OA16296A - Imidazopyridine derivatives, process for the preparation thereof and therapeutic use thereof. - Google Patents

Abstract

The invention relates to compounds corresponding to formula (I) : R4 NN R1 O R2 R3 (I) 5 6 7 8 in which - R2 and R3 together form, with the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered nitrogenous heterocycle corresponding to one of formula (A), (B) or (C) below : N N O O Ra Ra' N N O RbRb' N O RcRc'' Rc' (A) (B) (C) in which the wavy lines represent the phenyl nucleus to which R2 and R3 are attached. Preparation process and therapeutic use.

Description

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IMIDAZOPYRIDINE DERIVATIVES, PROCESS FOR THE PREPARATION THEREOF AND THERAPEUTIC USE THEREOF

The present invention relates to imidazopyridine derivatives which are inhibitors of FGFs (Fibroblast Growth Factors), to the process for the preparation thereof and to the therapeutic use thereof.

FGFs are a family of polypeptides synthesized by a large number of cells during embryonic development and by cells of adult tissues in various pathological conditions.

Indolizine derivatives, which are antagonists of the binding of FGFs to their receptors, are described in international patent applications WO 03/084956 and WO 2005/028476. Imidazo[1,5-a]pyridine derivatives which are FGF antagonists are described in international patent application WO 2006/097625. Novel imidazopyridine derivatives, which are antagonists of the binding of FGFs to their receptors, have now been identified.

The subject of the present invention is thus compounds, imidazopyridine derivatives, corresponding to formula (I):

in which:

- Ri represents . a hydrogen or halogen atom, . an alkyl group optionally substituted with -COOR₅, . an alkenyl group optionally substituted with -COOR₅, . a -COOR_S or -CONRsRe group, . an -NR₅COR₆ or -NR₅-SO₂R₆ group,

Ύ..

or . an aryl group, in particular phenyl, or a heteroaryl group, said aryl or heteroaryl group being optionally substituted with one or more groups selected from: halogen atoms, alkyl groups, cycloalkyl groups, -COOR₅, -CF₃, -OCF₃, -CN, C(NH₂)NOH, -OR_5j -O-Alk-COORs, -O-Alk-NR₅Re, -O-Alk-NR₇R₈, -Alk-OR₅, Alk-COOR₅, -CONR_sRe, -CO-NR_S-OR_S, -CO-NR₅-SO₂R₇, -CONR₅-Alk-NR₅R₆, CONR₆-Alk-NR₇R₈, -Alk-NR_SR₆₁ -NR₅R₆, -NC(O)N(CH₃)₂. -CO-Alk, -CO(OAIk)_nOH, COO-Alk-NR₅R₆, COO-Alk-NR₇R_e and 5-membered heteroaryl groups, said heteroaryl groups being optionally substituted with one or more groups selected from halogen atoms and alkyl, -CF₃, -CN, -COOR_5l -Alk-OR₅, -Alk-COOR_S, -CONR₅Re, -CONR₇R_8l -CO-NR₅-OR_B, -CO-NR₅-SO₂R₆, -NR₅Re and -Alk-NR₅R₆ groups, or with a hydroxyl group or with an oxygen atom,

- n is an integer ranging from 1 to 3,

- R₂ and R₃ together form, with the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered nitrogenous heterocycle corresponding to one of formula (A), (B) or (C) below:

in which the wavy lines represent the phenyl nucleus to which R₂ and R₃ are attached and:

. R_a represents a hydrogen atom or an alkyl, haloalkyl, -Alk-CF₃, -Alk-COORs, -Alk’-COORs , -Alk-CONR₅R₆, -Alk'-CONR.Rs -Alk-CONR₇R₈, -AlkNR₅Rs, -AlkCONRs-ORs, -Alk-NR₇R₈, -Alk-cycloalkyl, -Alk-O-R₅₁ -Alk-S-R₅, -Alk-CN, -OR₅, -OAlkCOORs, -NR₅R₆, -NR₅-COOR«, -Alk-aryl, -Alk-O-aryl, -Alk-O-heteroaryl, -Alk-heteroaryl or heteroaryl group, where the aryl or heteroaryl group is optionally substituted with one or more halogen atoms and/or alkyl, cycloalkyl, -CF₃, -OCF₃, -O-R₅ or -S-R₅ groups, . R_a· represents a hydrogen atom or a linear, branched, cyclic or

partially cyclic alkyl group, or an -Alk-OR_S, -Alk-NR₅R₆ or -Alk-NR₇R_B group, R_a· being optionally substituted with one or more halogen atoms, . R_b represents a hydrogen atom or an alkyl or -Alk-COOR₅ group, . R_b‘ represents a hydrogen atom or an alkyl, haloalkyl, cycloalkyl, phenyl or -Alk-COOR₅ group, . R_c represents a hydrogen atom or an alkyl, -CN, -COOR₅, -CO-NRsRe, -CONR₇R₈ -CO-NR₅-Alk-NR₅R₆, -CONR₅-Alk-OR₅, -CONR_sSO₂R₅, -Alkaryl or -Alk-heteroaryl group, where the aryl or heteroaryl group is optionally substituted with one or more halogen atoms and/or alkyl, cycloalkyl, -CF₃, -OCF₃, -O-alkyl or -S-alkyl groups, . Rc represents a hydrogen atom or an alkyl group, . Rc represents a hydrogen atom or an alkyl, alkenyl, haloalkyl, cycloalkyl, -Alk-NR₅R6, -Alk-NR₇R₈, -Alk-OR₅ or -Alk-SR₅ group,

- R4, located on position 6, 7 or 8 of the imidazopyridine nucleus, represents:

. a hydrogen atom, . a -COOR5 group, . a -CO-NRs-Alk-NRsRe group, . a -CO-NR₅-Alk-NR₇R₈ group, or . a -CO-NR₅-Alk-OR_e group,

- R₅ and Re, which may be identical or different, represent hydrogen atoms, haloalkyl groups or alkyl groups, cycloalkyl groups or an Ms (mesyl) group,

- R₇ and R₈, which may be identical or different, represent hydrogen atoms or alkyl or phenyl groups, or else R₇ and R₈ together form a 3- to 8-membered saturated ring which can optionally contain a heteroatom,

- Aik represents a linear or branched alkylene chain, and

- Aik’ represents a linear, branched, cyclic or partially cyclic alkylene chain, these compounds being optionally present in the form of a pharmaceutically acceptable salt thereof.

The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or of diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including

racemic mixtures, are part of the invention.

The compounds of formula (I) can exist in the form of bases or of acids or can be salified with acids or bases, in particular pharmaceutically acceptable acids or bases. Such addition salts are part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids or bases, but the salts of other acids or bases that are of use, for example, for purifying or isolating the compounds of formula (I) are also part of the invention.

The compounds of formula (I) can also exist in the form of hydrates or of solvates, namely in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates or solvates are also part of the invention.

In the context of the invention, and unless otherwise mentioned in the text, the term:

- “alkyl” is intended to mean: a linear or branched, saturated hydrocarbonbased aliphatic group containing from 1 to 6 carbon atoms;

- “cycloalkyl is intended to mean: a cyclic alkyl group comprising from 3 to 8 ring members, containing between 3 and 6 carbon atoms and optionally comprising one or more heteroatoms, for example 1 or 2 heteroatoms, such as nitrogen and/or oxygen, said cycloalkyl group being optionally substituted with one or more halogen atoms and/or alkyl groups. By way of examples, mention may be made of cyclopropyl, cyclopentyl, piperazinyl, pyrrolidinyl and piperidinyl groups;

- “partially cyclic alkyl group” is intended to mean: an alkyl group of which only a part forms a ring;

- “alkylene is intended to mean: a linear or branched divalent alkyl group containing from 1 to 6 carbon atoms;

- halogen is intended to mean: a chlorine, fluorine, bromine or iodine atom;

- “haloalkyl is intended to mean: an alkyl chain in which all or some of the hydrogen atoms are replaced with halogen atoms, such as fluorine atoms;

- “aryl” is intended to mean: a cyclic aromatic group containing between 5 and 10 carbon atoms, for example a phenyl group;

- “heteroaryl is intended to mean: a cyclic aromatic group containing between 3 and 10 atoms, including one or more heteroatoms, for example between 1 and 4 heteroatoms, such as nitrogen, oxygen or sulphur, this group comprising one or more, preferably one or two, rings. The heterocycles may comprise several

condensed rings. The heteroaryls are optionally substituted with one or more alkyl groups or an oxygen atom. By way of examples, mention may be made of thienyl, pyridinyl, pyrazolyl, imidazolyl, thiazolyl and triazolyl groups; and

- “5-membered heteroaryl is intended to mean: a heteroaryl group consisting of a 5-membered ring comprising 1 to 4 heteroatoms (such as oxygen and/or nitrogen atoms), optionally substituted with one or more alkyl groups or a hydroxyl group or with an oxygen atom. Mention may, for example, be made of oxadiazolyl and tetrazolyl groups;

- the halogens are preferably selected from F and Cl.

Among the compounds of formula (I) according to the invention, mention may be made of a subgroup of compounds in which Ri represents:

. a hydrogen or halogen atom, . an alkyl group which is unsubstituted or substituted with -COOR₅, . an alkenyl group which is unsubstituted or substituted with -COOR₅ . a -COORg group, . a -CONR₅R₆ group, . an -NRs-SOiRe group, or . a phenyl group optionally substituted with one or two groups selected from:

• halogen atoms;

• alkyl groups optionally substituted with -COOR₅;

• -CN (cyano), -C(NH₂)NOH, -COOR_S, -CONR₅Re, -CONR₅-OR_S, -CO-NR₅-SO₂Re, -COAIk, -CO(OAIk)_nOH, -OR₅, -OCF₃ , -O-Alk-COOR₅, -Alk-OR₅, -NR₅Re or NC(O)N(CH₃)₂ groups, • 5-membered heteroaryls optionally substituted with an alkyl group and/or a hydroxyl group or an oxygen atom, in which R₅ and Re, which may be identical or different, represent hydrogen atoms, or alkyl groups optionally substituted with an -NR_TR_S group,

R₇ represents a hydrogen atom, an alkyl group containing 1 or 2 carbon atoms or a phenyl group, n is an integer ranging from 1 to 3, or . a heteroaryl group which is optionally condensed and/or optionally substituted with one or two groups selected from alkyl groups, OR₅, -COOR₅, NR₅Re and cycloalkyl groups, and an oxygen atom, in which R₅ and R₆, which may be identical or different, represent hydrogen atoms or alkyl groups containing 1 or 2 bl

carbon atoms.

Among the compounds of formula (I) according to the invention, mention may be made of another subgroup of compounds in which R₂ and R₃ together form, with the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered nitrogenous heterocycle corresponding to either of formulae (A) and (B) defined above, preferably corresponding to formula (A).

Formula (A) or (B) is advantageously such that:

. R_a represents a hydrogen atom or an alkyl group, optionally substituted with one or more halogens; -AlkCONR₅Re; haloalkyl; -CH₂-COOR₅; -Alk-heteroaryl, Alk-O-phenyl or -Alk-phenyl, where the phenyl group is optionally substituted with one or two alkyl groups and/or OR₅ and/or halogen atoms; -Alk-cycloalkyl, . R_a represents a hydrogen atom or a linear, branched, cyclic or partially cyclic alkyl group, or a -CH₂-OR₅ or -Alk-NR₅R₆ group, . R_b represents a hydrogen atom or an alkyl group, . R_b' represents a hydrogen atom or an alkyl, phenyl or -CH_?-COOR₅ group, in which the alkyl groups contain 1 to 6 carbon atoms, R₅ being as defined above.

Among the compounds of formula (I) according to the invention, mention may be made of another subgroup of compounds in which R4 represents a hydrogen atom or a -COOH, -CO-NH-Alk-NR₇R₈ or -CO-NH-Alk-OH group, in which Aik, R₇ and R₈ are as defined above, or else an alkyl group, preferably containing 1 to 3 carbon atoms, which is unsubstituted.

In the compounds of formula (I) according to the invention, R4 is advantageously located on position 6 or 7 of the imidazopyridine nucleus.

Among the compounds which are subjects of the invention, mention may be made of the following compounds:

5-(3-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1 -yl}-2-fluorobenzoic acid

3-( 3-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid

3-(3-((1 -methyl-2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-616296 yi)carbonyl]imidazo[1,5-a]pyndin-1-yl}benzoic acid 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid 3-(3-{[3-(4-fluorobenzyl)-1 -(methoxymethyl)-2,4-dioxo-1,2,3,45 tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid 3-(3-{(3-(4-fluorobenzyl)-1-propyl-2₁4-dioxo-1 ,2,3,4-tetrahydroquinazolin-6yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid

3-[3-({3-[2-(4-fluorophenyl)ethyl]-1-methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yi}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic acid

3-(3-(( 1 -methyl-3-[(5-methy lthiophen-2-yl)methy l]-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic acid 3-[3-({3-[(5-methyithiophen-2-yl)methyl]-2,4-dioxo-1-propyl-1,2,3,4tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic acid 3-(3-((2,4-dioxo-1-propyt-3-(thiophen-2-ylmethyl)-1,2,3,415 tetrahydroquinazolin-6-yl]carbonyi}imidazo[1,5-a]pyridin-1-yl)benzoic acid 3-[3-({3-[2-(4-fluorophenoxy)ethy l]-1-propyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic acid

In the following text, the term “protective group” is intended to mean a group which 20 makes it possible, firstly, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, secondly, to regenerate the intact reactive function at the end of synthesis. Examples of protective groups and also methods of protection and deprotection are given in “Protective Groups in Organic Synthesis, Green et al., 3^rd Edition (John Wiley & Sons, Inc., New York).

In the remainder of the text, the term “leaving group is intended to mean a group that can be readily cleaved from a molecule by breaking a heterolytic bond, with the departure of a pair of electrons. This group can thus be readily replaced with another group during a substitution reaction, for example. Such leaving groups are, 30 for example, halogens or an activated hydroxyl group, such as a mesyl, tosyl, inflate, acetyl, para-nitrophenyl, etc. Examples of leaving groups and also methods for the preparation thereof are given in “Advances in Organic Chemistry”, J. March, 3^rd Edition, Wiley Interscience, p. 310-316.

In accordance with the invention, the compounds of general formula (I) can be

VtC16296

prepared according to the processes hereinafter.

The compounds of formula (IV) are obtained by methods known in the literature, starting from the suitably substituted corresponding 2-ami nomethylpyridines, according to the following reaction scheme, described in J. Chem. Soc. (1955), 2834-2836 (II) _R formylation

cyclization (Hl)

When R4 represents COOR₅, the compounds of formula (II) are obtained according to the reaction scheme described in WO 06/097625.

Scheme 1 presents a pathway for obtaining the compounds of formula (I) in which R₂ and R₃ together form a nitrogenous heterocycle of formula (A) as defined above, and in which R! and R_a-represent hydrogen atoms.

Scheme 1 (Method 1):

The compound of formula (IV), in which R4 is as defined for the compound of formula I, is condensed with the compound of formula V in order to obtain the '0.

compound of formula VI. The compound of formula VI is subjected to a basic hydrolysis reaction in order to obtain the compound of formula VII. The esterification of the compound of formula VII produces the compound of formula VIII. By reacting triphosgene, the isocyanate corresponding to the compound of formula VIII is formed, which is condensed with an amine of formula R_aNH₂ in order to obtain the urea of formula IX. The compound of formula IX is subjected to a cyclization reaction in a basic medium in order to obtain the compound of formula I in which Ftand Ra are as defined above.

Scheme 2 presents a pathway for obtaining the compounds of formula (I) in which R₂ and R₃ together form a nitrogenous heterocycle of formula (A) as defined above, and in which Ri represents a group as defined in the general formula, except for a hydrogen atom.

Scheme 2 (Method 2):

The compound of formula VIII is subjected to a bromination reaction in order to obtain the compound of formula X. By reacting triphosgene, the isocyanate corresponding to the compound of formula X is formed, which is condensed with an amine of formula RaNH₂ in order to obtain the urea of formula XI. The compound of formula XI is subjected to a cyclization reaction in a basic medium, in order to obtain the compound of formula XII. The compound XII is subjected to an alkylation reaction in the presence of a base and of a halogenated derivative Ra’X in order to obtain the compound of formula XIII. The compound of formula XIII is subjected, in

the presence of a palladium catalyst, of a ligand and of a base,

- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or heteroarylboronate ester derivatives according to a Suzuki coupling,

- or else to an imination reaction with benzophenoneimine followed by an acid hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula R_BSO₂CI,

- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis and by an esterification or a peptide coupling with an amine R₅ReNH₂, in order to obtain the compound of formula I in which R_t R4, R_a and R_a· are as defined above.

Scheme 3 presents a pathway for obtaining the compounds of formula (I) in which R₂ and R₃ together form a nitrogenous heterocycle of formula (A) as defined above, and in which R1 represents a group as defined in the general formula, except for a hydrogen atom, and in which R4 is as defined above.

Scheme 3 (Method 3):

The compound of formula X is subjected, in the presence of a palladium catalyst, of a ligand and of a base,

- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or heteroaryl boronate ester derivatives according to a Suzuki coupling,

- or else to an imination reaction with benzophenoneimine, followed by an acid hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula

ReSC^CI,

- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis and by an esterification or a peptide coupling with an amine R₅R6NH₂, R₅ and R« being defined above, in order to obtain the compound of formula XIV in which R-ι is as defined above. By reacting triphosgene, the isocyanate corresponding to the compound of formula XIV is formed, which is condensed with an amine of formula R_aNH₂ in order to obtain the urea of formula XV. The compound of formula XV is subjected to a cyclization reaction in a basic medium in order to obtain the compound of formula XVI. The compound XVI is subjected to an alkylation reaction in the presence of a base and of a halogenated derivative R_aX in order to obtain the compound of formula I.

Scheme 4 presents a pathway for obtaining the compounds of formula (I) in which R₂ and R₃ together form a nitrogenous heterocycle of formula (A) as defined above, and in which R_t represents a group as defined in the general formula, except for a hydrogen atom, and in which R4 is as defined above.

Scheme 4 (Method 4):

The compound of formula XII is subjected, in the presence of a palladium catalyst, of a ligand and of a base,

- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or heteroaryl boronate ester derivatives according to a Suzuki coupling,

- or else to an imination reaction with benzophenoneimine, followed by an acid hydrolysis and by a sulphonylation reaction with a sulphonyl chloride of formula ReSO₂CI,

- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis and by an esterification or a peptide coupling with an amine R₅R_eNH₂, in order to obtain the compound of formula XVI in which R1 is as defined above. The % »

compound XVI is subjected to an alkylation reaction in the presence of a base and of a halogenated derivative R_aX in order to obtain the compound of formula I.

Scheme 5 presents a pathway for obtaining the compounds of formula (I) in which R₂ and R₃ together form a nitrogenous heterocycle of formula (B) as defined above, in which Rq represents a hydrogen atom and in which R4 is as defined above.

Scheme 5 (Method 5):

The compound VIII is subjected to a saponification reaction in order to obtain the compound XXIV. The compound XXIV is subsequently subjected to a condensation reaction with an alkyl or aryl anhydride (R_bCO)₂O in order to obtain the compound of formula XVII. The compound of formula XVII is subjected to a condensation reaction with an amine R_bNH_z in order to obtain a compound of formula I in which R_b and R_b· are as defined above.

Scheme 6 presents a pathway for obtaining the compounds of formula (I) in which R_z and R₃ together form a nitrogenous heterocycle of formula (B) as defined above and in which Rq is as defined above, except for a hydrogen, and in which R4 is as defined above.

'ft C,

Scheme 6 (Method 6) :

The compound XIV is subjected to a saponification reaction in order to obtain the compound XXV. The compound XXV is subsequently subjected to a condensation reaction with an alkyl or aryl anhydride (R_bCO)₂O in order to obtain the compound of formula XVIII. The compound of formula XVI11 is subjected to a condensation reaction with an amine R_bNH₂ in order to obtain a compound of formula I in which 10 R_b and R_b· are as defined above.

Scheme 7 presents a pathway for obtaining the compounds of formula (I) in which R₂ and R₃ together form a nitrogenous heterocycle of formula (C) as defined above and in which R_c and also Ri and R< are as defined above.

- >

Scheme 7 (Method 7}:

The compound X is subjected to a saponification reaction in order to obtain the compound XIX. The compound XIX is subjected to a condensation reaction in the presence of triphosgene, in order to obtain the compound XX. The compound XX is subjected to an alkylation reaction in the presence of a halogenated derivative R^-X or of a protective group in order to obtain the compound XXI. The compound XXI is subjected to a condensation reaction with a malonic derivative in order to obtain the compound XXII in which Rc· and Rc are as defined above. The compound XXII is subjected, in the presence of a palladium catalyst, of a ligand and of a base,

- to a reaction with phenylboronic or heteroarylboronic or phenyl boronate ester or heteroaryl boronate ester derivatives according to a Suzuki coupling,

- or else to an imination reaction with benzophenoneimine, followed by an acid hydrolysis and by a sulphonylation reaction with a sulphonyl chloride of formula R₆SO₂CI,

- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis and by an esterification or a peptide coupling with an amine R₅ReNH₂, in order to obtain the compound of formula XXIII in which R. is as defined above.

* ,

The compound XXIII is subjected to a deprotection reaction in order to obtain the compounds of formula I in which R_c is a hydrogen atom.

In the preceding schemes, the starting compounds and the reactants, when the method for preparing them is not described, are commercially available or described in the literature, or else can be prepared according to methods which are described therein or which are known to those skilled in the art.

A subject of the invention, according to another of its aspects, is also the compounds of formulae II to XXIII defined above. These compounds are of use as synthesis intermediates for the compounds of formula (I).

The following examples describe the preparation of certain compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention. The numbers of the compounds exemplified refer back to those given in the table hereinafter, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

The reactants and intermediates, when their preparation is not explained, are known in the literature or commercially available. Some intermediates that are of use for preparing the compounds of formula I may also serve as final products of formula (I), as will become apparent in the examples given hereinafter. Similarly, some compounds of formula (I) of the invention can serve as intermediates that are of use for preparing other compounds of formula (I) according to the invention.

By way of example, the derivatives of formula (I) are selected from the following compounds:

6-(imidazo[1,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1H,3H)-dione₁ 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-

a]pyndin-1-yI}benzoic acid,

3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-

a]pyridine-6-carboxylic acid,

3-(3-{I3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3_T4-tetrahydroquinazolin-6yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid,

3-(3((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[ 1,5VL

J t

a]pyridin-1-yl}benzamide, 6-({1-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl-3propylquinazoline-2,4(1 H, 3H)-dione,

6-({1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)-3propylquinazoline-2,4(1 H, 3H)-dione,

N-(3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5a]pyridin-1-yl}methanesulphonamide,

2- morpholin-4-yl-ethyl 3-(3-{[3-(4-fluorobenzyl)-1-méthyl-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-6-yllcarbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate,

N-[2-(dimethylamino)ethylJ-3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl) benzamide,

3- (3-{[3-(4-fluorobenzy 1)-1 -propyl-2,4-dioxo-1,2,3,4-tetrahydroqui nazolin-6yl]carbony[}imidazo[1,5-alpyridin-1-yl)benzoic acid,

3-(4-fluorobenzyl)-1-methyl-6-((1-pyridin-3-ylimidazo[1,5-a]pyridin-3yl)carbonyl]quinazoline-2,4(1 H, 3H)-dione,

3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5a]pyridin-1-yl}benzoic acid,

3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5a]pyridin-1 -yl}benzamide,

6-(imidazo[1,5-a]pyridin-3-ylcarbonyl)quinazolin-4(3H)-one,

N,/V.1,2-tetramethyl-4-oxo-6-{[1-(pyndin-3-yl)imidazo[1,5-a]pyridin-3-yl]carbonyl}-

1,4-dihydroquinoline-3-carboxamide,

3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic acid.

Abbreviations

TOTU: 0-[(ethoxycarbonyl)cyanomethyieneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate

NMP: N-Methy I pyrrolidone

DME: Ethylene glycol dimethyl ether

DMF; Dimethylformamide

THF: Tetrahydrofuran

Binap: 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

The NMR analyses were carried out on Bruker Avance 250MHz, 300MHz and «

400MHz instruments.

- The melting points were measured on a Buchi B-450 instrument.

- The mass spectrometry analyses were carried out on a Waters Alliance 2695 (UV: PDA996, MS: LCZ), Alliance 2695 (UV: PDA 996, MS: ZQ (simple Quad) ZQ1), Alliance 2695 (UV: PDA 996, MS: ZQ (simple Quad) ZQ2), Waters UPLC Acquity (UV: Acquity PDA, MS: SQD (simple Quad) SQW), Agilent MSD, Waters ZQ, or Waters SQD instrument.

Example 1 : (compound No. 1 ) 6-(lmidazo[1,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1H,3H)-dione

Methyl 2-amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate

13.4 ml (96 mmol) of triethylamine are added to 3.5 g (30 mmol) of imidazo[1,5-a]pyridine [described in J. Chem. Soc.; (1955), 2834-2836] in 250 ml of 1,2-dichloroethane, followed, under a nitrogen atmosphere at 0°C, by 13.7 g (48 mmol) of 4-oxo-2-phenyl-4H-3,1-benzoxazine-6-carbonyl chloride (described in WO 05/028476). After stirring for 4.5 hours at ambient temperature, the reaction medium is filtered. The residue obtained is washed with 1,2-dichloroethane. After drying overnight at 40°C under reduced pressure, 3 g of a yellow solid are obtained.

The residue obtained is dissolved in 100 ml of NMP. A solution of 8.4 g ¢0.15 mol) of KOH in 10 ml of water is added dropwise, under a nitrogen atmosphere, at ambient temperature. The reaction medium is heated at 80°C for 6 hours and then poured, at ambient temperature, into a 1N aqueous solution of hydrochloric acid. The precipitate obtained is filtered off, rinsed with water and then dried at 40°C under reduced pressure overnight. After silica gel column chromatography, elution being carried out with a dichloromethane/methanol/0.1% triethylamine mixture, 5.5 g of a yellow solid are obtained.

g (0.022 mol) of caesium carbonate and then, dropwise, 1.34 ml (0.022 mol) of methyl iodide are added, under a nitrogen atmosphere at ambient temperature, to 5.5 g (0.02 mol) of the residue obtained, in 100 ml of DMF. After stirring for 24 hours at ambient temperature, the reaction medium is poured into water. The precipitate obtained is filtered off, rinsed with water and then dried overnight at 40°C under reduced pressure. 5.1 g of a yellow solid are obtained.

Melting point: 192°C

MH+: 296

Methyl 5-()midazo[1,5-a]pyridin-3-ylcarbonyl)-2«

[(propylcarbamoyl)aminoj benzoate

0.35 g (1.2 mmol) of triphosgene is added, at ambient temperature under a nitrogen atmosphere, to a suspension of 0.5 g (1.7 mmol) of methyl 2-amino-5(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate in 20 ml of anhydrous dioxane. After heating for 2 hours at 100°C, 0.28 ml (3.4 mmol) of n-propylamine and then 0.71 ml (5 mmol) of triethylamine are added to the reaction medium at ambient temperature. After stirring for 18 hours at ambient temperature, H₂O is added. The aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered, and concentrated under reduced pressure. The yellow solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (98/2) mixture. 0.410 g of a yellow solid is obtained.

Melting point: 205°C

MH+: 381

6-flmidazo[1,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1H,3H)-dione

1.38 ml (1.38 mmol) of a 1N aqueous solution of sodium hydroxide are added, at ambient temperature, to a suspension of 0.436 g (1.15 mmol) of methyl 5(imidazo[1,5-a]pyridin-3-ylcarbonyl)-2-[(propylcarbamoyl)amino]benzoate in 10 ml of methanol. After refluxing for 2 hours, the methanol is concentrated under reduced pressure. A 1N aqueous solution of hydrochloric acid is added. The precipitate obtained is filtered off, rinsed with water and then dried overnight at 40°C under reduced pressure. 0.27 g of a yellow solid is obtained.

Melting point: 304°C 'H-NMR (D6-DMSO, 400 MHz):

0.91 (t, J=7.17Hz, 3H), 1.63 (q, J=7.59Hz, 2H), 3.89 (t, J=7 17Hz, 2H), 7.25-7.37 (m, 2H), 7.39-7.43 (m, 1H), 7.82 (s, 1H), 7.97 (d, J=8.86Hz, 1H), 8.59 (d, J=8.86Hz, 1H), 9.18 (s, 1H), 9.74 (d, J=7.17Hz, 1H), 11.8 (s, 1H).

* >

Example 2: (compound No. 10)

Sodium salt of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-ajpyridin-1-yl}benzoic acid

Methyl 2-amino-5-[(1-bromoimidazo[1,5-a]pyridin-3yljcarbonyl] benzoate

0.42 g (2.4 mmol) of N-bromosuccinimide is added, under a nitrogen atmosphere at ambient temperature, to a solution of 0.67 g (2.4 mmol) of methyl 2amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoate in 20 ml of dichloromethane. After stirring for 2 h 30, water is added. The precipitate formed is filtered off, rinsed with water, and dried overnight at 40°C under reduced pressure. 0.77 g of a yellow solid is obtained.

Melting point: 230°C

MH+: 375, 377

Methyl 2-amino-5-({1-[³4^methoxycarbonyl)phenyl]imidazo[1,5a]pyridin-3-yl}carbonyl)benzoate

0.248 g (1.38 mmol) of [4-(methoxycarbonyl)phenyl)boronic acid, 0.57 g (2.30 mmol) of potassium carbonate in 2 ml of water, and 0.027 g (0.02 mmol) of tetrakis(triphenylphosphine)palladium are added to a solution of 0.43 g (1.15 mmol) of methyl 2-amino-5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate in 10 ml of DME, under an inert argon atmosphere. The reaction medium is heated at 90°C for 2 hours. The reaction medium is acidified with a 1N aqueous solution of hydrochloric acid, and extracted with dichloromethane. The organic phase is washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The solid obtained is dissolved in 5 ml of DMF. 30 pl (0.5 mmol) of methyl iodide and 0.052 g (0.16 mmol) of caesium carbonate are added. After stirring for 24 hours at ambient temperature, the reaction medium is hydrolysed with water and then extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is taken up in methanol. After filtration and drying overnight at 50°C under reduced pressure, 0.379 g of a yellow powder is obtained.

Melting point: 203°C

MH+: 430 *

Methyl 5-((1 -[3-(methoxycarbony l)phenyl]imidazo[1,5-a]py rid in-3yl}carbonyl)-2-[(propylcarbamoyl)amino]benzoate

0.181 g (0.61 mmol) of triphosgene is added, under an inert atmosphere, to 0.75 g (0.87 mmol) of methyl 2-amino-5-({1-[3(methoxycarbonyl)phenyl]imidazo(1,5-a]pyridin-3-yl}cartx)nyl)benzoate in 10 ml of dioxane. The reaction medium is heated at 100°C for 3 hours. 0.14 ml (1.75 mmol) of propylamine and 0.37 ml (2.62 mmol) of triethylamine are added at ambient temperature. After stirring for 2 hours at ambient temperature, the reaction medium is hydrolysed with water. The medium is filtered, washed with water, and dried under reduced pressure at 50°C overnight. The solid obtained is purified by silica gel column chromatography with a dichloromethane/methanol (95/5) mixture. 0.27 g of a yellow powder is obtained.

Melting point 212°C

MH+: 515

3-(3-((2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyljimidazo[1,5-a]pyridin-1-yl}benzoic acid

1.31 ml (1.31 mmol) of a 1N aqueous solution of sodium hydroxide are added to 0.27 g (0.52 mmol) of methyl 5-((1-(3(methoxycarbonyl)phenyllimidazo[1,5-a]pyridin-3-yl}cart>onyl)-2[(propylcarbamoyl)amino]benzoate in 8 ml of methanol. The reaction medium is heated at 70°C for 5.5 hours. The methanol is concentrated under reduced pressure. The residue is taken up in water. The aqueous phase is acidified with a 1N aqueous solution of hydrochloric acid, and then extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is taken up in methanol and then filtered, and dried at 50°C under reduced pressure overnight. 0.245 g of a yellow solid is obtained.

Melting point: 365°C

MH+: 469

Sodium salt of 3-(3-((2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl)benzoic acid

0.51 ml ¢0.51 mmol) of a 1N aqueous solution of sodium hydroxide is added «

to 0.245 g (0.52 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 5 ml of methanol. The reaction medium is stirred for 1.5 hours at ambient temperature. After the addition of di isopropyl ether, the precipitate formed is filtered off, rinsed with diisopropyl ether, and dried at 50°C under reduced pressure overnight. 0.242 g of a yellow powder is obtained.

Melting point: 383°C

MH+: 469 ¹H NMR (D6-DMSO, 400 MHz):

0.90 (t, J=7.82Hz, 3H), 1.58-1.67 (m, 2H), 3.88 (t, J=7.07Hz, 1H), 7.32-7.35 (m, 2H), 7.45 (t, J=7.82, 1H), 7.53 (t, J=7.82Hz, 1H), 7.88-7.94 (m, 2H), 8.22 (d, J=8.94Hz, 1H), 8.44 (t, J=1.7Hz, 1H), 8.74 (d, J=8.7Hz, 1H), 9.14 (d, J=1.9Hz, 1H),

9.82 (d, J=7Hz, 1H), 11.9 (bs, 1H).

Example 3 (compound No. 8) 3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5a]pyridine-6-carboxylic acid

3-[(4-Amino-3-carboxyphenyl)carbonyI]imidazo[1,5-a]pyridine-6carboxylic acid

3.68 ml (0.026 mol) of triethylamine and then, under a nitrogen atmosphere at ambient temperature, 1.5 g (8.5 mmol) of methyl imidazo(1,5-a]pyridine-6carboxylate [described in WO 06/097625] are added to 4.02 g (0.014 mol) of 4-oxo2-phenyl-4H-3,1-benzoxazin-6-carbonyl chloride in 60 ml of 1,2-dichloroethane. After stirring for 24 hours at ambient temperature, the reaction medium is filtered, and washed with 1,2-dichloroethane, then with a 1N aqueous solution of hydrochloric acid and then with water. After drying overnight under reduced pressure at 40°C, the product obtained is dissolved in 60 ml of NMP. 3.59 g (6.4 mmol) of potassium hydroxide dissolved in 11 ml of water are added. The reaction medium is heated at 100°C for 4 hours and then poured into a 1N aqueous solution of hydrochloric acid. After filtration, the solid obtained is rinsed with water and then dried overnight in an oven under reduced pressure at 40°C. 5.45 g of a yellow solid are obtained.

MH+: 326 ih L, *

Methyl 3-{[4-amino-3-(tnethoxycarbonyl)phenyl]carbonyl}imidazo[1,5ajpyridi ne-6 -carboxy late

9.4 g ¢2.9 mmol) of caesium carbonate and then 1.8 ml ¢2.9 mmol) of methyl iodide, at ambient temperature are added, under an inert atmosphere, to 4.2 g (1.3 mmol) of 3-[(4-amino-3-carboxyphenyl)carbonyl]imidazo[1,5-a]pyridine-6-carboxylic acid in 60 ml of DMF. After stirring for 4.5 hours at ambient temperature, the reaction medium is hydrolysed with water. The precipitate obtained is filtered off, rinsed with water, and then dried at 40°C under reduced pressure overnight. The solid obtained is purified by silica gel column chromatography, elution being carried out with dichloromethane. 1.3 g of a yellow solid are obtained.

MH+: 354

Methyl 3-({3-(methoxycarbonyl)-4[(propylcarbamoyl)amino]imidazo[1,5-a]pyridine-6 -carboxylate

0.14 g (0.49 mmol) of triphosgene is added, at ambient temperature under a nitrogen atmosphere, to 0.3 g (0.7 mmol) of methyl 3-([4-amino-3(methoxycarbonyl)phenylJcarbonyl}imidazo[1,5-a]pyridine-6-carboxylate in 10 ml of anhydrous dioxane. After heating for 1 h 15 at 100°C, 0.12 ml (1.4 mmol) of n-propylamine and 0.29 ml (2 mmol) of triethylamine are added to the reaction medium at ambient temperature. After stirring for 4 hours at ambient temperature, the reaction medium is hydrolysed with water. The precipitate obtained is filtered off, rinsed with water, and then dried under reduced pressure at 40°C overnight. The solid obtained is triturated from THF and then filtered and dried under reduced pressure at 40°C overnight. 0.21 g of a yellow solid is obtained.

Melting point: 266°C

MH+: 439

3-((2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridine-6-carboxylic acid

1.2 ml (1.2 mmol) of a 1N aqueous solution of sodium hydroxide are added, at ambient temperature, to 0.21 g of methyl 3-((3(methoxycarbonyl)-4-[(propylcarbamoyl)amino]imidazo[1,5-a]pyridine-6-carboxylate in 5 ml of methanol. After refluxing for 4 hours, the reaction medium is acidified with a 1N aqueous solution of hydrochloric acid. The precipitate obtained is filtered off and then rinsed with water and dried under reduced pressure at 40°C overnight.

* >

The solid obtained is recrystallized while hot from methanol and then dried under reduced pressure at 40°C overnight. 0.118 g of a yellow solid is obtained.

Melting point: 384°C

MH+: 393 ¹ H-NMR (D6-DMSO, 400 MHz) :

0.92 (t, J=7.2Hz, 3H), 1.59-1.68 (m, 2H), 3.87-3.94 (m, 2H), 7.33 (d, J=8.2Hz, 1H), 7.72 (d, J=9.3Hz, 1H), 7.98 (s, 1H), 8.06 (d, J=9.3Hz, 1H), 8.59 (d, J=8.51Hz, 1H), 9.20(d, J=2.03Hz, 1H), 11.8 (s, IH), 13.7 (s, 1H).

Example 4: (compound No. 49) Sodium salt of 3-{3-([3-(4-fluorobenzyl)-1 -methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid

Methyl 2-{[(4-fluorobenzyl)carbamoyl]amino}-5-({1-[3(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate

2.14 g (7.2 mmol) of triphosgene are added, at ambient temperature under an inert atmosphere, to 2.58 g (6 mmol) of methyl 2-amino-5-({1-[3(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)benzoate in 50 ml of dioxane. After refluxing for 7 hours, 2.25 g (18 mmol) of 4-fluorobenzy lamine and

1.82 g (18 mmol) of triethylamine are added at ambient temperature. The reaction medium is refluxed for 3 hours and then concentrated under reduced pressure. The residue is triturated from water. After filtration, the solid is rinsed with methanol and then dried under reduced pressure at 40°C overnight. 3.3 g of a yellow solid are obtained.

MH+: 581

3-(3-{[3-(4-Fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid

2.85 ml ¢0.0285 mol) of a 1N aqueous solution of sodium hydroxide are added to 3.3 g (5.7 mmol) of methyl 2-{[(4-fluorobenzyl)carbamoyl]amino}-5-({1-[3(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyI) benzoate dissolved in 250 ml of methanol. After refluxing for 2 hours, the reaction medium is acidified with 50 ml of a 1N aqueous solution of hydrochloric acid and then diluted with 700 ml of water. The precipitate obtained is filtered off, and dried under reduced pressure at 40°C overnight. 3.01 g of a yellow solid are obtained.

MH+: 535

Methyl 3-(3-{[3-(4-fluorobenzyl)-1 -methyI-2,4-dioxo-1,2,3,4tetrahydroquinazoIin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate

2.44 g (7.5 mmol) of caesium carbonate and 1.06 g (7.5 mmol) of methyl iodide are added, under an inert atmosphere, to 1.3 g (2.5 mmol) of 3-(3-((3-(4fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5a]pyridin-1-yl)benzoic acid in 50 ml of DMF. The reaction medium is stirred for 3 hours at ambient temperature under a nitrogen atmosphere and then concentrated under reduced pressure. The residue obtained is washed with 200 ml of water and then dried under reduced pressure at 40°C overnight. 1.35 g of a yellow solid are obtained.

MH+: 563

Sodium salt of 3-(3-((3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid ml (24 mmol) of a 1N aqueous solution of lithium hydroxide are added to 1.3 g (2.4 mmol) of methyl 3-(3-([3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate in 120 ml of THF. The reaction medium is refluxed for 5 hours and then acidified at 5°C with 45 ml of a 1N aqueous solution of hydrochloric acid and, finally, diluted with 200 ml of water. After filtration, the residue obtained is dried under reduced pressure at 40°C overnight.

0.62 ml (0.62 mmol) of a 1N aqueous solution of sodium hydroxide is added to 0.35 g (0.64 mmol) of the yellow solid obtained, in 20 ml of methanol. After filtration, the residue obtained is dried under reduced pressure at 40° C overnight. 0.38 g of a yellow solid is obtained.

MH+: 549 ¹H-NMR (D6-DMSO, 500 MHz):

3.62 (s, 3 H), 5.17 (s, 2 H), 7.11-7.18 (ps t, J = 8.9 Hz, 2 H), 7.35 - 7.40 (ps t, 8.9 Hz, 1 H), 7.42 - 7.48 (m, 3 H), 7.54 - 7.60 (ps t, J = 8.9 Hz, 1 H), 7.70 - 7.74 (ps d, J = 8.9 Hz, 1 H), 7.89 - 7.95 (ps t, J = 8.9 Hz, 2 H), 8.26 - 8.30 (ps d, J = 8.9 Hz, 1 H), 8.44 - 8.48 (m, 1 H), 8.96 - 9.01 (ps d, J = 8.9 Hz, 1 H), 9.22 - 9.24 (m, 1 H), 9.88 - 9.91 (ps d, J = 7.2 Hz, 1 H).

Example 5: (compound No. 29)

3-(3-((2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzamide

10.7 mg {0.2 mmol) of ammonium chloride, 5.17 mg (0.4 mmol) of N,Ndiisopropylethylamine and 49.2 mg (0.2 mmol) of TOTU are added, at 0°C, under an inert atmosphere, to 46.8 mg (0.1 mmol) of 3-f3-[(2,4-dioxo-3-propyl-1,2,3,4tetrahydroquinazolin-6-yl)carbonyl]imidazo(1,5-aJpyridin-1-yl}benzoic acid in 2 ml of DMF. The reaction medium is stirred for 12 hours at ambient temperature and then poured into 30 ml of a saturated solution of sodium hydrogen carbonate. The precipitate obtained is filtered off, washed with water, and dried under reduced pressure at 40’C overnight. 0.042 g of a yellow solid is obtained.

MH+: 468 ¹H-NMR (D6-DMSO, 500 MHz):

δ = 0.92 (t, 3 H, J = 7.7 Hz), 1.66 (tq, 2 H, J = 7.7 Hz, 7.3 Hz), 3.94 (t, 2 H, J = 7.3 Hz), 7.34-7.42 (2 m, 2 H), 7.52-7.61 (2m, 2 H). 7.69 (t. 1 H, J = 7.6 Hz), 7.96 ( m, 1 H), 8.10 -8.23 (2 m, 2 H), 8.41- 8.46 (m, 2 H), 8.80 (dd, 1 H, J = 8.9 Hz, 2.2 Hz),

9.27 (d, 1 H, 1.9 Hz), 9.88 (d, 1 H, J = 7.1 Hz), 11.83 (s, 1 H).

Example 6: (compound No. 34)

6-((1 -(3-( 5-Methy 1-1,3,4-oxadiazol-2-yl)phenyl]imidazo[1,5-a]pyridin-3yl}carbonyl-3-propylquinazoline-2,4(1H, 3H)-dione

N’-Acetyl-3-(3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl)benzohydrazide

29.6 mg (0.4 mmol) of acetohydrazide, 98.4 mg (0.3 mmol) of TOTU and 0.104 ml (0.6 mmol) of Ν,Ν-diisopropylethylamine are added, under an inert atmosphere, at 0°C, to 93.7 mg (0.2 mmol) of 3-(3-((2,4-dioxo-3-propyl-1,2,3,4tetrahydroquinazolin-6-yl)carbonyl]imidazo(1,5-a]pyridin-1-yl}benzoic acid in 6 mi of DMF. The reaction medium is stirred for 1 hour at 0°C and then for 6 hours at 50°C and then concentrated under reduced pressure. The residue is taken up in 10 ml of methanol. The precipitate obtained is filtered off, washed with dyethyl ether and with pentane, and then dried under reduced pressure at 40°C overnight. 45 mg of a yellow solid are obtained.

MH+: 525 • r

6-({1-[3-(5-Methyl-1,3,4-oxadiazol-2-yl)phenyl]imidazo[1,5-a]pyridin-3yl}carbonyl-3-propylquinazoline-2,4(1 H, 3H)-dione mg (0.066 mmol) of N’-acetyl-3-{3-[(2,4-dioxo-3-propyl-1,2,3,4tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzohydrazide in 1 ml of phosphorus oxychloride are heated at 100°C for 15 minutes. The reaction medium is concentrated under reduced pressure. The residue obtained is hydrolysed with water and with a saturated solution of sodium hydrogen carbonate. The aqueous phase is extracted with dichloromethane. The organic phase is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with methanol. 0.025 g of a yellow solid is obtained.

MH+: 507 ¹ H-NMR (D6-DMSO, 500MHz):

0.91 (t, J = 7.5 Hz, 3H), 1.65 (qt, J = 7.5 Hz, 7.5 Hz, 2 H), 2.67 (s, 3 H), 3.93 (t, J =

7.5 Hz, 2 H), 7.33 - 7.43 (m, 2 H), 7.58 - 7.64 (m, 1H), 7.77 - 7.84 (m, 1 H), 8.04 8.06 (m, 1 H), 8.28 - 8.32 (m, 1H), 8.39 - 8.43 (m, 1 H), 8.59 (s, 1 H), 8.71 - 8.74 (m, 1 H), 9.37 (s, 1 H), 9.86-9.90 (s, 1 H), 11.85 (br s, 1H).

Example 7: (compound No. 36) e-tfl-p-P-Methyl-l^^-oxadiazol-S-yOphenyllimidazon.S-aJpyridin-Syl}carbonyl)-3-propylquinazoline-2,4(1 H, 3H)-dione

3-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}-N-[(1E)hydroxyethan imidoyl] benzamide mg (0.24 mmol) of 1,T-carbonyldiimidazole are added, at ambient temperature under an inert atmosphere, to 94 mg (0.2 mmol) of 3-{3-[(2,4-dioxo-3-propy1-1,2,3,4tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 5 ml of DMF. After stirring for 12 hours at ambient temperature, 22.2 mg (0.3 mmol) of acetamidoxime are added. The reaction medium is stirred for 5 hours at ambient temperature and then concentrated under reduced pressure. The residue is triturated from dyethyl ether, filtered, and then dried under reduced pressure at 40°C overnight. 0.101 g of a yellow solid is obtained.

MH+: 525

6-((1-[3-(3-Methyl-1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,5-a]py rid in-3yl}carbonyl)-3-propylquinazoline-2,4(1H, 3H)-dione

A solution of 0.1 g (0.19 mmol) of 3-(3-((2,4-dioxo-3-propyl-1,2,3,4tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}-N-[(1E)hydroxyethanimidoyljbenzamide in 3 ml of DMF is heated at 120°C for 5 hours. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up in dyethyl ether, filtered, and then dried under reduced pressure at 40°C overnight. 0.083 g of a yellow solid is obtained.

MH+: 507 'H-NMR (D6-DMSO):

0.91 (t, J = 7.5 Hz, 3H), 1.65 (qt, J = 7.5 Hz. 7.5 Hz, 2 H), 2.47 (s. 3 H), 3.94 (t, J =

7.5 Hz, 2 H), 7.36-7.45 (m, 2 H), 7.59-7.66 (m, 1H), 7.82-7.89 (m, 1H), 8.13 8.19 (m, 1H), 8.36-8.45 (m, 2H), 8.68 (s, 1H). 8.75-8.79 (m, 1H), 9.25. 9.28 (m, 1 H), 9.85 - 9.90 (m, 1 H), 11.85 (br s, 1 H).

Example 8: (Compound No. 13) N-{3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}methanesulphonamide

Methyl 5-((1 -bromoimidazo(1,5-a)pyridin-3-yl)carbonyl]-2[(propylcarbamoyl)aminobenzoate

0.55 g (0.0019 mol) of triphosgene is added, at ambient temperature under an inert atmosphere, to 1 g (2.7 mmol) of methyl 2-amino-5-[1-bromo(imidazo[1,5a]pyridin-3-yl)carbonyl)]benzoate in 30 ml of anhydrous dioxane. The reaction medium is heated for 1.5 hours at 100°C. 0.44 ml (5.3 mmol) of n-propylamine and 1.12 ml (8 mmol) of triethylamine are added at ambient temperature. After 2 h 30, the reaction medium is hydrolysed with water. The aqueous phase is extracted with dichloromethane. The organic phase is dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is triturated from dichloromethane, filtered, and then dried under reduced pressure at 40°C overnight.

MH+: 459, 461

Melting point: 236°C

6-[(1-Bromoimidazo(1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline2,4(1 H, 3 H)-dione

3.14 ml (3.1 mmol) of a 1N aqueous solution of sodium hydroxide are added, at ambient temperature, to 1.2 g (2.6 mmol) of methyl 5-[(1-bromoimidazo(1,5a)pyridin-3-yl)carbonyl]-2-[(propylcarbamoyl)aminobenzoate in 20 ml of methanol. After refluxing for 3 hours, the reaction medium is hydrolysed with a 1N aqueous solution of hydrochloric acid. The precipitate obtained is filtered off, rinsed with methanol, and then dried under reduced pressure at 40°C overnight. 1.09 g of a yellow solid are obtained.

MH+: 427, 429

Melting point: 322°C

6-((1 -Aminoimidazo{1,5-a)pyridin-3-yl)carbonyl]-3-propylquinazoline2,4(1H,3H)-dione

1.45 g (4.7 mmol) of caesium carbonate, 1.13 ml (6.7 mmol) of benzophenoneimine, 0.278 g (0.45 mmol) of binap and 0.204 g (0.22 mmol) of dibenzylideneacetone dipalladium are added, at ambient temperature under an argon atmosphere, to 0.955 g (2 mmol) of 6-[(1-bromoimidazo(1,5-a)pyridin-3yi)carbonyl]-3-propylquinazoline-2_l4(1H,3H)-dione in 20 ml of DMSO. The reaction medium is heated at 110°C for 18 hours. The reaction medium is extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated under reduced pressure.

The residue obtained is dissolved in 40 ml of THF. 4.5 ml (9 mmol) of a 2N aqueous solution of hydrochloric acid are added at ambient temperature. After stirring for 4 hours at ambient temperature, the reaction medium is concentrated under reduced pressure. The residue obtained is washed with dichloromethane and with methanol, and then dried under reduced pressure at 40°C overnight. 0.558 g of a red solid is obtained.

MH+: 364

N-(3-[(2,4-Dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}methanesulphonamide

0.1ml (1.2 mmol) of mesyl chloride is added, at 0°C under an inert atmosphere, to 0.25 g (0.4 mmol) of 6-((1-aminoimidazo(1,5-a)pyridin-3yl)carbonyl]-3-propylquinazoline-2,4(1H,3H)-dione in 5 ml of pyridine. After the addition of methanol, the reaction medium is concentrated under reduced pressure. The residue is taken up with dichloromethane. The organic phase is washed with a

1N aqueous solution of hydrochloric acid and then with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The residue is recrystallized while hot from methanol, purified on a silica gel frit, elution being carried out with DMF. 0.057 g of an orange solid is obtained.

Melting point: 334°C

MH+: 442 ¹H-NMR (D6-DMSO, 400 MHz):

0.88 (t, J=7.37Hz, 3H), 1.55-1.65 (m, 2H), 3.29 (s, 3H), 3.87-3.90 (m, 2H), 7.27-

7.31 (m, 2H), 7.40-7.44 (m, 1H), 7.92 (d, J=9Hz, 1H), 8.52 (d, J=8.46Hz, 1H), 9.15 (d, J=2 18Hz, 1H), 9.71 (d, J=7.1Hz, 1H), 10.2 (s, 1H), 11.8 (s, 1H).

Example 9: (Compound No. 82) 2-Morpholin-4-yl-ethyl 3-(3-{[3-(4-fluorobenzyl)-1 -methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate hydrochloride

0.022 g (0.61 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.189 g (1.37 mmol) of potassium carbonate are added, under an inert atmosphere, to 0.3 g (0.55 mmol) of 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid in 8 ml of DMF. After stirring for 18 h at ambient temperature and then for 8 hours at 50°C, the reaction medium is hydrolysed with water, and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The yellow solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.61 ml of a 1N aqueous solution of hydrochloric acid is added to 0.334 g of the yellow solid obtained, in 5 ml of methanol. The reaction medium is stirred for 1 hour at ambient temperature. Dyethyl ether is added and then the reaction medium is filtered. The precipitate obtained is rinsed with dyethyl ether and then dried under reduced pressure at 50°C overnight. 0.298 g of a yellow solid is obtained.

Melting point: 215°C

MH+: 662 ¹H-NMR (D6-DMSO, 500 MHz):

3.21-3.31 (m, 2H), 3.31 (s, 3H), 3.46-3.54 (m, 2H), 3.6-3.7 (m, 2H), 3.61 (s, 3H),

T7C

3.70-3.80 (m, 2H), 3.90-4 (m, 2H), 4.65-4.75 (m, 2H), 5.16 (s, 2H), 7.11-7.16 (m, 2H), 7.37-7.39 (m, 1H), 7.42-7.45 (m, 2H), 7.55-7.58 (m, 1H), 7.67 (d, J=9.28Hz, 1H), 7.73 (t, J=7.69Hz, 1H), 8.07 (d, J=7.69Hz, 1H), 8.29-8.34 (m. 2H), 8.55 (s, 1H),

8.82 (d, J=9.01Hz, 1H), 9.27 (d, J=1.85Hz, 1H), 9.83 (d, J=7.16Hz, 1H), 10.9 (s, 1H).

Example 10: (Compound No. 117) N-[24Dimethylammo)ethyll-3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzamide hydrochloride

0.06 ml (0.55 mmol) of Ν,Ν-dimethylethylenediamine, 0.134 g ¢0.41 mmol) of TOTU and 0.14 ml (0.82 mmol) of diisopropylethylamine are added to 0.15 g (0.27 mmol) of 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid in 5 ml of DMF. The reaction medium is heated at 80°C for 16 hours. The reaction medium is hydrolysed with water, and extracted with ethyl acetate. The organic phase is washed with water, dried over sodium sulphate, filtered, and concentrated under reduced pressure. The yellow solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.23 ml of a 1N solution of hydrochloric acid in dyethyl ether is added to 0.095 g of the yellow solid obtained. After stirring for 1 hour, dyethyl ether is added. The precipitate obtained is filtered off, rinsed with water, and then dried under reduced pressure at 50°C overnight. 0.1 g of a yellow solid is obtained.

Melting point: 247°C

MH+: 619 ¹H-NMR (D6-DMSO, 400 MHz):

2.50(m, 6H), 2.84 (s, 2H), 3.31 (s, 3H), 3.61(s, 1H), 3.64-6.70 (m, 1H), 5.16 (s, 2H), 7.7.11-7.17 (m, 2H), 7.37-7.46 (m, 3H), 7.55-7.60 (m, 1H), 7.67-7.71 (m, 2H),

7.93 (d, J=8.19Hz, 1H), 8.19 (d, J=7.51Hz, 1H), 8.38-8.43 (m, 2H), 8.87 (d, J=8.88Hz, 1H), 8.92 (t, J=5 12Hz, 1H), 9.27 (d, J=2Hz, 1H), 9.81 (s, 1H), 9.84 (d, J=7.1Hz, 1H).

Example 11: (Compound No. 72)

Sodium salt of 3-(3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yi]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid

Propyl 3-(3-{[3-(4-f1uorobenzyl )-1-propyl-2,4-d ioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate

1.371 g (4.21 mmol) of caesium carbonate and 0.715 g (4.21 mmol) of propyl iodide are added, under an inert atmosphere, to 0.75 g (1.4 mmol) of 3-(3-((3-(4fluorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5a]pyridin-1-yl)benzoic acid in 30 ml of DMF. The reaction medium is stirred for 3 hours at ambient temperature under a nitrogen atmosphere, and then concentrated under reduced pressure. The residue obtained is washed with 100 ml of water and then dried under reduced pressure at 40°C overnight. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (75/1 ) mixture. 0.55 g of a yellow solid is obtained.

MH+: 619

Sodium salt of 3-(3-([3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid

8.9 ml (8.9 mmol) of a 1N aqueous solution of lithium hydroxide are added to 0.55 g (0.889 mmol) of propyl 3-(3-{[3-(4-fluorobenzy 1)-1-propyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate in 50 ml of THF. The reaction medium is refluxed for 6 hours and then acidified at 5°C with 17 ml of a 1N aqueous solution of hydrochloric acid and, finally, diluted with 100 ml of water. After filtration, the residue obtained is dried under reduced pressure at 40°C overnight.

0.408 ml (0.408 mmol) of a 1N aqueous solution of sodium hydroxide is added to 0.24 g (0.416 mmol) of the yellow solid obtained, in 20 ml of methanol. After filtration, the residue obtained is dried under reduced pressure at 40°C overnight. 0.24 g of a yellow solid is obtained.

MH+: 577

1H-NMR (D6-DMSO, 500 MHz):

0.97 (t, J = 7.5 Hz, 3H, 1.71 (tq, 3,/3₂= 7.5 Hz, 2 H), 4.18 (t, 3 = 7.5 Hz, 2 H), 5.20 (s, 2 H), 7.17 (ps t, 3 = 9.3 Hz, 2 H), 7.37 - 7.41 (m, 1 H), 7.44 - 7.49 (3 m, 3 H), 7.59 (m, 1 H), 7.78 (ps d, 3 = 8.5 Hz, 1 H), 7.91 (2 m, 2 H), 8.28 (ps d, 3 = 9.8 Hz, 1 H), 8.45 (m, 1 H), 8.99-9.02 (m, 1 H), 9.23 (m, 1 H), 9.90 (ps d, 3 = 7.5 Hz, 1 H).

Example 12: (Compound No. 113)

VL

3-(4-FluorobenzyI)-1 -methyl-6-[(1 -pyridin-3-ylimidazo[1,5-a]pyridin-3yl)carbonyl]quinazoline-2,4(1 H, 3H)-dione

Methyl 5-[(1-bromoimidazo[1,5-a]pyridjn-3-yl)carbonyl]-2-{[(4fluorobenzyl)carbamoyl]amino}benzoate g (10.4 mmol) of triphosgene diluted in 40 ml of dioxane are added to 5.57 g (14.9 mmol) of methyl 2-amino-5-[1-bromo(imidazo[1,5-a]pyridin-3yl)carbonyl]benzoate in 160 ml of dioxane, under an inert atmosphere. The reaction medium is refluxed for 1 hour. 3.7 g (0.030 mol) of 4-fluorobenzylamine and 6.22 ml (0.045 mol) of triethylamine are added at ambient temperature. The reaction medium is stirred for 4 hours at ambient temperature and then hydrolysed with water. The precipitate obtained is filtered off, rinsed with water, and dried under reduced pressure at 50°C overnight. The solid obtained is taken up with methanol, filtered, rinsed with methanol, and dried under reduced pressure overnight.

g of a yellow solid are obtained (yield=95.5%).

MH+: 525, 527

Melting point: 203°C

6-[(1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4fluorobenzyl)quinazoline-2,4(1H, 3H)-dione

22.33 ml (22.33 mmol) of a 1N aqueous solution of sodium hydroxide are added to 7.8 g (0.0149 mol) of methyl 5-[(1-bromoimidazo[1,5-a]pyridin-3yl)carbonyl]-2-{[(4-fluorobenzyl)carbamoyl]amino}benzoate in 100 ml of methanol. The reaction medium is refluxed for 2.5 hours. After hydrolysis with water, the precipitate obtained is filtered off, rinsed with water, and dried under reduced pressure at 50°C overnight.

The solid obtained is taken up in a 0.1 N aqueous solution of hydrochloric acid, filtered, rinsed with water, and dried under reduced pressure at 50°C overnight.

5.4 g of a yellow solid are obtained.

Melting point: 325°C

MH+: 494, 496

6-((1 -Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1 methylquinazoline-2,4(1H, 3H)-dione

1.87 g (5.7 mmol) of caesium carbonate and 0.39 ml (6.2 mmol) of methyl iodide are added, at anbient temperature under an inert atmosphere, to 2.6 g (5.17 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-(4fluorobenzyl)quinazoline-2,4(1H,3H)-dione in 50 ml of anhydrous DMF. The reaction medium is stirred for 18 hours at ambient temperature and then filtered. The precipitate is rinsed with water and then dried under reduced pressure at 50°C overnight. 2.54 g of a yellow solid are obtained.

Melting point 280°C

MH+: 507, 509

3-(4-Fluorobenzyl)-1-methyl-6-[(1-pyridin-3-ylimidazo[1,5-a]pyridin-3yl)carbonyl]quinazoline-2,4(1H, 3H)-dione

0.04 g (0.32 mmol) of 3-pyridylboronic acid, 0.2 g (0.81 mmol) of potassium phosphate dihydrate dissolved in 0.29 ml of water, and 6.2 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 0.15 g (0.27 mmol) of 6-((1bromoimidazo[1,5-aJpyridin-3-yl)carbonyl]-3-(4-fluorobenzyl)-1-methylquinazoline2,4(1/-/, 3H)-dione in 3 ml of DMF under an inert argon atmosphere. The reaction medium is microwave-heated at 150°C for 20 minutes. After filtration over talc, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (95/5) mixture. 0.12 g of a yellow solid is obtained.

Melting point: 207’C

MH+: 506

3-(4-Fluorobenzyl)-1-methyl-6-[(1-pyridin-3-ylimidazo[1,5-a]pyridin-3yl)carbonyl]quinazoline-2,4(1H, 3H)-dione hydrochloride

0.35 ml (0.35 mmol) of a 1N solution of hydrochloric acid in dyethyl ether is added to 0.12 g (0.23 mmol) of 3-(4-fluorobenzyl)-1-methyl-6-[(1-pyridin-3ylimidazo[1,5-a]pyridin-3-yl)carbonyl]quinazoline-2,4(1H, 3H)-dione in 3 ml of methanol. After stirring for 1 hour at ambient temperature, the reaction medium is filtered. The precipitate obtained is rinsed with dyethyl ether, and dried under reduced pressure at 50°C overnight. 0.12 g of a yellow solid is obtained.

MH+: 506

Melting point: 267°C ¹ H-NMR (D6-DMSO, 400 MHz):

3.60 (s, 3H), 5.16 (s, 2H), 7.14 (t, J=8.34Hz, 2H), 7.36-7.47 (m, 3H), 7.60 (t,

J=7.05Hz, 1H), 7.65 (d, J=8.98Hz, 1H), 7.83 (t, J=7.05Hz, 1H), 8.43 (d, J=8.98Hz, 1H), 8.66-8.75 (m, 2H), 8.83 (d, J=8.98Hz, 1H), 9.30(m, 2H), 9.81 (d, J=7.05Hz, 1H).

Example 13: (Compound No. 53) 3-{3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6yl)carbonyljimidazo[1,5-a]pyridin-1-yl}benzoic acid

2-Amino-5-(1 -bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid ml (60 mmol) of a 1N aqueous solution of sodium hydroxide are added, at ambient temperature, to 3.74 g (10 mmol) of methyl 2-amino-5-[1bromo(imidazo[1,5-a]pyridin-3-yl)carbonyl]benzoate in 300 ml of methanol and 125 ml of water. The reaction medium is refluxed for 6 hours and then 140 ml of a 1N aqueous solution of hydrochloric acid are added. After concentration of the methanol under reduced pressure, the precipitate obtained is filtered off, washed with water, and then dried under reduced pressure at 40°C for 18 hours. 3.53 g of a yellow solid are obtained.

MH+: 360, 362

2-(Acetylamino)-5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl] benzoic acid

0.92 g (2.56 mmol) of 2-amino-5-(1-bromoimidazo[1,5-a]pyridin-3ylcarbonyl)benzoic acid in 30 ml of acetic anhydride are refluxed for 5.5 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and then filtered and dried under reduced pressure overnight at 40°C. 1.1 g of a yellow solid are obtained.

MH+: 402, 404

6-((1 -Bromoimidazo[1,5-a] pyridin-3-yl)carbony l)-2-methyl-3propylquinazolin-4(3H)-one

1.32 g (22.4 mmol) of n-propylamine are added, at 0°C under an inert atmosphere, to 0.9 g (2.2 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]2-methyl-4H-3,1-benzoxazin-4-one in 15 ml of glacial acetic acid. The reaction medium is microwave-heated for 45 minutes at 160“C. The reaction medium is concentrated under reduced pressure. The residue obtained is taken up with a saturated aqueous solution of sodium carbonate. The precipitate obtained is filtered off and then dried under reduced pressure at 50°C overnight. 0.67 g of a yellow solid is obtained.

MH+: 425, 427

Methyl 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydr<jquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoate

0.35 g (1.95 mmol) of 3-methoxycarbonylphenylboronic acid, 0.689 g (3.24 mmol) of potassium phosphate dissolved in 3 ml of water, and 0.037 g (0.032 mmol) of tetrakis(triphenylphosphine)palladium are added to 0.69 g (1.62 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-methyl-3propylquinazolin-4(3H)-one in 15 ml of NMP. The reaction medium is microwaveheated for 15 minutes at 150°C and then concentrated under reduced pressure. After the addition of 100 ml of water, the precipitate is filtered off and then dried under reduced pressure at 50°C overnight. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (50/1) mixture.

MH+: 481

3-{3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid

7.65 ml of a 1N aqueous solution of sodium hydroxide are added to 0.735 g (1.53 mmol) of methyl 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoate in 30 ml of THF. The reaction medium is refluxed for 2.5 hours. After acidification with 10 ml of a 1N aqueous solution of hydrochloric acid, the reaction medium is concentrated under reduced pressure. The residue is taken up in 20 ml of water. The precipitate obtained is filtered off, and dried under reduced pressure at 50°C overnight. 0.52 g of a yellow solid is obtained.

MH+: 467 ¹H-NMR (D6-DMSO, 500 MHz):

0.97 (t, J = 7.6 Hz, 3 H), 1.69 - 1.76 (m, 2 H), 2.71 (s, 3H), 4.07 -4.11 (m, 2 H), 7.40 - 7.44 (m, 1H), 7.59 - 7.66 (m, 1H), 7.71 - 7.80 (m, 2 H), 8.01 - 8.05 (m, 1 H),

8.28 - 8.39 (2 m, 2 H), 8.55 - 8.58 (m, 1 H), 8.79 - 8.82 (m, 1 H), 9.30 - 9.34 (m, 1 H), 9.88-9.22 (m, 1 H), 13.23 (brs, 1H).

Example 14: (Compound No. 55) 3-(3-[(2-Methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6yl)carbonyl]imidazo[1,5-a]pyndin-1-yl}benzamide

0.107 g (2 mmol) of ammonium chloride, 0.328 g (1 mmol) of TOTU and 0.517 g (4 mmol) of Ν,Ν-diisopropylethylamine are added, at ambient temperature under an inert atmosphere, to 0.233 g (0.5 mol) of 3-{3-[(2-methyl-4-oxo-3-propyl-

3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 30 ml of DMF. The reaction medium is stirred for 5 hours at ambient temperature and then concentrated under reduced pressure. 50 ml of a saturated solution of sodium hydrogen carbonate are added to the residue. The precipitate obtained is filtered off, and then dried under reduced pressure at 50°C overnight. 0.230 g of a yellow solid is obtained.

MH+: 466 ¹H-NMR (D6-DMSO, 500 MHz):

0.98 (t, J = 8 Hz, 3H), 1.74 (m, 2 H), 2.71 (s, 3 H). 4.10 (t, J = 8.1 Hz, 2H), 7.40 -

7,45 (m, 1H), 7.54 - 7.64 (m, 2 H), 7.67 - 7.71 (m, 1 H). 7.75 - 7.80 (m, 1 H), 7.96

- 8.00 (m, 1 H), 8.19 - 8.23 (m, 2 H), 8.42 - 8.48 (m, 2H), 8.82 - 8.85 (m, 1H), 9.39

- 9.41 (m, 1 H), 9.90 - 9.95 (m, 1 H).

Example 15: (Compound No. 3) 6-(lmidazo[1,5-a]pyridin-3-ylcarbonyl)quinazolin-4(3H)-one

0.36 g (3.6 mmol) of formamidine acetate is added to 0.2 g (0.72 mmol) of 2amino-5-(imidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid (described in WO 06/097625) in 7 ml of ethanol. The reaction medium is microwave-heated at 150°C for 25 minutes. The reaction medium is hydrolysed with a 1N aqueous solution of sodium hydroxide. The aqueous phase is extracted with dichloromethane. The heterogeneous organic phase is filtered. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 54 mg of a yellow solid are obtained.

MH+: 291

Melting point: 289°C ¹H-NMR (D6-DMSO, 400 MHz):

7.29-7.47 (m, 2H), 7.80-7.82 (m, 1H), 7.96 (s, 1H), 8.04-8.07 (m. 1H), 8.23 (s, 1H), 8.67-8.70 (m, 1H), 9.29 (s, 1H), 9.52-9.53 (m, 1H), 12.5 (s, 1H).

Example 16: (Compound No. 177) N,N-1,2-Tetramethyl-4-oxo-6-([1-(pyridin-3-yl)imidazo[1,5-a]pyridin-3yl]carbonyl}-1,4-dihydroquinoline-3-carboxamide

6-((1 -Bromoimidazo[1, 5-a] py rid in-3-y I) carbonyl]-2 H-3,1 -benzoxazine2,4(1 H)-dione

1.30 g (4.37 mmol) of triphosgene dissolved in 10 ml of dioxane are added, under an inert atmosphere at ambient temperature, to 1.05 g (2.91 mmol) of 2amino-5-(1-bromoimidazo[1,5-a]pyridin-3-ylcarbonyl)benzoic acid. The reaction medium is refluxed for 4 hours, and then concentrated under reduced pressure. 100 ml of water are added to the residue. The precipitate obtained is filtered off under reduced pressure at 40°C for 18 hours. 1.1 g of a yellow solid are obtained.

MH+: 386, 388

6-[(1-Bromoimidazo[1,5-a]pyndin-3-yl)carbonyl]-1-methyl-2H-3,1benzoxazine-2,4(1 H) -dione

808 mg (5.7 mmol) of methyl iodide and 164 mg (3.42 mmol) of 50% sodium hydride are added, at ambient temperature under an inert atmosphere, to 1.1 g (2.85 mmol) of 6-[(1-bromoimidazo(1,5-a]pyridin-3-yl)carbonyl]-2H-3,1-benzoxazine2,4(1 H)-dione in 20 ml of DMF. After stirring for 3 hours, the reaction medium is poured into 200 ml of ice-cold water. The precipitate is filtered off, rinsed with water, and then dried under reduced pressure for 18 hours at 40°C. 1.13 g of a yellow solid are obtained.

MH+: 402, 403.95

6-((1 -Bromoimidazo[1,5-a] pyridin-3-yl)carbonyl]-N,N-1,2-tetramethyl-4oxo-1,4-dihydroquinoline-3-carboxamide

1.25 ml of a 2N aqueous solution of sodium hydroxide are added, at ambient temperature, to 333 mg (2.5 mmol) of Ν,Ν-dimethylacetoacetamide in 3 ml of DMF. After stirring for 1 hour, 400 mg (1 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3yl)carbonyl]-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione dissolved in 25 ml of DMF are added. The reaction medium is heated for 6 hours at 50°C under an inert atmosphere. The reaction medium is concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol 20/1 mixture. 220 mg of a yellow oil are obtained.

ι

MH+: 467, 469

Al,AM ,2-Tetramethyl-4-oxo-6-{[1 -(pyridin-3-yl)imidazo[1,5-a]pyridin-3yl]carbonyl)-1,4-dihydroquinoline-3-carboxamide

115 mg (0.37 mmol) of 3-pyridinylboronic acid, 331 mg (1.56 mmol) of potassium phosphate dissolved in 1 ml of water, and 18 mg (15.6 pmol) of tetrakis(triphenylphosphine)palladium are added, at ambient temperature under an inert atmosphere, to 365 mg (0.78 mmol) of 6-[(1-bromoimidazo[1,5-a]pyridin-3yl)carbonyl]-N,N-1,2-tetramethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide in 20 ml of N-methylpyrolidone. The reaction medium is microwave-heated at 150°C for 25 minutes and then concentrated under reduced pressure. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol 9/1 mixture. 0.290 g of a yellow oil is obtained.

MH+: 466 ¹ H-NMR (D6-DMSO, 500 MHz):

2.44 (s, 3 H), 2.89 (s, 3 H), 3.03 (s, 3 H), 3.89 (s, 3 H), 7.39 - 7.43 (m, 1 H). 7.59 - 7.64 (2 m, 2 H), 8.07 (d, J = 9.7 Hz, 1 H), 8.44 - 8.49 (2 m, 2 H), 8.67 (d, J = 4.8 Hz, 1 H), 8.86 (dd, J = 9.7 Hz and 2.2 Hz, 1 H), 9.32 - 9.34 (m, 1 H), 9.55 (d, J = 2.2 Hz, 1 H), 9.93 (d, J = 7.4 Hz, 1 H).

Example 17; (Compound No. 223)

Sodium salt of 3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1 -propyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic acid

Methyl 5-[(1-bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-2-({[2-(4fluorophenoxy)ethyl]carbamoyl}amino)benzoate

4.75 g (16 mmol) of triphosgene are added, at ambient temperature under an inert atmosphere, to 4.99 g (13.33 mmol) of methyl 2-amino-5-({1-[3(methoxycarbonyl)phenyl]imidazo[1,5-a]pyridin-3-yl)carbonyl)benzoate in 220 ml of dioxane. After refluxing for 5 hours, 6.21 g (40 mmol) of 2-(4-fluorophenoxy)-1ethylamine and 4.05 g (40 mmol) of triethylamine are added at ambient temperature. The reaction medium is refluxed for 3 hours and then concentrated under reduced pressure. The residue is triturated from water. After filtration, the solid is rinsed with methanol and then dried under reduced pressure at 40°C overnight. 6.67 g of a yellow solid are obtained.

MH+: 555

6-((1-Bromoimidazo[1,5-a]pyridin-3-yl)carbonyl] -3-(2-(4fluorophenoxy)ethyl] quinazoline-2,4(1 H,3H)-dione

60.1 ml (60.1 mmol) of a 1N aqueous solution of sodium hydroxide are added to 6.67 g (12 mmol) of methyl 5-[(1-bromoimidazo[1,5-a]pyndin-3-yl)carbonyl]-2-({[2(4-fluorophenoxy)ethyl]carbamoyl}amino)benzoate dissolved in 600 ml of methanol. After refluxing for 2 hours, the reaction medium is acidified with 120 ml of a 1N aqueous solution of hydrochloric acid and then diluted with 2000 ml of water. The precipitate obtained is filtered off, and dried under reduced pressure at 40°C overnight. 5.83 g of a yellow solid are obtained.

MH+: 523.2, 525.2

6-((1 -Bromoimidazo(1,5-aJpyridin-3-yl)carbonyfl-3-[2-(4fluorophenoxy)ethyl]-1-propylquinazoline-2,4(1H,3H)-dione

7.22 g (22.16 mmol) of caesium carbonate and 5.65 g (33.24 mmol) of propyl iodide are added, under an inert atmosphere, to 5.6 g (11.08 mmol) of 6-((1bromoimidazo[1,5-a]pyridin-3-yl)carbonyl]-3-[2-(4-fluorophenoxy)ethyl]quinazoline2,4(1 H,3H)-dione in 300 ml of DMF. The reaction medium is stirred for 12 hours at ambient temperature under a nitrogen atmosphere and then concentrated under reduced pressure. The residue obtained is washed with 700 ml of water and then dried under reduced pressure at 40°C overnight. 5.74 g of a yellow solid are obtained.

MH+: 565, 567

Methyl 3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1 -propyl-2,4-dioxo-1,2,3,4tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1 -yl] benzoate

2.178 g (12.1 mmol) of 3-methoxycarbonylphenylboronic acid, 4.279 g (20.16 mmol) of potassium phosphate dissolved in 30 ml of water, and 582.4 g (0.504 mmol) of tetrakis(triphenylphosphine)palladium are added to 5.7 g (10.08 mmol) of 6-[(1-bromoimidazo(1_T5-a]pyridin-3-yl)carbonyl]-3-[2-(4fluorophenoxy)ethyl]-1-propylquinazoline-2,4(1H,3H)-dione in 180 ml of NMP. The reaction medium is microwave-heated for 15 minutes at 120°C and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol

(100/1) mixture. 4.32 g of a yellow solid are obtained.

MH+: 621.3

Sodium salt of 3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-

1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic acid

69.6 ml (69.6 mmol) of a 1N aqueous solution of lithium hydroxide are added to 4.32 g (6.96 mmol) of methyl 3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4dioxo-1,2,3,4-tetrahydroquinazolin-6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoate in 500 ml of THF. The reaction medium is refluxed for 3 hours and then acidified at ambient temperature with 150 ml of a 1N aqueous solution of hydrochloric acid and, finally, diluted with 700 ml of water. After filtration, the residue obtained is dried under reduced pressure at 40°C overnight.

5.88 ml (5.88 mmol) of a 1N aqueous solution of sodium hydroxide are added to 4.11 g (6 mmol) of the yellow solid obtained, in 100 ml of methanol. After filtration, the residue obtained is dried under reduced pressure at 40°C overnight. 3.46 g of a yellow solid are obtained.

MH+: 607.3

Mp: 190-205°C (decomposition)

H-NMR (D6-DMSO, 500 MHz):

0.98 (t, J=7.7Hz, 3H), 1.71 (tq, J1=J2=7.7Hz, 2H), 4.17 (t, J=7.7Hz, 2H), 4.24 (t, >6 6Hz, 2H), 4.39 (t, J=6.6Hz, 2H), 6.97-7.00 (2m, 2H), 7.10-7.16 (2m, 2H), 7.38-7.41 (m, 1H), 7.47- 7.52 (m, 1H), 7.57-7.61 (m, 1H). 7.75-7.79 (m, 1H), 7.947.98 (2m, 2H), 8.26-8.30 (m, 1H), 8.49-8.52 (m, 1H), 8.97-9.02 (m, 1H), 9.26-9.28 (m, 1H), 9.89-9.93(m, 1H).

The table which follows illustrates the chemical structures and the physical properties of some compounds according to the invention. In this table:

- Me and Et represent, respectively, methyl and ethyl groups;

- the wavy lines indicate the bond attached to the rest of the molecule;

- “Mp represents the melting point of the compound, expressed in degrees Celsius;

- “M+H⁺ represents the mass of the compound, obtained by LC-MS (Liquid Chromatography - Mass Spectroscopy).

Ο

No.	Ri	id1.	R<	Salt	Mp (°C)	M+H*
1	H		H	/	304	349
2	H	Yd	H	/	341	307
3	H	-Y	H	/	289	291
4	H	γ^	7-COOH	!	380	393
5	H	Yd	7-COOH	!	404	365
7	-co-nh2	yÎy	H	/	/	392
8	H	Yd	6-COOH	!	384	393
9	H	Yd	H 6 O~Y	HCI	234	503
10	pY	Yd	H	Na	383	469
11	H	O zP Yi?	H	Na	398	365

12	H		0 HO /\ Jk. N x H 7	/	278	436
13	-NH-SO2Me		H	/	334	442
14		-dl·	H	Na	>41	441
15		-&l·	H	Na	>410	469
16	9^		H	/	257	497
17	P		H	/	361	455
18	P	o 7° 09	H	Na	345	440
19		V. //N --> H	H	Na	340	517
20		x0	H	Na	363	469
21		0^	H	Na	318	487

22	'p-<		H	Na	390	487
23	Η	ο ,0- ΑΑ’	H	!	308	379
24	çn		H	!	318	425
26	Η	0 1, Η ο	H	!	263	377
28	ÇH		H	!	271	483
29	ρΑ	αα	H	!	345- 346	468
30	ρΑ		H	f	371	523
31	ρ-<	\ Χθ V ζΑ~Ν	H	Na	317	535
32	ρΑ	F V // N F	H	Na	316	553
33	ρ<	A. t ZZN H	H	Na	325	551

34	°Ά (prV	o / ... Xy dp	H	/	/	507
35		dd	H	/	294- 296	450
36	P'N CrV-	dd	H	!	276- 277	507
37	hV N'$ γν	dd	H	!	250- 260	546
38	pA'™	dd	H	!	269	484
39		dd	H	!	387	509
40	0.	dd	H	!	184- 185	483
41		-Jr	H	!	255	498
42		V /Z~N '--Z H	H	1	341	516
43	p-L	d^d°	H	I	268	513

44	pt	__ F do! '-y H	H	!	340	552
45	pt.	Ύ v Y° V. Ζ^~~Ν	H	!	319	534
46	Η	o , d-N	H	!	/	409
47	Çp^N	Yd	H	!	230	464
48	pt	Yd	H	!	274	440
49	pt	/-.-.--d Λ ;L Y° V/Z Ny	H	Na	182	549
50	pt	__F /=< NC^Y Ύ do YY F	H	!	300- 301	567
51	pt	V Υθ 'r- YY' N F	H	!	290	566
52	pt	Ύ V Yo	H	!	305	548
53	pt	Yd	H	/	305	467

&L·

54	ρΛ		H	/	265	482
55	Çrt,		H	!	238	466
56	Çrt		H	!	311- 312	453
57			H	!	251	452
58	p4...	/=0 V //N -+ h	H	!	338	550
59	O-N		H	!	241	521
60	0-	V -^°	H	!	295	531
61	°—/ PpV		H	!	255	521
62	p4	^=O	H	!	298	530
63	p<		H	!	250	511

64	Ç0N	z-~/F Z~N V /} V0N F	H	/	285	548
65	p-L	0V	H	/	231	510
66	p-L	00° 97	H	/	271	523
67	p4	0,9 <f	H	/	254	522
68	p-L.	/^000-001 0 V 0° 00~N^	H	/	310	564
69		-_/F 90V 0O^\ V. #'-N F	H	!	319	591
70	p<	/^0000°1 0 \ 0° V0-N\	H	Na	255	564
71	p-<	/00000F 0 V 0° o \	H	Na	284- 286	579

VL

72		dd “Π	H	Na	239- 245	577
73		F Z~N V zZ F	H	/	258	605
74	ç>P.	apn v /i/'f JL· d=o t zZ~N Ί	H	/	250- 252	576
75	çA.	/==-< JL Z^o o \	H	/	297- 298	578
76	çd	O z_._ ,/ N	H	/	150- 153	481
77	pb.	Z·—Z~n/	H	/	140- 145	480
78	(M	/¾^ V~V^F L Z=O	H	/	263	563
79		/=/ N\fKÀF ~~~-d L. 1>N	H	/	203- 204	577
80	9<,	O Λ-ν	H	/	141- 143	494

81	0	O ^ y λ-·/ Ν	H	Na	226- 230	494
82	¢--0	z—p Ça/' F ''ÇÇ a?°	H	Na	215	662
83	¢--	Ά v Ao Vj/ N	H	!	238	620
84	çA	0 ^y Kn	H	Na	235- 238	493
85	çA	~v JL· do \_ zZ~N >	H	Na	244- 246	563
86	ÇA°dj	d do VjZ’-n	H	/	210	646
87		LL k A	H	/	234	593
88		Ά A do Άζν^	H	/	266- 268	587
89	p-<	O 7~~d /-n y -C\d^	H	Na	275- 278	549

90	p-<	θ F Λ~ν \\ J -cL>° ΐ Υ~·Ν ?	H	Na	222- 225	606
91			H	!	!	517
92	/= N		H	/	1	442
93	MeO	o /°	H	!	!	472
94	pA	, Y Yp	H	HCI	!	602
95	p-L	Ύρ	H	/	/	497
95a		Q />n /-y'”n\ V^ v V V // 'N	H	HCI	/	554
96	p-L.	kP	H	HCI	/	575

97	0.	Et 0 N	H	HCl	/	575
98	çX		H	/	/	511
99	çX	v.^0	H	HCl	/	583
100	çX	XXf	H	/	/	521
101	0.		H	/	!	524
102	ÇrL		H	/	!	521
103	çX.	Χ-Χ	H	!	!	538
104	ç:.X	X X’N ---Z h	H	HCl	/	568
105		K.+“ XX	H	/	/	512

106	çX	-0- --/ H	H	/	/	523
107		'if ~k 0o L/0n Me	H	HCl	!	550
108	N ! NHMe	Si 0=o V/11 Me	H	!	318	562
109	ρΛ	VjZ N F Me	H	/	!	548
110	qV f __Q	/==^NAVA-F % JL ΟΝ Me	H	HCl	177	690
111	0-0	~-~î\ ~V 0=0 Vjz'N Pr	H	HCl	187	674
112	P	V χ-° v/~n Me	H	!	224	505
113	P	V 0^ο V^zN Me	H	HCl	267	506

114	ό OH	/=/ n0V0f Me	H	/	106	637
115		/=:=0N0Vy'F V —'° 0Ο~Ν Me	H	!	/	530
116	0-0	'Ο \ Me	H	HCI	214	661
117	ο <	/==/ N^00~F JL· //'-ή Me	H	HCI	247	619
118		~dl·^ Me	H	Na	/	598
119	ç>ô	/=/ r000'F ' /=o 0/ F	H	Na	/	617
120	ρ-ί	/=0Nfv0F (f Z=o V /N ? ,0 Me	H	Na	/	593

6c

121a	p-t.	LT ό Xaz,s p	H	/	259	576
121		~ν \ 7=0 Pp-N Me	H	HCI	247	606
122	çp Me^N	if 7=0 ΚΛ-ν Me	H	HCI	287	592
123	çp 0	/k Nv%/ F 'if 7=0 \pp-n Me	H	HCI	274	634
124	Çy°H	/P \ I-4 F if 7=0 VZ-N, Me	H	/	216	521
125	pt	'P/OMe p ”v Ao Vi Me	H	Na	258	561
126	pt	P PP”OMe p V 7=0 Vt Pr	H	Na	240	589
127	P	/k^Nf~V+ F Λ L >=0 W~1 Pr	H	HCI	275	534
128	Ç,	,p Nfut p t. to VZi Pr	H	HCI	273	534

129	p-o	/¾^ nP~vz~f V 7=^o kz~n Pr	H	/	223	550
130		CL 9=0 Pr	H	Na	246	573
131	Ά	_/- M/VjT'F k/-f Pr	H	Na	256	591
132	o P	\ _ 7*0 w-t Pr	H	HCI	291	550
133		0	H	Na	I	632
134	P	/^A~nP<a'f -% ;L A PF	H	/	!	624
135	9	/A 1 P^F <· 0	H	!	!	605
136		A./p vPa -if V z^o kZ-f Pr	H	Na	236	627

137	Ο—\ ο	'ζ Αο VAn, Me	H	/	112	681
138		< Λ- W~t Me	H	Na	237	599
139	Ρ	/¾^ nPvA~f ,NMe Me	H	HCI	226	563
140	Ο-~/ Ο^'Ν	V t // 'N —7 H	H	!	/	573
141	°—/	/> ', '^F v vAt Me	H	!	/	587
142		/¾^ nPvA~f '-<Ao 1-	H	Na	!	667
143	0«	JL >=o y o	H	Na	!	646

144	0	'0 Y_ 0o 9 0	H	Na	!	648
145	9	v A- 00 0	H	/	!	603
146	P	Me	H	HCl	250	440
147	P	99 Pr	H	HCl	278	468
148	Çr	/0^000f 9 \ 0o VZ-'î Me	H	/	294	522
149		V 00^ 00 Me	H	Na	256	563
150	P	'0 \_ 0O VjX N Pr	H	HCl	225	516
151		/09 00 Me	H	/	257	536
152	P	.00000^ ~0 ~0-N0° Pr	H	!	259	549

153	Çr°	W~>( Pr	H	/	128	532
154	P-	X \ ao W->( Pr	H	/	233	537
155	OMe p	X’° VZ-, Pr	H	HCl	128	564
156	Çr	UH Me	H	/	/	504
157	NH, r	zxx 17^ X L X’° W-i Me	H	!	278	521
158	Me	/4 {và ~~~ζ Λ=ο Vz~, Pr	H	!	/	471
159	pX	1/X’ Pr	H	Na	221	591
160	P	v-X-f XÎX Pr	H	HCl	525	548
161	p-°	v-XX xxx Pr	H	/	250	564
162	OMe p	/X >f'V/''F X X Xo Me	H	HCl	230	536

'X

163	X-	Ύ V Yo vy~« Me	H	1	194	509
164	H Ο P	YvY Ύ Yo Pr	H	t	160	618
165	p	pY\ L· n-. “ o	H	!	/	617
166	P	Me	H	!	t	482
167	p	Ρ'ίΡΥ V /Y-n Ά H N^, O	H	!	!	587
168	P	F /==< Ύ v Υθ V/-H Me	H	!	!	506
169	p-°	F 'ΎΥ Yo Me	H	!	!	522
170	0«	^P°-\ Q	H	/	!	630
171	Me	Ύ Y Yo VZ·! Me	H	/	!	443

172	p<	dfd Μη	H	Na	/	525
173	P	-dd- Me	H	/	/	524
174	Η Ο 0	A- Pr	H	!	261	590
175	ρ-°	dfd Me	H	!	/	498
176	ρ	F d=o\ VjZ'N F Me	H	/	!	524
177	Ρ	O O A / L/~ CAï Me	H	/	!	466
178	ρ<	--PPX.. V Z^N \ /	H	Na	!	604
179	çP~	W! Pr	H	Na	236	591
180	ρ	\~ Xo Pr	H	HCI	229	530

181	0«	Ά X A'O VA, Me	H	Na	270	563
182	P	Ao VZy Me	H	HCl	261	502
183	P	F ~~ΡχΓ No VA^ Me	H	!	!	506
184	P	F /Y V Ά V A=o VAt Me	H	1	/	524
185	H 0 P	/Y lfVÀ'F Ά ko VA, Me	H	!	261	590
186	P	FL No VA», Me	H	HCl	261	502
187		—/ v No VA», Pr	H	Na	238	573
188	ÇA	-AÎ No VA», Me	H	Na	274	545
189	Çr	Me	H	!	/	498

190	P	F do^\ V/N F Me	H	/	/	524
191		ddL. da L y—n x H N-. /	H	Na	/	604
192	ΡΛ	/^^nPvP~f d V do VA», Pr	H	Na	236	591
193	P	v V V° Vl Pr	H	HCl	229	530
194	P	A A... do Me	H	HCl	198	520
195		Ά \ _ do VAt Me	H	Na	270	563
196	P	λ l do Vi Pr	H	HCl	218	548
197		/Y (vA Ά JL A=o VA, Pr	H	Na	233	591
198		~Ά=χΓ do vA Pr	H	Na	/	587

199		St Ao AP Me	H	Na	257	545
200	/Λ	-JA Pr	H	Na	285	575
201	P	X}X' Pr	H	HCl	264	560
202	çA	a/ v Ά Jv Ao kAt Pr	H	Na	258	603
203	Cf X-N / x z Me	Ά \ Ao kAt Me	H	!	/	509
204	P	-d-b Me	H	1	/	494
205	ÇA	y A db Me	H	Na	/	537
206	Ç“-°	k. A* db Me	H	!	!	510
207	çA	db Pr	H	Na	!	565

208	P	pz z 7 Pr	H	/	/	510
209	p7»	Pr	H	Na	!	553
210	P	{ %ÀF -ζ >=o k/-t Me	H	HCl	195	506
211	P	/=< n0V0f P' \ λ=ο i F	H	/	240	588
212	p	O zS\ yy Me	H	!	/	494
213		O zS\ yp1 Me	H	Na	/	537
214	p	q yp Pr	H	/	/	522
215	p<	q zs\ -yp1 Pr	H	Na	/	565
216	p	xPp Me	H	/	/	536
217	p	^^,Z-Z°~O-F Pr	H	/	/	564

218	P	/^0N0~C^~-F 0° VA, Me	H	!	243	511 l
219	XX.	/==0000f >O VAt Me	H	!	255	535
220	nBu	/==0000-F 0~L 0o Me	H	!	/	485
221	Çr	Pr	H	!	/	580
222	p	Me	H	t	/	508
223		Pr	H	Na	/	607
224	0	99 Pr	H	/	/	536
225		~0~V Xo X, V. zA~N \ H N—, Q	H	Na	!	645
226		XX Pr	H	Na	!	579
227	0	/00000f 'v X. 0° VAt Pr	H	Na	313	595

228	H	% Y 7=0 VZx Mb	H	!	/	429
229	ÇrOH	/^AnPvA'f Λ A- 7=0 Pr	H	!	146	549
230	P4·	NPVP~-F 7 Tl 7=o VZ-“, Pr	H	!	227	575
231	çyv	L/'f 7 7 7=o vz-t Me	H	!	/	573
232	N-N pv	{77'h 7 V Z=o vz», Pr	H	!	/	601
233	çP	7 7=0 VZ-» Me	H	HCl	290	556
234	nT V	nPvP~-f 7 z=o vz~t Pr	H	/	/	578
235	NH. m J HO	~7 Y. 7=o VZ-“. Pr	H	/	/	591
236	NH. M f HO	/Av 7Pf 7 l 7=0 VZi Me	H	/	/	563
237	COOH P	z^=< Hv~~Vz F 7 7=0 VZ-i Pr	H	Na	217	607

238	P^o«.	p L +--O Vi Me	H	/	182	591
239	*1/ OtBu	zk'V'vk ~·ζ Ao Vi Pr	H	/	108	619
240	\ N't V	^d>° Me	H	/	I	526
241	\ nP V	Pr	H	/	!	554
242		tip Pr	H	/	285	550
243	\ Ν' u P	} / 7 z o =o	H	!	!	625
244	çyv	/^<· nC~và~f p y. Ao V| Pr	H	!	!	617
245	ÇpV°	'LÀf λ7-Ν 0 Me	H	!	!	589
246	/-ï^COOH	P ~v Ao Vi Pr	H	Na	342	527

IK

247	\ U y	t/-A '%- Pr	H	!	/	566
248	^—^.COOH	P u A=o Me	H	Na	349	501
249	O 0	z==< Nv P-A F '''A V. A=O VAn Me	H	HCl	/	592
250	P	/^Nv<ÀF v Ao V/-N Me	H	HCl	!	495
251	A y	Ά k_ Ao VA« Me	H	HCl	!	551
252	P	î k a=° tri Me	H	HCl	!	520
253	y	y. VAt Me	H	HCl	!	495
254	A	j-fO. % jL Ao Vn Me	H	HCl	i	561
255	a 1 0CFj	A Ά. Ao Ln Me	H	HCl	!	589
256	k θ	/^(vA ~^A Au VAt Me	H	HCl	!	602

257	Μ»	0 GG	-N Me	-F	H	HCl	!	549
258	OMe	0 GG	-N Me	F	H	HCl	!	565
259	a 0	Gg	yp N \ Me	-F	H	HCl	!	539
260	OMe	ο GG	N \ Me	-F	H	HCl	/	553
261		ο GG	-N \ Me	F	H	HCl	i	541
262	Cio ο	ο GG	N V Me	F	H	HCl	!	571
263	G /	ο Gg	ίΐθ' N \ Me	-F	H	HCl	t	545
264	Cp	ο GG	N \ Me	~F	H	HCl	t	544
265	0 U /	ο gg	N \ Me	~F	H	HCl	t	590
266	OtBu φ	ο gg	N \ Me	-F	H	HCl	!	591

267	b	0 Ό·	/¾ -N Me	-F	H	HCl	/	557
268	OMe	o 0-	k^ ~N \ Me	-F	H	HCl	!	567
269	F P	o 0-	'N Me	'F	H	HCl	!	541
270	ο ο dp	o -0-	~N \ Me	-F	H	HCl	!	549
271		o -0-	N \ Me	F	H	HCl	!	589
272	Ph Ρ Çr4-	0 0-	k^ ‘N \ Me	~F	H	HCl	!	638
273	b	0 -0-	N \ Me	~F	H	HCl	!	545
274	ÇQ	o -0-	N À -N Me	~F	H	HCl	!	556
275	Y Û N ”φ	-0-	-N V Me	-F	H	HCl	!	632
276		-0-	-N Me	~F	H	HCl	/	509

he

277	ÇOOH P	Ό-	N \ Me	-F	H	HCl	/	555
278	ço	'W'	N \ Me	-F	H	HCl	/	556
279	ÇT	o	-N \\ A Pe -N Me	-F	H	HCl	/	573
280	NHM$	0 O-	N \ Me	F	H	HCl	t	598
281	F ^Y^COOH	o O·	'N Me	~F	H	HCl	t	567
282	r> Çr°	o -Ό-	'N Me	F	H	HCl	!	571
283	«T Λ N	o	\P“ 'N V Me	~F	H	HCl	1	522
284	L	o Ό-	N \ Me	F	H	HCl	/	522
285	\ H nA	0 Ό-	N \ Me	-F	H	HCl	/	550
286	N^O		-N \ Me	-F	H	HCl	/	522

287	o o X	A Me	H	HCI	!	563
288	FJp°“	YY' Me	H	HCI	!	553
289		Me	H	HCI	!	563
290	9	Ο kZ-t Me	H	!	/	395
291	'N- V	q Me γγ n /Xv. “e Y X ' '_Me Me	H	!	/	510
292	An Y	O Me Mi Pr	H	!	/	538
293	9	O ,Me X-/~N Me % X 2—Me VZ-N Me	H	!	/	466
294		Ay Me	H	Na	/	579
295	4»	YY Me	H	Na	!	551

The compounds according to the invention were the subject of pharmacological assays for determining their FGF-inhibiting effect,

Example 18: FGF-2-induced in vitro angiogenesis of HUVEC cells

In order to demonstrate the ability of the FGF-R antagonists of the present invention to inhibit FGF-induced angiogenesis, in vitro angiogenesis experiments were carried out with human endothelial cells of HUVEC type stimulated with FGF-2 or b-FGF.

To do this, matrices composed of matrigel (growth factor reduced matrigel, Becton Dickinson 356230) and collagen (rat tail collagen type I, Becton Dickinson 354236) are deposited, at a rate of 160 μΙ, into each chamberslide well (Biocoat Cellware collagen, Type I, 8-well culturesides: Becton Dickinson 354630), or 60 μΙ per well of 96-well plates (Biocoat collagen I cellware, Becton Dickinson 354407). The matrix is prepared by mixing 1/3 of matrigel, 1 mg/ml final concentration of collagen, 0.1N NaOH (0.026x the volume of collagen in μΙ) and 1x PBS, and the volume is then adjusted with water. The gels are kept at 37C for 1 hour so as to allow them to polymerize. Next, the human vein endothelial cells (HUVECs ref: C-12200 - Promocell) were seeded at 15 χ 10³ or 6 χ 10³ cells/well in 400 or 120 μΙ (for the 8-well or 96-well plates respectively) of EBM medium (Clonetics C3121) + 2% FBS + 10 pg/ml hEGF. They were stimulated with 1 or 3 ng/ml of FGF-2 (R&D systems, 133-FB-025; Invitrogen, PHG0026) for 24 h at 37°C in the presence of 5% CO₂. After 24 hours, the length of the network of microtubules formed was measured using a computer-assisted image analysis system (Imagenia Biocom, Courtaboeuf, France) and the total length of the pseudotubules in each well was determined. The average total length of the microcapillary network was calculated in μηι for each condition corresponding to the average of 6 replicates.

Stimulation with FGF2 makes it possible to induce the formation of new tubules. An FGF-R antagonist is considered to be active in this test as long as it is capable of partially inhibiting this angiogenesis at a dose less than or equal to 300 nM.

Example of screening for FGF-R antagonists

In this experiment, the molecules are evaluated at 3 and 30 nM on induction of the angiogenesis of HUVEC human cells by FGF-2. Compounds No. 71, 72 (example 11) and 68 are declared active since they exhibit an inhibitory activity of pseudotubule formation which is greater than or equal to 20% at a dose less than or equal to 300 nM.

Table 1: In vitro angiogenesis of HUVEC cells stimulated with FGF-2 and effect of

FGF-R antagonists (inhibition of angiogenesis as a percentage of the control)

Compounds No.	3nM	30 nM
71	-1	41
72	36	24
68	37	52

Example 19: FGF-2-induced in vitro proliferation of HUVEC cells

In order to demonstrate the ability of the FGF-R antagonists of the present invention to inhibit FGF-induced cell proliferation, in vitro proliferation experiments were carried out with human endothelial cells of HUVEC type stimulated with FGF-2 or b-FGF.

To do this, HUVEC human vein endothelial cells (promocell, C-12200) are seeded at a rate of 5000 cells per well of a 96-well plate (Biocoat collagen I cellware, Becton Dickinson 354650) in 100 pl of RPMI 1640 deprivation medium (Invitrogen, 31872-025) supplemented with 0.5% or 1% FCS, 2 mM glutamine, 1x sodium pyruvate (Invitrogen, 11360-039) and 1x NEAA (Invitrogen, 11140-035), overnight at 37°C in the presence of 5% CO₂. The following morning, the medium is suctioned-off and replaced with 50 μΙ of deprivation medium containing the antagonists at a 2x concentration, to which are added 50 μΙ of FGF-2 (R&D systems, 133-FB-025; Invitrogen, PHG0026) at 0.2 ng/ml (i.e. 2x). After 48 or 72 h, 100 μΙ of Cell Titer-GLO™ Luminescent Cell Viability Assay (Promega, G7571) are added for 10 min in order to measure, by means of a luminometer, the amount of ATP present in the cells and which is in relation to the number of cells per well corresponding to the cell proliferation.

The antagonists of the present invention are considered to be active as long as they are capable of inhibiting FGF-2-induced proliferation of HUVEC cells at a dose less than or equal to 300 nM.

Example of HUVEC cell proliferation induced by FGF-2 and inhibited by FGF-R antagonists

Compounds No. 49 (example 4), 71 and 72 (example 11) are capable of inhibiting the FGF-2-induced cell proliferation since, in their presence, a reduction in proliferation of greater than or equal to 20% is observed for doses less than or equal to 300 nM.

Table 2: Cell proliferation of HUVEC cells stimulated with FGF-2 and effect of

FGF-R antagonists (inhibition of proliferation as percentage of the control)

Compounds No.	30 nM	300 nM
49	9	29
71	35	34
72	38	55

More generally, all the compounds according to the invention are active, at the dose of 300 nM, in in vitro angiogenesis of HUVEC cells induced by FGF-2 or in in vitro proliferation of HUVEC cells induced by FGF-2.

Example 20: Model of inflammatory angiogenesis in mice

Angiogenesis is required for the development of chronic inflammatory diseases such as rheumatoid arthritis. The formation of new vessels allows not only the perfusion of pathological tissues, but also the transport of cytokines responsible for establishing the chronicity of the disease.

The model described by Colville-Nash et ai., in 1995, makes it possible to study pharmacological agents capable of modulating the occurrence of angiogenesis in an inflammatory context. The model is developed on OF1 female mice (Charles River Laboratories) weighing approximately 25 g, and by groups of

12. The animals are anaesthetized with sodium pentobarbital (60 mg/kg; Sanofi Nutrition Santé animale)) intraperitoneally. An air pocket is created on the back of the mouse by subcutaneous injection of 3 ml of air. After they have awoken, the animals receive a treatment generally by gavage, and receive an injection of 0.5 ml of Freund’s adjuvant (Sigma) with 0.1% of croton oil (Sigma) in the pocket. Seven days later, the mice are again anaesthetized and placed on a hot plate at 40°C. One ml of carmine red (Aldrich Chemicals, 5% in 10% of gelatin) is injected into the tail vein. The animals are then placed at 4°C for 2-3 hours. The skins are then taken and dried for 24 h in an oven at 56°C. The dry tissues are weighed and placed in 1.8 ml of digestion solution (2 mM dithiothreitol, 20 mM Na₂HPO₄, 1 mM EDTA, 12 U/ml papain) for 24 h. The dye is then dissolved in 0.2 ml of 5M NaOH. The skins are centrifuged at 2000 rpm for 10 min at ambient temperature. The supernatants are filtered through 0.2 pm cellulose acetate membranes. The filtrates are read in a spectrophotometer at 492 nm against a carmine red calibration range.

V1L

Two parameters are studyed: the dry weight of the granuloma and the amount of dye after digestion of the tissues. The results are expressed as mean values (± sem). The differences between the groups are tested with an ANOVA followed by a Dun nett’s test, of which the reference group is the “solvent control group.

The FGF-R antagonists are evaluated between 1 and 50 mg/kg using methylcellulose/tween (0.6% v/v) as vehicle or any other vehicle which allows the active ingredyent to be solubilized. The molecules are administered daily, orally (one or two times a day) by gavage. The antagonists of the present invention are considered to be active as long as they enable a significant reduction in the angiogenic parameter, i.e. a reduction in the amount of carmine red dye in the skins of the animals tested.

Example of evaluation of FGF-R antagonists in the model of inflammatory angiogenesis in mice. Compounds No. 49 (example 4) and 72 (example 11) at 10 mg/kg, after one week of daily treatment, significantly reduce the two parameters measured: the weight of the granuloma (dry weight of the skin) corresponding to the inflammation part of the model, and the dye content corresponding to the angiogenesis.

Table 3: Effect of the FGF-R antagonists, in a model of inflammatory angiogenesis, on the dry weight of the skins or on their content of carmine red dye.

Model of inflammatory angiogenesis	% inhibition of the inflammatory parameter (mass of the granuloma)	% inhibition of the angiogenic parameter (dye content)
Compound No. 49 (example 4); 10 mg/kg	40	46
Compound No. 223 (example 17); 10 mg/kg	25	43
Compound No. 72 (example 11); 10 mg/kg	38	43
Compound No. 71; 30 mg/kg	28	40
Compound No. 149; 10 mg/kg	14	30
Compound No. 215; 10 mg/kg	21	39
Compound No. 10 (example 2); 30 mg/kg	19	19

Example 21: 4T1 orthotopic mammary carcinoma model in mice

In order to evaluate the effect of the FGF-R antagonists in a murine tumour model, 4T1 mouse mammary carcinoma cells are injected into the mammary gland. The cells proliferate until the formation of a tumour after infiltration of the cells of the tumour microenvironment.

The 4T1 cells are cultured in RPMI 1640 medium containing 10% FCS and 1 % glutamine, supplemented with 1 mg/ml of geneticin. On the day of the injection into the mouse, the 4T1 cell concentration is adjusted to 2 χ 10^e cells/ml in PBS in order to inject 1 χ 10⁵ cells in 50 pl.

Mice (Balb/c, female, Charles River, approximately 8+/-2 weeks old) are anaesthetized by intraperitoneal injection of a mixture of 5% Rompun (xylazine), 10% Imalgene (ketamine) and 85% NaCI, in a proportion of 10 ml/kg. The injection zone (top-right nipple) is disinfected with hexomedine. After having vortexed the cells, 50 μΙ are removed in a syringe and injected into the nipple with a 26G needle. The day of injection corresponds to D1. There are 15 mice in each group of mice (10 mice will be devoted to the ELISA assays and 5 mice to the histology). The FGF-R antagonists are evaluated at between 1 and 50 mg/kg in methylcellulose/tween (0.6% v/v) or any other vehicle which makes it possible to solubilize the active ingredyent. The molecules are administered daily, orally (one or two times a day) by gavage, this taking place from D5 to D21, which is the day before the samples are taken. From D5, the tumours are measured as soon as possible, every two days, or even every day at the end of the experiment, using a caliper (sliding caliper). It is done in the following way: the longest length (L) and the perpendicular to the centre (I) are measured in mm. The volume in mm³ is then defined by means of the mathematical formula which determines the volume of an ellipsoid: (I² * L) χ 0.52. On the day the samples are taken, generally D22, the mice are sacrificed by means of an excess of sodium pentobarbital after having measured the volume of the tumours. The tumours are then cleared, photographed and weighed. The lungs are also removed and the metastases are counted after boin staining.

The antagonists of the present invention are considered to be active as long as they allow a significant reduction in the volume of the tumour and/or any number of lung metastases.

Example of 4T1 mammary carcinoma in mice

The compounds considered to be active in the inflammatory angiogenesis model are evaluated in the 4T1 mammary carcinoma model in mice at between 1 and 50 mg/kg and showed a reduction in tumour volume of up to 49% and a decrease in the number of lung metastases of up to 33%.

It therefore appears that the compounds of formula (I) according to the present invention, by virtue of their FGF antagonist effect, reduce in vitro and in vivo, angiogenesis, tumour growth and metastasization.

Generally, FGFs and their receptors play an important role, by means of autocrine, paracrine or juxtacrine secretions, in phenomena where there is dysrégulation of the stimulation of cancer cell growth. Furthermore, FGFs and their receptors affect tumour angiogenesis which plays a predominant role both on tumour growth and also on metastasization phenomena.

Angiogenesis is a process in which new capillary vessels are generated from preexisting vessels or by mobilization and differentiation of bone marrow cells. Thus, both uncontrolled proliferation of endothelial cells and mobilization of angioblasts from the bone marrow are observed in tumour neovascularization processes. It has been shown, in vitro and in vivo, that several growth factors stimulate endothelial proliferation, and in particular FGF-1 or a-FGF and FGF-2 or b-FGF. These two factors induce proliferation, migration and protease production by endothelial cells in culture and neovascularization in vivo. a-FGF and b-FGF interact with endothelial cells by means of two classes of receptors, high-affinity receptor tyrosine kinases (FGF-Rs) and low-affinity receptors of heparin sulphate proteoglycan type (HSPGs) located at the surface of celts and in extracellular matrices. Although the paracrine role of these two factors on endothelial cells is widely described, these FGFs could also intervene on the cells through an autocrine process. Thus, FGFs and their receptors represent very relevant targets for therapies aimed at inhibiting angiogenesis processes (Keshet E, Ben-Sasson SA., J. Clin. Invest, (1999), Vol. 501, pp. 104-1497; Presta M, Rusnati M, Dell’Era P, Tanghetti E, Urbinati C, Giuliani R et al, New York: Plenum Publishers, (2000), pp. 7-34, Billottet C, Janji B, Thiery J.P., Jouanneau J, Oncogene, (2002) Vol. 21, pp. 8128-8139).

Moreover, systematic studyes aimed at determining the expression due to FGFs and their receptors (FGF-Rs) of various types of tumour cells demonstrate that a cell response to these two factors is functional in a large majority of human tumour lines studyed. These results support the hypothesis that an FGF receptor antagonist could also inhibit tumour cell proliferation (Chandler LA, Sosnowski BA, Greenlees L, Aukerman SL, Baird A, Pierce GF., Int.J.Cancer, (1999), Vol. 58, pp. 81-451).

FGFs play an important role in the growth and maintenance of prostate cells. It has been shown, both in animal models and in humans, that an impairment in the cell response to these factors plays an essential role in the progression of prostate cancer. Specifically, in these pathological conditions, both an increase in the production of a-FGF, b-FGF, FGF-6, FGF-8 etc., by the fibroblasts, stromal cells, residual basal cells and endothelial cells present in the tumour and an increase in the expression of FGF receptors and ligands by the tumour cells are recorded. Thus, a paracrine stimulation of prostate cancer cells takes place, and this process appears to be a major component of this pathological condition. A compound which has an FGF receptor antagonist activity, such as the compounds of the present invention, may represent a therapy of choice in these pathological conditions (Giri D, Ropiquet F., Clin.Cancer Res., (1999), Vol. 71, pp. 5-1063; Doll JA, Reiher FK, Crawford SE, Pins MR, Campbell SC, Bouck NP., Prostate, (2001), Vol. 305, pp. 49-293) (Sahadevan et al., 2007) (Kwabi-Addo et al., 2004).

Several studyes show the presence of FGFs and of their receptors, FGF-Rs, both in human breast tumour lines (in particular MCF7) and in tumour biopsies. These factors appear to be responsible, in this pathological condition, for the appearance of the very aggressive phenotype and induce a strong metastasization. Thus, a compound which has FGF-R receptor antagonist activity, such as the compounds of formula I, may represent a therapy of choice in these pathological conditions (Vercoutter-Edouart A-S, Czeszak X, Crépîn M, Lemoine J, Boilly B, Le Bourhis X et al., Exp.Cell Res., (2001), Vol. 262, pp. 59-68) (Schwertfeger, 2009).

Cancerous melanomas are tumours which induce metastases with a high frequency and which are very resistant to the various chemotherapy treatments. The angiogenesis processes play a predominant role in the progression of a cancerous melanoma. Furthermore, it has been shown that the probability of the occurrence of metastases increases very greatly with the increase in the vascularization of the primary tumour. Melanoma cells produce and secrete various angiogenic factors, including a-FGF and b-FGF. Moreover, it has been shown that inhibition of the cellular effect of these two factors by means of the soluble FGF-R1 receptor blocks melanoma tumour cell proliferation and survival in vitro and blocks tumour progression in vivo. Thus, a compound which has an FGF receptor antagonist activity, such as the compounds of the present invention, may represent a therapy of choice in these pathological conditions (Rofstad EK, Halsor EF., Cancer Res., (2000); Yayon A, Ma Y-S, Safran M, Klagsbrun M, Halaban R., Oncogene, (1997), Vol. 14, pp. 2999-3009).

Glyoma cells produce a-FGF and b-FGF in vitro and in vivo, and have various FGF receptors at their surface. This therefore suggests that these two factors play a pivotal role, by means of an autocrine and paracrine effect, in the progression of this type of tumour. Furthermore, like most solid tumours, the progression of gliomas and their ability to induce metastases is highly dependent on the angiogenic processes in the primary tumour. It has also been shown that FGF-R 1 receptor antisenses block human astrocytoma proliferation. In addition, naphthalenesulphonate derivatives are described for inhibiting the cellular effects of a-FGF and b-FGF in vitro and the angiogenesis induced by these growth factors in vivo. An intracerebral injection of these compounds induces a very significant increase in apoptosis and a considerable decrease in angiogenesis, reflected by a considerable regression of gliomas in rats. Thus, a compound which has an a-FGF antagonist and/or b-FGF antagonist and/or FGF receptor antagonist activity, such as the compounds of the present invention, may represent a therapy of choice in these pathological conditions (Yamada SM, Yamaguchi F, Brown R, Berger MS, Morrison RS, Glia , (1999), Vol. 76, pp. 28-66; Auguste P, Giirsel DB, Lemière S,

Reimers D, Cuevas P, Carceller F et al., Cancer Res., (2001), Vol. 26, pp. 61-1717) (Loilome et al., 2008).

Active angiogenesis is also described for hepatocarcinomas or hepatocellular carcinoma (HCC). In vivo, tumour progression in HCCs requires a considerable supply of oxygen and nutrients. Hepatocarcinomas are tumours which are typically angiogenic, because a drastic modification is observed with respect to arterial vascularization, and this results in the acquisition of an uvasive and metastatic potential (Tanaka et al., 2006). FGFs participate actively in the development of tumour angiogenesis within HCCs and are frequently associated with the inflammatory process. They are also overexpressed in the context of chronic hepatitis and liver sclerosis (Uematsu et al., 2005) and the serum FGF level has been correlated with the clinicopathological progression of HCCs. Furthermore, the FGF-R4 receptor, and also FGF-R1, have been described as participating actively in HCC tumour genesis (Huang et al., 2006) (Nicholes et al., 2002). The antagonists of the present invention may therefore be a treatment of choice for hepatocellular carcinomas or hepatocarcinomas.

In lung cancers of NSCLC (Non-Small Cell Lung Cancer) type, recent studyes show that b-FGF, FGF-9, FGF-R1 and FGF-R2 are regularly coexpressed in NSCLC cancer lines and especially in those resistant to anti-EGFR treatment such as gefitinib. These expressions are connected to the capacity for proliferation via autocrine cell signalling and anchorage-independent growth of tumours of NSCLC type and mainly the type insensitive to treatment with gefitinib (Marek et al., 2008). Furthermore, b-FGF has been suggested as playing an important role in the survival of NSCLC cells during treatment by chemotherapy, by inducing the overexpression of the anti-apoptotic proteins BCL-2, BCL-X, XIAP or BIRC3 (Pardo et al., 2002, 2003 and 2006). Thus, an FGF receptor antagonist, such as those of the present invention, may represent a therapy of choice for lung cancers of NSCLC type, alone or in combination with EGF receptor inhibitors or chemotherapies.

In approximately 10% of gastric cancers, this FGF-R2 gene amplification is observed. This amplification is associated with a poor vital prognosis for cancers of diffuse type. The proliferation of tumour cells may be ligand-independent or dependent on paracrine activation by FGF-7 (Turner et al., 2010). The antagonists of the present invention may therefore be a treatment of choice for gastric cancers.

V.

More recently, the potential role of pro-angiogenic agents in leukaemias and lymphomas has been documented. Indeed, in general, it has been reported that cell clones in these pathological conditions can be destroyed naturally by the immune system or switch into an angiogenic phenotype which promotes their survival and then their proliferation. This change in phenotype is induced by an overexpression of angiogenic factors, in particular by macrophages, and/or a mobilization of these factors from the extracellular matrix (Thomas DA, Giles FJ, Cortes J, Albitar M, Kantarjian HM., Acta Haematol, (2001), Vol. 207, pp.106-190). Among the angiogenic factors, b-FGF has been detected in many lymphoblastic and hematopoietic tumour cell lines. FGF receptors are also present on the majority of these lines, suggesting a possible autocrine cellular effect of a-FGF and b-FGF inducing proliferation of these cells. Moreover, it has been reported that bone marrow angiogenesis via paracrine effects is correlated with the progression of some of these pathological conditions.

More particularly, it has been shown, in CLL (chronic lymphocytic leukaemia) cells, that b-FGF induces an increase in anti-apoptotic protein (Bcl2) expression, resulting in an increase in the survival of these cells, and that it therefore participates considerably in their cancerization. In addition, the b-FGF levels measured in these cells are very well-correlated with the stage of clinical advancement of the disease and the resistance to the chemotherapy applied in this pathological condition (fludarabine). Thus, a compound which has an FGF receptor antagonist activity, such as the compounds of the present invention, may represent a therapy of choice, either alone or in combination with fludarabine or other products that are active in this pathological condition (Thomas DA, Giles FJ, Cortes J, Albitar M, Kantarjian HM., Acta Haematol, (2001), Vol. 207, pp. 106-190; Gabrilove JL, Oncologist, (2001), Vol. 6, pp. 4-7).

Furthermore, it has been shown in many recent studyes that FGFs and FGF-Rs participate actively in the resistance of tumour and/or endothelial cells to treatments by chemotherapy, radiotherapy or else anti-VEGF treatments. These resistances use various cell mechanisms, such as protection against apoptosis by positive regulation of the Bcl-xl protein by FGF-R4 in the case of breast cancer resistance to doxorubicin (Roidl et al., 2009) or by FGF-2 production in the case of resistance of bladder tumours to cisplatin (Miyake et al., 1998), by activation of the PÎ3K/AKT pathway by the FGF2/FGF-R1 couple in the case of resistance of acute myeloidal leukaemia cells to cytarabin (Karajannis et al., 2006), by stimulation of the «iL

RAS/MAP-K, PI3-K and mTOR pathway by FGF-1 for certain breast tumours resistant to anti-oestrogen treatments (Manuvakhova et al., 2006). The FGFs/FGF-Rs couple is also involved in resistance to anti-VEGF treatments in the case of pancreatic carcinomas (Casanovas et al., 2005) or of glioblastomas (Batchelor et al., 2007) or else in radiotherapy resistance phenomena (Gu et al., 2004; Moyal et al., 2009). Thus, the compounds of the present invention could be combined with existing therapies in order to limit the appearance of resistance phenomena.

Furthermore, tumour invasion, which is one of the marks of malignancy, consists of the translocation of tumour cells from the initial neoplastic locus to the surrounding host tissues, allowing the tumour to penetrate into the vascular endothelium in order to circulate and to form metastatic loci remote from the primary tumour. An increasing number of recent articles suggest that changes in the tissue architecture at the peripherary of the tumour appear to be responsible for the epithelialmesenchymal transition (EMT) process. EMT is a cell process by which epithelial cells modulate their phenotype and acquire mesenchymal cell properties through the disruption of intercellular adhesion and an increase in cell motility, thus playing an essential role in tumour progression by conferring an invasive and metastatic phenotype on carcinomas. Growth factors such as FGFs participate in this cell process by virtue of their stimulatory activity on cell migration and invasion, but also, as regards FGF receptors, by virtue of their ability to interact with cadherins, thus facilitating tumour cell migration (Cowin et al., 2005). The FGF-R antagonists described herein may be used for preventing these metastatic phases in a large number of cancers.

A correlation exists between the bone marrow angiogenesis process and “extramedullar disease in CML (chronic myelomonocytic leukaemia). Various studyes demonstrate that the inhibition of angiogenesis, in particular by means of a compound which has an FGF receptor antagonist activity, could represent a therapy of choice in this pathological condition.

The proliferation and migration of vascular smooth muscle cells contributes to intimal hypertrophy of the arteries and thus plays a predominant role in atherosclerosis and in restenosis after angioplasty and endoarterectomy.

X

In vivo studyes show, after lesion of the carotid “balloon injury”, a local production of a-FGF and of b-FGF. In this same model, an anti-FGF2 neutralizing antibody inhibits vascular smooth muscle cell proliferation and thus decreases intimal hypertrophy.

A chimeric protein consisting of FGF2 linked to a molecule such as saporin inhibits vascular smooth muscle cell proliferation in vitro and intimal hypertrophy in vivo (Epstein CE, Siegall CB, Biro S, Fu YM, FitzGerald D., Circulation, (1991), Vol. 87, pp. 84-778; Waltenberger J., Circulation, (1997), pp. 96-4083).

Thus, FGF receptor antagonists, such as the compounds of the present invention, represent a therapy of choice, either alone or in combination with compounds that are antagonists of other growth factors involved in these pathological conditions, such as PDGF, in the treatment of pathological conditions related to vascular smooth muscle cell proliferation, such as atherosclerosis, post-angioplasty restenosis or restenosis following the implantation of endovascular prostheses (stents) or during aortocoronary bypasses.

Cardiac hypertrophy occurs in response to a stress of the ventricular wall induced by an overload in terms of pressure or volume. This overload can be the consequence of numerous physiopathological states, such as hypertension, AC (aortic coarctation), myocardial infarction, and various vascular disorders. The consequences of this pathological condition are morphological, molecular and functional changes such as cardiac myocyte hypertrophy, matrix protein accumulation and foetal gene reexpression. b-FGF is implicated in this pathological condition. Specifically, the addition of b-FGF to cultures of newborn rat cardiomyocytes modifies the profile of the genes corresponding to the contractile proteins, resulting in a foetal-type gene profile. In a complementary manner, adult rat myocytes show a hypertrophic response under the effect of b-FGF, this response being blocked by anti-b-FGF neutralizing antibodyes. Experiments carried out in vivo in b-FGF-knock-out transgenic mice show that b-FGF is the major factor stimulating cardiac myocyte hypertrophy in this pathological condition (Schultz JeJ, Witt SA, Nieman ML, Reiser PJ, Engle SJ, Zhou M et al., J.CIin. Invest., (1999), Vol. 19, pp. 104-709). Thus, a compound, such as the compounds of the present invention, which has an FGF receptor antagonist activity represents a therapy of choice in the treatment of heart failure and any other pathological condition associated with cardiac tissue degeneration. This treatment could be carried out alone or in combination with the common treatments (beta-blockers, diuretics, angiotensic antagonists, antiarrythmics, anti-calcium agents, antithrombotics, etc.).

Vascular disorders due to diabetes are characterized by an impairment of vascular reactivity and of blood flow, hyperpermeability, an exacerbated proliferative response and an increase in matrix protein deposits. More specifically, a-FGF and b-FGF are present in the preretinol membranes of patients having diabetic retinopathies, in the membranes of the underlying capillaries and in the vitreous humour of patients suffering from proliferative retinopathies. A soluble FGF receptor capable of binding both a-FGF and b-FGF is developed in diabetes-related vascular disorders (Tilton RG, Dixon RAF, Brock TA., Exp. Opin. Invest. Drugs, (1997), Vol, 84, pp. 6-1671). Thus, a compound, such as the compounds of formula I, which has an FGF receptor antagonist activity represents a therapy of choice, either alone or in combination with compounds that are antagonists of other growth factors involved in these pathological conditions, such as VEGF.

Fibrosis is the abnormal formation of scar tissues following a tissue lesion, and results in a chronic and progressive impairment of the affected organs that can result in serious dysfunction of the affected organ. It can occur in all tissues, but is mainly prevalent in organs exposed to chemical or biological attacks, such as the lungs, the skin, the kidneys, the digestive tract, the liver, etc. FGFs participate in this cell process by promoting the production and accumulation of extracellular matrices by fibroblasts, the proliferation of said fibroblasts and infiltration into many organs such as the kidneys or the lungs (Khalil et al., 2005) (Strutz et al., 2003). Antagonists of the activity of these FGFs, such as the molecules of the present invention, may be used alone or in combination in the treatment of fibrosis.

Rheumatoid arthritis (RA) is a chronic disease with an unknown etiology. Although it affects many organs, the most serious form of RA is a progressive synovial inflammation of the joints resulting in destruction. Angiogenesis appears to considerably affect the progression of this pathological condition. Thus, a-FGF and b-FGF have been detected in the synovial tissue and in the joint fluid of patients suffering from RA, indicating that this growth factor is involved in the initiation and/or the progression of this pathological condition. In models of AIA (adjuvant-induced model of arthritis) in rats, it has been shown that the overexpression of b-FGF increases the severity of the disease, whereas an anti-b-FGF neutralizing antibody blocks the progression of RA (Malemud, 2007) (Yamashita A, Yonemitsu Υ, Okano S, Nakagawa K, Nakashima Y, Irisa T et al., J.Immunol., (2002), Vol. 57, pp. 168450 ; Manabe N, Oda H, Nakamura K, Kuga Y, Uchida S, Kawaguchi H, Rheumatol, (1999), Vol. 20, pp. 38-714). Thus, the compounds according to the invention represent a therapy of choice in this pathological condition.

Recent scientific articles document the involvement of b-FGF in neuropathic pain. Specifically, an increase in astroglial b-FGF production is observed in astrocytes following a spinal cord lesion (Madiai et al., 2003). This b-FGF contributes to neuropathic pain due to contact or allodynia. Treatment using an anti-FGF2 neutralizing antibody reduces this mechanical allodynia (Madiai et al., 2005). The antagonists of the present invention are treatments of choice for pain by inhibiting the effect of FGF-2 on these receptors.

It has also been described that the level of growth factors having a pro-angiogenic activity, such as FGF-1 and -2, are greatly increased in the synovial fluid of patients suffering from osteoarthritis. In this type of pathological condition, a considerable modification is recorded in the balance between the pro- and anti-angiogenic factors inducing the formation of new vessels, and consequently, the vascularization of nonvascularized structures, such as joint cartilages or intervertebral discs. Thus, angiogenesis represents a key factor in bone formation (osteophytes), thus contributing to the progression of the disease. Additionally, the inervation of the new vessels can also contribute to the chronic pain associated with this pathological condition (Walsh DA., Curr Opin Rheumatol. 2004 Sep;16(5):609-15). Thus, the compounds according to the invention represent a therapy of choice in this pathological condition.

IBD (inflammatory bowel disease) includes two forms of chronic inflammatory diseases of the intestine: UC (ulcerative colitis) and Crohn's disease (CD). IBD is characterized by an immune dysfunction reflected by an inappropriate production of inflammatory cytokines inducing the establishment of a local microvascular system. This angiogenesis of inflammatory origin results in an intestinal ischemia induced by vasoconstriction. High circulating and local levels of b-FGF have been measured in patients suffering from these pathological conditions (Kanazawa S, Tsunoda T, Onuma E, Majima T, Kagiyama M, Kkuchi K., American Journal of Gastroenterology, (2001), Vol. 28, pp 96-822 ; Thom M, Raab Y, Larsson A, Gerdin B, Hallgren R., Scandinavian Journal of Gastroenterology, (2000), Vol. 12, pp. 3516296

408). The compounds of the invention which exhibit a high anti-angiogenic activity in an inflammatory angiogenesis model represent a therapy of choice in these pathological conditions.

Another disease which has a considerable inflammatory component and for which a strong implication of FGFs and FGF-Rs is described is benign prostatic hyperplasia (BPH). BPH is a disease related to ageing which is characterized by hyperplasia of the glandular tissues and of the stroma around the urethra until it becomes obstructed. At the cellular level, this pathological condition involves hyperplasia of the basal cells, an increase in the stromal mass, amplified matrix deposit or else a reduction in tissue elasticity (Untergasser et al., 2005). FGFs participate in the development of this disease by stimulating the proliferation of the prostatic stroma and epithelial cells, and in particular FGF-7 or KGF, but also FGF-2 or FGF-17 (Wang 2008, Boget 2001, Giri 2001). In addition, FGFs promote the transdifferentiation step by modifying epithelial cell/stromal cell interactions, in combination with TGF-β (Untergasser 2005). Finally, certain receptors, such as FGF-R1, are overexpressed in BPH, promoting induction of the pathological condition and potentiating the paracrine effects of FGF-2 (Boget 2001). An antagonist of the effect of these FGFs is therefore a treatment of choice for benign prostatic hyperplasia.

Psoriasis is a chronic skin disease caused by a hyperproliferation of the epidermal kératinocytes, while clear cell acanthoma (CCA) is a benign neoplasm of the epidermis which also involves an abnormal proliferation of kératinocytes. These two skin diseases have similar histological characteristics despite different underlying causes: a thickening of the epidermis, inflammatory infiltrations of lymphocytes and neutrophils, dilation and tortuosity of the papillary capillaries. In both cases, KGF or FGF-7 plays a predominant role in the development of the pathological condition (Kovacs et al., 2006) (Finch et al., 1997). The use of the antagonists of the present invention may make it possible to slow down the development of such skin diseases.

FGF-R1, -R2 and -R3 receptors are involved in chronogenesis and osteogenesis processes. Mutations resulting in the expression of FGF-Rs that are always activated have been connected to a large number of human genetic diseases reflected by malformations of the skeleton, such as Pfeiffer syndrome, Crouzon syndrome, Apert syndrome, Jackson-Weiss syndrome and Bear-Stevenson cutis V gyrate syndrome. Some of these mutations affect more particularly the FGF-R3 reoeptor, resulting in particular in achondroplasias (ACH), hyperchondroplasias (HCH) and TD (thanatophoric dysplasia); ACH being the most common form of dwarfism. From a biochemical point of view, the sustained activation of these receptors takes place via a dimerization of the receptor in the absence of ligand (Chen L, Adar R. , Yang X. Monsonego E.O., LI C., Hauschka P.V, Yagon A. and Deng C.X., (1999), The Joum. Of Clin, invest, Vol. 104, n° 11, pp. 1517-1525). Thus, the compounds of the invention which exhibit an FGF antagonist or FGF receptor antagonist activity and which inhibit FGF-R-dependent intracellular signalling represent a therapy of choice in these pathological conditions.

It is also known that adipose tissue is one of the rare tissues that, in adults, can develop or regress. This tissue is highly vascularized and a very dense network of microvessels surrounds each adipocyte. These observations have resulted in the testing of the effect of anti-angiogenic agents on adipose tissue development in adults. Thus, it appears that, in pharmacological models in ob/ob mice, the inhibition of angiogenesis is reflected by significant weight loss in the mice (Rupnick MA ef al, (2002), PNAS, Vol. 99, n°16, pp. 10730-10735). Furthermore, FGFs appear to be key regulators of adipogenesis in humans (Hutley et at, 2004). Thus, an FGF receptor antagonist compound which has a powerful anti-angiogenic activity may represent a therapy of choice in obesity-related pathological conditions.

By virtue of their low toxicity and their pharmacological and biological properties, the compounds of the present invention are of use in the treatment and prevention of any carcinoma which has a high degree of vascularization, such as lung, breast, prostate, oesophageal, pancreatic, liver, colon or kidney carcinomas, or which induces metastases, such as colon, breast, liver or stomach carcinomas, or melanomas, or which is sensitive to a-FGF or to b-FGF in an autocrine manner or else in pathological conditions of glioma type, lymphomas and leukaemias or, finally, in any therapy-resistance phenomenon. These compounds represent a therapy of choice, either alone or in combination with a chemotherapy, a radiotherapy or any other suitable treatment. The compounds according to the invention are also of use in the treatment and prevention of cardiovascular diseases, such as atherosclerosis, or restenosis post-angioplasty, in the treatment of diseases related to complications occurring following the implantation of endovascular stents and/or aortocoronary bypasses or other vascular grafts, and cardiac hypertrophy or vascular complications of diabetes, such as diabetic retinopathies. The compounds according to the invention are also of use in the treatment and prevention of chronic inflammatory diseases such as rheumatoid arthritis, IBD or benign prostatic hyperplasia. Finally, the compounds according to the invention can be used in the treatment and prevention of achondroplasias (ACH), hypochondroplasias (HCH) and TD (thanatophoric dysplasia), as also in the treatment of obesity.

The products according to the invention are also of use in the treatment and prevention of macular degeneration, in particular age-related macular degeneration (or ARMD). A major characteristic of the loss of sight in adults is the neovascularization and the subsequent haemorrhages which cause considerable functional disorders in the eye and which are reflected by early blindness. Recently, studying the mechanisms involved in ocular neovascularization phenomena has made it possible to demonstrate the involvement of pro-angiogenic factors in these pathological conditions. By using a laser-induced choroidial neoangiogenesis model, it has been possible to confirm that the products according to the invention also make it possible to modulate neovascularization of the choroid.

Moreover, the products of the invention can be used in the treatment or prevention of thrombopenias due in particular to anticancer chemotherapy. It has in fact been demonstrated that the products of the invention can improve circulating platelet levels during chemotherapy.

Finally, the products according to the invention are of use in the treatment and prevention of skin diseases, such as psoriasis or clear cell acanthoma, in combating the progression of liver, kidney or lung fibrosis, and also in the treatment of neuropathic pain.

A subject of the invention is, according to another of its aspects, medicaments which comprise a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid or base, or else a hydrate or a solvate of the compound of formula (I).

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredyent, a compound of formula (I) according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable

47L salt or a hydrate or solvate of said compound, and also at least one pharmaceutically acceptable excipient. Said excipients are selected, according to the pharmaceutical form and the method of administration desired, from the usual excipients which are known to those skilled in the art.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredyent of formula (I) above, or optional salt, solvate or hydrate thereof, can be administered in unit administration form, as a mixture with conventional pharmaceutical excipients, to animals and to human beings for the prophylaxis or the treatment of the disorders or the diseases mentioned above.

The suitable unit administration forms comprise forms for oral administration, such as tablets, soft or hard gel capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular or intranasal administration forms, forms for administration by inhalation, topical, transdermal, subcutaneous, intramuscular or intravenous administration forms, rectal administration forms, and implants. For topical application, the compounds according to the invention can be used in creams, gels, ointments or lotions.

The pharmaceutical compositions according to the present invention are preferably administered orally.

By way of example, a unit administration form of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg

Mannitol 223.75 mg

Sodium croscaramellose 6.0 mg

Maize starch 15.0 mg

Hydroxypropyl methylcellulose 2.25 mg

Magnesium stearate 3.0 mg

The present invention also relates to a pharmaceutical composition as defined above, as a medicament.

VA

A subject of the present invention is also the use of a compound of formula (I), as defined above, for use thereof in the treatment and prevention of diseases requiring a modulation of FGFs.

A subject of the present invention is also the use of a compound of formula (I), as defined above, for use thereof in the treatment and prevention of cancers, in particular carcinomas which have a high degree of vascularization, such as lung, breast, prostate, pancreatic, colon, kidney and oesophageal carcinomas, cancers which induce metastases, such as colon cancer, liver cancer and stomach cancer, melanomas, gliomas, lymphomas and leukaemias.

A compound of formula (I) according to the present invention can be administered alone or in combination with one or more compound(s) which has (have) an antiangiogenic activity or with one or more cytotoxic compound(s) (chemotherapy), or else in combination with a radiation treatment. Thus, a subject of the present invention is also the use of a compound of formula (I), as defined above, in combination with one or more anticancer active ingredyent(s) and/or with radiotherapy.

A subject of the present invention is also the use of a compound of formula (I), as defined above, in the treatment and prevention of cardiovascular diseases, such as atherosclerosis or post-angioplasty restenosis, diseases related to complications occurring following the implantation of endovascular stents and/or aortocoronary bypasses or other vascular grafts, cardiac hypertrophy, or vascular complications of diabetes, such as diabetic retinopathies.

A subject of the present invention is also the use of a compound of formula (I), as defined above, in the treatment or prevention of chronic inflammatory diseases such as rheumatoid arthritis or IBD.

A subject of the present invention is also the use of a compound of formula (I), as defined above, in the treatment or prevention of osteoarthritis, achondroplasias (ACH), hypochondroplasias (HCH) and TO (thanatophoric dysplasia).

A subject of the present invention is also the use of a compound of formula (I), as defined above, in the treatment or prevention of obesity.

A subject of the present invention is also the use of a compound of formula (I), as defined above, in the treatment or prevention of macular degeneration, such as age-related macular degeneration (ARMD).

The compositions according to the invention, for oral administration, contain recommended doses of 0.01 to 700 mg. There may be particular cases where higher or lower dosages are appropriate; such dosages do not depart from the context of the invention. According to the usual practice, the dosage appropriate for each patient is determined by the physician according to the method of 10 administration and the age, weight and response of the patient, and also according to the degree of progression of the disease.

According to another of its aspects, the present invention also relates to a method for treating the pathological conditions indicated above, which comprises the 15 administration, to a patient, of an effective dose of a compound according to the invention, or a pharmaceutically acceptable sait, hydrate or solvate thereof.

2012

Claims (17)

1. Compound of formula (I):

(I) in which:

- Ri represents . a hydrogen or halogen atom, . an alkyl group optionally substituted with -COOR₅, . an alkenyl group optionally substituted with -COOR_5] . a -COOR5 or -CONR₅R₈ group, . an -NRsCORe or -NR₆-SO₂R₆ group, or . an aryl group, in particular phenyl, or a heteroaryl group, said aryl or heteroaryl group being optionally substituted with one or more groups selected from: halogen atoms, alkyl groups, cycloalkyl groups, -COOR₅, -CF₃, -OCF₃, -CN, C(NH₂)NOH, -OR_5j -O-Alk-COORs, -O-Alk-NR₆R₆, -O-Alk-NR₇R₈, -Alk-OR₅, Alk-COOR_S, -CONR₆R₆, -CO-NRs-ORs, -CO-NR_s-SO₂R₇, -CONR₅-Alk-NR₅R₆ CONR₅-Alk-NR₇R₈, -Alk-NR₅Re, -NR₅R₆, -NC(O)N(CH₃)₂, -CO-Alk, -CO(OAIk)_nOH, COO-Alk-NR₅Re, COO-Alk-NR₇R₈ and 5-membered heteroaryl groups, said heteroaryl groups being optionally substituted with one or more groups selected from halogen atoms and alkyl, -CF₃, -CN, -COOR₅, -Alk-OR₅, -Alk-COOR₅, -CONR₅R₆, -CONR₇R₈, -CO-NR₅-OR₆, -CO-NR₅-S0₂R6, -NR₅R₈ and -Alk-NR₅R_B groups, or with a hydroxyl group or with an oxygen atom,

- n is an integer ranging from 1 to 3,

- R₂ and R₃ together form, with the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered nitrogenous heterocycle corresponding to one of formula (A), (B) or (C) below:

in which the wavy lines represent the phenyl nucleus to which R₂ and R₃ are attached and:

. R_a represents a hydrogen atom or an alkyl, haloalkyl, -Alk-CF₃, -Alk-COORs, -Alk’-COORg , -Alk-CONR₆R₆, -Alk’-CONR₅R₆, -Alk-CONR₇R₈, -AlkNR₅R₆, -AlkCONR₅-OR_6l -Alk-NR_ZR_S, -Alk-cycloalkyl, -Alk-O-R₅, -Alk-S-R₅, -Alk-CN, -OR₅, -OAIkCOOR₅, -NR5R6, -NR₅-COOR_6t -Alk-aryl, -Alk-O-aryl, -Alk-O-heteroaryl, -Alk-heteroaryl or heteroaryl group, where the aryl or heteroaryl group is optionally substituted with one or more halogen atoms and/or alkyl, cycloalkyl, -CF₃, -OCF₃, -O-R₆ or -S-R5 groups, . R_a· represents a hydrogen atom or a linear, branched, cyclic or partially cyclic alkyl group, or an -Alk-OR₅, -Alk-NR₅R₆ or -Alk-NR₇R_e group, R_a· being optionally substituted with one or more halogen atoms, . R_b represents a hydrogen atom or an alkyl or -Alk-COOR₅ group, . R_b· represents a hydrogen atom or an alkyl, haloalkyl, cycloalkyl, phenyl or -Alk-COOR₆ group, . R_c represents a hydrogen atom or an alkyl, -CN, -COOR_S, -CO-NR₅R₆, -CONR₇R₈ -CO-NR₅-Alk-NR₅R₆, -CONR₅-Alk-OR₅,-CONR₅SO₂R₆, -Alkaryl or -Alk-heteroaryl group, where the aryl or heteroaryl group is optionally substituted with one or more halogen atoms and/or alkyl, cycloalkyl, -CF₃, -OCF₃, -O-alkyl or -S-alkyl groups, . R_c· represents a hydrogen atom or an alkyl group, . R_c·· represents a hydrogen atom or an alkyl, alkenyl, haloalkyl, cycloalkyl, -Alk-NR₆R6, -Alk-NR₇R₈, -Alk-OR_S or -Alk-SR₅ group,

- R4, located on position 6, 7 or 8 of the imidazopyridine nucleus, represents:

. a hydrogen atom, . a -COOR5 group, . a -CO-NR₆-Alk-NR₅R₆ group, . a -CO-NR₅-Alk-NR₇R_e group, or . a -CO-NR₅-Alk-OR₆ group,

- R_s and R₆, which may be identical or different, represent hydrogen atoms, haloalkyl groups or alkyl groups, cycloalkyl groups or an Ms group,

- R₇ and R_e, which may be identical or different, represent hydrogen atoms or alkyl or phenyl groups, or else R₇ and R_e together form a 3- to 8-membered saturated ring which can optionally contain a heteroatom,

- Aik represents a linear or branched alkylene chain, and

- Aik’ represents a linear, branched, cyclic or partially cyclic alkylene chain, optionally in the form of a pharmaceutically acceptable salt thereof.

2. Compound according to Claim 1, in which Ri represents:

. a hydrogen or halogen atom, . an alkyl group which is unsubstituted or substituted with -COOR₅ . an alkenyl group which is unsubstituted or substituted with -COOR₅, . a -COOR5 group, . a -CONR₅R_e group, . an -NRs-SO₂R6 group, or . a phenyl group optionally substituted with one or two groups selected from:

• halogen atoms;

• alkyl groups optionally substituted with -COOR₅;

• -CN, -C(NH₂)NOH, -COOR5, -CONR₅R₆, -CO-NR₅-OR_6i CO-NR₆-SO₂R₆, -COAIk, -CO(OAIk)_nOH, -OR₅ -OCF₃ , O-Alk-COORs, -Alk-OR₅, -NR₅R_S or -NC(O)N(CH₃)₂ groups, • 5-membered heteroaryls optionally substituted with an alkyl group and/or a hydroxyl group or an oxygen atom, in which R₆ and Re, which may be identical or different, represent hydrogen atoms, or alkyl groups optionally substituted with an -NR₇R_B group,

R₇ represents a hydrogen atom, an alkyl group containing 1 or 2 carbon atoms or a phenyl group, n is an integer ranging from 1 to 3, or . a heteroaryl group which is optionally condensed and/or optionally substituted with one or two groups selected from alkyl groups, OR_S] -COOR_S, NR_gRe and cycloalkyl groups, and an oxygen atom, in which R₅ and R_e, which may be identical or different, represent hydrogen atoms or alkyl groups containing 1 or 2 carbon atoms, optionally in the form of a pharmaceutically acceptable salt thereof.

3. Compound according to Claim 1, in which R₂ and R₃ together form, with the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered nitrogenous heterocycle corresponding to either of formulae (A) and (B) as defined in Claim 1, optionally in the form of a pharmaceutically acceptable salt thereof.

4. Compound according to Claim 1, in which R₂ and R₃ together form, with the carbon atoms of the phenyl nucleus to which they are attached, a 6-membered nitrogenous heterocycle corresponding to formula (A) as defined in Claim 1, optionally in the form of a pharmaceutically acceptable salt thereof.

5. Compound according to any one of the preceding claims, in which formula (A) or (B) is such that:

. R_a represents a hydrogen atom or an alkyl group, optionally substituted with one or more halogens; -AlkCONR₅Re; haloalkyl; -CH2-COOR_S; -Alk-heteroaryl, Alk-O-phenyl or -Alk-phenyl, where the phenyl group is optionally substituted with one or two alkyl groups and/or OR_S and/or halogen atoms; -Alk-cycloalkyl, . R_a· represents a hydrogen atom or a linear, branched, cyclic or partially cyclic alkyl group, or a -CH₂-OR₅ or -Alk-NR₅Re group, . R_b represents a hydrogen atom or an alkyl group, . Rb· represents a hydrogen atom or an alkyl, phenyl or -CH₂-COOR₅ group, in which the alkyl groups contain 1 to 6 carbon atoms, R₅ being as described in Claim 1, optionally in the form of a pharmaceutically acceptable salt thereof.

6. Compound according to any one of the preceding claims, in which R4 represents a hydrogen atom or a -COOH, -CO-NH-Alk-NR₇Re or -CO-NH-Alk-OH group, or else an alkyl group, preferably containing 1 to 3 carbon atoms, which is unsubstituted, in which Aik, R₇ and Re are as described in Claim 1.

7. Compound according to one of the preceding claims, selected from the following compounds:

6-(imidazo[1,5-a]pyridin-3-ylcarbonyl)-3-propylquinazoline-2,4(1H,3H)-dione. 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-

a]pyridin-1-yl}benzoic acid,

3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-

a]pyridine-6-carboxylic acid,

3-(3-{(3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid,

3-{3[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-

a]pyridin-1-yl}benzamide,

6-({1-[3-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl-3propylquinazoline-2,4(1H, 3H)-dione,

6-({1-[3-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]imidazo[1,5-a]pyridin-3-yl}carbonyl)-3propylquinazoline-2,4(1H, 3H)-dione,

N-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-

a]pyridin-1-yl}methanesulphonamide,

2- morpholin-4-yl-ethy! 3-(3-{[3-(4-fluorobenzyl)-1-methyl-2,4-dioxo-1,2,3,4- tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoate,

N-[2-(dimethy lamino)ethyl]-3-(3-{[3-(4-fluorobenzyl)-1 -methy I-2,4-d ioxo-1,2,3,4tetrahydroquinazolin-6-yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzamide.

3- (3-{[3-(4-fluorobenzyl)-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6yl]carbonyl}imidazo[1,5-a]pyridin-1-yl)benzoic acid,

3-(4-fluorobenzyl)-1 -methyl-6-[( 1 -py ridin-3-ylimidazo[ 1,5-a] py rid i n-3yl)carbonyl]quinazoline-2,4(1H, 3H)-dione, 3~(3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-

a]pyridin-1-yl}benzoic acid,

3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-

a] py ridin-1 -yljbenzamide,

6-(imidazo[1,5-a]pyridin-3-ylcarbonyl)quinazolin-4(3H)-one,

Λ/, Λ/, 1,2-tetramethyl-4-oxo-6-{[1 -(pyridin-3-yl)imidazo[ 1,5-a] py rid i n-3-yl]carbony I}-

1,4-dihydroquinoline-3-carboxamide,

3-[3-({3-[2-(4-fluorophenoxy)ethyl]-1-propyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin6-yl}carbonyl)imidazo[1,5-a]pyridin-1-yl]benzoic acid,

Vit optionally in the form of a pharmaceutically acceptable salt thereof.

8. Process for preparing the compounds of formula (I) according to any one of Claims 1 to 7 in which R₂ and R₃ together form a nitrogenous heterocycle of 5 formula (A) as defined in Claim 1, in which R, and R_a represent hydrogen atoms, characterized in that:

- the compound of formula (IV) (IV) in which R4 is as defined in Claim 1, is condensed with the compound of in order to obtain the compound of formula (VI)

- the compound of formula (VI) is subjected to a basic hydrolysis

15 reaction in order to obtain the compound of formula (VII):

- a reaction of esterification of the compound of formula (VII) is carried out so as to obtain the compound of formula (VIII)

100

- the compound of formula (VIII) is subjected to the action of triphosgene so as to form the isocyanate corresponding to the compound (VIII), and then this isocyanate is condensed with an amine of formula R_aNH₂, R_a being as defined in Claim 1, in order to obtain the urea of formula (IX),

- the urea of formula (IX) is subjected to a cyclization reaction in a basic medium.

9. Process for preparing a derivative of formula (I) according to one of Claims 1 to 7 in which R₂ and R₃ together form a nitrogenous heterocycle of formula (A) as defined in Claim 1, Ri is as defined in Claim 1, with the proviso that Ri does not represent a hydrogen atom, and R₄ is as defined in Claim 1, characterized in that:

- the compound of formula (IV) (IV) in which R4 is as defined in Claim 1, is condensed with the compound of in order to obtain the compound of formula (VI)

101

- the compound of formula (VI) is subjected to a basic hydrolysis reaction in order to obtain the compound of formula (VII):

(VII)

5 - a reaction of esterification of the compound of formula (VII) is carried out so as to obtain the compound of formula (VIII)

- the compound of formula (VIII) is subjected to a bromination reaction in order to obtain the compound of formula (X):

10 <x>

- the derivative of formula (X) is subjected to the action of triphosgene and the isocyanate corresponding to the compound of formula (X) is formed, which is condensed with an amine of formula R_aNH₂, Ra being as defined in Claim 1, in order to obtain the urea of formula (XI):

102

- the compound of formula (XI) is subjected to a cyclization reaction in a basic medium in order to obtain the compound of formula (XII),

- the compound of formula (XII) is subjected to an alkylation reaction in the presence of a base and of a halogenated derivative R_aX, R_a· being as defined in Claim 1, in order to obtain the compound of formula (XIII):

Br (xiii) r!

- the compound of formula (XIII) is subjected, in the presence of a palladium catalyst, of a ligand and of a base:

to a reaction with phenyiboronic or heteroarylboronic or phenylboronate ester or heteroarylboronate ester derivatives according to a Suzuki coupling, . or else to an imination reaction with benzophenoneimine, followed by an acid hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula ReSC^CI, . or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis and by an esterification or a peptide coupling with an amine R₅RbNH₂, R_s and R₆ being defined in Claim 1.

103

10. Process for preparing the compounds of formula (I) according to any one of Claims 1 to 7 in which R₂ and R₃ together form a nitrogenous heterocycle of formula (A) as defined in Claim 1, and in which R, and R4 represent groups as defined in Claim 1, with the proviso that R, is not a hydrogen atom, 5 characterized in that:

- the compound of formula (IV) (IV) in which R4 is as defined in Claim 1, is condensed with the compound of in order to obtain the compound of formula (VI)

- the compound of formula (VI) is subjected to a basic hydrolysis reaction in order to obtain the compound of formula (VII):

- a reaction of esterification of the compound of formula (VII) is carried out so as to obtain the compound of formula (VIII):

104

- the compound of formula (VIII) is subjected to a bromination reaction in order to obtain the compound of formula (X):

(X)

- the compound of formula (X) is subjected, in the presence of a palladium catalyst, of a ligand and of a base:

. to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or heteroarylboronate ester derivatives according to a Suzuki coupling, , or else to an imination reaction with benzophenoneimine, followed by an acid hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula ReSO₂CI, . or else to a cyanation reaction with zinc chloride, followed by an acid hydrolysis and by an esterification or a peptide coupling with an amine R₅R5NH₂, R₅ and R₆ being defined in Claim 1, in order to obtain the compound of formula (XIV):

- the derivative of formula (XIV) is subjected to the action of tri phosgene so as to form the corresponding isocyanate, the isocyanate obtained is condensed with an amine of formula R_aNH₂ in order to obtain the urea of formula (XV), Ra being as defined in Claim 1:

- the derivative of formula (XV) is subjected to a cyclization reaction in a

105 basic medium in order to obtain the compound of formula (XVI):

- the compound of formula (XVI) is subjected to an alkylation reaction in the presence of a base and of a halogenated derivative R_aX, R_a· being as defined in Claim 1 and X being a halogen.

11. Process for preparing the compounds of formula (I) according to Claims 1 to 7 in which R₂ and R₃ together form a nitrogenous heterocycle of formula (A) and in which Rt represents a group as defined in Claim 1, with the proviso that Rt does not represent a hydrogen atom, R4 being as defined in claim, characterized in that:

- the compound of formula (IV) (IV) in which R4 is as defined in Claim 1, is condensed with the compound of in order to obtain the compound of formula (VI)

- the compound of formula (VI) is subjected to a basic hydrolysis reaction in order to obtain the compound of formula (VII):

106 out so as to obtain the compound of formula (VIII)

5 - the compound of formula (VIII) is subjected to a bromination reaction in order to obtain the compound of formula (X):

Br (X)

- the derivative of formula (X) is subjected to the action of triphosgene and the isocyanate corresponding to the compound of formula (X) is formed, which 10 is condensed with an amine of formula RaNH₂, R_a being as defined in Claim 1, in order to obtain the urea of formula (XI):

- the compound of formula (XI) is subjected to a cyclization reaction in a basic medium in order to obtain the compound of formula (XII)

107

- the compound of formula (XII) is subjected, in the presence of a palladium catalyst, of a ligand and of a base,

- to a reaction with phenylboronic or heteroarylboronic or phenylboronate ester or heteroarylboronate ester derivatives according to a Suzuki coupling,

- or else to an imination reaction with benzophenoneimine, followed by an acid hydrolysis and by a sulphonylation reaction with a sulphonyl chloride of formula RgSChCI,

- or else to a cyanation reaction with zinc cyanide, followed by an acid hydrolysis and by an esterification or a peptide coupling with an amine R₅R₆NH₂, R₅ and R₆ being as defined in Claim 1, in order to obtain the compound of formula (XVI) in which R, is as defined in Claim 1, with the proviso that Ri does not represent a hydrogen atom,

- the compound of formula (XVI) is subjected to an alkylation reaction in the presence of a base and of a halogenated derivative R_aX, R_a· being as defined in Claim 1 and X being a halogen.

12. Process for preparing the compounds of formula (I) according to Claims 1 to 7, in which R₂ and R₃ together form a nitrogenous heterocycle of formula (B) as defined in Claim 1, R₄ being as defined in Claim 1, and Ri represents a hydrogen atom, characterized in that:

- the compound of formula (IV) (IV)

108 in which R4 is as defined in Claim 1, is condensed with the compound of formula (V) in order to obtain the compound of formula (VI)

- the compound of formula (VI) is subjected to a basic hydrolysis reaction in order to obtain the compound of formula (VII):

(VID

- a reaction of esterification of the compound of formula (VII) is carried

10 out so as to obtain the compound of formula (VIII)

- the compound (VIII) is subjected to a saponification reaction in order to obtain the compound (XXIV):

15 - the compound (XXIV) is then subjected to a condensation reaction with an alkyl or aryl anhydride (R_aCO)₂O in order to obtain the compound of formula 'CC

109 (xvii),

- the compound of formula (XVII) is subjected to a condensation reaction with an amine R_bNH₂ Ro and R_b· being as defined in Claim 1.

13. Process for preparing the compounds of formula (I) according to Claims 1 to 7, in which R₂ and R₃ together form a nitrogenous heterocycle of formula (B) as defined in Claim 1, R4 being as defined in Claim 1 and Rq being as defined in Claim 1, with the proviso that Rq does not represent a hydrogen atom, 10 characterized in that:

- the compound of formula (IV) (IV) in which R4 is as defined in Claim 1, is condensed with the compound of in order to obtain the compound of formula (VI):

- the compound of formula (VI) is subjected to a basic hydrolysis reaction in order to obtain the compound of formula (VII):

110 out so as to obtain the compound of formula (VIII):

5 - the compound of formula (VIII) is subjected to a bromination reaction in order to obtain the compound of formula (X):

- the compound of formula (X) is subjected, in the presence of a palladium catalyst, of a ligand and of a base,

10 - to a reaction with phenylboronic or heteroarylboronic or phenyl boronate ester or heteroarylboronate ester derivatives according to a Suzuki coupling,

- or else to an imination reaction with benzophenoneimine, followed by an acid hydrolysis and by an alkylation reaction with a sulphonyl chloride of formula

15 R₆SO₂CI,

- or else to a cyanation reaction with zinc chloride, followed by an acid hydrolysis and by an esterification or a peptide coupling with an amine R₅R₆NH₂, R& and R_e being defined in Claim 1,

- in order to obtain the compound of formula XIV:

111

- the compound (XIV) is subjected to a saponification reaction in order to obtain the compound (XXV):

- the compound (XXV) is then subjected to a condensation reaction with an alkyl or aryl anhydride (R_bCO)₂O, Rb· being as defined in Claim 1, in order to obtain the compound of formula (XVIII):

- the compound of formula (XVIII) is subjected to a condensation reaction with an amine R_bNH₂, R_b being as defined in Claim 1.

14. Pharmaceutical composition containing, as active ingredient, a derivative of formula (I) according to any one of Claims 1 to 7, optionally in combination with one or more suitable inert excipients.

15. Compound according to any one of Claims 1 to 7, for use thereof in the treatment and prevention of diseases requiring a modulation of b-FGFs.

16. Compound according to any one of Claims 1 to 7, for use thereof in the treatment and prevention of cancers, in particular carcinomas which

112 have a high degree of vascularization, such as lung, breast, prostate, pancreatic, colon, kidney and oesophageal carcinomas, cancers which induce metastases, such as colon cancer, liver cancer and stomach cancer, melanomas, gliomas, lymphomas, leukaemias, and also thrombopenias.

17. Compound according to Claim 16, for use thereof in combination with one or more anticancer active ingredient(s) and/or with radiotherapy and/or with any anti-VEGF treatment.

10 18. Compound according to any one of Claims 1 to 7, for use thereof in the treatment and prevention of cardiovascular diseases, such as atherosclerosis or post-angioplasty restenosis, diseases related to complications that occur following the implantation of endovascular stents and/or aortocoronary bypasses or other vascular grafts, cardiac hypertrophy, vascular complications of diabetes, such as

15 diabetic retinopathies, liver, kidney and lung fibroses, neuropathic pain, chronic inflammatory diseases, such as rheumatoid arthritis or IBD, prostatic hyperplasia, psoriasis, clear cell acanthoma, osteoarthritis, achondroplasias (ACH), hypochondroplasias (HCH), TD (thanatophoric dysplasia), obesity, and macular degeneration, such as age-related macular degeneration (ARMD).

112 pages ORIGINAL

SANOFI

PAR PROCURATION

DEC. 2012

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