WO2014113859A1 - 2-chloro-4-anilino-quinazoline compounds inhibiting protein tyrosine kinases, pharmaceutical compositions comprising the same, method for producing the same and tyrosine kinase inhibition method - Google Patents

Abstract

The present invention relates to 2-chloro-4-anilino-quinazoline derivatives with EGFR and/or VEGFR-2 protein tyrosine kinase inhibiting activity, to anti-tumour pharmaceutical compositions that comprise said compounds, and to methods for producing the same. The present invention further provides a method for treating solid tumours by inhibition of tyrosine kinases.

Description

 Patent Invention Descriptive Report

 2-CHLORINE-4-ANYLINE-QUINAZOLINIC COMPOUNDS PROTEIN TYROSINE KINASE INHIBITORS, PHARMACEUTICAL COMPOSITIONS UNDERSTANDING THE PROCESS FOR THEIR PRODUCTION AND

 METHOD FOR INHIBITING TYROSINE KINASES

Field of the Invention

 The present invention relates to 2-chloro-4-anilino-quinazoline derivatives which exhibit EGFR and / or VEGFR-2 protein tyrosine kinase inhibitory activity, anti-tumor pharmaceutical compositions comprising such compounds, and processes for their production. The present invention further provides a method of treating solid tumors due to the tyrosine kinase inhibiting property.

Background of the Invention

 Different cell signaling pathways are associated with the evolution, aggressiveness and metastasis potential of malignant tumors. This diversity of mechanisms results in heterogeneity, redundancy and the possibility for the tumor to bypass blocking only one signaling pathway, resulting in primary or acquired resistance. [Tabernero, J., Mol. Cancer Res., 2007, 5, 203 [Thus, the multifactorial nature of cancer determines the need for multiple or multifunctional therapeutic approaches, eg a single compound capable of modulating different signaling pathways involved in the pathology. of the disease. [Antonello, A. et al., J. Med. Chem., 2006, 49, 6642.

 Protein kinases play a prominent role in regulating various cellular processes, including cell proliferation, differentiation and survival. [Ishikawa, T. et al., J. Med. Chem., 2011, 54, 8030.

Several members of the protein kinases family have been identified so far. These enzymes catalyze the phosphorylation reaction of different substrates, performing primary functions at virtually every stage of cell life. Considering that about 1/3 of the Known mammalian proteins contain covalently bound phosphate, any change in the functioning of these proteins can generate inadequate cellular responses, contributing to the development of conditions such as diabetes, cancer, rheumatoid arthritis, among others [Cohen, P., J. Biol. Chem. 1999, 3, 459].

 Particularly, the epidermal growth factor receptor (EGFR), also known as ErbB1, HER1) is a transmembrane receptor tyrosine kinase belonging to the ErbB receptor family [Chilin, A. et al, J. Med. Chem., 2010, 53, 1862]; ie a four-member family of growth factor receptor kinase tyrosines that includes EGFR (HER1), ErbB2 (HER2 / neu), ErbB3 (HER3), and ErbB4 (HER4) [Antonello, A. et al., J. Med. Chem., 2006, 49, 6642. The binding of specific growth factors to the extracellular domain of ErbB receptors promotes dimerization and autophosphorylation, activating cytoplasmic tyrosine kinase domains and leading to activation of signaling pathways that regulate cell differentiation, cell growth, differentiation, migration and apoptosis. [Chilin, A. et al., J. Med. Chem., 2010, 53, 1862

 EGFR-mediated cell signaling pathways have been implicated in several human malignant tumors, promoting tumor growth, tissue and organ invasion, angiogenesis and metastasis. EGFR overexpression and / or dysregulation are common clinical findings in solid tumors and are generally associated with an unfavorable prognosis. [Antonello, A. et al., J. Med. Chem., 2006, 49, 6642] Activation of EGFR also stimulates the release of vascular endothelial growth factor (VEGF), considered the primary inducer of the angiogenesis process. [Arora, A. & Scholar E., J. Pharmacol. Exp. Ther., 2005, 315, 971]

VEGF is also considered in the literature the growth factor responsible for inducing angiogenesis in solid tumors, promoting vascular endothelial cell activation and migration; and increasing vascular permeability in tumors. The key step in this process is mediated by a specific VEGFR receptor, ie type 2 vascular endothelial growth factor receptor (VEGFR-2). [Garofalo, A. et al., J. Med. Chem., 2012, 55, 1189]

 EGFR and VEGFR-2 receptor tyrosine kinases are closely related, playing a relevant role in tumor growth and angiogenesis. The relationship between these tyrosine kinases in cancer treatment is also known, i.e. inhibition of VEGFR-2 mediated signaling contributes to the antitumor effects of EGFR inhibitors; whereas EGFR receptor-independent pathway-mediated VEGF growth factor overexpression is considered to be one of the possible resistance-inducing mechanisms of anti-EGFR therapy. [Tabernero, J., Mol. Cancer Res., 2007, 5, 203]

 Thus, EGFR and VEGFR-2 tyrosine kinases are validated therapeutic targets for cancer treatment and several inhibitors are already approved for clinical use in solid tumors where overexpression of these protein kinases is observed, such as the inhibitors shown in Figure 1. [Arora, A. & Scholar E., J. Pharmacol. Exp. Ther., 2005, 315, 971] [Antonello, A. et al., J. Med. Chem., 2006, 49, 6642] [McTigue, M. et al., PNAS, 2012, 109, 18281]

 Secondary resistance after the initial benefits seen with treatment using clinically available EGFR inhibitors, eg compounds 1, 2 and 3 (Figure 1), still constitutes a major challenge in cancer therapy, indicating the need for the development of new alternatives. Therapeutic [Usui, T. et al., Bioorg. Med. Chem. Lett, 2008, 18, 285] Thus, dual inhibition of EGFR and VEGFR-2 tyrosine kinases represents a promising approach for the treatment of solid malignant tumors, as inhibition of VEGFR-2 is able to increase the associated efficacy. EGFR inhibition due to a synergistic effect. [Garofalo, A. et al., J. Med. Chem., 2012, 55, 1189]

The patent literature contains several examples of compounds that act to inhibit EGFR and VEGFR-2 tyrosine kinases. One can cite by US 2012/295965, which describes fused thiophenic rings useful as dual EGFR and VEGFR inhibitors, for example.

 WO 2009/036066 also describes VEGFR inhibitors, but such inhibitors differ from those described in the present invention in that they have a pyrazole ring fused to a 6 membered ring.

 US 2012/309766 describes quinoline / qinoxaline derivatives which have a distinct structure from the compounds described in the present invention. Furthermore, such document does not show any specificity to EGFR or VEGFR and is indicated for inhibition of protein kinases in general.

 US 5760041, US 2010/143295 and US 201 1/295004 may be considered as the closest state of the art to the present invention for describing quinazoline compounds as inhibitors of tyrosine kinases, especially EGFR. However, the present invention differs from these compounds by the presence of a chlorine atom attached to the quinazoline ring as well as by the different substituents employed.

 There is still room for the development of new tyrosine kinase inhibitors, especially EGFR and VEGFR, and even more for the use of quinazoline skeletons.

 It can then be seen that the compounds of the present invention are indeed new, and considering the studies carried out, it can be stated that a person skilled in the art would not be motivated to modify, without further difficulties, the existing structures of the state of the art. in order to achieve the compounds of the present invention, thereby conferring inventive activity thereon.

Summary of the Invention

 In a first aspect, the present invention relates to the identification of 2-chloro-4-anilino-quinazoline derivatives that exhibit EGFR and / or VEGFR-2 protein tyrosine kinase inhibitory activity.

Accordingly, objects of the invention are 2-chloro-4-anilino-quinazoline derivatives having a structure according to the general formula (I):

 Where:

Y is SO ₂ or CO;

R 1 is C 1 -C 5 alkyl, OH, NR R ₅ , morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (CC ₅ alkyl) piperazinyl, 4-aryl piperazinyl;

R ₂ and R ₃ independently correspond to H, CC ₅ alkyl, C ₁ -C ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 selected atoms independently from O, N, S;

R ₄ and R ₅ independently correspond to H, CC ₃ alkyl;

 or pharmaceutically acceptable salts thereof.

 A further object of the present invention is a process for producing 2-chloro-4-anilino-quinazoline derivatives comprising the steps of: a) cyclization of a compound of formula (II):

to produce a compound of formula (III):

b) chlorination of the compound obtained in the previous step generating a compound of formula (IV):

onde: c) amination of the compound obtained in the previous step with an amine of formula (V):

Where:

Y is SO ₂ or CO;

R 1 is CC ₅ alkyl, OH, NR ₄ R ₅ , morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (CC ₅ alkyl) piperazinyl, 4-aryl piperazinyl;

R ₂ and R ₃ independently correspond to H, C ₁ -C ₅ alkyl, CC ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 selected atoms independently from 0, N, S;

R and R ₅ independently correspond to H, C _r C ₃ alkyl; and

R ₆ corresponds to H or NH ₂ .

In a second aspect, the present invention provides alternatives for the treatment of solid tumors characterized by protein kinases dysregulation and / or overexpression, especially EGFR and VEGFR-2 tyrosine kinases.

 It is therefore a further object of the present invention a pharmaceutical composition comprising:

(a) a 2-chloro-4-anilino-quinazoline derivative having a structure according to general formula (I):

 Where:

Y is SO ₂ or CO;

₅ corresponds to the DC alkyl, OH, NR ₄ R _5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (C _r C ₅ alkyl) piperazinyl, 4-aryl-piperazinyl;

R ₂ and R ₃ independently correspond to H, C 1 -C 6 alkyl, CC ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5 or 6 membered heterocyclic ring containing 1 to 2 independently selected atoms from O, N, S;

R ₄ and R ₅ independently correspond to H, CC ₃ alkyl;

 or pharmaceutically acceptable salts thereof; and

 b) a pharmaceutically acceptable carrier.

 A further object of the present invention is a method of treating solid tumors comprising a step of administering to a patient a 2-chloro-4-anilino-quinazoline derivative of the structure according to formula

 Where:

Y is SO ₂ or CO;

RT is C _r C ₅ alkyl, OH, NR ₄ R _5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (CC ₅ alkyl) piperazinyl, 4-aryl piperazinyl;

R ₂ and R ₃ independently correspond to H, CC ₅ alkyl, CC ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 independently selected atoms. O, N, S;

R and R ₅ independently correspond to H, C _r C ₃ alkyl;

 or pharmaceutically acceptable salts thereof.

 In a preferred embodiment, the derivatives are chosen from the group comprising:

 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonamide (8c; LASSBio-1815)

 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) -Î ”, β-dimethylbenzene sulfonamide (8g; LASSBio-1807);

 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonamide (9c; LASSBio-1814);

 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”-methylbenzenesulfonamide (9e, LASSBio-1816);

 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) - [V] [V] dimethylbenzene sulfonamide (9g; LASSBio-1808)

Description of the Figures

 Figure 1: EGFR and VEGFR receptor tyrosine kinase inhibitors.

Figure 2: Genesis of the new 2-chloro-4-anilino-quinazolinic derivatives (8, 9 and 10), drawn from prototypes PD153035 (4), Tivozanib (6) and 7.

Figure 3: (A) Overlap of 9c (yellow) with Gefitinib (2, purple) at the EGFR tyrosine kinase molecular recognition site; (B) Interaction of derivative 9c (yellow) with EGFR; (C) Interaction of derivative 9g (magenta) with EGFR; (D) Interaction of derivative 9a (green) with EGFR; (E) Interaction of derivative 9e (blue) with EGFR; (F) Interaction of derivative 9p (pink) with EGFR. Semi-rigid molecular mooring studies were performed in the GOLD 5.1 program (CCDC; License Number: G / 414/2006).

 Figure 4: (A) Overlap of 9c (yellow) with Tivozanibe (6, orange) at the VEGFR-2 tyrosine kinase molecular recognition site; (B) Interaction of derivative 9c (yellow) with VEGFR-2; (C) Interaction of derivative 9e (blue) with VEGFR-2; (D) Interaction of derivative 9p (pink) with VEGFR-2. Semi-rigid molecular mooring studies were performed using the GOLD 5.1 program (CCDC; License Number: G / 414/2006).

Detailed Description of the Invention

 The following examples are for illustration purposes only, without limiting the scope of the present invention. Any variations that may be made by one of ordinary skill in the art should be considered to be within the scope of the present invention.

2-Chloro-4-anilino-quinazoline derivatives

 The derivatives of the present invention are 2-chloro-4-anilino-quinazoline derivatives having a structure according to general formula (I):

 Where:

Y is SO ₂ or CO;

R 1 is CC ₅ alkyl, OH, NR ₄ R s, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (C 1 -C ₅ alkyl) piperazinyl, 4-aryl piperazinyl;

R ₂ and R ₃ independently correspond to H, C _r C ₅ alkyl, CC ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 selected atoms regardless of ON S;

R ₄ and R ₅ independently correspond to H, CC ₃ alkyl;

 or pharmaceutically acceptable salts thereof.

 In a preferred embodiment, the heterocyclic ring formed by R2 and R3 together with the quinazoline ring forms the structure [1,3] Dioxolo [4,5-gjquinazoline.

 By way of example, this report describes the synthesis of the compounds:

 2-chloro-6,7-methylenedioxy-N- (4- (methylsulfonyl) phenyl) quinazolin-4-amine (8a)

2-chloro- / V- (4- (ethylsulfonyl) phenyl) -6,7-methylenedioxyquinazolin-4-amine (8b)

4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonamide (8c - hereafter called LASSBio-1815)

4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonic acid (8d) 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) -Î ”-methylbenzenesulfonamide (Be)

 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) -Î ”-ethylbenzenesulfonamide (8f) 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) - / V, / V-dimethylbenzene

sulfonamide (8g - hereafter called LASSBio-1807)

2-chloro-6,7-methylenedioxy-N- (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (8h)

 2-chloro-6,7-methylenedioxy-β- (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (8i) 2-chloro-6,7-methylenedioxy-β- (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (8j) 2-chloro-6,7-methylenedioxy-N- (4- (piperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (8k)

 2-Chloro-6,7-methylenedioxy-N- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (81)

 2-chloro-6,7-methylenedioxy-N- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (8m)

 1- (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) ethanone (8n)

 1- (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) propan-1-one (8th)

4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzamide (8p) 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzoic acid (8q)

4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) - [N-methylbenzamide (8r)

4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) - [N-ethylbenzamide (8s)

4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) -Î ”, β-dimethylbenzamide (8t) (4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) phenyl) (piperidin-1-yl ) metan

(8u)

 (4- (2-chloro-6-methylenedioxyquinazolin-4-ylamino) phenyl) (morpholino) methanone (8v)

(4- (2-chloro-6-methylenedioxyquinazolin-4-ylamino) phenyl) (thiomorpholino) methanone

(8w)

 (4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) phenyl) (piperazin-1-yl) methanone (8x)

 (4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone (8y)

 (4- (2-Doro-67-methylenedioxyquinazolin-4-ylamino) phenyl) (4-phenylpiperazin-1-yl) methanone (8z)

 2-chloro-6β-dimethoxy-N- (4- (methylsulfonyl) phenyl) quinazolin-4-amine (9a)

2-chloro-A / - (4- (ethylsulfonyl) phenyl) -6,7-dimethoxyquinazolin-4-amine (9b)

4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonamide (hereinafter called LASSBio-1814)

4- (2-chloro-6,7-direthoxyquinazolin-4-ylamino) benzenesulfonic acid (9d)

4- (2-chloro-67-dimethoxyquinazolin-4-ylamino) - [N-methylbenzenesulfonamide (hereinafter called LASSBio-1816)

 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”-ethylbenzenesulfonamide (9f) 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) - [?] dimethylbenzenesulfonamide (9g - hereafter called LASSBio-1808)

 2-chloro-6,7-dimethoxy-A / - (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (9h) 2-chloro-6,7-dimethoxy-A / - (4- ( morpholinosulfonyl) phenyl) quinazolin-4-amine (9i)

2-chloro-6,7-dimethoxy-N- (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (9j) 2-chloro-6,7-dimethoxy-A / - (4- (piperazin-1 - Ylsulfonyl) phenyl) quinazolin-4-amine (9k) 2-chloro-6,7-dimethoxy-N- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (9I) 2-chloro-6-dimethoxy-N- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazin-4-am

(9m)

 1- (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) ethanone (9n)

 1- (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) propan-1-one (9th)

4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzamide (9p - hereinafter called LASSBio-1819)

4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzoic acid (9q)

4- (2-chloro-67-dimethoxyquinazolin-4-ylamino) -Î ”-methylbenzamide (9r)

4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”-ethylbenzamide (9s)

4- (2-chloro-67-dimethoxyquinazolin-4-ylamino) - [N, N-dimethylbenzamide (9t)

(4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) (piperidin-1-yl) methan (9u) (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl ) (morpholino) metanon (9v) (4- (2-chloro-67-dimethoxyquinazolin-4-ylamino) phenyl) (thiomorpholino) methan (9w) (4- (2-chloro-6-dimethoxyquinazolin-4-ylamino) phenyl !) (piperazin-1-yl) methan (9x) (4- (2-chloro-67-dimethoxyquinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone (9y)

 (4- (2-chloro-67-dimethoxyquinazolin-4-ylamino) phenyl) (4-phenylpiperazin-1-yl) m

(9z)

 2-chloro-N- (4- (methylsulfonyl) phenyl) quinazolin-4-amine (10a)

2-chloro- / V- (4- (ethylsulfonyl) phenyl) quinazolin-4-amine (10b)

4- (2-chloro-quinazolin-4-ylamino) benzenesulfonamide (10c)

4- (2-chloro-quinazolin-4-ylamino) benzenesulfonic acid (10d)

4- (2-chloro-quinazolin-4-ylamino) -Î ”-methylbenzenesulfonamide (10e)

4- (2-chloro-quinazolin-4-ylamino) -Î ”-ethylbenzenesulfonamide (10f)

4- (2-chloro-quinazolin-4-ylamino) -NJV-dimethylbenzenesulfonamide (10g)

2-chloro-A / - (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (10h)

2-chloro- / V- (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (10 O)

2-chloro-N- (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (10j)

2-chloro-A / - (4- (piperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (1 Ok)

2-chloro-A / - (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (101)

2-chloro- / V- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (10m) 1- (4- (2-chloro-quinazolin-4-ylamino) phenyl) ethanone (1 On)

1- (4- (2-chloro-quinazolin-4-ylamino) phenyl) propan-1-one (10o)

4- (2-chloro-quinazolin-4-ylamino) benzamide (1 Op)

4- (2-chloro-quinazolin-4-ylamino) benzoic acid (10q)

4- (2-chloro-quinazolin-4-ilarnino) -Î ”-methylbenzamide (1 Or)

4- (2-chloro-quinazolin-4-ylamino) - [N-ethylbenzamide (1 Os)

4- (2-doro-quinazolin-4-ylamino) -? V,? V-dimethylbenzamide (10t)

(4- (2-chloro-quinazolin-4-ylamino) phenyl) (piperidin-1-yl) methanone (10u)

(4- (2-chloro-quinazolin-4-ylamino) phenyl) (morpholino) methanone (10v)

(4- (2-chloro-quinazolin-4-ylamino) phenyl) (thiomorpholino) methanone (10w)

(4- (2-chloro-quinazolin-4-ylamino) phenyl) (piperazin-1-yl) methanone (10x)

(4- (2-chloro-quinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone (10O)

(4- (2-chloro-quinazolin-4-ylamino) phenyl) (4-phenylpiperazin-1-yl) methanone (10z)

 Pharmaceutical Composition

 The main limitations and complications associated with drug therapy usually employed in the treatment of solid tumors, including the development of resistance to hitherto available therapies, are circumvented / minimized with the pharmaceutical composition of the present invention comprising:

 a) a 2-chloro-4-anilino-quinazoline derivative having a structure according to the general formula

 Where:

Y is SO ₂ or CO;

R 1 is CC ₅ alkyl, OH, NR ₄ R 5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (C _r C5 alkyl) piperazinyl, 4-aryl-piperazinyl;

R ₂ and R ₃ independently correspond to H, CC ₅ alkyl, CC ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 independently selected atoms. O, N, S;

R ₄ and R ₅ independently correspond to H, C ₁ -C ₃ alkyl;

 or pharmaceutically acceptable salts thereof; and

 b) a pharmaceutically acceptable carrier.

 The pharmaceutical composition described herein preferably comprises an active ingredient selected from LASSBio-1807 (8g), LASSBio-1808 (9g), LASSBio-1814 (9c), LASSBio-1815 (8c), LASSBio-1816 (9e), LASSBio-1819 ( 9p) and their counterparts (8a-z, 9a-z, 10a-z, 11a-z), agents designed as dual inhibitors of EGFR and VEGFR-2 protein kinases (Figure 2).

 Pharmaceutical compositions containing the compounds of the invention are usually prepared following conventional methods and may be administered in a variety of dosage forms, for example, orally, in the form of tablets, capsules, sugar or film-coated tablets, liquid solutions or suspensions; rectal route in the form of suppositories; parenterally, ie intramuscularly, or by intravenous and / or intrathecal and / or intraspinal infusion or injection.

For example, solid oral forms may contain along with the active compound diluents, ie lactose, dextrose, sucrose, cellulose, cornstarch or potato starch; lubricants, ie silica, talc, stearic acid, magnesium or calcium stearate, and / or polyethylene glycols; binding agents, for example starches, gum arabic, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disintegrating agents, for example a starch, alginic acid, alginates or sodium starch glycolate; effervescent mixture; dyes; sugars; wetting agents such as lectin, polysorbates, lauryl sulfates; and, generally, pharmacologically inactive and non-toxic substances used in pharmaceutical formulations. Said pharmaceutical preparations can be manufactured in a manner known, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.

 Liquid dispersions for oral administration may be, for example, syrups, emulsions and suspensions. Syrups may contain as a carrier, for example, sucrose or sucrose with glycerine and / or manita and / or sorbitol. Suspensions and emulsions may contain as a carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.

 Suspensions or solutions for intramuscular injection may contain, together with the active compound, a pharmaceutically acceptable carrier, i.e. sterile water, olive oil, ethyl oleate, glycols, ie propylene glycol, and, if desired, appropriate amount of lidocaine hydrochloride. Solutions for intravenous injections or infusions may contain as a carrier, for example sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline or they may contain as a propylene glycol carrier.

 Suppositories may contain together with the active compound a pharmaceutically acceptable carrier, for example cocoa butter, polyethylene glycol, sorbitan polyoxyethylene, fatty acid ester surfactant or lecithin.

 Production Process of 2-Chloro-4-Anilino-Quinazoline Derivatives The compounds of the present invention were designed by convergent syntheses obtained in good to excellent chemical yields using the synthetic methodology described herein (Schemes 1 and 2) and using reactions classic as:

^■ Interconversion of Functional Groups

^■ Regioselective Aromatic Electrophilic Substitution

^■ Cyclization followed by chlorination with phosphorus oxychloride

^■ Regioselective Aromatic Nucleophilic Substitution

^■ Buchwald-Hartwig Amination

Reactors and conditions: (a) (1) AcOH, H ₂ O, 35 ° C, 15 '(2) KOCN, H ₂ O, 35 ° C, 30' (3) NaOH (4) HCl _aq 37%, rt, 85-87%; b) cone. HN0 _3, cat. H ₂ SO _4> 0 ° C, 2 h, 67%; c) (1) oxalyl chloride, CH ₂ CI ₂ , cat. DMF, rt, 2 h (2) NH ₃ 7N in methanol, rt, 20 ', 100%; d) ⁰ Fe, NH ₄ Cl, EtOH, H ₂ 0, 78 ° C, 12 h, 85%; e) CDI, THF, 66 ° C, 12 h, 89%; f) POCI ₃ , 100 ° C, 24 h, 71-77%.

Scheme ^to

Reagents and conditions: (g) DIPEA, dioxane, 80 ° C, 12 h, 60-66%; h) isopropanol, 82 ° C, 24 h, 67-72%; i) ethanol, 78 ° C, 24 h, 64-73%; j) Pd (AcO) ₂ , XPhos, tBuONa, tBuOH, toluene, 90 ° C, 1h, 45-55%.

The process of producing derivatives of formula (I) then comprises the steps of:

 a) cyclization of a compound of formula (II):

to produce a compound of formula (III):

 b) chlorination of the compound obtained in the previous step generating a compound of formula (IV):

onde: c) amination of the compound obtained in the previous step with an amine of formula (V):

Where:

Y is SO ₂ or CO;

R is C _r C ₅ alkyl, OH, NR ₄ R _5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (C _r C ₅ alkyl) piperazinyl, 4-aryl-piperazinyl;

R ₂ and R ₃ independently correspond to H, CC ₅ alkyl, C _r C ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5 or 6 membered heterocyclic ring containing from 1 to 2 selected atoms independently from O, N, S;

R ₄ and R ₅ independently correspond to H, C _r C ₃ alkyl;

R ₆ corresponds to H or NH ₂ .

More specifically, the compounds (8a-z; 9a-z; 10a-z) of the present invention may be prepared by a key condensation step comprising the reaction between 2,4-dichloroquinazoline intermediates (18a-c) and the corresponding anilines by Regioselective Aromatic Nucleophilic Substitution and / or Regioselective Buchwald-Hartwig Amination (Scheme 2).

 Even more particularly, 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonamide derivatives (8c; LASSBio-1815); 4- (2-chloro-6,7-methylenedioxy quinazolin-4-ylamino) -Î ”, β-dimethylbenzene sulfonamide (8g; LASSBio-1807); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonamide (9c; LASSBio-1814); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) - [N-methylbenzenesulfonamide (9e, LASSBio-1816); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”, β-dimethylbenzene sulfonamide (9g; LASSBio-1808); its isosters and regioisomers (8a-z, 9a-z, 10a-z) were designed from structural modifications in prototypes 4, 6 and 7 (Figure 2); and rationally designed as EGFR and VEGFR-2 tyrosine kinase inhibitors using semi-rigid mooring molecular modeling (Figures 3 and 4).

 A detailed description of the synthetic methods of this invention for some of the claimed compounds is reported in the following examples.

Example 1 - Quinazoline-2,4 (1 H, 3H) -dione (17a)

 In a 100 ml reflux condenser flask, a suspension of anthranilic acid (0.82 g, 5.98 mmol) in distilled water (36 mL) and glacial acetic acid (0.7 mL) was stirred and heated to 35 ° C for 15 minutes. Subsequently, potassium cyanide (1.21 g, 14.92 mmol) was dissolved in water and slowly added to the reaction medium, which was stirred at 35 ° C for 30 minutes. Subsequently, sodium hydroxide was carefully added (10.68 g, 267 mmol). The reaction medium was cooled to room temperature and the pH adjusted to 4 using concentrated hydrochloric acid. The precipitated white solid was filtered off and washed with ice water, yielding the desired compound in 87% yield, m.p.> 300 ° C.

Example 2 - 6,7-dimethoxy-quinazoline-2,4 (1 Y, 3H) -dione (17b) 17b was synthesized according to the procedure described above for the synthesis of 17a in 85% yield, mp> 300 ° C.

 Example 3 - 6-Nitrobenzo [c] [1,3] dioxola-5-carboxylic acid (13)

In a 100 mL flask containing piperonylic acid (2.00 g, 12.04 mmol), concentrated nitric acid (15.17 g, 10 mL, 240.78 mmol) was carefully added by magnetic stirring at 0 ° C Subsequently, 16 drops of concentrated sulfuric acid were slowly added, resulting in a gradual color change from colorless to yellow. After 2 hours, the reaction was isolated by the addition of crushed ice to the flask, resulting in the precipitation of a yellow solid, which was filtered off and washed with ice water. The product was purified by washing with hot hexane followed by filtration to give a yellow solid in 67% yield, mp 167 ° C (dec).

 Example 4-6-nitrobenzo [c] [1,3] dioxola-5-carboxamide (14)

 In a 250 mL flask, compound 13 (1.00 g, 4.74 mmol) was dissolved in dichloromethane (50 mL). Subsequently, oxalyl chloride (0.66 g, 477 µL, 5.21 mmol) and 3 drops of dimethylformamide were added. The resulting solution was stirred at room temperature for 2 hours. Subsequently, the second step was performed one-pot by adding 2.0 mL of 7 N ammonia solution in methanol. The reaction medium was stirred at room temperature for 20 minutes. Reaction isolation was accomplished by addition of hexane in the reaction medium and filtration of the precipitate obtained, giving the desired product in 100% yield after the completion of both steps as a light yellow solid, m.p. 192 ° C.

¹ H NMR (200 MHz, DMSO-cfe) δ (ppm): 6.26 (s, 2H, OChUO); 7.12 (s, 1H, H6); 7.58 (sl, 1 H, exchange D ₂₀ , RCONH _to H _b ); 7.62 (s, 1H, H3); 7.96 (sl, 1 H, D ₂ 0 exchange D ₂ 0, RCONHaH _b ).

3 C NMR (50 MHz, DMSO-cfe) δ (ppm): 103.6 (C H ₂ O); 104.7 (C6); 107.7 (C3); 129.3 (C5); 141.3 (C4); 148.0 (C2); 151.1 (C1); 166.8 (Ç_ONH ₂ ).

IR (ATR: cm ^-1 ): 3362, 3179, 2921, 1653, 1526, 1347.

Example 5 - 6-Aminobenzo [d] [1,3] dioxola-5-carboxamide (15) In a 250 mL flask equipped with reflux condenser, the reaction medium containing 14 (2.00 g, 9.52 mmol), metal iron (3.72 g, 66.62 mmol), ammonium chloride (1.02 g, 19.03 mmol), 100 mL ethanol and 20 mL distilled water, was stirred and heated at 78 ° C for 12 hours. The end of the reaction was verified by CCD. The product was isolated by filtration on Celite ^® , followed by washing with ethanol. Subsequently, ethanol was concentrated under reduced pressure and crushed ice was added to the reaction flask, resulting in precipitation of the product as a dark yellow solid, which was filtered off and washed with ice water, yielding 85% yield, mp 172-18 ° C. 173 ° C. ¹ H NMR (200 MHz, DMSO - </ ₆₎ δ (ppm): 5.88 (s, 2H, OCH ₂ 0); 6.27 (s, 1H, H3); 6.63 (sl, 2H, exchange D ₂₀ , RCONH ₂ ); 7.13 (m, 3H, H6, ArNHa).

¹³ C NMR (50 MHz, DMSO-d _e ) δ (ppm): 96.6 (C3); 100.6 (C H ₂ O); 104.4 (C6); 107.0 (C5); 137.3 (C1); 148.2 (C4); 150.5 (C2); 170.8 (Ç_ONH ₂ ).

IR (ATR: cm ^-1 ): 3380, 3284, 3189, 2910, 1644, 1618.

 Example 6 - 6,7-Methylenedioxy-quinazoline-2,4 (1 H, 3 y) -dione (17c) In a 100 mL reflux condenser flask, the reaction mixture containing 15 (1.00 g, 5 µM) 0.15 mmol), 1,1'-carbonyldiimidazole (CDI) (1.08 g, 6.66 mmol) and 20 mL of anhydrous THF was stirred and heated at 66 ° C for 12 hours in argon atmosphere. The product was isolated by the addition of crushed ice to the flask, resulting in the precipitation of a white solid, which was vacuum filtered and washed with ice water, yielding the desired product in 89% yield, m.p.> 300 ° C.

¹ H NMR (200 MHz, DMSO-cfe) δ (ppm): 6.1 1 (s, 2H, OCH ₂ 0); 6.64 (s, 1H, H8); 7.21 (s, 1H, H5); 1 1 .00 (bs, 1H, exchanges D ₂ 0, H3); 11.16 (sl, 1 H, exchange D ₂₀ , H1). ¹³ C NMR (50 MHz, DMSO-d ₆ ) δ (ppm): 95.3 (C8); 102.3 (C H ₂ O); 104.0 (C5); 107.6 (C4a); 138.2 (C8a); 143.6 (C6); 150.2 (C7); 153.2 (C2); 162.1 (C4).

IR (ATR: cm ^-1 ): 3141, 3083, 3009, 2954, 1725, 1673, 1626, 1497, 1453.

 Example 7 - General methodology for the synthesis of 2,4-dichloroquinazolines

In a 100 mL flask equipped with reflux condenser, the reaction mixture containing the quinazolinediones (1.00 g) and POCI ₃ (15 mL; 24.77 g; 161.53 mmol) was stirred and heated at 100 ° C for 24 hours. Isolation was performed by slowly and carefully pouring the reaction medium into a mixture of ice and water by vigorous stirring. The precipitate obtained was vacuum filtered and purified by filtration on silica gel using dichloromethane as eluent.

 Example 8 - 2,4-Dichloroquinazoline (18a)

 18a was obtained from 17a as a white solid, 75% yield after purification; mp 17-120 ° C.

 Example 9 - 2,4-Dichloro-6,7-dimethoxyquinazoline (18b)

 18b was obtained from 17b as a pink solid, 77% yield after purification; mp 172 ° C.

¹ H NMR (400 MHz, CDCl ₃₎ δ (ppm): 4.07 (s, 3H, _OCH3); 4.08 (s, 3H, OCH ₃ ); 7.27 (s, 1H, H5); 7.35 (s, 1H, H8).

¹³ C NMR and DEPT 135 (100 MHz, CDCl ₃ ) δ (ppm): 56.6 (C H ₃ ); 56.9 (C H ₃ ); 102.9 (C5); 106.4 (C8); 11.0 (C4a); 150.7 (C8a); 151.8 (C6); 153.8 (C2); 158.0 (C4); 160.3 (C7).

IR (ATR: cm ^-1 ): 3023, 2978, 2945, 1610, 1552, 1507, 1459, 747.

GC-MS (EI): R t = 13.3 min; m / z 258 [M] ⁺ (100%); 260 [M + 2] ⁺ (64%); 262 [M + 4] ⁺

(10%).

 Example 10 - 2,4-Dichloro-6,7-methylenedioxy-quinazoline (8c)

 18c was obtained from 17c as a white solid, 71% yield after purification; mp 217-219 ° C.

1 H NMR (400 MHz, CDCl ₃ ) δ (ppm): 6.24 (s, 2H, OCH 3 O); 7.24 (s, 1H, H5); 7.44 (s, 1H, H8).

¹³ C NMR and DEPT 135 (100 MHz, CDCl ₃ ) δ (ppm): 101.2 (C5); 103.3 (OÇH ₂₀ ); 104.7 (C8); 11.6 (C4a); 150.0 (C8a); 152.5 (C6); 154.1 (C2); 156.0 (C4); 160.9 (C7).

IR (ATR: cm ^-1 ): 3053, 2921, 1607, 1556, 1468, 1420, 715.

GC-MS (EI): R t = 12.6 min; m / z 242 [] ⁺ (100%); 244 [M + 2] ⁺ (64%); 246 [M + 4] ⁺

(10%). Example 11 - General procedure for Buchwald-Hartwig amination

A reaction mixture containing 0.63 mmol of aryl chloride, 0.63 mmol of aniline, 1.89 mmol of t-BuONa base, 0.19 mmol of X-Phos and 0.03 mmol of Pd (OAc) ₂ in 6 mL of ether-butanol and 10 mL of toluene was stirred and heated at 90 ° C for 1 hour under argon atmosphere. When the end of the reaction was detected by CCD, the reaction mixture was cooled to room temperature, diluted with water and extracted with dichloromethane. The obtained organic phases were combined and washed with saturated sodium chloride solution. Subsequently, anhydrous Na ₂ SO _{4 was} added and the solvent was removed under reduced pressure. The obtained residue was purified by recrystallization from a mixture of dichloromentane and hexane.

 Example 12 - 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -W, N-dimethylbenzene sulfonamide (9g)

 Compound 9g was synthesized as a yellow solid in 53% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 258-259 ° C. HPLC: 230 nm: 100%; 254 nm: 100%.

¹ H NMR (400 MHz, DMSO-a ^* ₆₎ δ (ppm): 2.64 (s, 6H, RS0 ₂ N (CH _{3) 2);} 3.93 (s, 3H, OCH ₃ ); 3.96 (s, 3H, OCH ₃ ); 7.20 (s, 1H, H5); 7.81 (d, 2H, J = 8.5 Hz, H 3 'and H 5'); 7.87 (s, 1H, H8); 8.08 (d, 2H, J = 8.5 Hz, H2 'and H6'); 10.04 (s, 1H, NH). ¹³ C NMR and DEPT 135 (100 MHz, DMSO-d _e ) δ (ppm): 37.7 (RS0 ₂ N (CH ₃ ) ₂ ); 56.1 (OC_H ₃ ); 56.3 (OÇH ₃ ); 102.1 (C5); 106.7 (C8); 107.5 (C4a); 121.5 (C3 'and C5'); 128.4 (C2 'and C6'); 129.0 (C1 '); 143.1 (C4 '); 148.6 (C8a); 149.3 (C6); 153.7 (C2); 155.3 (C7); 157.4 (C4).

IR (ATR: cm ^-1 ): 3398, 2935, 2828, 1597, 1572, 1512, 1420, 1327, 1234, 1149, 838, 723.

MS: posFAB: m / z 423 [M + 1] ⁺ ; 425 [M + 1 + 2] ⁺ .

Example 13 - 4- (2-chloro-6,7-methylenedioxyquinazolin-4-Mamino) -Î ”Î ± -Dimethylbenzene sulfonamide (8g) Compound 8g was synthesized as a yellow solid in 45% yield after precipitation from a mixture of dichloromethane and hexane, mp 245-247 ° C. HPLC: 230 nm: 100%; 254 nm: 100%.

¹ H NMR (400 MHz, DMSO-cfe) δ (ppm): 2.63 (s, 6H, RS0 ₂ N (CH _{3) 2);} 6.29 (s, 2H, OCH ₂ O); 7.22 (s, 1H, H5); 7.79 (d, 2H, J = 8.7Hz, H3 "and H5 '); 8.04 (s, 1H, H8); 8.10 (d, 2H, J = 8.7Hz, H2' and H6 '); 9.96 (s, 1H, NH).

¹³ C NMR and DEPT 135 (100 MHz, DMSO-d _e ) δ (ppm): 37.6 (RS0 ₂ N (CH ₃ ) ₂ ); 99.2 (C5); 102.9 (C ₂₀ H ₂₀ ); 104.2 (C8); 109.0 (C4a); 121.2 (C3 'and C5'); 128.4 (C2 'and C6'); 129.1 (C1 '); 143.1 (C4 '); 147.8 (C8a); 150.2 (C6); 153.6 (C2); 154.0 (C7); 157.8 (C4).

IR (ATR: cm ^-1 ): 3323, 2917, 2848, 1595, 1568, 1499, 1458, 1325, 1260, 1158,

837,731.

MS: negFAB: m / z 405 [M-1] ^" ; 407 [M-1 + 21 /.

 Example 14 - 4- (2-Chloro-quinazolin-4-ylamino) - [V] / V-dimethylbenzenesulfonamide (10g)

 Compound 10g was synthesized as a yellow solid in 55% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 245-246 ° C. HPLC: 230 nm: 100%; 254 nm: 97.3%.

¹ H NMR (400 MHz, DMSO-cfe) δ (ppm): 2.64 (s, 6H, RS0 ₂ N (CH _{3) 2);} 7.75 (m, 4H, H5, H6, H3 'and H5'); 7.93 (t, 1H, J = 7.5 Hz, H7); 8.15 (d, 2H, J = 8.7 Hz, H2 'and H6'); 8.62 (d, 1H, J = 7.5 Hz, H8); 10.42 (s, 1H, NH).

¹³ C NMR and DEPT 135 (100 MHz, DMSO-d ₆ ) δ (ppm): 37.6 (RS0 ₂ N (CH ₃ ) ₂ ); 13.8 (C4a); 121.8 (C3 'and C5'); 123.5 (C8); 126.8 (C6); 127.0 (C5); 1 28.3 (C ²¹ and C ⁶ '); 129.6 (CV); 134.3 (C7); 142.6 (C4 '); 151.0 (C8a); 155.6 (C2); 159.1 (C4). IR (ATR: cm ^-1 ): 3357, 2972, 2835, 1597, 1564, 1494, 1408, 1327, 1279, 1157,

838,727.

MS: posFAB: m / z 363 [M + 1] ⁺ ; 365 [M + 1 + 2] ⁺ .

 Example 15 - 2-Chloro-6,7-dimethoxy-A / - (4-

(methylsulfonyl) phenyl) quinazolin-4-amine (9a) W

 24

Compound 9a was synthesized as a beige solid in 50% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 184- 186 ° C. HPLC: 230 nm: 96.4%; 254 nm: 97.2%.

1 H NMR (400 MHz, DMSO-cfe) δ (ppm): 3.23 (s, 3H, RS ₂ CH ₃ ); 3.94 (s, 3H, OCH ₃ ); 3.97 (s, 3H, OCH ₃ ); 7.22 (s, 1H, H5); 7.89 (s, 1H, H8); 7.97 (d, 2H, J = 8.4 Hz, H3 'and H5'); 8.05 (d, 2H, J = 8.4 Hz, H2 'and H6'); 10.11 (s, 1H, NH).

¹³ C NMR and DEPT 135 (100 MHz, DMSO-cfe) δ (ppm): 43.8 (RS0 ₂ δ H ₃ ); 56.1 (OÇH ₃ ); 56.3 (OÇH ₃ ); 102.2 (C5); 106.7 (C8); 107.5 (C4a); 121.8 (C3 'and C5'); 127.8 (C2 'and C6'); 135.2 (C1 '); 143.4 (C4 '); 148.6 (C8a); 149.3 (C6); 153.7 (C2); 155.3 (C7); 157.5 (C4).

IR (ATR: cm ^-1 ): 3369, 2916, 2835, 1597, 1572, 1505, 1423, 1338, 1283, 1134, 834, 738.

MS: posFAB: m / z 394 [M + 1] ⁺ ; 396 [M + 1 + 2] ⁺ .

 Example 16 - 2-Chloro-6,7-methylenedioxy - (4-

(methylsulfonyl) phenyl) quinazolin-4-amine (8a)

 Compound 8a was synthesized as a yellow solid in 52% yield after precipitation from a mixture of dichloromethane and hexane, m.p.> 300 ° C. HPLC: 230 nm: 95.7%; 254 nm: 97.8%.

1H NMR (400 MHz, DMSO-cfe) δ (ppm): 3.21 (s, 3H, RS ₂ CH ₃ ); 6.27 (s, 2H, OCH ₂ O); 7.17 (s, 1H, H5); 7.91 (d, 2H, J = 8.7 Hz, H3 ^* and H5 '); 8.03 (m, 3H, H8, H2 'and H6'); 10.04 (s, 1H, NH).

¹³ C NMR (100 MHz, _DMSO-d6) δ (ppm): 43.8 (RS0 ₂ CH _3); 99.5 (C5); 102.8 (OÇH ₂₀ ); 104.0 (C8); 109.5 (C4a); 121.6 (C3 'and C5'); 127.7 (C2 'and C6'); 134.5 (Cf); 144.6 (C4 '); 147.5 (C8a); 150.0 (C6); 153.4 (C2); 154.3 (C7); 158.0 (C4). IR (ATR: cm ^-1 ): 3361, 2935, 2905, 1590, 1557, 1509, 1449, 1286, 1234, 1138, 871, 764.

MS: negFAB: m / z 376 [M-1] ^" ; 378 [M-1 +2] \

MS: posFAB: m / z 378 [M + 1] ⁺ ; 380 [M + 1 + 2] ⁺ .

Example 17 - 2-Chloro-6,7-methylenedioxy-N- (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (8h) Compound 8h was synthesized as a yellow solid in 55% yield after precipitation from a mixture of dichloromethane and hexane, mp 160-162 ° C. HPLC: 230 nm: 98.3%; 254 nm: 100%.

¹ H NMR (400 MHz, DMSO-cfe, TMS) δ (ppm): 1 .37 (m, 2H, RS0 ₂ N (CH ₂ CH _{2) 2} CH _2); 1.56 (m, 4H, RS ₂ N (CH ₂ CH 3) ₂ CH ₂ ); 2.91 (t, 4H, J = 4.5 Hz, RS ₂ N (CH ₂ CH ₂ ) ₂ CH ₂ ); 6.29 (s, 2H, OCH 3); 7.21 (s, 1H, H5); 7.76 (d, 2H, J = 8.2 Hz, H 3 'and H 5'); 8.03 (s, 1H, H8); 8.09 (d, 2H, J = 8.2 Hz, H2 'and H6'); 9.95 (s, 1H, NH).

¹³ C NMR and DEPT 135 (100 MHz, DMSO-cfe, TMS) δ (ppm): 22.8 (RS ₂ N (CH ₂ CH ₂ ) ₂ CH ₂ ); 24.7 (RS ₂ N (CH ₂ CH ₂ ) ₂ CH ₂ ); 46.5

(RS0 ₂ N (CH ₂ Ç_H _{2) 2} CH _2); 99.2 (C5); 102.9 (C ₂₀ H ₂₀ ); 104.1 (C8); 109.0 (C4a); 121 .1 ⁽¹ C3 and C5 '); 128.2 (C2 'and C6'); 129.8 (CV); 143.0 (C4 '); 147.7 (C8a);

150.1 (C6); 153.6 (C2); 154.0 (C7); 157.8 (C4).

IR (cm ^-1 ): 3336, 2913, 2854, 1599, 1567, 1494, 1451, 1328, 1236, 1145, 838, 725.

MS: negFAB: m / z 445 [M-1] ^" ; 447 [M-1 +2] ^" .

 Example 18 - 2-Chloro-6,7-methylenedioxy-N- (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (8i)

 Compound 8i was synthesized as a yellow solid in 45% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 262-264 ° C. HPLC: 230 nm: 100%; 254 nm: 96.3%.

¹ H NMR (400 MHz, DMSO-cfe, TMS) δ (ppm): 2.89 (t, 4H, J = 4.3 Hz,

(RS0 ₂ N (CH ₂ CH ₂ ) ₂ 0); 3.65 (t, 4H, J = 4.3 Hz, RS _{2 2} N (CH ₂ CH ₂ ) ₂₀ ); 6.29 (s, 2H, OCH ₂₀ ); 7.21 (s, 1H, H5); 7.77 (d, 2H, J = 8.8 Hz, H 3 'and H 5'); 8.03 (s, 1H, H8); 8.13 (d, 2H, J = 8.8 Hz, H2 'and H6'); 9.98 (s, 1H, NH).

¹³ C NMR (100 MHz, DMSO-cfe, TMS) δ (ppm): 45.9 (RS ₂ N (CH ₂ CH ₂ ) ₂₀ ); 65.3 (RS0 ₂ N (CH ₂ Ç_H _{2) 2} 0); 99.2 (C5); 102.9 (C ₂₀ H ₂₀ ); 104.1 (C8); 109.0 (C4a);

121.2 (C3 'and C5'); 128.4 (C2 'and C6'); 128.6 (CV); 143.4 (C4 '); 147.8 (C8a); 150.2 (C6); 153.6 (C2); 154.0 (C7); 157.8 (C4).

IR (cm ^-1 ): 3586, 2926, 2861, 1592, 1568, 1488, 1450, 1327, 1239, 1150, 836, 736. MS: negFAB: m / z 447 [M-1] ^" ; 449 [M-1 +2] \

 Example 19 - 2-οΙθΓθ-6,7-ιηβΙιΙθηο <ϋοχί-Λ ^ (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (8j)

 Compound 8j was synthesized as a white solid in 54% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 266-268 ° C. HPLC: 230 nm: 100%; 254 nm: 100%.

1 H NMR (400 MHz, DMSO-c / ₆ , TMS) δ (ppm): 2.68 (t, 4H, J = 3.8 Hz,

RS0 ₂ N (CH ₂ CH ₂ ) ₂ S); 3.23 (t, 4H, J = 3.8 Hz, RS ₂ N (CH ₂ CH ₂ ) ₂ S); 6.29 (s, 2H, OCH 3 O); 7.22 (s, 1H, H5); 7.78 (d, 2H, J = 8.8 Hz, H 3 'and H 5'); 8.04 (s, 1H, H8); 8.12 (d, 2H, J = 8.8 Hz, H2 'and H6'); 9.99 (s, 1H, NH).

 3 C NMR and DEPT 135 (100 MHz, DMSO-cfe, TMS) δ (ppm): 26.4

(RS0 ₂ N (CH ₂ CH ₂ ) ₂ S); 47.8 (RS0 ₂ N (CH ₂ CH _{2) 2} O); 99.2 (C5); 102.9 (C ₂₀ H ₂₀ );

104.2 (C8); 109.0 (C4a); 121.3 (C3 'and C5'); 128.1 (C2 'and C6'); 130.1 (C1 '); 143.3

(C4 '); 147.8 (C8a); 150.2 (C6); 153.6 (C2); 154.0 (C7); 157.8 (C4).

IR (cm ^-1 ): 3387, 2903, 2848, 1596, 1563, 1497, 1453, 1328, 1259, 1148, 829,

719.

MS: nepFAB: m / z 463 [M-1] ^" ; 465 [M-1 +2] ^" .

 Example 20 - 2-Chloro-6,7-methylenedioxy-N- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (81)

 Compound 81 was synthesized as a yellow solid in 53% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 160 ° C. HPLC: 230 nm: 97.8%; 254 nm: 98.7%.

¹ H NMR (400 MHz, DMSO-cfe, TMS) δ (ppm): 2.14 (s, 3H, RNCH _3); 2.37 (t, 4H, J = 4.4 Hz, RS ₂ N (CH ₂ CH ₂ ) ₂ NCH ₃ ); 2.91 (t, 4H, J = 4.4 Hz, RS _{2 2} N (CH 3 CH ₂ ) ₂ NCH ₃ ); 6.28 (s, 2H, OCH 2 O); 7.20 (s, 1H, H5); 7.76 (d, 2H, J = 8.8 Hz, H3 'and H5'); 8.01 (s, 1H, H8); 8.10 (d, 2H, J = 8.8 Hz, H2 'and H6'); 9.96 (s, 1H, NH).

¹³ C NMR (100 MHz, DMSO-cfe, TMS) δ (ppm): 45.2 (RNÇ_H _3); 45.7 (RS0 ₂ N (CH ₂ CH ₂ ) ₂ NCH ₃ ); 53.5 (RS0 ₂ N (CH ₂ Ç_H _{2) 2} NCH _3); 99.2 (C5); 102.9 (OCH ₂₀ ); 104.1 (C8); 109.0 (C4a); 121.2 (C3 'and C5'); 128.4 (C2 'and C6'); 129.0 (C1 '); 143.2 (C4 '); 147.7 (C8a); 150.1 (C6); 153.6 (C2); 154.0 (C7); 157.8 (C4). IR (cm ^-1 ): 3562, 2855, 2810, 1589, 1566, 1487, 1445, 1324, 1245, 1154, 852, 731.

MS: negFAB: m / z 460 [M-1] ^' ; 462 [M-1 +2] ^" .

MS: posFAB: m / z 462 [M + 1] ⁺ ; 464 [M + 1 + 2] ⁺ .

 Example 21 - 2-Chloro-6,7-methylenedioxy-N- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (8m)

 Compound 8m was synthesized as a beige solid in 47% yield after precipitation from a mixture of dichloromethane and hexane, m.p. 180 - 182 ° C. HPLC: 230 nm: 95.9%; 254 nm: 100%.

¹ H NMR (400 MHz, DMSO-d ₆ , TMS) δ (ppm): 3.04 (sl, 4H, RS ₂ N (CH ₂ CH ₂ ) ₂ NPh); 3.21 (sl, 4H, RS ₂ N (CH ₂ CH ₂ ) ₂ NPh); 6.27 (s, 2H, OCH ₂₀ ); 6.79 (t, 1H, J = 7.0Hz, H4 "); 6.90 (d, 2H, J = 8.2Hz, H2" and H6 "); 7.19 (m, 3H, H5, H3" and H5 "); 7.80 (d, 2H, J = 8.7Hz, H3 'and H5'); 8.01 (s, 1H, H8); 8.12 (d, 2H, J = 8.7Hz, H2 'and H6'); 9.96 (s, 1 H, NH).

¹³ C NMR and DEPT 135 (100 MHz, DMSO-cfe, TMS) δ (ppm): 45.8

(RS0 ₂ N (CH ₂ CH ₂ ) ₂ NPh); 48.0 (RS0 ₂ N (CH ₂ Ç_H _{2) 2} NPh); 99.2 (C5); 102.9

(C ₂₀ H ₂₀ ); 104.1 (C8); 109.0 (C4a); 1 6.1 (C3 "and C5"); 11.6 (C4 '); 121.2 (C3' and C5 '); 128.5 (C2' and C6 '); 128.8 (C2' and C6 '); 12.9 (Cf); 143.4 (C4'); 147.8

(C8a); 150.2 (C6); 150.4 (C1 "); 153.6 (C2); 154.0 (C7); 157.8 (C4).

IR (cm ^-1 ): 3258, 2914, 2848, 1596, 1563, 1494, 1450, 1325, 1234, 1153, 850,

740.

MS: negFAB: m / z 522 [M-1] ^' ; 524 [M-1 + 2] -.

 Example 22 - General Procedure for SwAr

 A reaction mixture containing 0.80 mmol of aryl chloride and 0.80 mmol of aniline in 20 mL of ethanol or isopropanol was stirred and refluxed for 24 hours. The resulting precipitate was hot filtered and purified as described below.

Example 23 - 4- (2-Chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonamide hydrochloride (9c) Compound 9c was synthesized as a white solid in 68% yield after recrystallization from methanol, mp> 300 ° C. HPLC: 230 nm: 95.8%; 254 nm: 96.8%.

¹ H NMR (400 MHz, DMSO-cfe) δ (ppm): 3.80 (sl, 1 H, D ₂₀ H exchange of hydrochloride); 3.93 (s, 3H, OCH ₃ ); 3.97 (s, 3H, OCH ₃ ); 7.19 (s, 1H, H5); 7.32 (sl, 2H, exchange D ₂₀ , RSO ₂ NH 2); 7.86 (d, 2H, J = 8.7 Hz, H3 'and H5'); 7.95 (m, 3H, H8, H2 'and H6'); 10.13 (s, 1H, NH).

¹³ C NMR (100 MHz, DMSO-cfe) δ (ppm): 56.0 (OCH ₃ ); 56.4 (OCH ₃ ); 102.3 (C5); 106.6 (C8); 107.4 (C4a); 122.0 (C3 'and C5'); 126.3 (C2 'and C6'); 139.0 (C1 '); 141.7 (C4 '); 148.4 (C8a); 149.2 (C6); 153.9 (C2); 155.2 (C7); 157.7 (C4).

IR (ATR: cm ^-1 ): 3391, 3331, 2979, 2939, 1594, 1568, 1509, 1449, 1323, 1234, 1149, 834, 701.

MS: posFAB: m / z 395 [M + 1] ⁺ ; 397 [M + 1 + 2] ⁺ .

 Example 24 - 4- (2-Chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonamide hydrochloride (8c)

 Compound 8c was synthesized as a white solid in 67% yield after recrystallization from methanol, m.p.> 300 ° C. HPLC: 230 nm: 96.6%; 254 nm: 98.1%.

¹ H NMR (400 MHz, DMSO-c / ₆ ) δ (ppm): 3.43 (sl, 1 H, hydrochloride exchange D ₂₀ , H); 6.27 (s, 2H, OCH ₂₀ ); 7.18 (s, 1H, H5); 7.31 (sl, 2H, exchange D ₂₀ , RS ₂ NH ₂ ); 7.84 (d, 2H, J = 8.4 Hz, H3 'and H5'); 7.94 (d, 2H, J = 8.4 Hz, H2 'and H6'); 7.99 (s, 1H, H8); 9.93 (s, 1H, NH).

¹³ C NMR and DEPT 135 (100 MHz, DMSO-cfe) δ (ppm): 99.2 (C5); 102.8 (OÇH ₂₀ ); 104.1 (C8); 108.8 (C4a); 121.7 (C3 'and C5'); 126.3 (C2 'and C6'); 138.9 (C1 '); 141.7 (C4 '); 147.6 (C8a); 150.0 (C6); 153.5 (C2); 154.2 (C7); 158.0 (C4). IR (ATR: cm ^-1 ): 3369, 3343, 2998, 1601, 1571, 1523, 1446, 1327, 1231, 1145, 838, 620.

MS: posFAB: m / z 379 [M + 1] ⁺ ; 381 [M + 1 + 2] ⁺ .

Example 25 - 4- (2-Chloro-6,7-dimethoxyquinazolin-4-ylamino) -A-methylbenzene sulfonamide hydrochloride (9e) Compound 9e was synthesized as a white solid in 68% yield after recrystallization from methanol, mp> 300 ° C. HPLC: 230 nm: 100%; 254 nm: 100%.

¹ H NMR (400 MHz, DMSO-cfe) δ (ppm): 6.2 (d, 3H, J = 5.2 Hz, RS0 ₂ NHCH _3); 3.73 (bs, 1H, exchanges D ₂ 0, H hydrochloride); 3.93 (s, 3H, OCH ₃ ); 3.97 (s, 3H, OCH ₃ ); 7.20 (s, 1H, H5); 7.38 (q, 1 H, exchange D ₂₀ , J = 5.2 Hz, RS ₂ NHCH ₃ ); 7.82 (d, 2H, J = 8.8 Hz, H 3 'and H 5'); 7.90 (s, 1H, H8); 8.00 (d, 2H, J = 8.8 Hz, H2 'and H6'); 10.08 (s, 1H, ArNHAr).

¹³ C NMR (100 MHz, DMSO-cf ₆ ) δ (ppm): 28.7 (RS ₂ NH ₄ H ₃ ); 56.0 (C H ₃ ); 56.3 (OCH3); 102.3 (C5); 106.6 (C8); 107.5 (C4a); 121 .8 ^(* C3 and C5 '); 127.4 (C2 'and C6'); 133.8 (C1 '); 142.3 (C4 '); 148.5 (C8a); 149.2 (C6); 153.8 (C2); 155.3 (C7); 157.5 (C4).

IR (ATR: cm ^-1 ): 3398, 3008, 2974, 2932, 1599, 1565, 1508, 1463, 1315, 1285, 1145, 842, 694.

MS: posFAB: m / z 409 [M + 1] ⁺ ; 41 1 [M + 1 + 2] ⁺ .

 Example 26 - 4- (2-Chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonic acid hydrochloride (9d)

 Compound 9d was synthesized as a beige solid in 66% yield after recrystallization from a mixture of DMSO and methanol, m.p.> 300 ° C. HPLC: 230 nm: 97.9%; 254 nm: 97.3%.

¹ H NMR (400 MHz, DMSO-afe) δ (ppm): 3:33 (bs, 2H, hydrochloride and RSO 3 H); 3.93 (s, 3H, OCH ₃ ); 3.96 (s, 3H, OCH ₃ ); 7.18 (s, 1H, H5); 7.65 (m, 4H, H2 ', H3, H5' and H6 '); 7.90 (s, 1H, H8); 9.92 (s, 1H, NH).

H NMR (400 MHz, D ₂ 0) δ (ppm): 3.26 (s, 3H, _OCH3); 3.43 (s, 3H, OCH ₃ ); 5.89 (s, 1H, H5); 6.35 (s, 1H, H8); 7.43 (d, 2H, J = 8.4 Hz, H 3 'and H 5'); 7.62 (d, 2H, J = 8.4 Hz, H2 'and H6').

¹³ C NMR (100 MHz, D ₂₀ ) δ (ppm): 55.6 (C H ₃ ); 55.9 (OCH ₃ ); 99.7 (C5); 104.6 (C8); 105.9 (C4a); 121.3 (C3 'and C5'); 126.2 (C2 'and C6'); 138.0 (CV); 140.3 (C4 '); 146.1 (C8a); 148.2 (C6); 153.3 (C2); 154.0 (C7); 155.9 (C4).

IR (ATR: cm ^-1 ): 3065, 2978, 2946, 1635, 1552, 1520, 1468, 1346, 1251, 1147, 830, 700. MS: negFAB: m / z 394 [Μ-1] ^' ; 396 [Μ-1 +2] ^" .

 Example 27 - Biochemical Assessment

 The 2-chloro-4-amino-quinazoline derivatives designed as dual inhibitors of EGFR and VEGFR-2 tyrosine kinases as candidates for antitumor drugs were evaluated for their ability to inhibit the enzymatic activity of the protein kinases in question, ie as to their ability to inhibit enzyme substrate phosphorylation by the previously activated enzyme.

 The spectroscopically synthesized and synthesized 2-chloro-4-amino-quinazoline analogs showed inhibitory ability on both EGFR and VEGFR-2 receptor tyrosine kinases, such as derivatives 8c, 8g, 9c, 9e, 9g and 9p, as shown in Table 1 . A direct correlation was observed between inhibitory potencies against the two tyrosine kinases evaluated.

Table 1: Inhibitory activity of prototype 7 and 2-chloro-4-anilino-quinazoline derivatives against EGFR and VEGFR-2 receptor tyrosine kinases

8g OCH ₂ 0 to ₂ N (CH ₃ ) ₂ 18.3 23.4

9c OCH _{3j 2} NH ₂ 2.371.02 OCH ₃

8c OCH ₂ 0 S0 ₂ NH ₂ 34.6 26.9

OCH ₃₎

9p C = 0 NH ₂ 0.90 1.17

OCH ₃

a Radiometric assay of protein kinase activity (PanQinase) was employed to measure the inhibitory effect of EGFRwt and VEGFR-2 tyrosine kinases. ^b Cl ₅₀ values were calculated using Quattro Workflow V3.1.0 (Quattro Research GmbH, Munich, Germany; www.quattroresearch.com) and are given in μΜ. ^c Compound previously described by Abouzid & Shouman, Bioorganic & Medicinal Chemistry 2008, 16, 7543-7551.

The novel 2-chloro-4-amino-quinazoline analogs 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonamide (9c; LASSBio-1814; EGFR, IC ₅₀ = 2.37 μΜ; VEGFR-2, IC ₅₀ = 1.02 μΜ); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”-methylbenzenesulfonamide (9e, LASSBio-1816; EGFR, IC ₅₀ = 1.63 μ; VEGFR-2, IC ₅₀ = 0.85 μΜ ); and 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzamide (9p; LASSBio-1819; EGFR, IC ₅₀ = 0.9 μΜ; VEGFR-2, IC ₅₀ = 1,17 μΜ), with higher power than the prototype of the literature, ie compound 7 (EGFR, IC ₅₀ = 9.70 μΜ; VEGFR-2, IC ₅₀ = 7.79 μΜ).

 Example 28 - Methodology used for bioassays

Biochemical assay of EGFR and VEGFR-2 tyrosine kinase activity

A radiometric tyrosine kinase activity assay ( ³³ PanQinase ^® ) was employed to measure the inhibition ability of the enzymatic activity of the protein kinases in question by the synthesized derivatives, ie their ability to inhibit enzyme substrate phosphorylation by the previously activated enzyme. All assays were performed in a 96-well plate (Perkin Élmer, Boston, MA, USA) in a reaction volume of 50 μΙ_. The assay for all enzymes contained 70 mM HEPES-NaOH, pH 7.5, 3 mM MgCl ₂ , 3 mM MnCl ₂ , 3 μΜ sodium orthovanate, 1.2 mM DTT, 1 μΜ ΑΤΡ / [γ- ³³ Ρ ] -ΑΤΡ (approx. 5 x 10 ⁵ cpm / well). The enzyme and substrate amounts per well employed were: EGF-Rwt / poly (Glu, Tyr) _4: i: 10 ng / 125 ng and VEGF-R2 / poly (Glu, Tyr) _4: i: 25 ng / 125 ng . Reaction mixtures were incubated at 30 ° C for 60 minutes. Reactions were stopped by the addition of 50 μΙ 2% (v / v) H3PO4, plates were aspirated and washed twice with 200 μΙ 0.9% (w / v) NaCl. Incorporation of ³³ Pi into the enzyme substrate was determined on the scintillation counter (Microbeta, PerkinElmer, Boston, MA, USA). Residual kinase activity for each compound and Cl ₅₀ values were calculated using Quattro Workflow V3.1.0 (Quattro Research GmbH, Munich, Germany; www.quattroresearch.com).

Claims

Claims 1 . 2-Chloro-4-anilino-quinazolinic compounds characterized by inhibiting protein tyrosine kinases and having general formula (I):

 Where: Y is SO ₂ or CO; R ₅ represents DC alkyl, OH, NR ₄ R _5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (Ci-C ₅ alkyl) piperazinyl, 4-aryl-piperazinyl; R ₂ and R ₃ independently correspond to H, C ₁ -C ₅ alkyl, C 1 -C ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5 or 6 membered heterocyclic ring containing 1 to 2 independently selected atoms. O, N, S; R ₄ and R ₅ independently correspond to H, CC ₃ alkyl;  or pharmaceutically acceptable salts thereof.  Compounds according to claim 1, characterized in that the tyrosine kinases are EGFR and / or VEGFR-2.  Compounds according to claim 1, characterized in that they are selected from the group comprising;  2-chloro-6,7-methylenedioxy-N- (4- (methylsulfonyl) phenyl) quinazolin-4-amine (8a); 2-chloro-N- (4- (ethylsulfonyl) phenyl) -6,7-methylenedioxyquinazolin-4-amine (8b); 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonamide (8c - hereinafter called LASSBio-1815); 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonic acid (8d); 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) - [N-methylbenzenesulfonamide (8e); 4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) -N-ethylbenzenesulfonamide (8f); 4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) -A / ₎ N -dimethylbenzene sulfonamide (8g - hereafter called LASSBio-1807); 2-Chloro-6-methylenedioxy-N- (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-am (8h);  2-chloro-6β-methylenedioxy-Î ± - (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (8i); 2-chloro-6-methylenedioxy-N- (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (8j); 2-chloro-6-methylenedioxy- N- (4- (piperazin-1-ylsulfonyl) phenyl) quinazoline-4-amine (8k);  2-chloro-6-methylenedioxy-N- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (81);  2-chloro-6,7-methylenedioxy-N- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazolinamine (8m);  1- (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) ethanone (8n);  1- (4- (2-chloro-6,7-methylenedioxyquinazin-4-ylamino) phenyl) propan-1-one (8th); 4- (2-chloro-6-methylenedioxyquinazolin-4-ylamino) benzamide (8p); 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzoic acid (8q);  4- (2-chloro-67-methylenedioxyquinazolin-4-namino) -N-methylbenzamide (8r);  4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) - [V-ethylbenzamide (8s);  4- (2-doro-6,7-methylenedioxyquinazolin-4-ylamino) - [R, N] -dimethylbenzam (8t); (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) (piperidin-1-yl) methanone (8u);  (4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) phenyl) (morpholino) meta (8v);  (4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) phenyl) (thiomorpholino) methyl (8w);  (4- (2-Doro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) (piperazin-1-yl) m (8x); (4- (2-chloro-67-methylenedioxyquinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone (8y); (4- (2-chloro-67-methylenedioxyquinazolin-4-yarynino) phenyl) (4-phenylpiperazin-1-yl) methanone (8z);  2-chloro-6,7-dimethoxy-N- (4- (methylsulfonyl) phenyl) quinazolin-4-amine (9a); 2-chloro-N- (4- (ethylsulfonyl) phenyl) -67-dimethoxyquinazolin-4-amine (9b); 4- (2-chloro-6-dimethoxyquinazolin-4-ylamino) benzenesulfonamide (9c - hereinafter called LASSBio-1814); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonic acid (9d); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) - [N-methylbenzenesulfonamide (hereinafter called LASSBio-1816);  4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) - [N-ethylbenzenesulfonamide (9f); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”, Î ± -dimethylbenzenesulfonamide (9g - hereinafter called LASSBio-1808);  2-chloro-6,7-dimethoxy-N- (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (9h); 2-chloro-6,7-dimethoxy-N- (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (9i); 2-chloro-6,7-dimethoxy-N- (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (9j); 2-chloro-6,7-dimethoxy-N- (4- (piperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (9k); 2-chloro-6,7-dimethoxy-N- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (91);  2-chloro-67-dimethoxy-N- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (9m);  1- (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) ethanone (9n); 1- (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) propan-1-one (9th); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzamide (hereinafter called LASSBio-1819); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzoic acid (9q); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”-methylbenzamide (9r); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”-ethylbenzamide (9s); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) - [R], N-dimethylbenzamide (9t); (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) (piperidin-1-yl) methanone (9u); (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) (morpholino) methanone (9v); (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) (thiomorpholino) methanone (9w); (4- (2-chloro-6-dimethoxyquinazolin-4-ylamino) phenyl) (piperazin-1-yl) methanone (9x); (4- (2-chloro-6-dimethoxyquinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone (9y);  (4- (2-chloro-6-dimethoxyquinazolin-4-ylamino) phenyl) (4-phenylpiperazin-1-yl) methanone (9z);  2-chloro-N- (4- (methylsulfonyl) phenyl) quinazolin-4-amine (10a); 2-chloro- [N- (4- (ethylsulfonyl) phenyl) quinazolin-4-amine (10b); 4- (2-chloro-quinazolin-4-ylamino) benzenesulfonamide (10c); 4- (2-chloro-quinazolin-4-ylamino) benzenesulfonic acid (10d); 4- (2-chloro-quinazinin-4-ylamino) -Î ”-methylbenzenesulfonamide (10e); 4- (2-chloro-quinazolin-4-ylamino) -Î ”-ethylbenzenesulfonamide (10f); 4- (2-chloro-quinazolin-4-ylamino) -Î ”Î ±, Î ± -dimethylbenzenesulfonamide (10g); 2-chloro-N- (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (10h); 2-chloro- [V- (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (10i); 2-chloro-N- (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (10j); 2-chloro-N- (4- (piperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (10k); 2-chloro- [N- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (101); 2-chloro-N- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (10m); 1- (4- (2-chloro-quinazolin-4-ylamino) phenyl) ethanone (10n); 1- (4- (2-chloro-quinazolin-4-ylamino) phenyl) propan-1-one (10 O); 4- (2-chloro-quinazolin-4-ylamino) benzamide (10p); 4- (2-chloro-quinazolin-4-ylamino) benzoic acid (10q); 4- (2-chloro-quinazolin-4-ylamino) -Î ”-methylbenzamide (10r); 4- (2-chloro-quinazolin-4-ylamino) -Î ”-ethylbenzamide (10s); 4- (2-chloro-quinazolin-4-ylamino) - N, N-dimethylbenzamide (10t); (4- (2-chloro-quinazinin-4-ylamino) phenyl) (piperidin-1-yl) methanone (10u); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (morpholino) methanone (10v); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (thiomorpholino) methanone (10w); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (piperazin-1-yl) methanone (10x); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone (10y); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (4-phenylpiperazin-1-yl) methanone (10z); and combinations thereof.  4. Pharmaceutical composition comprising:  a) 2-chloro-4-anilino-quinazolinic protein tyrosine kinase inhibitors and p

 Where: Y is SO ₂ or CO; R is C _r C ₅ alkyl, OH, NR ₄ R _5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- (C _r C ₅ alkyl) piperazinyl, 4-aryl-piperazinyl; R ₂ and R ₃ independently correspond to H, C ₁ -C ₅ alkyl, C ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5 or 6 membered heterocyclic ring containing from 1 to 2 independently selected atoms. O. N, S; R ₄ and R ₅ independently correspond to H, C _r C ₃ alkyl;  or pharmaceutically acceptable salts thereof; and  b) a pharmaceutically acceptable carrier.  Composition according to Claim 4, characterized in that the tyrosine kinases are EGFR and / or VEGFR-2.  Composition according to Claim 5, characterized in that the compounds are selected from the group comprising: 2-chloro-6,7-methylenedioxy-Î ± - (4- (methylsulfonyl) phenyl) quinazolin-4-amine (8a); 2-chloro-N- (4- (ethylsulfonyl) phenyl) -6,7-methylenedioxyquinazolin-4-amine (8b); 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonamide (8c - hereinafter called LASSBío-1815); 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzenesulfonic acid (8d); 4- (2-chloro-6-methylenedioxyquinazolin-4-ylamino) -Î ”-methylbenzenesulfonamide (8e);  4- (2-chloro-6-methylenedioxyquinazolin-4-ylamino) -Î ”-ethylbenzenesulfonamide (8f); 4- (2-chloro-6-methylenedioxyquinazolin-4-ylamino) -? V,? V-dimethylbenzene sulfonamide (8g - hereafter called LASSBio-1807); 2-chloro-6α-methylenedioxy-Î ± - (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-ami (8h);  2-chloro-6-methylenedioxy-N- (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (8i); 2-chloro-6'-methylenedioxy-N- (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (8j); 2-chloro-6-methylenedioxy-N- (4- (piperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (8k);  2-chloro-6,7-methylenedioxy-N- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolinamine (81);  2-chloro-6,7-methylenedioxy- N- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazolinamine (8m);  1- (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) ethanone (8n);  1- (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) propan-1-one (8th); 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzamide (8p); 4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) benzoic acid (8q);  4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) -Î ”-methylbenzamide (8r);  4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) -Î ”-ethylbenzamide (8s);  4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) -N, N-dimethylbenzamide (8t); (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) (piperidin-1-yl) methanone (8u);  (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) (morpholino) methanone (8v);  (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) (thiomorpholino) methanone (8w);  (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) (piperazin-1-yl) methanone (8x); (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) (1) methanone (8y);  (4- (2-chloro-6,7-methylenedioxyquinazolin-4-ylamino) phenyl) (4-phenylpiperazin-1-yl) methanone (82);  2-chloro-67-dimethoxy-N- (4- (methylsulfonyl) phenyl) quinazolin-4-amine (9a); 2-chloro-N- (4- (ethylsulfonyl) phenyl) -6,7-dimethoxyquinazolin-4-amine (9b); 4- (2-chloro-6-dimethoxyquinazolin-4-ylamino) benzenesulfonamide (9c - hereinafter called LASSBio-1814); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzenesulfonic acid (9d); 4- (2-chloro-67-dimethoxyquinazolin-4-ylamino) - [N-methylbenzenesulfonamide (hereinafter called LASSBío-1816);  4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) - [N-ethylbenzenesulfonamide (9f); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”, Î ± -dimethylbenzenesulfonamide (9g - hereinafter called LASSBio-1808);  2-chloro-6,7-dimethoxy-N- (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (9h); 2-chloro-6,7-dimethoxy-N- (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (9i); 2-chloro-6,7-dimethoxy-N- (4- (thiomorpholinenesulfonyl) phenyl) quinazolin-4-amine (9j); 2-chloro-6,7-dimethoxy-N- (4- (piperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (9k); 2-chloro-6,7-dimethoxy-N- (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (91);  2-Chloro-6-dimethoxy-N- (4- (4-phenylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (9m);  1- (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) ethanone (9n); 1- (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) propan-1-one (9th); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzamide (hereinafter called LASSBio-1819); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) benzoic acid (9q); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”-methylbenzamide (9r); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) - N-ethylbenzamide (9s); 4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) -Î ”, N-dimethylbenzamide (9t); (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) (piperidin-1-yl) methanone (9u); (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) (morpholino) methanone (9v); (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) (thiomorpholino) methanone (9w); (4- (2-chloro-6-dimethoxyquinazolin-4-ylamino) phenyl) (piperazin-1-yl) methanone (9x); (4- (2-chloro-6,7-dimethoxyquinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone (9y);  (4- (2-chloro-6β-dimethoxyquinazolin-4-ylamino) phenyl) (4-phenylpiperazin-1-yl) methanone (9z);  2-chloro- [N- (4- (methylsulfonyl) phenyl) quinazolin-4-amine (10a); 2-chloro- [N- (4- (ethylsulfonyl) phenyl) quinazolin-4-amine (10b); 4- (2-chloro-quinazolin-4-ylamino) benzenesulfonamide (10c); 4- (2-chloro-quinazolin-4-ylamino) benzenesulfonic acid (10d); 4- (2-chloro-quinazolin-4-ylamino) -Î ”-methylbenzenesulfonamide (10e); 4- (2-chloro-quinazolin-4-ylamino) - [N-ethylbenzenesulfonamide (10f); 4- (2-chloro-quinazolin-4-ylamino) -N, p-dimethylbenzenesulfonamide (10g); 2-chloro- [N- (4- (piperidin-1-ylsulfonyl) phenyl) quinazolin-4-amine (10h); 2-chloro- [V- (4- (morpholinosulfonyl) phenyl) quinazolin-4-amine (10i); 2-chloro-N- (4- (thiomorpholinosulfonyl) phenyl) quinazolin-4-amine (10j); 2-chloro- [N- (4- (piperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (10k); 2-chloro-Î ± - (4- (4-methylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (101); 2-chloro- [N- (4- (4-enylpiperazin-1-ylsulfonyl) phenyl) quinazolin-4-amine (10m); 1- (4- (2-chloro-quinazolin-4-ylamino) phenyl) ethanone (10n); 1- (4- (2-chloro-quinazolin-4-ylamino) phenyl) propan-1-one (10 °); 4- (2-chloro-quinazinin-4-ylamino) benzamide (10p); 4- (2-chloro-quinazolin-4-ylamino) benzoic acid (10q); 4- (2-chloro-quinazolin-4-ylamino) -1H-methylbenzamide (10r); 4- (2-chloro-quinazolin-4-ylamino) -Î ”-ethylbenzamide (10s); 4- (2-chloro-quinazolin-4-ylamino) -Î ”Î ±, Î ± -dimethylbenzamide (10t); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (piperidin-1-yl) methanone (10u); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (morpholino) methanone (10v); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (thiomorpholino) methanone (10w); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (piperazin-1-yl) methanone (10x); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (4-methylpiperazin-1-yl) methanone (10y); (4- (2-chloro-quinazolin-4-ylamino) phenyl) (4-phenylpiperazin-1-yl) methanone (10z); and combinations thereof.  7. Process of producing compounds according to general formula d):

characterized by comprising the steps of: a) cyclization of a compound of formula (II):

to produce a compound of formula (III):

b) chlorination of the compound obtained in the previous step generating a compound of formula (IV):

and c) amination of the compound obtained in the previous step with an amine of formula (V):

Where: Y is SO ₂ or CO; R is C _r C ₅ alkyl, OH, NR ₄ R _5, morpholinyl, thiomorpholinyl, piperidinyl, piperazinyl, 4- {C ^ C ₅ alkyl) piperazinyl, 4-aryl-piperazinyl; R ₂ and R ₃ independently correspond to H, C _r C ₅ alkyl, CC ₅ alkyl ether, aryl, aryl ether or R ₂ and R ₃ together form a 5- or 6-membered heterocyclic ring containing from 1 to 2 selected atoms independently from O, N, S; R ₄ and R ₅ independently correspond to H, CC ₃ alkyl; and R ₆ corresponds to H or NH ₂ .  Process according to Claim 7, characterized in that it further comprises steps of interconversion of functional groups and / or regioselective aromatic electrophilic substitution.