineyl)pyrimido[5,4-d]pyrimidin-4-ami ne (compound 7s) was performed. Compound 7s (0.23 g, 0.59 mmol, 95%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6e) (0.18 g, 0.62 mmol) with 1.2 equiv. of 4- fluorobenzaldehyde after 1h of reaction in DMSO. Mp 250-255 °C; IR (nujol mull) ʋ/cm ^-1: 3381, 3347, 3046, 1639, 1594, 1566, 1539; ¹H NMR (400 MHz, DMSO-d ₆) ^: 13.0-11.0 (br s, 1H, NH exchangeable by D ₂O), 10.2 (s, 1H, NH exchangeable by D ₂O), 8.73 (s, 1H, H6), 8.66 (s, 2H, H2; H9), 8.29 (t, 1H, J= 2.0 Hz, Ho’), 7.95 (dd, 1H, J= 2.0, 8.0 Hz, Ho), 7.81 (dd, 2H, J= 5.6, 8.4 Hz Ho’’), 7.39 (t, 1H, J= 8.0 Hz, Hm), 7.30 (dd, 2H, J= 5.6, 8.4 Hz, Hm’’), 7.16 (dd, 1H, J= 2.0, 8.0 Hz, Hp); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 164.4 (d, J = 246 Hz), 156.4, 154.8, 155.4, 153.9, 148.1, 140.1, 132.8, 132.2 (2C), 131.0 (d, J = 2.7 Hz), 130.1, 129.4 (d, J = 8 Hz), 123.4, 120.8, 119.9, 116.1 (d, CH, J = 22 Hz). Anal. Calcd. for C ₁₉H ₁₃ClFN ₇: C, 57.95; H, 3.33; N, 24.90. Found: C, 57.83; H, 3.31; N, 24.78. [0098] In an embodiment, synthesis of N-(3-chlorophenyl)-8-(2-(3- fluorobenzylidene)hydrazineyl)pyrimido[5,4-d]pyrimidin-4-ami ne (compound 7t) was performed. Compound 7t (0.11 g, 0.28 mmol, 52%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6e) (0.16 g, 0.54 mmol) with 1.5 equiv. of 3- fluorobenzaldehyde after 1h of reaction in DMSO. Mp 256-260 °C; IR (nujol mull) ʋ/cm ^-1: 3308, 3252, 3068, 1600, 1550, 1527; ¹H NMR (400 MHz, DMSO-d6) ^: 12.1 (s, 1H, NH exchangeable by D2O), 10.3 (s, 1H, NH exchangeable by D2O), 8.74 (s, 1H, H6), 8.69 (s, 1H, H2), 8.64 (s, 1H, H9), 8.27 (s, 1H, Ho’), 7.94 (d, 1H, J= 8.0 Hz, Ho), 7.6-7.4 (m, 3H, Ho’’’; Hm’’; Ho’’), 7.39 (t, 1H, J= 8.0 Hz, Hm), 7.26 (td, 1H, Hp’), 7.15 (dd, 1H, J= 2.0, 8.0 Hz, Hp); ¹³C NMR (100 MHz, DMSO-d6) ^: 163.7 (d, J = 420 Hz), 156.4, 155.3, 154.9, 154.1, 147.3, 140.1, 137.1 (d, J = 8 Hz), 132.9, 131.1 (2C), 131.0 (d, CH, J = 8 Hz), 130.2, 123.5, 120.9, 120.0, 117.0 (d, J = 22 Hz), 113.0 (d, J = 22 Hz), 123.8. Anal. Calcd. for C ₁₉H ₁₃ClFN ₇: C, 57.95; H, 3.33; N, 24.90. Found: C, 57.87; H, 3.31; N, 24.79. [0099] In an embodiment, synthesis of 4-((2-(8-((3-chlorophenyl)amino)pyrimido[5,4-d]pyrimidin-4- yl)hydrazineylidene)methyl) benzene-1,2-diol (compound 7u) was performed. Compound 7u (0.23 g, 0.56 mmol, 77%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a yellow solid, by reaction of pyrimidopyrimidine (compound 5e) (0.21 g, 0.72 mmol) with 1.5 equiv. of 3,4- dihydroxybenzaldehyde after 30 minutes of reaction in DMSO. Mp 295-300 °C; IR (nujol mull) ʋ/cm ^-1: 3353, 3263, 3062, 1594, 1561, 1533; ¹H NMR (400 MHz, DMSO-d6) ^: 11.7 (br. s, 1H, NH exchangeable by D ₂O), 10.2 (br. s, 1H, NH exchangeable by D ₂O) , 10.0 – 8.90 (br. s, 2H, m,p-OH exchangeable by D ₂O), 8.72 (s, 1H, H6), 8.67 (s, 1H, H2), 8.29 (s, 1H, Ho’), 8.49 (s, 1H, H9), 7.95 (d, J = 8.4 Hz, 1H, Ho), 7.39 (t, J = 8.4 Hz, 1H, Hm), 7.29 (d, J = 2.0, 1H, Ho’’’), 7.16 (d, J = 8.4 Hz, 1H, Hp), 6.95 (d, J = 8.0 Hz, 1H, Ho’’), 6.79 (d, J = 8.0 Hz, 1H, Hm’’); ¹³C NMR (100 MHz, DMSO-d ₆) ^:156.4, 155.1, 155.0, 153.7, 149.5, 148.1, 145.8, 140.1, 132.9, 132.4, 130.2, 123.4, 125.8, 120.9, 120.8, 119.9, 115.7, 112.9; Anal. Calcd. for C ₁₉H ₁₄ClN ₇O ₂: C, 55.96; H, 3.46; N, 24.04. Found: C, 56.03; H, 3.43; N, 24.21. [00100] In an embodiment, synthesis of 5-((2-(8-((3-chlorophenyl)amino)pyrimido[5,4-d]pyrimidin-4- yl)hydrazineylidene)methyl) benzene-1,2,3-triol (compound 7v) was performed. Compound 7v (0.24 g, 0.56 mmol, 88%) was obtained, through method A, as a bright orange solid by reaction of pyrimidopyrimidine (compound 6e) (0.18 g, 0.64 mmol) with 1.05 equiv. of 3,5,5-trihydroxybenzaldehyde after 30 minutes of reaction in DMSO. Mp 280 °C (Dec.); IR (nujol mull)ʋ/cm ^-1: 3353, 3263, 3062, 1594, 1561, 1533; ¹H NMR (400 MHz, DMSO-d ₆) ^: 0.2 (br. s, 1H, NH exchangeable by D ₂O),8.70 (s, 1H, H6), 8.59 (s, 1H, H2), 8.40 (s, 1H, H9), 8.24 (t, 1H, J = 2.0 Hz, Ho’), 7.91 (dd, 1H, J = 2.0; 8.4 Hz, Ho), 7.38 (t, 1H, J = 8.4 Hz, Hm), 7.15 (d, 1H, J = 2.0; 8.4 Hz, Hp), 6.77 (s, 2H, Ho’’); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 156.4, 155.1, 153.9, 153.6, 151.0, 146.3, 140.1, 136.4, 133.0, 132.0 (2C), 130.3, 124.6, 123.7, 121.0, 120.1, 106.9. Anal. Calcd. for C ₁₉H ₁₄ClN ₇O ₃: C, 53.85; H, 3.33; N, 23.13. Found: C, 53.73; H, 3.32; N, 23.25. [00101] In an embodiment, synthesis of N-(3-chlorophenyl)-8-(2-(pyridin-4- ylmethylene)hydrazineyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7x) was performed. Compound 7x (0.26 g, 0.68 mmol, 96%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a yellow solid, by reaction of pyrimidopyrimidine (compound 5e) (0.20 g, 0.71 mmol) with 1.5 equiv. of isonicotinaldehyde after 30 minutes of reaction. Mp 249-251 °C; IR (nujol mull) ʋ/cm ^-1: 3420, 3302, 3057, 1600, 1567, 1544; ¹H NMR (400 MHz, DMSO-d6) ^: 12.0-10.0 (sl, 1H, NH exchangeable by D2O), 10.0 (br. s, 1H, NH exchangeable by D2O), 8.73 (s, 1H, H6), 8.71 (br. s, 1H, H2), 8.65 (m, 3H, H9), 8.24 (t, J = 2.0 Hz, 1H, Ho’), 7.92 (dd, J = 2.0, 8.0 Hz, 1H, Ho), 7.39 (t, J = 8.0 Hz, 1H, Hm), 7.16 (dd, J = 2.0, 8.0 Hz, 1H, Hp), 8.65 (d, J = 4.8 Hz, 2H, Hm’’), 7.69 (d, J = 4.8 Hz, 2H, Ho’’); ¹³C NMR (100 MHz, DMSO-d6) ^: 156.2, 154.8 (2C), 153.8, 149.9, 146.6, 141.4, 139.7, 132.7, 132.3, 131.5, 129.8, 123.3, 120.8 (2 C), 119.7. Anal. Calcd. for C ₁₈H ₁₃ClN ₈: C, 57.38; H, 3.48; N, 29.74. Found: C, 57.41; H, 3.46; N, 29.81. [00102] In an embodiment, synthesis of N-(3-chlorophenyl)-8-(2-(3,4- dimethoxybenzylidene)hydrazineyl)pyrimido[5,4-d]pyrimidin-4- amine (compound 7z) was performed. Compound 7z (0.25 g, 0.59 mmol, 92%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a yellow solid, by reaction of pyrimidopyrimidine (compound 5e) (0.18 g, 0.63 mmol) with 1.5 equiv. of 3,4-dimethoxybenzaldehyde after 30 minutes of reaction. Mp 240-242 °C; IR (nujol mull) ʋ/cm ^-1: 3297, 3258, 3051, 1594, 1550, 1539; 1511; ¹H NMR (400 MHz, DMSO-d6) ^: 12.6 - 11,0 (br. s, 1H, NH exchangeable by D2O), 10.2 (br. s, 1H, NH exchangeable by D2O), 8.71 (s, 1H, H6), 8.66 (s, 1H, H2), 8.57 (s, 1H, H9), 8.28 (t, 1H, J = 2.0 Hz , Ho’), 7.94 (d, 1H, J = 8.4 Hz, Ho), 7.39 (t, 1H, J = 8.4 Hz, Hm), 7.41 (s, 1H, Ho’’’), 7.21 (d, 1H, J = 8.4 Hz, Ho’’), 7.16 (dd, 1H, J= 2.0, 8.4 Hz, Hp), 7.02 (d, 1H, J = 8.4 Hz, Hm’’), 3.83 (s, 3H, p-OCH ₃), 3.80 (s, 3H, m-OCH ₃); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 156.4, 155.0, 155.0, 153.9, 150.9, 149.5, 149.1, 140.1, 132.9, 132.3, 130.2, 131.4, 127.1, 123.4, 122.0, 120.8, 119.9, 111.5, 108.5, 55.6, 55.6. Anal. Calcd. for C ₂₁H ₁₈ClN ₇O ₂: C, 57.87; H, 4.16; N, 22.49. Found: C, 57.73; H, 4.15; N, 22.55. [00103] In an embodiment, synthesis of 8-(2-(4-chlorobenzylidene)hydrazineyl)-N-(3- chlorophenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7ab) was performed. Compound 7ab (0.21 g, 0.51 mmol, 77%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a yellow solid, by reaction of pyrimidopyrimidine (compound 5e) (0.19 g, 0.67 mmol) with 1.5 equiv. of 4- chlorobenzaldehyde after 30 minutes of reaction. Mp 288 -290 °C; IR (nujol mull) ʋ/cm ^-1: 3531, 3353, 3247, 3113, 1600, 1561, 1533; ¹H NMR (400 MHz, DMSO-d ₆) ^:12.0 (sl, 1H, NH exchangeable by D ₂O), 10.30 (s, 1H, NH exchangeable by D2O), 8.74 (s, 1H, H6), 8.73 (s, 1H, H2), 8.65 (s, 1H, H9), 8.29 (t, J = 2.0 Hz, 1H, Ho’), 7.95 (dd, J = 2.0, 8.0 Hz, 1H, Ho), 7.76 (d, J = 8.8 Hz, 2H, Ho’’), 7.51 (d, J = 8.8 Hz, 2H, Hm’’), 7.40 (t, J = 8.0 Hz, 1H, Hm), 7.16 (dd, J = 2.0, 8.0 Hz, 1H, Hp); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 156.5, 153.4, 155.0, 153.9, 147.3, 140.1, 134.6, 133.4, 132.9, 132.7, 131.2, 130.2, 129.0, 128.8, 123.5, 120.9, 120.1. Anal. Calcd. for C ₁₉H ₁₃Cl ₂N ₇: C, 55.63; H, 3.19; N, 23.90. Found: C, 55.71; H, 3.20; N, 23.78. [00104] In an embodiment, synthesis of 2-((2-(8-((4-chloro-3- (trifluoromethyl)phenyl)amino)pyrimido[5,4-d]pyrimidin-4-yl) hydrazineylidene)methyl)phenol (compound 7ac) was performed. Compound 7ac (0.17 g, 0.38 mmol, 86%) was obtained, through method A, as an orange solid by reaction of pyrimidopyrimidine (compound 6f) (0.16 g, 0.44 mmol) with salicylaldehyde (0.05 mL, 0.48 mmol), after 22 minutes of reaction in DMSO. Mp 260-261 °C; IR (nujol mull) ʋ/cm ^-1: 3338, 3311, 3116, 1617, 1600, 1564, 1537; ¹H NMR (400 MHz, DMSO-d6) ^ 12.39 (s, <1H, OH exchangeable by D2O), 11.54 (s, 1H, NH-4 exchangeable by D2O), 10.59 (s, 1H, NH-8 exchangeable by D2O), 8.78 (s, 1H, H9), 8.78-8.72 (br s, 1H, H2), 8.72 (s, 1H, H6), 8.64 (d, J = 2.4 Hz, 1H, Ho’), 8.33 (dd, J = 8.8, 2.4 Hz, 1H, H _o), 7.68 (d, J = 8,8 Hz, 1H, H _m), 7.46 (d, J = 8.0 Hz, 1H, H _o’’), 7.31 (td, J = 8.0, 2.0 Hz, 1H, H _p’’), 6.94- 6.90 (m, 2H, Hm’’’+m’’); ¹³C NMR (100 MHz, DMSO-d6) ^ 157.6, 156.4, 154.9, 153.8, 149.7, 138.1, 131.7, 131.5, 130.1, 126.67 (q, J = 31 Hz), 122.83 (q, J = 271 Hz), 126.2, 124.48 (q, J = 2 Hzp), 120.33 (q, J = 6 Hz), 119.4, 118.6, 115.6; MS (ESI) 458 [M-1]-; Anal. Calcd. for C ₂₀H ₁₃ClF ₃N ₇O: C, 52.24; H, 2.85; N, 21.32. Found: C, 52.33; H, 2.86; N, 21.41. [00105] In an embodiment, synthesis of 4-((2-(8-((4-chloro-3- (trifluoromethyl)phenyl)amino)pyrimido[5,4-d]pyrimidin-4-yl) hydrazineylidene)methyl)benzene-1,2-diol (compound 7ad) was performed. Compound 7ad (0.17 g, 0.39 mmol, 86%) was obtained, through method A, as an orange solid by reaction of pyrimidopyrimidine (compound 6f) (0.15 g, 0.43 mmol) with 3,4- dihydroxybenzaldehyde (0.07 g, 0.47 mmol), after 15 minutes of reaction in DMSO. Mp 250 °C (dec.); IR (nujol mull) ʋ/cm ^-1: 3444, 3344, 3100, 1652, 1599, 1573, 1538, 1504; ¹H NMR (400 MHz, DMSO-d ₆) ^: 10.56 (s, 1H, NH-8 exchangeable by D ₂O), 10.0-9.0 (br s, <2H, OH exchangeable by D ₂O), 8.76 (s, 1H, H ₆), 8.70 (d, J = 2.4 Hz, 1H, H _o’), 8.62 (s, 1H, H ₂), 8.52 (s, 1H, H ₉), 8.38 (dd, J = 8.8, 2.4 Hz, 1H, H _o), 7.73 (d, J = 8,8 Hz, 1H, Hm), 7.33 (d, J = 1.6 Hz, 1H, Ho’’’), 7.01 (dd, J = 8.0, 1.6 Hz, 1H, Ho’’), 6.80 (d, J = 8.0 Hz, 1H, Hm’’); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 156.3, 154.1, 153.2, 152.4, 151.5, 148.7, 145.8, 138.1, 132.4, 131.8, 131.7, 126.57 (q, J = 30 Hz), 122.85 (q, J = 271 Hz), 126.47 (q, J = 2 Hz), 126.3, 125.5, 121.3, 120.41 (q, J = 6 Hz’), 115.7, 113.5. Anal. Calcd. for C ₂₀H ₁₃ClF ₃N ₇O ₂: C, 50.49; H, 2.75; N, 20.61. Found: C, 50.54; H, 2.74; N, 20.57. [00106] In an embodiment, synthesis of 5-((2-(8-((3-chloro-4-fluorophenyl)amino)pyrimido[5,4- d]pyrimidin-4-yl)hydrazineylidene) methyl)benzene-1,2,3-triol (compound 7aj) was performed. Compound 7aj (0.19 g, 0.42 mmol, 86%) was obtained, through method A, as a reddish orange solid by reaction of pyrimidopyrimidine (compound 6g) (0.15 g, 0.49 mmol) with 3,4,5-trihydroxybenzaldehyde mono hydrate (0.09 g, 0.54 mmol), after 40 minutes of reaction in DMSO. Mp 203 °C, dec; IR (nujol mull) ʋ/cm ^-1: 3374, 1655, 1629, 1611, 1568, 1533, 1500; ¹H NMR (400 MHz, DMSO-d6) ^: 10.43 (s, 1H, NH-8 exchangeable by D2O), 9.2-8.7 (br s, <2H, OH exchangeable by D2O), 8.74 (s, 1H, H6), 8.57 (s, 1H, H2), 8.47 (s, 1H, H ₉), 8.32 (dd, J = 6.8, 2.8 Hz, 1H, H _o’), 7.93 (ddd, J = 9.2, 4.4, 2.8 Hz, 1H, H _o), 7.44 (t, J = 9.2 Hz, 1H, Hm), 6.83 (s, 2H, Ho’’); ¹³C NMR (100 MHz, DMSO-d6) ^ 156.3, 153.77 (d, J = 243 Hz), 153.1, 154.6, 151.8, 150.3, 146.3, 137.0 _, 135.39 (d, J = 3 Hz), 132.5, 131.6, 123.5, 123.9, 122.53 (d, J = 7 Hz), 119.00 (d, J = 18 Hz), 116.74 (d, J = 22 Hz), 107.4; MS (ESI) 440 [M-1]-. Anal. Calcd. for C ₁₉H ₁₃ClFN ₇O ₃: C, 51.65; H, 2.97; N, 22.19. Found: C, 51.58; H, 2.98; N, 22.26. [00107] In an embodiment, synthesis of N-(3-((8-(2-(3,4-dihydroxybenzylidene)hydrazineyl)pyrimido[5 ,4- d]pyrimidin-4-yl)amino)phenyl)isonicotinamide (compound 7ao) was performed. Compound 7ao (0.15 g, 0.30 mmol, 76%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a yellow solid, by reaction of pyrimidopyrimidine (compound 5h) (0.15 g, 0.39 mmol) with 1.2 equiv. of 3,4- dihydroxybenzaldehyde after 20 minutes of reaction. Mp > 300 °C; IR (nujol mull) ʋ/cm ^-1: 3347, 3263, 3046, 1661, 1600, 1533; ¹H NMR (400 MHz, DMSO-d ₆) ^: 11.71 (br. s, 1H, NH exchangeable by D ₂O), 10.58 (s, 1H, NH exchangeable by D2O), 10.07 (s, 1H, NH exchangeable by D2O), 9.43 (br. s, 1H, OH exchangeable by D2O), 9.29 (br. s, 1H, OH exchangeable by D2O), 8.78 (d, J = 4.8 Hz, 2H, Hm’’), 8.67 (s, 1H, H2), 8.66 (s, 1H, H6), 8.50 (s, 1H, Ho’), 8.49 (s, 1H, H9), 7.87 (d, J = 4.8 Hz, 2H, Ho’’), 7.67 (dd, J = 2.0, 8.0 Hz, 1H, Ho), 7.53 (dd, J = 2.4, 8.0 Hz, 1H, Hp), 7.38 (t, J = 8.0 Hz, 1H, Hm), 7.29 (dd, J = 2.0, 8.4 Hz, 1H, Ho’’’), 6.94 (d, J = 2.0 Hz, 1H, Ho’’’’), 6.79 (d, J = 8.4 Hz, 1H, Hm’’’); ¹³C NMR (100 MHz, DMSO-d6) ^: 164.1, 156.5, 155.0, 155.0, 153.8, 150.3, 149.3, 148.1, 145.8, 141.9, 138.7, 138.6, 132.3, 131.1, 128.7, 125.8, 121.7, 120.7, 118.0, 116.5, 115.7, 114.3, 112.8; MS (ESI) 494 [M+1] ⁺. Anal. Calcd. for C ₂₅H ₁₉N ₉O ₃: C, 60.85; H, 3.88; N, 25.55. Found: C, 60.73; H, 3.89; N, 25.37. [00108] In an embodiment, synthesis of 2-(3-((8-(2-(3-chlorobenzylidene)hydrazineyl)pyrimido[5,4- d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (compound 7aq) was performed. Compound 7aq (0.22 g, 0.51 mmol, 83%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a pale orange solid, by reaction of pyrimidopyrimidine (compound 5i) (0.19 g, 0.62 mmol) with 1.5 equiv. of 3- chlorobenzaldehyde after 1h and 35 minutes of reaction. Mp 250-253 °C; IR (nujol mull) ʋ/cm ^-1: 3386, 3341, 3068, 1606, 1567, 1539; ¹H NMR (400 MHz, DMSO-d ₆) ^: 12.7-11.3 (br. s, 1H, NH exchangeable by D ₂O), 9.98 (br. s, 1H, NH exchangeable by D ₂O), 8.69 (s, 2H, H6; H2), 8.62 (s, 1H, H9), 7.83 (s, 1H, Ho’’’), 7.74 (t, J= 2.4 Hz, 1H, Ho’), 7.74 (t, J= 2.4 Hz, 1H, Ho’), 7.58 (dd, J= 2.4, 8.4 Hz,1H, Ho), 7.48 (m, 2H, Hm’’; Hp’), 7.26 (t, J= 8.4 Hz, 1H, Hm), 6.70 (dd, J= 2.4, 8.0 Hz, 1H, Hp), 4.92 (br s, 1H, OH exchangeable by D2O), 3.99 (t, J= 4.8 Hz, 2H, H10), 3.73 (s, 2H, H11); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 158.9, 156.4, 155.1, 154.8, 154.2, 147.2, 139.6, 136.7, 133.7, 132.4 (2C), 130.8, 129.8, 129.4, 126.2, 126.1, 113.7, 109.7, 108.0, 69.5, 59.6. Anal. Calcd. for C ₂₁H ₁₈ClN ₇O ₂: C, 57.87; H, 4.16; N, 22.49. Found: C, 57.73; H, 4.15; N, 22.53. [00109] In an embodiment, synthesis of 2-(3-((8-(2-(4-chlorobenzylidene)hydrazineyl)pyrimido[5,4- d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (compound 7ar) was performed. Compound 7ar (0.09 g, 0.20 mmol, 73%) was obtained, through method B, after addition of water and acetonitrile to reaction mixture, as a pale-yellow solid, by reaction of pyrimidopyrimidine (compound 5i) (0.09 g, 0.28 mmol) with 1.5 equiv. of 4-chlorobenzaldehyde after 1h and 5 minutes of reaction. Mp 239-242 °C; IR (nujol mull) ʋ/cm- ¹: 3358, 3302, 3219, 3057, 1600, 1572, 1539; ¹H NMR (400 MHz, DMSO-d6) ^: 12.0 (br. s, 1H, NH exchangeable by D2O), 9.99 (bs, 1H, NH exchangeable by D2O), 8.68 (s, 2H, H2; H6), 8.62 (s, 1H, H9), 7.77 (d, J= 8.8 Hz, 2H, Ho’’), 7.73 (s, 1H, Ho’), 7.57 (d, J= 8.4 Hz, 1H, Ho), 7.51 (d, J= 8.8 Hz, 2H, Hm’’), 7.26 (t, J= 8.4 Hz, 1H, Hm), 6.69 (dd, J= 2.0, 8.4 Hz, 1H, Hp), 4.93 (br. s, 1H, OH exchangeable by D ₂O), 3.99 (t, J= 4.8 Hz, 2H, H10), 3.73 (q, J= 4.8 Hz, 2H, H11); ¹³C NMR (100 MHz, DMSO) ^: 158.9, 156.4, 155.3, 154.9, 154.2, 147.3, 139.6, 134.6, 133.4, 132,7, 131.0, 129.4, 129.0, 128.9, 113.8, 109.8, 108.0, 64.6, 59.7. Anal. Calcd. for C ₂₁H ₁₈ClN ₇O ₂: C, 57.87; H, 4.16; N, 22.49. Found: C, 57.75; H, 4.17; N, 22.65. [00110] In an embodiment, synthesis of 2-(3-((8-(2-(3-fluorobenzylidene)hydrazineyl)pyrimido[5,4- d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (compound 7as) was performed. Compound 7as(0.16 g, 0.39 mmol, 70%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as yellow solid, by reaction of pyrimidopyrimidine (compound 5i) (0.18 g, 0.56 mmol) with 1.5 equiv. of 3- fluorobenzaldehyde after 40 minutes of reaction. Mp 252 -253 °C; IR (nujol mull) ʋ/cm ^-1: 3375, 3336, 3280, 3230, 1600, 1583, 1567, 1539; ¹H NMR (400 MHz, DMSO-d ₆) ^: 12.0 (br. s, 1H, NH exchangeable by D ₂O), 9.99 (br. s, 1H, NH exchangeable by D ₂O), 8.69 (br. s, 2H, H6, H2), 8.66 (s, 1H, H9), 7.76 (t, J = 2.0 Hz, 1H,Ho’), 7.61-7.47 (m, 4H, Ho, Ho’’’, Hm’’, Ho’’), 7.26 (m, 2H, Hm, Hp’), 6.69 (dd, J = 2.0, 8.0 Hz, 1H, Hp), 4.88 (s, 1H, OH exchangeable by D2O), 3.99 (t, J = 4.8 Hz, 2H, H10), 3.74 (q, J = 4.8 Hz, 2H, H11); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 162.4 (d, J = 240 Hz), 158.8, 156.3, 154.9 (2C), 154.8, 154.1, 147.4, 139.5, 137.1 (d, J = 10 Hz), 132.0 (2C), 131.0 (d, CH, J = 10 Hz), 129.2, 123.7, 116.8 (d, CH, J = 20 Hz), 113.7, 112.8 (d, J = 20 Hz), 109.7, 107.9, 69.5, 59.6. Anal. Calcd. for C ₂₁H ₁₈FN ₇O ₂: C, 60.14; H, 4.33; N, 23.38. Found: C, 60.31; H, 4.34; N, 23.23. [00111] In an embodiment, synthesis of 2-(3-((8-(2-(4-bromobenzylidene)hydrazineyl)pyrimido[5,4- d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (compound 7at) was performed. Compound 7at (0.18 g, 0.38 mmol, 77%) was obtained, through method B, after addition of water and acetonitrile to reaction mixture, as a pale-yellow solid, by reaction of pyrimidopyrimidine (compound 5i) (0.15 g, 0.49 mmol) with 1.5 equiv. of 4-bromobenzaldehyde after 1h of reaction. Mp 247-251 °C; IR (nujol mull) ʋ/cm ^-1: 3358, 3302, 3224, 3057, 1594, 1572, 1539; ¹H NMR (400 MHz, DMSO-d6) ^: 11.9 (br. s, 1H, NH exchangeable by D2O), 9.99 (br. s, 1H, NH exchangeable by D ₂O), 8.70 (s, 1H, H2), 8.67 (s, 1H, H6), 8.59 (s, 1H, H9), 7.77 (d, J= 8.8 Hz, 2H, Ho’’), 7.74 (s, 1H, Ho’), 7.70-7.50 (m, 3H, Ho), 7.51 (d, J= 8.8 Hz, 2H, Hm’’), 7.25 (t, J= 8.0 Hz, 1H, Hm), 6.69 (dd, J= 2.0, 8.0 Hz, 1H, Hp), 4.93 (br. s, 1H, OH exchangeable by D ₂O), 3.99 (t, J= 4.8 Hz, 2H, H10), 3.73 (s, 2H, H11); ¹³C NMR (100 MHz, DMSO-d6) ^: 158.9, 156.4, 155.3, 154.9, 154.1, 147.3, 139.6, 133.8, 133.8, 131.9, 130.9, 129.4, 129.0, 123.4, 113.7, 109.7, 107.9, 69.5, 59.7. Anal. Calcd. for C ₂₁H ₁₈BrN ₇O ₂: C, 52.51; H, 3.78; N, 20.41. Found: C, 52.47; H, 3.77; N, 20.52. [00112] In an embodiment, synthesis of 2-(3-((8-(2-(pyridin-3-ylmethylene)hydrazineyl)pyrimido[5,4- d]pyrimidin-4-yl)amino)phenoxy)ethan-1-ol (compound 7au) was performed. Compound 7au (0.16 g, 0.47 mmol, 59%) was obtained, through method B, after addition of water and acetonitrile to reaction mixture, as a yellow solid, by reaction of pyrimidopyrimidine (compound 5i) (0.22 g, 0.69 mmol) with 1.5 equiv. of nicotinaldehyde after 1h and 20 minutes of reaction. Mp 243 - 245 °C; IR (nujol mull) ʋ/cm ^-1: 3308, 3168, 3046, 1600, 1567, 1539; ¹H NMR (400 MHz, DMSO-d ₆) ^: 12.10 (br. s, 1H, NH exchangeable by D ₂O), 10.01 (s, 1H, NH exchangeable by D ₂O), 8.87 (s, 1H, Ho’’’), 8.69 (s, 3H, H2, H6, H9), 7.74 (s, 1H, Ho’), 8.60 (dd, J = 1.6, 4.8 Hz, 1H,Hp’), 8.17 (d, J = 4.8 Hz, 1H, Ho’’), 7.58 (d, J = 8.0 Hz, 1H, Ho), 7.48 (dd, J = 4.8, 8.0 Hz, 1H, Hm’’), 7.26 (t, J = 8.0 Hz, 1H, Hm), 6.69 (dd, J = 2.0, 8.0 Hz, 1H, Hp), 4.92 (t, J = 5.2 Hz; 1H, OH exchangeable by D2O), 3.99 (t, J = 4.8 Hz, 2H, H10), 3.73 (q, J = 4.8. 5.2 Hz, 2H, H11); ¹³C NMR (100 MHz, DMSO-d6) ^:156.3, 155.3, 154.8, 154.2, 150.7, 148.7, 145.7, 133.6, 132.7, 130.9, 130.4, 158.8, 139.5, 129.3, 124.1, 113.7 109.7, 107.9, 64.51, 59.61. Anal. Calcd. for C ₂₀H ₁₈N ₈O ₂: C, 59.69; H, 4.51; N, 27.85. Found: C, 59.74; H, 4.50; N, 27.78. [00113] In an embodiment, synthesis of 8-(2-benzylidenehydrazineyl)-N-(3-(2- morpholinoethoxy)phenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7av) was performed. Compound 7av (0.07 g, 0.14 mmol, 54%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a pale-yellow solid by reaction of pyrimidopyrimidine (compound 5j) (0.10 g, 0.26 mmol) with 1.5 equiv. of benzaldehyde after 1h and 40 minutes of reaction in DMSO. Mp 140-143 °C; IR (nujol mull) ʋ/cm ^-1: 3353, 3313, 3068, 1628, 1606, 1583, 1572, 1539; ¹H NMR (400 MHz, DMSO-d6) ^: 11.9 (br. s, 1H, NH exchangeable by D2O), 10.0 (br. s, 1H, NH exchangeable by D2O), 8.70 (s, 2H, H2; H6), 8.68 (s, 1H, H9), 7.75 (m, 2H, Ho’; Ho’’), 7.61 (d, J= 8.4 Hz, 1H, Ho), 7.47 (m, 2H, Hm’’; Hp), 7.27 (t, J= 8.4 Hz, 1H, Hm), 6.71 (dd, J= 2.0, 8.4 Hz, 1H, Hp), 4.09 (t, J= 5.6 Hz, 2H, H10), 3.56 (t, J= 4.4 Hz, 4H, H13), 2.69 (t, J= 5.6 Hz, 2H, H11), 2.46 (t, J= 5.6 Hz, 4H, H12); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 158.9, 156.4, 155.3, 154.9, 154.0, 148.6, 139.6, 134.4, 132.6, 130.1, 129.3, 128,9, 127.3, 127.2, 113.8, 109.8, 107.9, 66.2, 65.3, 57.0, 53.7; MS (ESI) 471 [M+1] ⁺. Anal. Calcd. for C ₂₅H ₂₆N ₈O ₂: C, 63.82; H, 5.57; N, 23.81. Found: C, 63.76; H, 5.55; N, 23.93. [00114] In an embodiment, synthesis of 8-(2-(3-chlorobenzylidene)hydrazineyl)-N-(3-(2- morpholinoethoxy) phenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7ax) was performed. Compound 7ax (0.10 g, 0.19 mmol, 80%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a pale-yellow solid by reaction of pyrimidopyrimidine (compound 5j) (0.09 g, 0.24 mmol) with 1.5 equiv. of 3-chlorobenzaldehyde after 1h of reaction. Mp 150-154 °C; IR (nujol mull) ʋ/cm- ¹: 3341, 3302, 3185, 1057, 1606, 1583, 1572, 1539; ¹H NMR (400 MHz, DMSO-d ₆) ^: 12.1 (br. s, 1H, NH exchangeable by D2O), 10.0 (br. s, 1H, NH exchangeable by D2O), 8.75 (s, 1H, H2), 8.72 (s, 1H, H6), 8.66 (s, 1H, H9), 7,80 (s, 1H, Ho’’’) 7,75 (t, J= 2,0 Hz, 1H, Ho’) 7,68 (s, 1H, Ho’’) 7,64 (d, J= 8,0 Hz, 1H, Ho) 7,50 (m, 2H, Hp’, Hm’’), 7,27 (t, J= 8,0 Hz, 1H, Hm) 6,71 (dd, J= 2,0; 8,0 Hz, 1H, Hp) 4,09 (t, J= 5,6 Hz, 2H, H10) 3,58 (t, J= 4,4 Hz, 4H, H13) 2,70 (t, J= 5,6 Hz, 2H, H11) 2,47 (t, J= 4,4 Hz, 4H, H12); ¹³C NMR (100 MHz, DMSO- d6) ^: 158.6, 156.4, 155.4, 154.8, 154.1, 146.8, 139.6, 136.7, 133.7, 132.7, 130.9, 129.3, 126.1, 126.0, 113.8, 109.8, 107.9, 66.2, 65.3, 57.0, 53.7; MS (ESI) 505 [M+1] ⁺. Anal. Calcd. for C ₂₅H ₂₅ClN ₈O ₂: C, 59.46; H, 4.99; N, 22.19. Found: C, 59.58; H, 4.98; N, 22.25. [00115] In an embodiment, synthesis of 8-(2-(4-chlorobenzylidene)hydrazineyl)-N-(3-(2- morpholinoethoxy)phenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7az) was performed. Compound 7az (0.07 g, 0.13 mmol, 54%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a pale-yellow solid by reaction of pyrimidopyrimidine (compound 5j) (0.09 g, 0.24 mmol) with 1.5 equiv. of 4-chlorobenzaldehyde after 2h of reaction. Mp 180-184 °C; IR (nujol mull) ʋ/cm- ¹: 3392, 3358, 3336, 3062, 1600, 1572, 1544; ¹H NMR (400 MHz, DMSO-d ₆) ^: 12.0 (br. s, 1H, NH exchangeable by D2O), 9.99 (br. s, 1H, NH exchangeable by D2O), 8.69 (br. s, 2H, H2; H6), 8.65 (s, 1H, H9), 7,78 (d, J= 8,8 Hz, 2H, Ho’’) 7,74 (s, 1H, Ho’) 7,61 (d, J= 8,0 Hz, 1H, Ho) 7,52 (d, J= 8,8 Hz, 2H, Hm’’) 7,52 (d, J= 8,8 Hz, 2H, Hm’’); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 158.6, 156.3, 155.3, 154.7, 154.1, 147.2, 139.6, 134.5, 134.4, 132.6, 131.2, 129.3, 129.0, 128.8, 113.8, 109.8, 107.9, 66.2, 65.3, 57.0, 53.7; MS (ESI) 505 [M+1] ⁺. Anal. Calcd. for C ₂₅H ₂₅ClN ₈O ₂: C, 59.46; H, 4.99; N, 22.19. Found: C, 59.53; H, 5.00; N, 22.26. [00116] In an embodiment, synthesis of 8-(2-(3-chlorobenzylidene)hydrazineyl)-N-(3-(2- thiomorpholinoethoxy)phenyl)pyrimido[5,4-d]pyrimidin-4-amine (compound 7ba) was performed. Compound 7ba (0.19 g, 0.36 mmol, 87%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a pale-yellow solid by reaction of pyrimidopyrimidine (compound 5k) (0.16 g, 0.41 mmol) with 1.5 equiv. of 3-chlorobenzaldehyde after 1h of reaction . Mp 143-145 °C; IR (nujol mull) ʋ/cm- ¹: 3336, 3258, 3057, 1600, 1567, 1544; ¹H NMR (400 MHz, DMSO-d6) ^: 11.9 (br. s, 1H, NH exchangeable by D2O), 9.99 (br. s, 1H, NH exchangeable by D2O), 8.69 (br. s, 2H, H2; H6), 8.65 (s, 1H, H9), 7.83 (s, 1H, Ho’’’), 7.74 (t, J= 2.0 Hz, 1H, Ho’), 7.69 (s, 1H, Ho’’), 7.62 (d, J= 8.0 Hz, 1H, Ho), 7.49 (m, 2H, Hp’; Hm’’), 7.27 (t, J= 8.0 Hz 1H, Hm), 6.71 (dd, J= 2.0, 8.0 Hz, 1H, Hp), 4.08 (t, J= 5.6 Hz, 2H, H10), 2.76 (m, 6H, H11; H12), 2.60 (t, J= 4.8 Hz, 4H, H13); ¹³C NMR (100 MHz, DMSO-d6) ^: 158.6, 156.3, 154.8 (2C), 154.1, 147.0, 139.6, 136.7, 133.7, 132.4, 131.2, 130.8, 129.7, 129.3, 126.1, 126.0, 113.8, 109.8, 107.9, 65.3, 57.2, 54.8, 27.2; MS (ESI) 521 [M+1] ⁺. Anal. Calcd. for C ₂₅H ₂₅ClN ₈OS: C, 57.63; H, 4.84; N, 21.51; S, 6.15. Found: C, 57.67; H, 4.83; N, 21.51; S, 6.32. [00117] In an embodiment, synthesis of ethyl 4-(2-(3-((8-(2-(3- chlorobenzylidene)hydrazineyl)pyrimido[5,4-d]pyrimidin-4-yl) amino)phenoxy)ethyl)piperazine-1- carboxylate (compound 7bb) was performed. Compound 7bb (0.08 g, 0.14 mmol, 60%) was obtained, through method B, after addition of acetonitrile to reaction mixture, as a pale-yellow solid by reaction of pyrimidopyrimidine (compound 5l) (0.12 g, 0.23 mmol) with 1.5 equiv. of 3-chlorobenzaldehyde after 40 minutes of reaction. Mp 224-226 °C; IR (nujol mull) ʋ/cm ^-1: 3509, 3353, 3330, 3057, 1678, 1600, 1567, 1538; ¹H NMR (400 MHz, DMSO-d ₆) ^: 12.1 (br. s, 1H, NH exchangeable by D ₂O), 10.0 (br. s, 1H, NH exchangeable by D2O), 8.73 (s, 1H, H2), 8.69 (s, 1H, H6), 8.63 (s, 1H, H9), 7.80 (s, 1H, Ho’’’), 7.73 (s, 1H, Ho’), 7.68 (s, 1H, Ho’’), 7.61 (d, J= 8.0 Hz, 1H, Ho), 7.48 (m, 2H, Hp’; Hm’’), 7.26 (t, J= 8.0 Hz, 1H, Hm), 6.69 (dd, J= 2.0, 8.0 Hz, 1H, Hp), 4.09 (t, J= 5.6 Hz, 2H, H10), 4.01 (q, J= 7.2 Hz, 2H, OEt), 3.37 (t, J= 4.8 Hz, 4H, H13), 2.73 (t, J= 5.6 Hz, 2H, H11), 2.47 (t, J= 4.8 Hz, 4H, H12), 1.16 (t, J= 7.2 Hz, 3H, OEt); ¹³C NMR (100 MHz, DMSO-d ₆) ^: 158.6, 156.3, 155.4, 154.9, 154.1, 146.8, 139.6, 136.7, 133.7, 132.7, 130.9, 130.8, 129.7, 129.3, 126.1, 126.0, 113.8, 109.8, 107.9, 65.3, 60.7, 56.5, 52.8, 43.4, 14.6; MS (ESI) 576 [M+1] ⁺. Anal. Calcd. for C ₂₈H ₃₀ClN ₉O ₃: C, 58.38; H, 5.25; N, 21.88. Found: C, 58.47; H, 5.24; N, 21.76. [00118] The disclosure should not be seen in any way restricted to the embodiments described and a person with ordinary skill in the art will foresee many possibilities to modifications thereof. [00119] The above-described embodiments are combinable. [00120] The following claims further set out particular embodiments of the disclosure. [00121] References 1) Al-Azmi, A.; Booth, B.L.; Carpenter, R.A.; Carvalho, A.; Marrelec, E.; Pritchard, R. G.; Proença. M.F.J.R.P. Facile Synthesis of 6-Cyano-9-Substituted-9H-Purines and Their Ring Expansion to 8- (Arylamino)-4-Imino-3-Methylpyrimidino[5,4-d]Pyrimidines. J. Chem. Soc. Perkin Trans. 1 2001, 2532–2537. https://doi.org/10.1039/b106539b 2) Carvalho, M. A.; Esperança, S.; Esteves, T.; Proença, M. F. An Efficient Synthesis of 7,8- Dihydropyrimido[5,4-d]pyrimidines Eur. J. Org. Chem.2007, 1324–1331

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