OA16290A - Heterocyclic compounds, their preparation and their therapeutic application. - Google Patents

Abstract

The invention is directed to certain novel compounds, methods for producing them and methods for treating or ameliorating a kinasemediated disorder.

Description

HETEROCYCLIC COMPOUNDS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION.

The invention is directed to certain novel compounds, methods for producing them and methods for treating or ameliorating a disorder involving tyrosine kinase dysrégulation such as disorder associated with increased vascular permeability or angiogenesis. More particularly, this invention is directed to substituted triazolopyridine compounds useful as sélective kinase inhibitors, methods for producing such compounds and methods for treating, preventing or ameliorating a kinase-mediated disorder. In particular, the methods relate to treating or ameliorating a disorder involving tyrosine kinase dysrégulation including cardiovascular diseases, diabètes, diabetes-associated disorders, inflammatory diseases, immunological disorders, cancer and diseases of the eye such as rétinopathies, macular degeneration or other vitreoretinal diseases, and the like.

Passage of fluid and cells out of blood vessels is a signifîcant contributing factor to inflammation, tissue injury, oedema and death in a variety of circumstances. These include ischémie injury, toxic shock, burns, trauma, allergie and immune reactions. Vascular permeability is regulated in part by cell-cell adhesions between endothélial cells. The endothélial cell monolayer lining the vasculature forms a barrier that maintains the integrity of the blood fluid compartment, but permits passage of soluble factors and leukocytes in a regulated manner. Dysrégulation of this process results in vascular leakage into surrounding tissues, which accompanies the inflammation associated with pathological oedematous conditions. Vascular permeability is a finely-tuned function that can positively contribute to protective immune responses and wound healing; however, in a number of pathological situations, massive and/or chronic leakage of fluid as well as migration of immune cells into tissues can hâve serious, and sometimes, life-threatening conséquences.

Abnormal retinal vascular permeability leading to oedema in the area of the macula is the leading cause of vision loss in diseases such as diabetic retinopathy, exudative macular degeneration, retinal vascular occlusions, and inflammatory and neoplastic conditions. Although a variety of disease processes may lead to increased vascular permeability through different mechanisms, the cytokine VEGF is known to play a major rôle as inducer of vascular leakage. VEGF was first described as a potent vascular permeability factor (VPF) secreted by tumour cells that stimulated a rapid and réversible increase in microvascular permeability. Increased vascular permeability in ischémie rétinopathies and possibly also in exudative macular degeneration and uveitis, for example, correlated with VEGF levels and VEGF antagonists hâve been successfully

-2used to reduce retinal/macular oedema in neovascular eye dîseases such as age-related macular degeneration leading to stabilization or even improvement of visual acuity in a subset of affected patients. The way by which VEGF induces vascular permeability has recently been unravelled and it has been shown that VEGF-induced vascular leakage is mediated by cytoplasmic protein kinase members of the Src proto oncogene family.

Protein kinases play a central rôle in the régulation and maintenance of a wide variety of cellular processes and cellular fonctions. For example, kinase activity acts as a molecular switch regulating cell prolifération, activation, and/or différentiation. It is now widely accepted that many dîseases resuit from abnormal cellular responses triggered by overactive protein kinase-mediated pathways.

Src kinases form a family of membrane-attached non receptor-dependent tyrosine kinases encompassing eight members in mammals: Src, Fyn, Yes, Fgr, Lyn, Hck, Lck, and Blk which have important rôles in receptor signalling and cellular communication. While most Src kinases are broadly expressed (i.e. Src, Fyn, Yes), certain members of the family such as Hck, Blk or Lck exhibit a restricted expression. Src kinases play a pivotai rôle as membrane-attached molecular switches that link a variety of extracellular eues to intracellular signalling pathways. This is the basis for the involvement of Src kinases in cell prolifération and différentiation as well as cell adhesion and migration.

It has been well-documented that Src protein levels and Src kinase activity are signifîcantly elevated in human cancers including breast cancers, colon cancers, pancreatic cancers, certain B-cell leukemias and lymphomas, gastrointestinal cancer, non-small cell lung cancers, bladder cancer, prostate and ovarian cancers, melanoma and sarcoma. Thus, it has been anticipated that blocking signalling through the inhibition ofthe kinase activity of Src will be an effective means of modulating aberrant pathways that drive oncologie transformation of cells.

Similarly, it is well documented that Src-family kinases are also important for signalling downstream of immune cell receptors. Fyn, like Lck, is involved in TCR signalling in T cells. Hck and Fgr are involved in Fcy receptor signalling leading to neutrophil activation. Lyn and Src also participate in Fcy receptor signaling leading to release of histamine and other allergie mediators. These findings suggest that Src family kinase inhibitors may be useful in treating allergie dîseases and asthma.

In accordance with the effect of VEGF on vascular permeability, several reports support a rôle of Src kinase in the development of oedema. For instance, Src but not Fyn deficiency or blockade of Src reduced brain oedema by about 55% following permanent

-3cerebral ischemia in mice. Recently, PP1, a Src tyrosine kinase inhibitor was found to decrease oedema, to decrease breakdown of the brain-blood barrier (BBB), to reduce expression of VEGF. Similariy, Scheppke et al. hâve shown that Src kinases are critical mediators of VEGF- and ischemia-induced retinal vascular leakage.

Furthermore, Src tyrosine kinases fully médiate VEGF receptor signalling in vascular endothélial cells. Thus, activation of Src kinases resulting from stimulation of VEGF receptor or other growth factor located on endothélial cells or progenitors triggers angiogenesis, a response which can be deleterious in retinal and comeal diseases and which markedly contributes to tumor development and metastasis migration.

Several classes of compounds hâve been disclosed that modulate or, more specifically, inhibit kinase activity as potential treatments of kinase-mediated disorders, particularly cancer.

For example, W02001038315 describes aminoquinazolines as inhibîtors of cyclindependent kinases.

W02008068507 describes pyridinylquinazolines as Raf serine/threonine kinase inhibîtors for treating cancer.

W02008079988 describes quinazolines as PDK1 kinase inhibîtors for treating proliférative diseases such as cancer.

W02006118256 describes quinazoline dérivatives as p38MAPK inhibîtors for inhalation and for treating various inflammatory diseases and cancer.

W02006039718 describes aryl nitrogen-containing bicyclic compounds for use in treating protein kinase-mediated disease, including inflammation, cancer and related conditions.

W02005037285 describes 2,6-disubstituted bicyclic heterocycles as Raf senne/threonine kinase inhibîtors for treating disorders such as cancer.

W02009046448 describes PI3 kinase activity modulators having substituted aminoquinazoline on the pyrimidine part of the quinazoline bicycle.

W02009084695 describes aminoquinazoline dérivatives substituted by two nonaromatic substituents.

W02008020203 describes aminoquinazoline dérivatives substituted by pyridine on the phenyl part of the quinazoline bicycle and having B-Raf inhibiting activity.

-4US20100093698 describes aminotriazolopyridines dérivatives substituted in position 5 and having Syk kinase inhibition activity.

W02004065378 describes 2-aminopyridines as cdk4 inhibitors for treating cell proliférative disorders such as cancer, atherosclerosis and restenosis.

Interestingly, W02006024034 describes heterocyclic compounds derived from benzotriazine, triazines, triazoles and oxadiazoles, such as benzotriazine compounds (W02005096784) or pyrimidine compounds (W02006101977) which are capable of inhibiting kinases, such as members of the Src kinase family. Nevertheless, these drugs while they are claimed as potentially useful as for treatment of various ophthalmological diseases (e.g. age-related macular degeneration, diabetic retinopathy, diabetic macular oedema, cancer, and glaucoma) are lipophilie and water insoluble (see W02006133411). According to the inventors of W02006133411, these spécifie properties are particularly advantageous, particularly for ophthalmic uses, since these drugs being insoluble in water (water solubility of less than about 0.1 mg/mL at a pH range of 4-8) possess high efficiency of loading and negligible leakage due to high partrtioning of the drug into the liposome used for delivering them compared to the water.

WO 2010076238 describes mono-substituted aminoquinazoline dérivatives having a good IC50 against src and lyn kinases.

Src kinases inhibitors described in US2005/0245524 are bright red in colour and very insoluble in formulations suitable for delivery by eye drops. These two parameters represent an important drawback for the compounds disclosed in US2005/0245524.

The eye is a tightly protected organ. In this respect, treating diseases of the backof-the-eye is probably the most difficult and challenging task of drug discovery as evidenced by the paucity of therapeutic options. One of the most convenient and safest form of drug delivery to the eye is eye drops, since it is non invasive, does not require medical assistance and requires small volumes of drug solution. However, in order to be suitable for topical instillation, molécules hâve to be potent enough towards their molecular target, to présent physico-chemical properties allowing crossing of cell membranes, and to be sufficiently soluble in aqueous medium to be applied as solution onto the comea. In addition, it is crucial that such drug molécules are as colourless as possible to prevent staining of ocular tissue which ultimately may interfer with vision. Additionally, due to the multiple cross reactivity between kinases, it is highly désirable that said drug molécules inhibit the targeted kinases with a high degree of selectivity.

-5A feature of the présent invention is to provide novel compounds which hâve increased water solubility compared to competitors.

Another feature of the présent invention is to provide compounds that are highly potent, particularly towards src kinase inhibitors.

Another feature of the présent invention is to provide compounds which are useful for treating, preventing or ameliorating a disorder, including an ophthalmic disorder, involving tyrosine kinase dysrégulation such as for example disorder associated with increased vascular permeability or angiogenesis.

Another feature of the présent invention is to provide compounds which are 10 colourless or almost colourless, especially in solution.

Additional features and advantages of the présent invention will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of the présent invention. The objectives and other advantages of the présent invention will be realized and attained by means of the éléments and 15 combinations particularly pointed out in the description and appended claims.

The invention relates to compound of the general formula below:

R3 I

R5 wherein

A is an aryl, an heterocycloalkyl, a -N-aryl, a -O-aryl, an heteroaryl, or a partially saturated heterocycloalkyl;

B is an heteroaryl or an aryl;

R1 and R2 are linked on a cycle and represent independently from each other: Ή,

-OH, an halogen atom,

-OiCiCeJalkyl, (CrCe) alkyle,

-(CH_;)_nOH,

-NH₂, t?

-6N-oxide wherein the nitrogen atom belongs to A, with the provisio that R1 and R2 can both be hydrogen atoms only when A is a heterocycloalkyl, a -O-aryl, an heteroaryl or a partially substituted heterocycloalkyle;

R3, R4 and R5 are, independently from each other,

-H,

-(CH₂)_nOH,

-OCCAJalkyl,

-(CH₂)_ri-CO-heterocycloalkyl,

-OH,

-heterocycloalkyl-(CH₂)_n-OH,

-(Ο,-Οο) alkyl,

-(CH₂)n-heterocycloalkyl,

-(CH₂)_n-heterocycloalkyl-(CH₂)_n-OH,

-0-(CH₂)_n-heterocycloalkyl,

N-oxide wherein the nitrogen atom belongs to B, -0-(CH₂)_n-CO-heterocycloalkyl,

-O-(CH₂)_n-OH,

-O(CiC₆)alkyl-NR7R8,

-(CiCeJalkyl-NRÏRS, with the provisio that when A and B are aryl, at least two of R3, R4 and R5 are not hydrogen;

R6 is H, -O(C_tC₆)alkyl, or (CiC₆)alkyl;

R7 and R8 are independently from each other H or (CjCelalkyl;

n is 1, 2 or 3;

X is N or C; and

Y is C or a bond, as well as a prodrug thereof.

According to one embodiment, the invention concems compounds of formula (I) as well as a prodrug of compounds of formula (I) :

R6 (D

N

-7wherein

A is phenyl;

B îs phenyl, pyridine, or pyrimidine

R1 and R2 represent independently from each other:

-H,

-OH, a halogen atom, with the provisio that R1 and R2 are not simultaneously hydrogen atoms;

R3, R4 and R5 are, independently from each other,

-H,

-(CH₂)_nOH,

-OfC^alkyl,

-(C H₂)_n-CO-heterocycloalkyl,

-OH,

-heterocycloalkyl-(CH₂)_n-OH,

-(CrCa) alkyl,

-(CH₂)_n-heterocycloalkyl,

-(CH₂)_n-heterocycloalkyl-(CH₂)_n-OH,

-0-(CH₂)_n-heterocycloalkyl,

N-oxide wherein the nitrogen atom belongs to B,

-0-(CH₂)_n-CO-heterocycloalkyl,

-O-(CH₂)_n-OH,

-O(CX₆)alkyl-NR7R8,

-(C,C₆)alkyl-NR7R8,

- or R3 and R4 form together with B a fused bicycle (such as for example indole or benzimidazole, optionally substituted by R5, with the provisio that when A and B are aryl, at least two of R3, R4 and R5 are not hydrogen;

R6 is H, -OfC^alkyl, or (CiC₆)alkyl;

R7 and R8 are independently from each other H or an optionally substituted (C-iCsialkyl optionally forming a cycloalkyl;

n is 1,2 or 3;

X is N or C; and

Y is CH or a covalent bond.

H

-8This group of compounds of the Invention can be represented by formula (la) below :

R3 l

B'R4

R5 wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defïned in the invention according to any embodiment or combination thereof.

In the context of the présent spécification, the terms defïned below should be uderstood as having the meaning defïned next to each term:

- “a” and “an” are used in the sense that they mean “at least one, “at least a first, “one or more or “a plurality of the referenced compounds or steps, unless the context dictâtes otherwise. More specifically, “at least one and “one or more” means a number which is one or greater than one, with a spécial preference for one, two or three;

- and/or'’ wherever used herein includes the meaning of and, or and ail or any other combination of the éléments connected by said term;

- about or approximately means within 20%, preferably within 10%, and more preferably within 5% of a given value or range;

- comprising, “containing” when used to define products, compositions and methods, is intended to mean that the products, compositions and methods include the referenced compounds or steps, but not excluding others;

- treatment or “treating encompasses prophylaxis and/or therapy. Accordingly the compositions and methods of the présent invention are not limited to therapeutic applications and can be used in prophylaxis ones. Therefore treating or treatment of a state, disorder or condition includes: (i) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a subject that may be afîlicted with or predisposed to the state, disorder or condition but does not yet expérience or display clinical or su b clinical symptoms of the state, disorder or condition, (ii) inhibiting the state, disorder or condition, i.e., arresting or reducing the development of the disease or at least one clinical or subclinical symptom thereof, or (iii) relieving the disease, i.e. causing

-9regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms;

- patient and “subject in need thereof are intended to mean any animal; such as a vertebrate, a member of the mammalian species and includes, but is not limited to, domestic animais (e.g. cows, hogs, sheep, horses, dogs, and cats), primates including humans. The terms “patient “subject in need thereof are in no way limited to a spécial disease status, it encompasses both patients who hâve already developed a disease of interest and patients who are not sick.

-“therapeutically active compound” means any compound, optionally in a composition, that will elicit a desired biological response of a tissue, animal, or human, cell, or organ, for example.

- “therapeutically effective amount” means any amount of a therapeutically active compound or composition.- “prodrug” means any compound administered in an inactive or significantly less active form than after its bioactivation. Once administered, the prodrug is metabolised in vivo into a therapeutically active compound (drug). This process is termed bioactivation. This bioactivation takes place in one or more steps, i.e. by providing one or more métabolites. A prodrug is usually not a therapeutically active compound itself and will usually not elicit in vitro the biological response of the corresponding therapeutically active compound after bioactivation. According to the présent invention bioactivation takes place particularly in the comea. This can be tested with Ussing chambers for example.

- “halogen” means any one of fluoro, chloro, bromo or iodo;

- “cycle”: means a cycloalkyl, a heterocycloalkyl, a heterocycloalkyl partially substituted, an aryl or a heteroaryl;

- “cycloalkyl” means a saturated monocyclic carbocycle containing from 3 to 7 carbon atoms. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl and the like;

- “heterocycloalkyl means a saturated mono- or bicyclic heterocycle having from 3 to 14 atoms, for example from 5 to 10 or from 5 to 6 atoms, and comprising at least one heteroatom selected from nitrogen, oxygen and sulphur. If the heterocycloalkyl contains more than one heteroatom, the heteroatoms can be identical or different. When substituted, the moiety can be substituted either on a carbon atom or on a heteroatom; similarly, the heterocycloalkyl can be attached to the rest of the molécule via a carbon atom or a heteroatom. Examples of heterocycloalkyl are pyrrolidine, piperidine, piperazine, morpholine and the like;

- “heterocycloalkyl partially saturated” means an heterocycloalkyl comprising at least one double bond, but not enough double bonds to be considered as aromatic ;

- “aryl includes mono- and bicyclic aromatic carbocycles. Examples of aryl include phenyl, 1-naphthyl, 2-naphthyl,;

- “heteroaryl means an aromatic mono- or bicyclic aryl wherein each cycle comprises from 5 to 10 atoms, for example from 5 to 6 atoms, and comprising at least one heteroatom selected from nitrogen, oxygen and sulphur. If the heteroaryl contains more than one heteroatom, the heteroatoms can be identical or different. When substituted, the moiety can be substituted either on a carbon atom or on a heteroatom; similarly, the heteroaryl can be attached to the rest of the molécule via a carbon atom or a heteroatom. Examples of heteroaryl are pyridine, indole, benzofuran, oxazole, triazole, pyrimidine, pyrazole , indazole, benzimidazole and the like ;

- in “(C_rC₆)”, the numbers define the possible number of atoms présent in the chain or the cycle ;

- “alkyl is a saturated aliphatic group, either linear or branched. For example, a Ο_ν C₆alkyl represents a carbonated chain comprising from 1 to 6 carbon atoms, either linear or branched, such as for example a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, pentyl.

The term “compound herein is in general referring to compounds of formula I, or pharmaceutically acceptable prodrug, thereof.

Among the compounds of formula (I) that are subject matter of the invention, a first group is compounds of formula (11) below:

Among the compounds of formula (I) a second group is compounds of formula (III) below:

- Il -

below:

Among the compounds of formula (I) a third group is compounds of formula (IV)

Among the compounds of the Invention, a fourth group of compounds is those having R1 and R2 in positions 3 and 6 ofthe phenyl ring.

Among the compounds of formula (I) a fifth group is compounds of formula (V) below:

Among the compounds of formula (I) a sixth group is compounds of formula (VI) below:

(VI)

Among the compounds of formula (I) a seventh group is compounds of formula (VII) below:

R5 (VII)

!6

-12Among the compounds of formula (I) a eighth group is compounds of formula (VIII) below:

(VIII)

Among the compounds of formula (I) a ninth group is compounds of formula (IX)

(IX)

Among the compounds of formula (I) a tenth group is compounds of formula (X) below:

(X)

Among the compounds of formula (I) an eleventh group is compounds of formula (XI) below:

wherein R10 is

-H,

-(CH₂)_nOH,

-OtCnCeialkyl,

-(CH2)_n-CO-heterocycloalkyl, -OH,

-heterocycloalkyl-(CH2)n-OH,

-(C_rC₆) alkyl,

-(CH₂)_n-heterocycloalkyl,

- 13-(CH₂)_n-heterocycloalkyl-(CH₂)_n-OH,

-O-(CH₂)_n-heterocycloalkyl,

N-oxide wherein the nitrogen atom belongs to B,

-O-(CH₂)_n-CO-heterocycloalkyl,

-O-(CH₂)_n-OH,

-OtC^eJalkyl-NRÏRe, or

-(CiCeJalkyl-NRTRS.

In above formulae R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in the invention according to any embodiment or combination thereof.

As apparent from skeletal formulae above, R6 is only bonded to the left ring of the bicycle.

In above formulae, a group of compounds is those wherein R1 is OH and R2 is a halogen atom. A particular halogen atom is chlorine or fluorine, and especially chlorine.

In above formulae, a group of compounds is those wherein R3, R4 and R5 represent independently from each other O-alkyl or hydroxyalkyl.

In above formulae, a group of compounds is those wherein R3, R4 and R5 represent independently from each other -CH₂OH, -0-CH₂-CH₂-heterocycloalkyl. For example, the heterocycloalkyl can be an optionally substituted pyrolidine, pyrrolidone, piperazine, or a morpholine. Particular substituents are -(C_rC₆) alkyl, and -(C<C₆)hydroxyalkyl.

In above formulae, a group of compounds is those wherein X represents a carbon atom and Y represents CH.

In above formulae, a group of compounds is those wherein X represents a nitrogen, and Y represents a bond.

In above formulae, a group of compounds is those wherein R6 represents a hydrogen atom or CH₃. R6 is a hydrogen atom in a particular embodiment.

Compounds of the invention include those of the Examples herein, in particular the following, and their prodrugs:

compound 1: 4-Chloro-3-[2-(pyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-ylJphenol compound 2: 4-Chloro-3-[2-(pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenol compound 3: 4-Chloro-3-[2-(pyrimidin-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenol compound 4: 4-Chloro-3-[2-(5-hydroxymethyl-pyridin-3-ylamino)- [1,2,4]triazolo[1,5-a]pyridin-6-yl]-phenol

- 14compound 5: 3-[2-(3,5-Bis-hydroxymethyl-phenylamino)-[1,2.4]triazolo[1,5-

a]pyridin-6-yl]-4-chloro-phenol compound 7: 4-Chloro-3-[2-(6-methoxy-pyridin-3-ylamino)-[1,2,4]triazolo[1,5-

a]pyridin-6-yl]-pheno[ compound 8: 4-Chloro-3-{2-[5-(2-pyrrolidin-1-yl-ethoxy)-pyridin-2-ylamino]- [1.2.4] triazolo[1,5-a]pyridin-6-yl}-phenol compound 10:4-Chloro-3-(2-{6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-3ylamino}-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenol compound 12:4-Chloro-3-[2-(pyridin-2-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phenol compound 13:4-Chloro-3-[2-(2-hydroxymethyl-pyridin-4-ylamino)- [1.2.4] triazolo[ 1,5-a]pyridin-6-ylJ-phenol compound 14:4-Chloro-3-[2-(6-hydroxymethyl-pyridin-3-ylamino)- [1,2,4]triazolo[ 1,5-a]pyridin-6-yl]-phenol compound 16:3-[2-(3,5-Bis-hydrOxymethyl-phenylamino)-quinazolin-6-yl]-4-chlorophenol

Compound 17:	4-Chloro-3-[2-(pyridin-3-ylamino)-quinazolin-6-yl]-phenol
Compound 18: a]pyridin-6-yl]-phenol	4-Chloro-3-i2-(1 H-indol-6-ylamino)-[1,2,4]triazolo[1,5-
Compound 19:	4-[6-(2-Chloro-5-hydroxy-phenyl)-[1,2,4]triazolo[1,5-aJpyridin-

2-ylamino]-pyridin-2-ol

Compound 20: 4-Chloro-3-[2-(2-methoxy-pyridin-4-ylamino)- [1,2,4]triazolo[1,5-a]pyridin-6-yl]-phenol

Compound 21:

4-Chloro-3-[2-(5-hydroxymethyl-pyridin-3-ylamino)-

qu i nazolin-6-yl]-phenol

Compound 25: 4-Chloro-3-{2-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-ylamino]- [1.2.4] triazolo[1,5-a]pyridin-6-yl}-phenol

Compound 26: 4-Chloro-3-{2-[5-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-ylamino]- [1.2.4] triazolo[1,5-a]pyridin-6-yl)-phenol

Compound 27: 4-Chloro-3-(2-[6-[4-(2-hydroxy-ethyi)-piperazin-1-yl]-2methyl-pyrimidin-4-ylamino}-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenol

Compound 28: 4-Chloro-3-(2-[3-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]-5methyl-phenylamino}-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenol

Compound 29: 4-Chloro-3-[2-(3,4,5-trimethoxy-phenylamino)- [1,2,4]triazolo[1,5-a]pyridin-6-yl]-phenol

K

-15Compound 30: 4-Chloro-3-{2-[3-(2-hydroxy-ethyl)-3H-benzoimidazol-5ylamrno]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-phenol

Compound 31: 4-Chloro-3-t2-(pyridin-3-ylamino)-[1,2,4]triazolo[1,5-a]pyridin7-yl]-phenol

Compound 33: 4-Chloro-3-(2-[2-(2-pyrrolidin-1-yl-ethoxy)-pyridin-4-ylamino]- [1,2,4]triazolo[1,5-a]pyridin-6-y[}-phenol

Compound 34: 3-[2-(3,5-Bis-hydroxymethyl-phenylamino)-[1,2,4]triazolo[1,5-

a]pyridin-7-yl]-4-chloro-phenol

Compound 35: 3-[2-(3,4-Bis-hydroxymethyl-phenylamino)-[1,2,4]triazolo[1,5-

a]pyridin-6-yl]-4-chloro-phenol

Compound 36: 4-Chloro-3-[2-(3,4,5-trimethoxy-phenylamino)-quinazolin-6yl]-phenol

Compound 38: 4-Chloro-3-(2-(2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-

4-ylamino}-[1,2,4]triazolo[1,5-a]pyridÎn-6-yl)-phenol

Compound 39: 4-Chloro-3-(7-methoxy-2-[4-(2-pyfTolidin-1-yl-ethoxy)phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}-phenol

Compound 40: 4-Chloro-3-[2-(6-methoxy-pyridin-3-ylamino)-quinazolin-6-yl]phenol

Compound 41: 4-Chloro-3-(2-(4-[2-(1 -oxy-pyrrolidin-1 -yl)-ethoxy]phenylamino}-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenol

Compound 42:	4-Chloro-3-[2-(1H-indol-6-ylamino)-quinazolin-6-yl]-phenol
Compound 43: quinazolin-6-yl]-phenol	4-Ch[oro-3-[2-(2-hydroxymethyl-pyridin-4-ylamino)-

Compound 44: 1-(2-{5-[6-(2-Chloro-5-hydroxy-phenyl)-[1,2,4]triazolo[1,5-

a]pyridin-2-ylamino]-pyridin-2-yloxy}-ethyl)-pyrrolidin-2-one

Compound 45: 4-Chloro-3-{2-[1-(2-hydroxy-ethyl)-1H-benzoimidazol-5ylamino]-quinazolin-6-yl}-phenol

Compound 46: 4-Chloro-3-(2-{3-[4-(2-hydroxy-ethyl)-piperazin-1 -y l]-5methyl-phenylamino}-quinazolin-6-yl>-phenol

Compound 47: 4-Chloro-3-(2~(3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-5hydroxymethyl-phenylamino}-[1>2,4]triazolo[1,5-a]pyridin-6-yl)-phenol

Compound 48: Benzoic acid 4-chloro-3-(2-(3-[4-(2-hydroxy-ethyl)-piperazin-

1-yl]-5-methyl-phenylamino}-[1.2,4]triazolo[1,5-a]pyridin-6-yl)-phenyl ester

Compound 49: Benzoic acid 4-chloro-3-(2-{3-[4-(2-hydroxy-ethyl)-piperazin1 -yl]-5-methyl-phenylamino)-quinazolin-6-yl)-phenyl ester $ C16290

-16Compound 50: 4-Chloro-3-(2-[3-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]-5hydroxymethyl-phenylamino}-quinazolin-6-yî)-phenol;

and any prodrug thereof.

A group of prodrugs is esters of compounds of above formulae, and in particular esters of benzoic acid with the phénol ring of above formulae (where R1 or/or R2 is -OH). Examples of prodrugs are:

Benzoic acid 4-chloro-3-(2-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-5-methylphenylaminoH¹,2,4]triazoio[1,5-a]pyridin-6-yl)-phenyl ester, and

Benzoic acid 4-chloro-3-(2-(3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-5-methylphenylam i no}-q uinazolin-6-yl)-phenyl ester.

According to another embodîment, the compounds of the Invention are either white or with a pale colour when in powder, and are uncoloured and transparent when in aqueous solution at active concentrations.

The compounds of the présent invention act primarily on src kinase.

According to another embodîment, the compounds of the Invention are src kinase inhibitors.

According to another embodîment, particular compounds of the Invention hâve an IC50 towards Src of less than about 15 nM, advantageously less than about 10 nM, for example less than about 1 nM, less than about 0,9 nM, or even less than about 0,5 nM.

According to another embodîment, there are provided compositions including one or more compounds of the Invention and a pharmaceutically acceptable carrier or aqueous medium.

As used herein, the term “pharmaceutically acceptable” refers to carriers that do not produce an adverse, allergie or other unwanted reaction when administered to an animal, or human, as appropriate. As used herein, “pharmaceutically acceptable carrier'’ includes any and ail solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonie and absorption delaying agents and the like. The use of such carriers for pharmaceutical active substances is well known in the art. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E. W. Martin. In a particular embodîment, the compounds of the Invention are formulated in accordance with routine procedures as a pharmaceutical composition adapted for

-17administration to the eye. Supplementary active ingrédients, such as anti-inflammatory agent, chemotherapeutic agent, anti-cancer agent, immunomodulatory agent, gene-based therapeutic vaccine, immunotherapy product, therapeutic antibody and/or protein kinase inhibitors can also be incorporated into the compositions,

According to one embodiment, the compounds of the présent invention will be formulated for parentéral administration, e.g., formulated for injection via the intravenous, intramuscular, subcutaneous, or even intraperitoneal routes. The préparation of an aqueous composition that contains a compound or compounds of the Invention will be within the skill of those in the art, in light of the présent dîsclosure. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for using to prépare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the préparations can also be emulsified.

According to a particular embodiment, the compounds of the présent invention will be formulated for topical administration of the compounds of the Invention, especially for the treatment of ophthalmic disorders. The préparation of a composition that contains a compound or compounds of the Invention will be within the skill of those in the art, in light of the présent dîsclosure. Typically, such compositions for topical administration can be prepared as ointment, gel or eye drops. The topical ophthalmic composition may further be an în situ gel formulation. Such a formulation comprises a gelling agent in a concentration effective to promote gelling upon contact with the eye or with lacrimal fluid in the exterior of the eye. Suitable gelling agents include, but are not limited to, thermosetting polymers such as tetra-substituted ethylene diamine block copolymers of ethylene oxide and propylene oxide (e.g., poloxamine); polycarbophil; and polysaccharides such as gellan, carrageenan (e.g., kappa-carrageenan and iotacarrageenan), chitosan and alginate gums. The phrase in situ gel labié” as used herein embraces not only liquids of low viscosity that form gels upon contact with the eye or with lacrimal fluid in the exterior of the eye, but also more viscous liquids such as semi-fluid and thixotropic gels that exhibit substantially increased viscosity or gel stiffness upon administration to the eye.

According to another embodiment, the compounds of the présent invention will be formulated for oral administration of the compounds of the Invention. The préparation of a composition that contains a compound or compounds of the Invention will be within the skill of those in the art, in light of the présent dîsclosure. Typically, such compositions for oral administration can be prepared as liquid solutions or suspensions, tablets, time release capsules and other solids for oral administration.

-18According to another embodiment, the compounds of the présent invention will be formulated for intratumoral administration of the compounds of the Invention. The préparation of a composition that contains a compound or compounds of the Invention will be within the skill of those in the art, in light of the présent disclosure. Typically, such compositions for intratumoral administration can be prepared as disclosed above for the other routes of administration.

According to another embodiment, the compounds of the présent invention will be formulated for inhaled administration of the compounds of the Invention. The préparation of a composition that contains a compound or compounds of the invention will be within the skill of those in the art, in light of the présent disclosure. Typically, such compositions for inhalation can be prepared as disclosed above for the other routes of administration.

According to another particular embodiment, the compounds of the présent invention will be combined with ophthalmologically acceptable preservatives, viscosîty enhancers, pénétration enhancers, buffers, sodium chloride, and water to form an aqueous, stérile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving a compound in a physiologically acceptable isotonie aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the compound. Furthermore, the ophthalmic solution may contain an agent to increase viscosîty, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxy propylmethylcellulose, methylcellulose, polyvinylpyrrolidone, or the like, to improve the rétention of the formulation in the conjunctival sac. Gelling agents can also be used, including, but not limited to, gellan and xanthan gum. In order to préparé stérile ophthalmic ointment formulations, the active ingrédient can be combined with a preservative in an appropriate vehicle, such as, minerai oil, liquid lanolin, or white petrolatum. The compounds are preferably formulated as topical ophthalmic suspensions or solutions, with a pH of about 5 to 8, and more preferably from about 6.5 to about 7.5. The compounds will normally be contained in these formulations in an amount 0.001% to 5% by weight, but preferably in an amount of 0.025% to 2% by weight. Thus, for topical présentation 1 to 2 drops of these formulations would be delivered to the surface of the eye 1 to 4 times per day according to the discrétion of a skilled clinician.

In another embodiment, there are provided methods of treating a disorder involving tyrosine kinase dysrégulation such as disorder associated with increased vascular permeability or angiogenesis, including the administration of a therapeutically

- 19effective amount of one or more compound of the Invention to a subject in need of such treatment.

According to one embodiment, the said disorder involving tyrosine kinase dysrégulation is a disorder associated with increased vascular permeability.

According to another embodiment, the said disorder involving tyrosine kinase dysrégulation is a disorder associated with angiogenesis.

In particular embodiment, the disorder involving tyrosine kinase dysrégulation is a disorder associated with a src kinase dysrégulation.

According to one embodiment, the said disorder involving tyrosine kinase dysrégulation is selected in the group consîsting of myocardial infarction, stroke, congestive heart failure, an ischemia or reperfusion injury, trauma, cancer, oedema, arthritis or other arthropathy, transplant rejection, autoimmune disease, bum, or acute or adult respiratory distress syndrome (ARDS), or ophthalmic disorders such as retinopathy or vitreoretinal disease, diabetic retinopathy, macular oedema, including diabetic macular oedema, macular degeneration, glaucoma, vascular leakage syndrome, inflammatory disease, or oedema, for example.

ln another embodiment, there are provided methods of treating an ophthalmic disorder associated with increased vascular permeability, including the administration of a therapeutically effective amount of one or more compound of the Invention to a subject in need of such treatment.

ln another embodiment, there are provided methods of treating a subject having or at risk of having cancer including administering to the subject a therapeutically effective amount of one or more compound of the Invention thereby treating the subject.

In another embodiment, there are provided methods of treating a subject having or at risk of having oedema and/or angiogenesis including administering to the subject a therapeutically effective amount of one or more compound of the Invention, thereby treating the subject.

ln another embodiment, there are provided methods of treating a subject having or at risk of having macular degeneration including administering to the subject a therapeutically effective amount of one or more compound of the Invention, thereby treating the subject.

ln another embodiment, there are provided methods of treating a subject having or at risk of having diabetic retinopathy including administering to the subject a

-20therapeutically effective amount of one or more compound of the Invention, thereby treating the subject.

In another embodiment, there are provided methods of treating a subject having or at risk of having macular oedema, including diabetic macular oedema, including admînistering to the subject a therapeutically effective amount of one or more compound of the Invention, thereby treating the subject.

In another embodiment, there are provided methods of treating a subject having or at risk of having glaucoma including admînistering to the subject a therapeutically effective amount of one or more compound of the Invention, thereby treating the subject.

In another embodiment, there are provided methods of treating a subject having or at risk of having retinopathy including admînistering to the subject a therapeutically effective amount of one or more compound of the Invention, thereby treating the subject.

In another embodiment, there are provided methods of treating a subject having or at risk of having vitreoretinal disease including admînistering to the subject a therapeutically effective amount of one or more compound of the Invention, thereby treating the subject.

In another embodiment, there are provided methods of treating a subject having or at risk of having inflammatory disease, including admînistering to the subject a therapeutically effective amount of one or more compound of the Invention, thereby treating the subject.

In yet another embodiment, there are provided methods of treating a disorder, including an ophthalmic disorder and cancer, associated with compromised vascular permeability including the administration of a therapeutically effective amount of one or more compound of the Invention in combination with an anti-inflammatory agent, chemotherapeutic agent, antitumoral agent, immunomodulatory agent, gene-based therapeutic vaccine, immunotherapy product, therapeutic antibody and/or a kinase inhibitor, to a subject in need of such treatment.

Administration of the compounds of the Invention, especially for ophthalmic applications, is preferably by topical administration. However, the invention is not limited to topical delivery in that it also includes for example intraocular and periocular injection, systemic delivery (e.g. oral or other parentéral route such as for example subcutaneous, intramuscular, intravenous administrations) or intratumoral delivery.

«L·

-21 In yet another embodiment, there are provided methods of delivering a compound of the Invention to the back of the eye, the method including preparing a composition including a pharmaceutically effective amount of at least one compound of the Invention and delivering said composition to the eye of a subject in need of such delivery.

In yet another embodiment, there are provided methods of delivering a compound of the Invention intratumoraly, the method including preparing a composition including a pharmaceutically effective amount of at least one compound of the Invention and delivering said composition to the tumor of a subject in need of such delivery.

To préparé a composition of the Invention, and more specifically an ophthalmic composition or antitumoral composition, a therapeutically effective amount of one or more compound of the Invention is placed in a vehicle as is known in the art. For example, topical ophthalmic formulations containing steroids are disclosed in US 5,041,434, whilst sustaîned release ophthalmic formulations of an ophthalmic drug and a high molecular weight polymer to form a highly viscous gel hâve been described in US 4,271,143 and US 4,407,792. Further GB 2007091 describes an ophthalmic composition in the form of a gel comprising an aqueous solution of a carboxyvinyl polymer, a water-soluble basic substance and an ophthalmic drug. Alternatively, US 4,615,697, discloses a controlled release composition and method of use based on a bioadhesive and a treating agent, such as an anti- inflammatory agent.

The amount of the compounds of the Invention to be administered and its concentration in the compositions used in the method of the Invention dépend upon the selected dissolving agent, delivery system or device, clinical condition of the patient, side effects and stability of the compound within the composition. Thus, the physician employs the appropriate préparation containing the appropriate concentration of the compounds of the Invention and selects the amount of formulation administered, depending upon clinical expérience with a given patient or with similar types of patients.

In another embodiment, there are provided processes for making one or more compound of the Invention or a prodrug thereof.

There are multiple synthetic routes for the préparation of the compounds of the invention, but ail rely on chemistry known to the synthetic organic chemist. Thus, compounds represented by Formula I can be synthesized according to procedures described in the literature and are well-known to one skilled in the art. Typical literature sources are “Advanced organic chemistry”, 4th Edition (Wiley), J March, “Comprehensive Organic Transformation”, 2nd Edition (Wiley), R. C. Larock, “Handbook of Heterocyclic

-22Chemistry”, 2nd Edition (Pergamon), A. R. Katritzky), review articles such as found in “Synthesis, “Acc. Chem. Res, “Chem. Rev, or primary literature sources identified by standard literature searches online or from secondary sources such as “Chemical Abstracts” or “Beilstein. Compounds of the invention can be synthesized by methods analogous to those exemplified in the Examples herein for certain représentative compounds. Using the procedures described in the Examples section, and well known procedures, one skilled in the art can préparé the compounds disclosed herein.

In another embodiment, there are provided kit including packaging material and a composition contained within the packaging material, wherein the packaging material includes a label which indicates that the composition can be used for treatment of disorders associated with compromised vascular permeability and wherein the composition includes one or more compound of the Invention.

In another embodiment, there are provided kit including packaging material and a composition contained within the packaging material, wherein the packaging material includes a label which indicates that the composition can be used for treatment of disorders associated with compromised vascular permeability and selected from myocardial infarction, stroke, congestive heart failure, an ischemia or reperfusion injury, cancer, arthritis or other arthropathy, retinopathy or vitreoretinal disease, macular degeneration, autoimmune disease, vascular leakage syndrome, infiammatory disease, edema, transplant rejection, bum, or acute or adult respiratory distress syndrome (ARDS) and wherein the composition includes one or more compound of the Invention.

In one particular embodiment, there are provided kit including packaging material and a composition contained within the packaging material, wherein the packaging material includes a label which indicates that the composition can be used for treatment of ophthalmic disorders associated with compromised vascular permeability and wherein the composition includes one or more compounds of the Invention, or one or more prodrugs of a compound of the Invention.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. The invention includes ail such variation and modifications. The invention also includes ail of the steps, features, formulations and compounds referred to or indicated in the spécification, individually or collectively and any and ail combinations or any two or more of the steps or features.

c16290

-23The présent invention is not to be limited in scope by the spécifie embodiments described herein, which are intended for the purpose of exemplification only. Functionally équivalent products, formulations and methods are clearly within the scope of the invention as described herein.

The invention described herein may include one or more range of values (eg size, concentration etc). A range of values will be understood to include ail values within the range, including the values defining the range, and values adjacent to the range which lead to the same or substantially the same outcome as the values immediately adjacent to that value which defines the boundary to the range.

The following examples are given to illustrate the préparation of compounds that are the subject of this invention but should not be construed as implying any limitations to the claims. The proton magnetic résonance spectrum of each compound of the Examples was consistent with the assigned structure.

EXAMPLES

- SYNTHESIS OF COMPOUNDS OF GENERAL FORMULA (I)

1.1. General method

Step A - Coupling of 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine or 6Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine to 1 eq of optionally substituted R1,R2-phenyl boronic acid in a polar solvent at -100 to 300°C, most preferably 50150°C

Step B - Coupling of (R3, R4, R5)-substituted bromo-phenyl to 1 eq of optionally substituted 7-phenyl (R1, R2 substituted)-[1,2,4ltriazolo[1,5-a]pyridin-2ylamine or 6-phenyl (R1, R2 substituted)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine in a polar solvent at -100°C to 300°C, most preferably 50-150°C

-24Cpn

The compounds of the formula I and also the starting materials for their préparation, are prepared by methods as described in the examples or by methods known per se, as described in the literature (for example in standard works, such as HoubenWeyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), to be précisé under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants which are known per se, but are not mentioned here in greater detail.

The starting materials for the claimed process may, if desired, also be formed in situ by not isolating them from the reaction mixture, but instead immediately converting them further into the compounds of the formula I. On the other hand, it is possible to carry out the reaction stepwise.

Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents are hydrocarbons, such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons, such as trichlorethylene, 1,2dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols, such as méthanol, éthanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones, such as acetone or butanone; amides, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl pyrrolidinone (NMP); nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO); nitro compounds, such as nitromethane or nitrobenzene; esters, such as ethyl acetate, or mixtures of the said solvents or mixtures with water. Polar solvents are in general preferred. Examples for suitable polar solvents are chlorinated hydrocarbons, alcohols, glycol ethers, nitriles, amides and sulfoxides or mixtures thereof. More preferred are amides, especially dimethylformamide (DMF).

As stated above, the reaction température is between about -100°C and 300°C, depending on the reaction step and the conditions used.

Reaction times are generally in the range between some minutes and several days, depending on the reactivity of the respective compounds and the respective reaction conditions. Suitable reaction times are readily determinable by methods known in

-25the art, for example reaction monitoring. Based on the reaction températures given above, suitable reaction fîmes generally lie in the range between 10 min and 48 hrs.

Every réaction step described herein can optionally be followed by one or more working up procedures and/or isolating procedures. Suitable such procedures are known in the art, for example from standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart). Examples for such procedures include, but are not limited to evaporating a solvent, distilling, crystallization, fractionised crystallization, extraction procedures, washing procedures, digesting procedures, filtration procedures, chromatography, chromatography by HP LC and drying procedures, especially drying procedures in vacuo and/or elevated température.

List of Abbreviations and Acronyms:

AcOH acetic acid, anh anhydrous, atm atmosphere(s), BOC tert-butoxycarbonyl CDI 1,1-carbonyl diimidazole, conc concentrated, d day(s), dec décomposition, DMAC NN-dimethylacetamide, DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(IH)-pyrimidinone, DMF NN-dimethylformamide, DMSO dimethylsulfoxide, DPPA diphenylphosphoryl azide, EDCI

1-(3-dirnethylaminopropyl)-3-ethylcarbodiimide, EtOAc ethyl acetate, EtOH éthanol (100%), Et₂O diethyl ether, Et₃N triethylamine, h hour(s), MeOH méthanol, pet. ether petroleum ether (boiling range 30-60°C), temp. température, THF tetrahydrofuran, TFA trifluoroAcOH, Tf trifluoromethanesulfonyl.

The compounds of general formula I of the présent invention can be prepared according to the procedures of the following Steps A and B above disclosed and the examples. In ail préparative methods, ail starting material is known or may easily be prepared from known starting materials.

1.2. Intermediates

In ail préparative methods, ail starting materials are known or may be prepared from known starting materials by the following general methods,

Either:

The compounds can be prepared by the general method, following procedures depicted in W02007/095588 (Novartis).

Or:

Br	CHO ' '''w'	nh2	Br	N
	l· + ' ' F	N NH2		: N NH

The compounds can be prepared by the general method, following procedures depicted in J. Heterocyclic Chem.34, 385 (1997).

Method 1:

Synthesis of intermediate 1: 6-(2-Chloro-5-methoxy-phenyl)-[1,2,4]triazoIo[1,5-

a]pyridin-2-y lamine

To a solution of 2-Chloro-5-methoxy-phenylboronic acid (3.38g, 22.5 mmol, 1.5eq), 6Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3.2g, 15 mmol, 1eq) and Na2CO3 (6.36g, 60 mmol, 4eq) in a mixture of 40ml DMF/10ml EtOH/10ml H2O, was added 1.733g (1.5 mmol, 0.1 eq) of tetrakis(triphenylphospine) palladium. The reaction was refluxed for 2 hours under argon. It was then cooled off to room température and the product was precipitated by water, filtered, rinsed with water, ether and pentane to give a pale yellow powder (3.21 g, 13 mmol, 90% yield).

-27Intermediate 2: 7-(2-Chloro-5-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-

2-ylamine has been synthesized according to the method disclosed for Intermediate 1 starting from 7-Bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine.

Synthesîs of intermediate 3: 3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-4chloro-phenol

To a suspension of 5.560g (20.24 mmol, 1eq) of 6-(2-Chloro-5-methoxy-phenyl)- [1,2,4]triazolo[1,5-a]pyridin-2-ylamine in 90 ml of dichloromethane cooled to 0°C was added carefully 60 ml of a 1M solution of 1M BBr3. The solution is stirred for 2hrs. The pH is then adjusted to pH8 by adding a sturated solution of NaHCO3. The precipitated product is filtered and washed with ether and dried to give 4.856g (19 mmol, 92%) of a white powder.

Intermediate 4: 3-(2-Amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-4-chlorophenol has been synthesized according to the method disclosed for Intermediate 3 starting from 7-(2-Chloro-5-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine.

The compounds can also be prepared by the general method 2.

Method 2:

Synthesîs of intermediate 5: 6-(2-Chloro-5-methoxy-phenyl)-quinazolin-2ylamine

To a solution of 2-chloro-5-methoxy boronic acid (14.42g, 77.34 mmol, 1.5eq), 6Bromo-quinazolin-2-ylamine (11.55g, 51.56 mmol, 1eq) and Na2CO3 (21.86g, 206.23 mmol, 4eq) in a mixture of 120ml DMF/30ml EtOH/30ml H2O, was added 2.311g (5.16 mmol, 0.1 eq) of tetrakis(triphenylphospine) palladium. The reaction was refluxed (100°C) for 2 hours under argon. It was then cooled off to room température to extract the product by DCM and brine. The product is then washed with water and ether, then dried to give 9.010 g (32 mmol, 61%) of a pale yellow powder.

’f) a

Intermediate 6: (6-(2,6-Dimethyl-phenyl)-quinazolin-2-y lamine) has been synthesized according to the method disclosed for Intermediate 1.

Synthesis of intermediate 7: 3-(2-Amino-qutnazolin-6-yl)-4-chloro-phenol

To a suspension of 9.010g (31.53 mmol, 1eq) of 6-(2-Chloro-5-methoxy-phenyl)quinazolin-2-ylamine in 300 ml of dichloromethane cooled to 0°C was added carefully 95 ml of a 1M solution of 1M BBr3. The solution is stirred for 16hrs. The pH is then adjusted to pH8 by adding a sturated solution of NaHCO3. The precipitated product is filtered and washed with ether and dried to give 7.596g (27.96 mmol, 89%) of a pale yellow powder.

1.3. Compounds of the Invention

Synthesis of compound of the Invention N°5 - Method 1

To 49mg (0.05 mmol, 0.03eq) of Pd_z(dba)₃, 16 mg (0.03 mmol, 0.02eq) of 5-(Ditert-butyl-phosphanylJ-T^'.S'-triphenyl-TI-l-fM'jbipyrazolyl and 241 mg (4.30 mmol, 2.15 eq) of KOH, was added 3 ml tertamylacohol and 400pl of water and the suspension is stirred for 10 minutes at 90“C. 521 mg (2.00 mmol, 1eq) of 3-(2-Amino-[1,2,4Jtriazolo[1,5-

a]pyridin-6-yl)-4-chloro-phenol and 744 mg (3.43 mmol, 1.2eq) of (3-Bromo-5hydroxymethyl-phenyl)-methanol are then added, followed by another 3m I of tertamyl alcohol and 400μΙ of water and the mixture is stirred at 90C under argon for 10 hours. The compound is extracted by 3 times Ethyl acetate, washed with brine. The organic layers are then dried over Na₂SO₄, filtered and evaporated. The compound is cristallized in methanol/ether and is filtered and washed with ether. It is then purified by préparative HPLC using a ZORBAX, SB-C18 column (21,2mmx100mm, 5pm). The gradient was performed using a H20/Acetonitrile gradient (from 30% water to 95% acetonitrile) at a flow rate of 50ml/mn during 15 min togive 70 mg (0.177 mmol, 9 %).

(3-Bromo-5-hydroxymethyl-phenyl)-methanol could be synthetically obtained using classical methods of organic synthesis starting from 5-Bromo-isophthalic acid dimethyl

-29ester which has been purchased at Alfa Aesar. Other dérivatives could be synthetically obtained using classical methods of organic synthesis.

Synthesis of cornpound ofthe Invention N°19- Method 2

To 49mg (0.05 mmol, 0.03eq) of Pd₂(dba)₃, 16 mg (0.03 mmol, 0.02eq) of 5-(Ditert-butyl-phosphanyl)-1',3',5’-triphenyl-TH-[1,4']bipyrazolyl and 241 mg (4.30 mmol, 2.15 eq) of KOH, was added 3 ml tertamylacohol and 400μΙ of water and the suspension is stirred for 10 minutes at 90°C. 543 mg (2.00 mmol, 1eq) of 3-(2-Amino-quinazolin-6-yl)-4chloro-phenol and 668 mg (2.40 mmol, 1.2eq) of (3-Bromo-5-hydroxymethyl-phenyl)methanol are then added, followed by another 3ml of tertamyl alcohol and 400μΙ of water and the mixture is stirred at 90°C under argon for 10 hours. The cornpound is extracted by 3 times Ethyl acetate, washed with brine. The organic layers are then dried over Na₂SO_4] filtered and evaporated. The cornpound is cristallized in methanol/ether and is filtered and washed with ether. It is then purified by préparative HPLC using a ZORBAX, SB-C18 column (21,2mmx100mm, 5pm). The gradient was performed using a H2O/Acetonitrile gradient (from 30% water to 95% acetonitrile) at a flow rate of 50ml/mn during 15 min to give 70 mg (0.122 mmol, 6 %).

Ail compounds could also be purified by prep HPLC. We have used an Agi lent 1200 sériés semi-prep with UV detector monitoring at 254 nm. Compounds were purified on a ZORBAX, SB-C18 column (21,2mmx100mm, 5pm). The gradient was typically performed using a H20/Acetonitrile gradient (from a range starting from 5 to 50% water to 95% acetonitrile) at a flow rate of 50ml/mn during 15 min.

Compounds n° 1 to 50 of table 1 were made in a similar way as described above.

Measurement of inhibition constants ofthe compounds ofthe Invention.

The screening and profiling experiments described here were performed using Caliper Life Sciences’ proprietary LabChip™ technology. Caliper LC3000 and EZ Reader Il instruments are widely used throughout the drug discovery process for assay development, primary screening, selectivity screening, génération of Structure-Activity Relationships (SARs) and Mechanism of Action (MOA) studies. The LabChip ™ technology is particularly well suited for enzymatic ‘targets’ such as kinases, proteases,

-30phosphatases, historié deacetyiases (HDAC), phosphodiesterases (PDE), and acyltransferases. The key benefit of the technology is the séparation and direct measurement of substrates and products, which allows for higher signal-to-noise ratios and fewer false positive/negative results. This direct measurement also allows for the identification and élimination of enzymatic activities that are not associated with the kinase reaction of interest.

General:

The off-chip incubation mobility-shift kinase assay uses a microfluidic chip to measure the conversion of a fluorescent peptide substrate to a phosphorylated product. The reaction mixture, from a microtiter plate well, is introduced through a capillary sipper onto the chip, where the nonphosphorylated substrate and phosphorylated product are separated by electrophoresis and detected via laser-induced fluorescence. The signature of the fluorescence signal over time reveals the extent of the reaction. The phosphorylated product migrâtes through the chip faster than the non-phosphorylated substrate, and signais from the two forms of the peptide appear as distinct peaks. Caliper’s data analysis software (HTSWA) détermines peak heights, from which the ratio of product to the peak sum P/(P+S) and percent (% ) conversion is calculated. This value is used to compare compound wells to control wells présent on the plate, and thereby détermine the % inhibition values for the compound. The formula used to calculate % inhibition is as follows, where C₁₀o% is the average % conversion of the 100% activity wells and Co% is the average % conversion of the 0% activity wells:

(1-(%conversionofsample - Cq%)/(C_1O0%.Cq%))*100

Spécifie:

LC3000 Src Assays

Compounds were dissolved in 100% DMSO and diluted to 25X the final desired screening concentration. Serial dilutions were performed to obtain the concentrations specified for particular studies. One pL of each concentration was transferred, in duplicate, to a 384-well Greiner microtiter plate. Generally, 12 pL of enzyme buffer containing purified kinase (various suppliers), 100 mM HEPES, pH 7.5, 1 mM DTT (Calbiochem, 2333153), 10 mM MgCI₂ (Sigma, M-1028) or 10 mM MnCI₂ (Sigma, M1787) (assay spécifie), and 0.002% Brij-35 (Sigma, B4184) was added to each well. Compound and enzyme were allowed to pre-incubate for 15 minutes. 12 μΙ_ of peptide/ATP buffer containing 100 mM HEPES, pH 7.5, 1.5 μΜ fluorescein-labeled peptide (spécifie to kinase of interest), ATP (at Km apparent, Sigma, A9187), and 0.002%

-31Brij-35 was then added to each well to initiate the reaction. Generally, reactions were incubated for 1-1.5 hours at room température to obtain adéquate (15-40%) conversion of peptide to phosphorylated product in the linear range of the reaction. Reactions were terminated with the addition of 45 μΙ_ of Stop Buffer (containing 20 mM EDTA). Plates 5 were then read on the LabChip 3000 using a 12-sipper LabChip. % conversion values and % inhibition values were obtained as described and lC₅₀ curves of compounds were generated using Graphpad Prism Version 4 or 5.01. A nonlinear curve fit using the sigmoidal dose response - variable slope fit was used to graph IC_M curves and détermine IC₅₀ values and hillslopes.

It has been shown that the compounds of the Invention hâve IC50 against Src kinases of < 200nM. Preferred compounds are those having IC50 against Src kinases of < 100 nM.

Table 1

Examples	Name	Structure	MS NMR (200MHz, DMSOd6)	1C50 (nM) h Src
compound 1	4- Chloro-3-[2(pyridin-4ylamino)[1,2,4]triazolo[1, 5- a]pyridin-6yl]-phenol	I /~N Msn b	M + 1 =338.1 NMR: 10.28 (s, 1H); 10.00 (bb, 1H); 8.94 (s, 1H); 8.36 (d, 2H); 7.66 (m,4H); 7.39 (d, 1H); 6.88 (m, 2H)	73
compound 2	4- Chloro-3-[2(pyridin-3ylamino)- [1,2,4Jtriazolo[1, 5- a]pyridin-6yl]-phenol	N=/	M + 1 = 338.1 NMR: 9.87 (s, 1 H); 8.80 (s, 2H); 8.16(d,1H); 8.09 (d, 1H); 7.63 (s, 2H); 7.35 (m, 2H); 6.88 (m, 2H)	120

[h'L

compound 3	4- Chloro-3-[2(pyrimidin-5ylamino)- [1,2,4]triazolo[1, 5- a]pyridin-6yl]-phenol	HO^A^M-Vy A w	M+1 =339.1 I NMR: 10.17 (s, 1H); 9.96 (s, 1H); 9.15 (s, 2H); 8.95 (s, 1H); 8.75 (s, 1H); 7.67 (s, 2H); 7.39 (d, 1H); 6.91 (m, 2H)	150
compound 4	4- Chloro-3-[2(5hydroxymethylpyridin-3ylamino)- [1,2,4Jtriazolo[1, 5- a]pyridin-6yl]-phenol	K/	M + 1 = 368.1 NMR: 10.89 (s, 1H); 9.85 (s, 1H); 8.79 (s, 1H); 8.70 (d, 1H); 8.10(s, 1H); 8.04(8, 1 H); 7.63 (s, 2H); 7.37 (d,1H);6.87 (m, 2H); 5.64 (bb, 1H), 4.52 (d, 2H)	39
compound 5	3-[2-(3,5-Bishydroxymethylphenylamino)[1,2,4]triazolo[1, 5-a]pyridin-6yl]-4-chlorophenol	OH XXCI Ia	M + 1 = 397.1 NMR: 9.94(8, 1 H); 9.60 (s, 1H); 8.84 (s, 1H); 7.61 (s, 2H); 7.54 (s, 2H); 7.39 (d, 1H); 6.87(m, 3H); 5.15 (t. 2H, OH); 4.47 (d, 4H)	5
compound 7	4- Chloro-3-[2(6-methoxypyridin-3ylamino)[1,2,4]triazolo[1, 5- a]pyridin-6yl]-phenol	rc. X AAA H	M + 1 = 368.1 NMR: 9.95 (s, 1 H); 9.57 (s, 1H); 8.84 (s, 1H); 8.50 (s, 1H); 8.05 (d, 1H); 7.60 (s, 2H); 7.41 (d, 1H);6.89(m, 3H); 3.81 (s, 3H)	80

W16290

compound 8	4- Chloro-3-{2[5-(2-pyrrolidin1-yl-ethoxy)pyridin-2ylamino]- [1,2,4]triazolo[1, 5- aJpyridin-6ylj-phenol	ΓΤ ό	M + 1 =451.1 NMR: 10.05 (s, 1H); 10.02 (s, 1H); 8.87 (s, 1H); 8.08 (m, 2H); 7.64 (s, 2H); 7.53 (dd, 1H); 7.39 (d, 1 H); 6.92 (m, 2H); 4.30 (t, 2H); 3.35 (t, 2H); 3.13 (bb, 4H); 1.88 (bb, 4H)	100
compound 10	4- Chloro-3-(2{644-(2hydroxy-ethyl)piperazin-1-yl]pyridin-3ylamino}- [1,2,4]triazolo[1, 5- a]pyridin-6yl)-phenol	OH O r1 i y—*· W «	M + 1 =466.2 NMR: 10.85 (s, 1H); 10.01 (s, 1H); 8.88 (s, 1H); 8.61 (s, 1H); 8.21 (d, 1 H); 7.66 (s, 2H); 7.38 (m, 2H); 6.89 (m, 2H); 4.35 (t, 2H); 3.83 (t, 2H); 3.63 (m, 4H); 3.25 (m, 4H)	14
compound 12	4- Chloro-3-[2(pyridin-2ylamino)- [1,2,4]triazolo[1, 5- a]pyridin-6yl]-phenol	rr O	M + 1 = 338.0 NMR: 12.42 (s, 1H); 10.17 (bb, 1H);9.07 (s, 1H); 8.46 (d, 1H); 8.26 (t, 1H); 7.85 (m, 3H); 7.41 (d, 1H); 7.32 (t, 1H); 6.97 (m, 2H)	170
compound 13	4- Chloro-342(2hydroxymethylpyridin-4ylamino)- [1,2,4]triazolo[1, 5- a]pyridin-6yl]-phenol	JÛC O- H	M + 1 = 368.1 NMR: 10.26 (s, 1H); 8.88 (s, 1H); 8.26 (d, 1H); 7.67 (m, 4H); 7.31 (d, 1H); 6.83 (m, 2H); 4.50 (s, 2H)	27

compound 14	4- Chloro-3-[2(6hydroxymethylpyridin-3ylamino)[1,2,4]triazolo[1, 5- a]pyridin-6yl]-phenol	/ OH . 0	M + 1 = 368.0 NMR; 9.85 (s, 1H); 8.78 (d, 2H); 8.18 (d, 1H); 7.63 (s, 2H); 7.39 (d, 2H); 6.90 (m, 2H); 5.32 (bb. 1 H); 4.50 (s, 2H)	47
compound 16	3- i2-(3,5-Bishydroxymethylphenylammo)quinazolin-6-yl]- 4- chloro-phenol	.OH 0|l	M + 1 = 408.0 NMR: 10.0 (bb, 1H,OH); 9.91 (s, 1H); 9.35 (s, 1H); 7.95-7.83 (m, 4H); 7.69 (d, 1H); 7.37 (d, 1H); 6.94 (s, 1H); 6.84 (m, 2H); 5.18 (bb, 2H); 4.51 (s, 4H)	0.1
Compoun d 17	4-Chloro-3-[2(pyridin-3ylamino)quinazolin-6-yl]phenol	H	M + 1 = 349.0 NMR: 10.18 (s, 1H); 9.41 (s, 1H); 9.10 (s, 1H); 8.47(d, 1H); 8.21 (d, 1 H); 7.99 (s, 1H); 7.88 (dd, 1H); 7.75 (d, 1H); 7.38 (m, 2H); 6.84 (m, 2H)	2
Compoun d 18	4- Chloro-3-[2(1 H-indol-6ylamino)[1,2,4]triazolo[1, 5- a]pyridin-6yl]-phenol	HO	M + 1 =376.1 NMR: 10.93 (s, 1H); 9.48 (s, 1H); 8.79 (s, 1H); 7.99 (s, 1H); 7.58 (s, 2H); 7.39 (m, 2H); 7.16 (m, 2H); 6.89 (m, 2H); 6.31 (s,1H)	39

Compoun d 19	4- [6-(2-Chloro- 5- hydroxyphenyl)[1,2,4]triazolo[1, 5-a]pyridin-2ylamino]pyridin-2-ol	Cl /=( T T il HO	M + 1 = 354.1 NMR: 10.93 (s, 1H); 10.06 (s,1H); 9.97 (s, 1H); 9.94(5,1 H); 7.68 (s, 2H); 7.39 (s, 1H); 7.24 (s, 1H); 6.89 (m, 3H); 6.35 (d,1H)	28
Compoun d 20	4- Chloro-3-[2(2-methoxypyridin-4ylamino)[1,2,4Jtriazolo[1, 5- a]pyridin-6yl]-phenol	/MA HO	M + 1 =368.1 NMR: 11.11 (s, 1 H); 10.03 (s, 1H); 9.02 (s, 1H); 8.10 (d,1H); 7.76 (m, 2H); 7.58 (s, 1H); 7.40 (m, 2H); 6.93 (m, 2H); 4.01 (s, 3H)	6
Compoun d 21	4-Chloro-3-[2(5hydroxymethylpyridin-3ylamino)quinazolin-6-yl]phenol	Y°H Λ H	M + 1 = 379.0 NMR : 10.17(s, 1H); 9.94 (bb, 1H); 9.41 (s, 1H); 9.02 (s, 1H); 8.41 (s, 1H); 8.16 (s, 1H);7.99 (d, 1H); 7.89 (dd, 1H); 7.75 (d, 1H); 7.38 (d, 1H); 6.85 (m, 2H); 5.37 (bb, 1H); 4.57 (s, 2H)	0.4
Compoun d 25	4- Chloro-3-{2[6-(2-pyrrolidin1-yl-ethoxy)pyridin-3ylamino][1,2,4]triazolo[1, 5- a]pyndin-6yl}-phenol	A AA ΊΠ o (AA n- HO	M + 1 =451.1 NMR: 9.98 (bb, 1H); 9.58(5, 1H); 8.83 (s, 1H); 8.49 (s, 1H); 8.04 (d, 1H); 7.60 (s, 2H); 7.38 (d, 1H); 6.84 (m, 3H); 4.33 (t, 2H); 2.89 (t, 2H); 2.64 (m,4H); 1.72 (m, 4H)	23

Compoun d 26	4- Chloro-3-{2[5-(2-pyrrolidin1 -yl-ethoxy)pyridin-3ylamino][1,2,4]triazolo[1, 5- a]pyridin-6yl}-phenol	V o HO	M + 1 =451.2 NMR :9.97 (s, 1H); 8.91 (s, 1H); 8.44 (s, 1H); 7.88 (m, 2H); 7.64 (s, 2H); 7.37 (d, 1H); 6.89 (m, 2H);4.14(t, 2H); 2.81 (t, 2H); 2.55 (m, 4H); 1.68 (m, 4H)	14
Compoun d 27	4- Chloro-3-(2{6-(4-(2hydroxy-ethyl)piperazin-1-yl]2-methylpyrimidin-4ylamino}- [1,2,4]triazolo[1, 5- a]pyridin-6yl)-phenol	OH rV Cl N .NH HO	M+1 =481.2 NMR: 10.35 (bb, 1H); 10.17 (s, 1H); 8.93 (s, 1H); 7.67 (s, 2H); 7.37 (m, 2H); 6.93 (m, 2H); 4.50 (bb, 1H); 3.56 (m, 6H); 2.48 (m, 4H); 2.42 (t, 2H); 2.31 (s, 3H)	83
Compoun d 28	4- Chloro-3-(2{3-(4-(2hydroxy-ethyl)piperazin-1-yl]- 5- methylphenylamino}[1,2,4]triazolo[1, 5-a]pyridin-6y!)-phenol	rX'Y'™ ΛΑ H	M+ 1 =479.1 NMR :9.88 (bb, 1H); 9.35 (s, 1H); 8.81 (s, 1H); 7.55 (s, 2H); 7.34 (d, 1H);7.12(s, 1H); 6.95 (s, 1H); 6.84 (m, 2H); 6.27 (s, 1H); 4.57 (t, 1 H); 3.49 (q, 2H); 3.07 (m, 4H); 2.52 (m, 4H); 2.39 (t, 2H); 2.19 (s, 3H)	3
Compoun d 29	4- Chloro-3-[2(3,4,5trimethoxyphenylamino)[1,2,4Jtriazolo[1, 5- a]pyridin-6-	/ \ O o jX. . X	M + 1 = 427.1 NMR : 9.92 (s, 1 H); 9.51 (s, 1H); 8.86 (s, 1H); 7.60 (s, 2H); 7.39 (d, 1H); 7.12 (s, 2H); 6.91 (m, 2H); 3.78 (s, 6H); 3.61 (s,	2

	yl]-phenol		3H)
Compoun d 30	4- Chloro-3-{2[3-(2-hydroxyethyl)-3Hbenzoimidazol- 5- ylamino][1,2,4Jtriazolo[1, 5-a]pyridin-6yl}-phenol		M + 1 =421.2 NMR: 10.21 (bb, 1H, OH); 9.68 (s, 1H); 8.86 (s, 1H); 8.04 (s, 1H); 8.03 (S, 1H); 7.60 (s, 2H); 7.53 (dd, 1H); 7.44 (d, 1 H); 7.38 (d, 1H); 6.93 (s, 1H); 6.86 (d, 1H); 4.69 (bb, 1H); 4.23 (m, 2H); 3.80 (m, 2H)	7
Compoun d 31	4- Chloro-3-[2(pyridin-3ylamino)[1,2,4]triazolo[1, 5- a]pyridin-7yl]-phenol	rrcl o	M + 1 = 337.9 NMR: 10.11 (bb, 1 H); 9.90 (s, 1H); 8.84 (m, 2H); 8.19 (d,1H); 8.12 (d, 1H); 7.60 (s, 1H); 7.36 (m, 2H); 7.08 (dd, 1H); 6.88 (m, 2H)	69
Compoun d 33	4- Chloro-342[2-(2-pyrrolidin1-yl-ethoxy)pyridin-4ylamino][1,2,4]triazolo[1, 5- a]pyridin-6yl}-phenol	HO	M+ 1 =451.2 NMR : 10.10 (bb, 1H); 9.21 (s, 1H); 8.73 (s, 1H); 7.88 (s, 1H); 7.54 (s, 2H); 7.46 (s, 1H); 7.37 (d, 1H); 6.89 (m, 2H); 4.171, 2H); 3.2 (m, 4H); 2.86 (m,4H); 2.71 (t, 2H)	29
Compoun d 34	3-[2-(3,5-Bishydroxymethylphenylamino)[1,2,4Jtriazolo[1, 5-a]pyridin-7yl]-4-chlorophenol	OH nrci o-7*	M + 1 = 297.0 NMR: 10.01 (bb, 1H); 9.58 (s, 1H); 8.81 (d, 1H); 7.54 (m, 3H); 7.39 (d, 1H); 7.03 (dd, 1H); 6.86 (m, 3H); 5.15 (t, 2H); 4.47 (d, 4H)	9

Compoun d 35	3-[2-(3,4-Bishydroxymethylphenylamino)[1,2,4]triazolo[1, 5-a]pyridin-6yl]-4-chlorophenol	/—OH r-' °π I Z- N	M + 1 = 397.0 NMR: 9.96 (bb, 1H); 9.60 (s, 1H); 8.84(s, 1H); 7.61 (m, 4H); 7.39 (d, 1H); 7.25 (d, 1 H); 6.90 (m, 2H); 5.09 (t, 1H); 4.93 (t, 1H);4.54(d, 2H); 4.47 (d, 2H)	34
Compoun d 36	4-Chloro-3-[2(3,4,5trimethoxyphenylamino)quinazolin-6-yl]phenol	^Cl q'' H I	M + 1 = 438.0 NMR :9.90 (bb, 1H); 9.86 (s, 1H); 9.34(s, 1H); 7.94 (d, 1H); 7.86 (dd, 1H); 7.71 (d, 1H); 7.50 (s, 2H); 7.38 (d, 1H); 6.87 (m, 2H); 3.82 (s, 6H); 3.64 (s, 3H)	0.5
Compoun d 38	4- Chloro-3-(2{2-(4-(2hydroxy-ethyl)piperazin-1-yl]pyridin-4ylamino}- [1,2,4]triazolo[1, 5- a]pyridin-6yl)-phenol	xT \=N VOH	M + 1 = 466.0 NMR : 9.93 (bb, 2H, NH, OH); 8.92(s, 1H); 7.92 (d, 1H); 7.65 (m, 2H); 7.39 (d, 1H); 7.19(s, 1H);6.99 (d, 1 H); 6.92 (d, 1H); 6.87 (dd, 1H); 4.44 (t, 1H, OH); 3.54 (q, 2H); 3.43 (m, 4H); 2.52 (m, 4H); 2.44 (t, 2H)	13
Compoun d 39	4- Chloro-3-{7methoxy-2-[4(2-pyrrolidin-1yl-ethoxy)phenylamino][1,2,4)triazolo[1, 5- a]pyridin-6-	OO H	M + 1 = 480.2 NMR :9.83 (s, 1H); 9.29 (s, 1H); 8.55 (s, 1H); 7.58 (d, 2H); 7.31 (d, 1H); 7.06 (s, 1H); 6.84 (m, 4H); 4.01 (t, 2H); 3.84 (s, 3H); 2.78 (t, 2H); 2.55	69

	yl}-phenol		(m, 4H); 1.69 (m, 4H)
Compoun d40	4-Chloro-3-(2(6-methoxypyridin-3ylamino)quinazolin-6-yl]phenol	kx, .N N N H	M + 1 = 379.0 NMR: 9.91 (s, 1H); 9.90 (bb, 1H); 9.34 (s, 1H); 8.80 (d, 1H); 8.21 (dd, 1H); 7.95 (d, 1H); 7.85 (dd, 1H); 7.78 (d, 1H); 7.38 (d, 1H); 6.85 (m, 3H); 3.84 (s, 3H)	10
Compoun d 41	4- Chloro-3-(2{4-[2-(1-oxypyrrolidin-1-yl)ethoxy]phenylamino}[1,2,4]triazolo[1, 5- a]pyridin-6yl)-phenol	HO H	M + 1 =466.2 NMR : 11.07 (bb, 1H); 9.44(s, 1H); 8.78 (s, 1H); 7.60 (d, 2H); 7.55 (s, 2H); 7.33 (d, 1H); 6.89 (m, 3H);6.82 (dd, 1H); 4.48 (t, 2H); 3.68 (t, 2H); 3.47 (m, 4H); 2.16 (m, 2H); 1.93 (m, 2H)	55
Compoun d 42	4-Chloro-3-[2(1 H-indol-6ylamino)quinazolin-6-yl]phenol	^OCâXXJ H H	M + 1 = 387.0 NMR : 11.02 (s, 1H); 9.99 (bb, 1H); 9.87 (s, 1H); 9.313(s, 1H); 8.37 (s, 1H); 7.94 (d, 1H); 7.83 (dd, 1H); 7.66 (d, 1H); 7.40 (m, 3H); 7.25 (t, 1H); 6.85 (m, 2H); 6.36 (s, 1H)	100
Compoun d 43	4-Chloro-3-[2- (2hydroxymethylpyridin-4ylamino)quinazolin-6-yl]-	Î^N XAnaO OH	M + 1 =379.1 NMR: 10.39 (s, 1H); 9.97 (bb, 1H); 9.46 (s, 1H); 8.33 (d, 2H); 8.04 (dd, 1H);7.94 (m, 2H); 7.81 (d, 1H); 7.38 (d,	0.7

ViL·

	phénol		1H); 6.90 (d, 1 H); 6.85 (dd, 1H); 5.36 (bb, 1H, OH); 4.54 (s, 2H)
Compoun d44	1-(2-{5-[6-(2Chloro-5hydroxyphenyl)[1,2,4]triazolo[1, 5-a]pyridin-2ylamino]pyridin-2-yloxy}ethyl)pyrrolidin-2-one	A' n HO	M + 1 = 466.1 NMR :9.92 (s, 1H); 9.55 (s, 1H); 8.83 (s, 1 H); 8.49 (s, 1H); 8.04 (d, 1 H); 7.60 (s, 2H); 7.38 (d, 1H); 6.90 (s, 1H); 6.86 (d, 1H); 6.80 (d, 1H); 4.32 (t, 2H); 3.53 (t, 2H); 3.47 (t, 2H); 2.20 (t, 2H); 1.90 (quint, 2H)	57
Compoun d45	4-Chloro-3-{2[1-(2-hydroxyethyl)-1Hbenzimidazol-5ylamino]quinazolin-6-yl)phenol	nr Z H	M + 1 =432.1 NMR :9.89 (s, 1H); 9.88 (bb, 1H); 9.33 (s, 1H); 8.48 (s, 1H); 8.12 (s, 1H); 7.94 (s, 1H); 7.83 (d, 1H); 7.68 (m, 2H); 7.54 (d, 1H); 7.38 (d, 1H); 6.89 (d, 1H); 6.84 (dd, 1H); 4.99 (bb, 1H,OH); 4.27 (t, 2H); 3.75 (m, 2H)	0.5
Compoun d46	4- Chloro-3-(2{344-(2hydroxy-ethyl)piperazin-1-yl]- 5- methylphenylamino}quinazolin-6-yl)phenol	πΑΑρρ,, Λ ΌΗ	M + 1 = 490.2 NMR: 9.19(s, 1H); 8.46 (s, 1H); 7.84 (m, 2H); 7.70 (d, 1H); 7.62 (s, 1H); 7.32 (d, 1H); 7.15 (s, 1H); 6.88 (d, 1H); 6.81 (dd, 1H);6.56(s, 1H); 3.85 (t, 2H); 3.41 (m, 4H); 3.16 (m, 4H);	0.8

			3.00 (t, 2H); 2.34 (s, 3H) I
Compoun d 47	4- Chloro-3-(2{3-(4-(2hydroxy-ethyl)piperazin-1-ylj- 5hydroxymethylphenylamino}[1,2,4)triazolo[1, 5-a]pyridin-6yl)-phenol	xc x L .n. ‘xX^-QH	M + 1 =495.1 NMR :9.43(s,1 H); 8.85 (s, 1H); 8.18 (s, 1H); 7.59(s, 2H); 7.38 (d, 1H); 7.27 (s, 1H>, 7.10 (S, 1H); 6.91 (d, 1H);6.86(dd, 1H); 6.46 (s, 1H); 4.41 (s, 2H); 3.54 (t, 2H); 3.13 (m, 4H); 2.58 (m, 4H); 2.45 (t, 2H)	1
Compoun d48	Benzoic acid 4chloro-3-(2-(3[4-(2-hydroxyethyl)piperazin-1-yl]5-methylphenylamino}[1,2,4Jtriazolo[1, 5-a]pyridin-6yl)-phenyl ester	,C1	M + 1 = 583.1 NMR : 9.41 (s, 1H); 8.94 (s, 1H); 8.15 (d,2H); 7.80-7.61 (m, 7H); 7.46 (dd, 1H); 7.16 (s, 1H); 7.00 (s, 1H); 6.32 (s, 1H); 4.54 (bb, 1H); 3.54 (q, 2H); 3.11 (m, 4H); 2.57 (m, 4H); 2.45 (t, 2H); 2.22 (s, 3H)	NA (not appli cable )
Compoun d 49	Benzoic acid 4chloro-3-(2-(3[4-(2-hydroxyethyl)piperazin-1-yl]5-methylphenylamino}quinazolin-6-yl)phenyl ester	ΟΛ k..-*-	M + 1 = 594.1 NMR: 9.74 (s, 1H); 9.34(5, 1H); 8.15 (d, 2H); 8.03 (d, 1H); 7.93 (dd, 1H); 7.73 (m, 3H); 7.62 (m, 3H); 7.55 (d, 1H); 7.43 (dd, 1H); 7.18 (s, 1H); 6.43 (s, 1H); 4.45 (bb, 1H); 3.55 (q, 2H); 3.15 (m, 4H); 2.58 (m, 4H); 2.45 (t, 2H); 2.26 (s,	11

			3H)
Compoun d 50	4-Chloro-3-(2{3-(4-(2hydroxy-ethy l)-piperazîn-1yi]-5hydroxymethyl- phenylamino}quinazolin-6-yl)phenol	.oh (Ai CL·^ OH	M + 1 = 506.01 NMR :9.77 (s, 1H); 9.33 (s, 1H); 8.16(s, 1H); 7.94(s, 1H); 7.86 (dd, 1H); 7.71 (s, 1H); 7.67 (d, 1H);7.38 (d, 1H), 7.31 (s, 1H); 6.88 (s, 1H); 6.86 (dd, 1H); 6.58 (s, 1 H); 4.44 (s, 2H); 3.56 (t, 2H); 3.17 (m, 4H); 2.61 (m, 4H); 2.47 (t, 2H)	0.2

-43Ail compounds of the invention are white or pale yellow powders, and in solution become pale yellow or colourless when in solution at the maximum concentration of solubilisation at pH 5.

Other data regarding some compounds ofthe invention are as follows:

Table 2

Cornpound	In vitro potency IC50 (nM) Src / Lyn (h)	Colour	Solubility HPbCD 7% pH5 (mg/ml) measured	Flux between 2 and 4 hours through 0,5 cm2 of rabbit comea (pg/h/cm2)
Cornpound 16	< 1 nM	Pale Yellow	1,2	17
Cornpound 43	0.7 nM	Pale Yellow	1,5	6
Cornpound 45	1 nM	Pale Yellow	2,3	8

Ve

Compound 46	0,8 nM	Pale Yellow	> 10	13
Compound 5	5nM	White	1.3	13
Compound 10	14 nM	White	5,69	30
Compound 13	27 nM	White	2,38	13
Compound 25	23 nM	White	6,5	14

5C

Compound 27	83 nM	White	>10	19
Compound	3nM	White	7,5	8
28

Compounds n°1 to 50, including prodrugs (compounds n°48 and 49), not listed in table 2 show sîmilar solubility and Corneal flux.

Accordingly above-recited problème of insolubility and coloration of compounds of the prior art hâve been solved by the compounds of the current invention. Compounds □f the invention are both colourless and readily soluble in aqueous formulations suitable for delivery by eye drops.

Experimental - Ussing chamber

Ussing chambers were used for the perméation study each day of experiment.

mL of solution were placed in donor side of Ussing chambers and 3mL of Ringer solution were in receiver side. Freshly removed rabbit corneal tissue were placed between the two half chambers.

Température was maintained at 37°C during ail the flux study and oxygénation 15 was provided by a continuous perfusion of carbogen (oxygen/carbonic acid) (95/5),

Rabbits were euthanized and the 6 corneas were removed and used immediately. 500 pL of receptor side liquid were removed from Ussing chambers and replaced by fresh buffer. The samples were analyzed immediately (less than 10 hours after collection).

-46100μΙ_ of donor side liquid were removed from Ussing chambers and not replaced. The samples were diluted immediately (less than 1 hour) after collection and analyzed less than 10 hours after dilution. Analysis was performed on HPLC (Stationary phase: C18 (Particle size: 3 pm Length: 5 cm, using a gradient from 5 to 95% ACN/water (0.1 % formic acid)).

At the end of the sampling period, ail corneas were discarded.

According to this protocol, it has been demonstrated that compounds of the current invention in these aqueous formulations readily cross the cornea, thus making them suitable for treatment of ophthalmic indications.

inhibition of neovascularization in a rat model of Laser-induced Choroidal neovascularization (CNV)

We investigated the efficacy of topical administration of compound 25 of the invention in reducing choroidal neovascularisation in the rat (Brown Norway, 8 weeks of âge).

On day 1, CNV was performed by laser photocoagulation-induced rupture of Bruch’s membrane as previously described (Edelman and Casto 2000). An Argon green laser irradiation was delivered through the slit lamp for induce photocoagulation. In each eye, 6-7 focal laser spots were applied concentrically approximately two optic dises from the center. Immediately afterwards, rats were treated with topical solution 6mg/mL (1 OpL) two times daily until sacrifice. 14 days after laser induction of CNV blood vessels were visualized on retinal pigment epithelium -choroid-sclera flat-mount by immunostaining with isolectinB4.

Assessment of CNV response to treatment was performed after capture and area measurement of immunostained vessels representing CNV at the site of laser bum.

Pixel area of vascular budding was traced by 2 trained masked investigators and converted to pm².

Results

It has been found that compound 25 of invention reduced CNV by 15 % compared to control providing evidence that the compounds of the invention are useful to reduce choroidal neovascularization associated with wet age-related macular degeneration.

Claims (21)

1. Compound of formula (I):

R1

R3

I

N H

BR4 R5 (D wherein A is phenyl,

B is phenyl, pyridine, orpyrimidine

R1 and R2 represent independently from each other:

-H,

-OH, a halogen atom, with the provisio that R1 and R2 are not simultaneously hydrogen; R3, R4 and R5 are, independently from each other,

-H,

-(CH₂)_nOH,

-O(CiC₆)alkyl,

-(CH₂)_n-CO-heterocycloalkyl,

-OH,

-heterocycloalkyl-(CH₂)_n-OH,

-(C.-Cb) alkyl,

-(CH₂)_n-heterocycloalkyl, -(CH₂)_n-heterocycloalkyl-(CH₂)_n-OH, -O-(CH₂)_n-heterocycloalkyl,

N-oxide wherein the nitrogen atom belongs to B,

-0-(CH₂)_ri-CO-heterocycloalkyl,

-O-(CH₂)_n-OH,

-OfC^eJalkyl-NRÏRS,

-(C^eJalkyl-NRïRS,

-48- R3 and R4 form together with B a fused bicycle optionally substituted by R5 with the provisio that when B is phenyl, at least two of R3, R4 and R5 are not hydrogen;

R6 is H, -O(CiC₆)alkyl, or (C-C₆)alkyi;

R7 and R8 are independently from each other H or an optionally substituted (C^eJalkyl optionally forming a cycloalkyl;

n is 1,2 or 3;

X is N or C; and

Y is CH or a covalent bond, or a prodrug thereof.

2, Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defîned in claim 1,

3, Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defîned in claim 1.

4. Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defîned in claim 1.

5. Compound according to daim 1, wherein said compound has the formula 'h wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in claim 1.

6. Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in claim 1.

7. Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in claim 1.

8. Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in claim 1.

9. Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in claim 1.

-5010. Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 are as defined in claim 1.

11. Compound according to claim 1, wherein said compound has the formula wherein R1, R2, R3, R4, R5, R6, R7, and R8 as defined in claim 1, and wherein

R10 is

-H,

-(CH₂)_nOH,

-OCC^eJalkyl,

-(CH₂)_n-CO-heterocycloalkyl,

-OH,

-heterocycloalkyl-(CH₂)_n-OH,

-(CrCe) alkyl,

-(CH₂)_n-heterocycloalkyl,

-(CH^-heterocycloalkyHCH^n-OH,

-O-(CH₂)_n-heterocycloalkyl,

N-oxide wherein the nitrogen atom belongs to B,

-0-(CH₂)_n-CO-heterocycloalkyl,

-O-(CH₂)_n-OH,

-O(CiC_fi)alkyl-NR7R8, or

-(C₁C₆)alkyl-NR7R8.

12. Compound according to any one of preceding claims, wherein R1 is OH and R2 is a halogen atom.

13. Compound according to any one of preceding claims, wherein R3, R4 and R5 represent independently from each other O-alkyl or hydroxyalkyl.

-5l -

14. Compound according to any one of preceding claims, wherein R3, R4 and R5 represent independently from each other -CH₂OH and -O-CH₂-CH₂-heterocycloalkyl.

15. Compound according to any one of preceding claims, wherein X represents a carbon atom and Y represents CH, or wherein X represents a nitrogen, and Y represents a bond.

16. Compound according to any one of preceding claims, wherein R6 represents a hydrogen atom orCH₃.

17. Compound according to any one of preceding claims, wherein it is selected from the group consisting of:

4-Chloro-3-[2-(pyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-phenol; 4-Chloro-3-[2-(pyndin-3-ylamino)-[1_T2,4]triazolo[1,5-a]pyridin-6-yl]-phenol; 4-Chloro-3-[2-(pyrimidin-5-ylamino)-[1_I2,4]triazolo[1_I5-a]pyridin-6-yl]-phenol;

4-Chloro-3-[2-(5-hydroxymethyl·pyridin-3-ylamino)-[1,2,4]tπazolo[1_I5-a]pyΓidin-6-yl]phénol;

3- (2-(3,5-Bis-hydroxymethyl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-4-chlorophenol;

4- Chloro-3-[2-(6-methoxy-pyridin-3-ylamino)-[1,2_I4]triazolo[1,5-a]pyridin-6-yl]-phenol; 4-Chloro-3-(2-[5-(2-pyrrolidin-1 -yl-ethoxy)-pyridin-2-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-

6-yl}-phenol;

4-Chloro-3-(2-(6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-3-ylamino}-[1,2,4]triazolo[1,5-

a]pyridin-6-yl)-phenol;

4-Chloro-3-[2-(pyridin-2-ylamino)-[1,2,4ltriazolo[1,5-a]pyridin-6-yl]-phenol; 4-Chloro-3-[2-(2-hydroxymethyl-pyridin-4-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]phénol;

4-Chloro-3-[2-(6-hydroxymethyl-pyndin-3-yiamino)-[1,2,4]tnazolo[1,5-a]pyridin-6-yl]phénol;

3- [2-(3,5-Bis-hydroxymethyl-phenylamino)-quinazolin-6-yl]-4-chloro-phenol;

4- Chloro-3-[2-(pyridin-3-ylamino)-quinazolin-6-yl]-phenol ;

4-Chloro-3-[2-(1H-indol-6-ylamino)-[1,2,4]triazoloI1,5-a]pyridin-6-yl]-phenol ; 4-[6-(2-Chloro-5-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-pyndin-2-ol ; 4-Chloro-3-[2-(2-methoxy-pyridin-4-ylamino)-[1,2,4Jtriazolo[1,5-a]pyridin-6-yl]-phenol;

4-Chloro-3-[2-(5-hydroxymethyl-pyridin-3-ylamino)-quinazolin-6-yl]-phenol;

-524-Chloro-3-{2-[1-(2-hydroxy-ethy[)-1H-pyrazol-4-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-6-yl}phenol;

4-Chloro-3-[2-(1 -methyl-1 H-pyrazol-4-ylamino)-[1 _l2,4]triazolo[1,5-a]pyridin-6-yl]-phenol ; 4-Chloro-3-[2-[6-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyridin-

6-yl}-phenol;

4-Chloro-3-{2-[5-(2-pyrrolidin-1-yl-ethoxy)-pyridin-3-ylamino]-[1,2,4]triazolo[1,5-a]pyridÎn-

6-yl}-phenot;

4-Chloro-3-(2-(6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-2-methyl-pyrimidin-4-ylamino}- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenol;

4-Chloro-3-(2-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-5-methyl-phenylamino}- [1,2,4]triazolo[1,5-a]pyridin-6-yl)-phenol;

4-Chloro-3-[2-(3,4,5-trimethoxy-phenylamino)-[1,2,4]triazolo[1,5-a]pyridÎn-6-yl]-phenol;

4-Chloro-342-[3-(2-hydroxy-ethyl)-3H-benzoimidazol-5-ylamino]-[1,2,4]triazolo[1,5-

a]pyridin-6-yl)-phenol;

4-Chloro-3-{2-(pyridin-3-ylamino)-[1,2_I4]triazolo[1,5-a]pyridin-7-yl]-phenol;

4-Chloro-3-{2-[2-(2-pyrTolidin-1-y[-ethoxy)-pyridin-4-ylarTiino]-[1_I2,4]triazolo[1,5-a]pyridin6-yl}-phenol;

3-[2-(3,5-Bis-hydroxymethyl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-4-chlorophenol;

3- [2-(3,4-Bis-hydroxymethyl-phenylamino)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-4-chlorophénol;

4- Chloro-3-[2-(3,4,5-trimethoxy-phenylamino)-quinazolin-6-yl]-phenol;

2-{4-[6-(2-Chloro-5-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-pyrazol-1 -yl}~

1 -piperazin-1 -yl-ethanone;

4-Chloro-3-(2-(2-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-pyridin-4-ylamino}-[1,2,4]triazolo[1,5-

a] pyr idin-6-yl)-phenol;

4-Chloro-3-(7-methoxy-2-[4-(2-pynOlidin-1-yl-ethoxy)-phenylamino]-[1_I2_l4]triazolo[1,5-

a]pyrid i n-6-y l}-phenol ;

4-Chloro-3-[2-(6-methoxy-pyridin-3-ylamino)-quinazolin-6-yl]-phenol;

4-Chloro-3-(2-[4-[2-(1-oxy-pyrrolidin-1-yl)-ethoxy]-phenylamino}-[1,2,4]triazolo[1,5-

a]pyridin-6-yl)-phenol;

4-Chloro-3-[2-(1H-indol-6-ylarrtino)-quinazolin-6-yl]-phenol;

4-Chloro-3-[2-(2-hydroxymethyl-pyridin-4-ylamino)-quinazolin-6-yl]-phenol;

1-(2-{5-[6-(2-Chloro-5-hydroxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-pyridin-2yloxy}-ethyl)-pyrrolidin-2-one;

4-Chloro-3-{2-[1-(2-hydroxy-ethyl)-1H-benzoimidazol-5-ylamino]-quinazolin-6-yl}-phenol;

Vi

-534-Chloro-3-(2-{3-[4-(2-hydroxy-ethyi)-piperazin-1-yl]-5-methyl-phenylamino}-quinazolin-6yl)-phenol;

4-Chloro-3-(2-{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-5-hydroxymethyl-phenylamino}- [1.2.4] triazolo[1,5-a]pyridin-6-yl)-phenol;

Benzoic acid 4-chloro-3-(243-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]-5-methyl-phenylamino}- [1.2.4] triazolo[1,5-a]pyridin-6-yl)-phenyl ester;

Benzoic acid 4-chloro-3-(2-[3-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]-5-methyl-phenylamino}quinazolin-6-yl)-phenyl ester;

4-Chloro-3-(2-{3-[4-(2-hydroxy-ethy[)-piperazin-1-yl]-5-hydroxymethylphenylamino}-quinazolin-6-yl)-phenoi;

and any prodnjg thereof.

18. Médicament, characterized in that it comprises a cornpound of formula (I) according to any one of daims 1 to 17.

19. Pharmaceutical composition, characterized in that it comprises a cornpound of formula (I) according to any one of Claims 1 to 17,or a prodrug of a cornpound of formula (I), and also at least one pharmaceutically acceptable excipient.

20. Use of a cornpound of formula (I) according to any one of Claims 1 to 17 for preparing a médicament intended for treating, preventing or ameliorating retinal/macular oedema, age-related macular degeneration, ischemia-related retinal vascular leakage, diabetic retinopathy, retinal vein occlusion, or vitreoretinal disease.

21. Src kinase antagonist of formula (I) as defined in claims 1 to 17.

22. Cornpound of formula (I) according to any one of Claims 1 to 17 as a médicament.