OA19003A - New ammonium derivatives, a process for their preparation and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6 and Y are as defined in the description. Medicaments

Description

NEW AMMONIUM DERIVATIVES, A PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The présent invention relates to new ammonium dérivatives, to a process for their préparation and to pharmaceutical compositions containing them.

The compounds of the présent invention are new and hâve very valuable pharmacological characteristics in the field of apoptosis and oncology.

Apoptosis, or programmed cell death, is a physiological process that is crucial for embryonic development and maintenance of tissue homeostasis.

Apoptotic-type cell death involves morphological changes such as condensation of the nucléus, DNA fragmentation and also biochemical phenomena such as the activation of caspases which cause damage to key structural components of the cell, so inducing its disassembly and death. Régulation of the process of apoptosis is complex and involves the activation or repression of several intracellular signalling pathways (Cory et al. Nature Review Cancer 2002. 2, 647-656).

Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease and ischaemia. Converseiy, déficits in the implémentation of apoptosis play a significant rôle in the development of cancers and their chemoresistance, in auto-immune diseases, inflammatory diseases and viral infections. Accordingly, absence of apoptosis is one of the phenotypic signatures of cancer (Hanahan et al. Cell 2000, 100, 57-70).

The anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies. The involvement of proteins of the Bcl-2 family is described in numerous types of cancer, such as colon cancer, breast cancer, small-cell lung cancer, non-small-cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphoid leukaemîa, lymphoma, myeloma, acute myeloid leukemia. pancreatic cancer, etc. Overexpression of the antiapoptotic proteins of the Bcl-2 family is involved in tumorigenesis, in résistance to chemotherapy and in the clinical prognosis of patients affected by cancer. Notably, Mcl-l, an anti-apoptotic Bcl-2 family member, is overexpressed in varions types of cancer (Beroukhim et al. Nature 2010, 899-905). There is, therefore, a therapeutîc need for compounds that inhibit the anti-apoptotic activity of the proteins of the Bcl-2 family.

Recently, thienopyrimidine dérivatives hâve been described as potent Mcl-l inhibitors useful for the treatment of cancers (WO 2015/097 i 23).

The présent invention provides novel ammonium dérivatives that hâve pro-apoptotic properties making it possible to use them in pathologies involving a defect in apoptosis, 5 such as, for example, in the treatment of cancer and of immune and auto-immune diseases.

Moreover, the compounds of the présent invention hâve high solubility as well as remarkable and unexpected pharmacological effects which could lead to very interesting candidates for oncology.

wherein:

♦ Y represents a -NH- group or an oxygen atom, ♦ Ri represents a linear or branched (Ci-Cô)alkyl group, a linear or branched (C2-Cû)alkenyl group, a linear or branched (Cz-Cèjalkynyl group, a linear or branched (Ci-C₆)alkoxy group, a -S-(Ci-C₆)alkyl group, a linear or branched (Ci-C6)polyhaloalkyl group, a hydroxy group, a hydroxy(Ci-Cô)alkyl group, a cyano group, -NR9R9’, -Cyi or a halogen atom, ♦ R₂, R 3 and R4 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Ci-Cô)aikyl group, a linear or branched (C2-Cô)alkenyl group, a linear or branched (Cj-Côjalkynyl group, a linear or branched (Ci-Céjpolyhaloalkyl, a hydroxy group, a hydroxy(Ci-Cé)alkyl group, a linear or branched (Ci-Cô)alkoxy group, a -S-(Ci-Câ)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NR₉R9’, -O-alkyl(Ci-C6)-NR₉R₉’, -C(O)-OR9, -O-C(O)-R₉, -C(O)-NR₉R₉’, -NR₉-C(O)-R₉’, -NR₉-C(O)-0R₉’,

-alkyl(Ci-C6)-NR₉-C(O)-R₉’, -SO2-NR9R9', -SO₂-alkyl(Ci-C₆), ♦ Rî represents a hydrogen atom, ♦ R₆ represents the group

♦ R7 represents a hydrogen atom or a linear or branched (Ci-Cô)alkyl group, ♦ Rs represents a -O-P(O)(O’)(O) group, a -0-P(0)(0)(ORio) group, a -0-P(0)(ORio)(ORio’) group, a -O-SO₂-O‘ group, a -O-SO2-OR10 group, -Cy2, a -O-C(O)-R₉ group, a -O-C(O)-OR₉ group or a -O-C(O)-NR₉R₉’ group;

♦ R₉ and R₉’ independentiy of one another represent a hydrogen atom, a linear or branched (Ci-Cô)alkyl group or a linear or branched amino(Ci-Cô)alkyl group, ♦ Rio and Rio’ independentiy of one another represent a hydrogen atom, a linear or branched (Ci-C6)alkyl group or an arylalkyl(Ci-Cô) group, ♦ Cyi and Cy₂ independentiy of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, it being possible for the ammonium so defined to exist as a zwitterionic form or to hâve a monovalent anîonic counterion.

it being understood that:

- “aryl” means a phenyl or naphthyl group,

- “heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen,

- “cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members,

- “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from I to 4 groups selected from linear or branched (Ci-C6)alkyl, linear or branched (C2-Cs)alkenyl group, linear or branched (C2-Cô)alkynyl group, linear or branched (Ci-Cô)alkoxy, (Cj-C&)alkyl-S-, hydroxy, oxo (or A-oxide where appropriate), nitro, cyano, -C(O)-OR’, -O-C(O)-R’, -C(O)-NR’R”, -NR’R, -(C=NR’)-OR”, linear or branched (Ci-Côjpolyhaloalkyl, trifluoromethoxy or halogen, it being understood that R’ and R” independently of one another represent a hydrogen atom or a linear or branched (Ci-Ce)alkyl group, their enantîomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonîc acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonîc acid, camphoric acid etc.

Among the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, /erz-butylamine etc.

Depending on their electronic charge, compounds of formula (I) can hâve a zwitterionic form which means a neutral molécule with a positive and a négative electrîcal charge. For compounds according to the invention, examples of a zwitterionic form can be as follows:

Depending on their electronic charge, compounds of formula (l) can contain one pharmaceutically acceptable monovalent anionic counterion ΜΓ, which can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, or the like. For compounds according to the invention, an exampie can be as 10 follows:

Depending on their electronic charge, compounds of formula (I) can contain one pharmaceutically acceptable monovalent cationic counterion Mî⁺, which can be selected from sodium, potassium, lithium, ammonium, aminoacid or the like. For compounds 5 according to the invention, examples can be as follows:

Depending on their electronic charge, compounds of formula (1) can contain one pharmaceutically acceptable divalent cationic counterion Mî²⁺, which can be selected from calcium, magnésium, aluminium, aminoacid or the like, or two pharmaceutically 5 acceptable monovalent cationic counterions Mi^-, identical or different. For compounds according to the invention, an example can be as follows:

Y preferably represents an oxygen atom.

Advantageously, at least one of the groups selected from R?, R 3 and R_i does not represent a hydrogen atom.

In another embodiment of the invention, an advantageous possibility consists of

wherein Ri, R2, Ri. Rr, R5, Rô and Y are as defined for formula (I).

(La)

In the preferred compounds of the invention, Ri represents a linear or branched (Ci-C6)alkyl group or a halogen atom. More preferabiy, Ri represents a methyl group, an ethyl group, a chlorine atom or a bromîne atom. Even more preferabiy, Ri represents an ethyl group or a bromîne atom. More particularly, Ri represents a bromîne atom. Advantageously, Ri represents a methyl group.

Atropisomers are stereoisomers arising because of hindered rotation about a single bond, where energy différences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers (Bringmann et al. Angew. Chem. Int. Ed. 2005, 44, 5384-5427). For compounds according to the invention, atropisomers are as follows:

Preferred atropisomer is (55^).

Advantageously, R? represents a halogen atom, a hydroxy group, a linear or branched (Ci-Ce)alkoxy group. More preferably, R2 represents a chlorine atom.

R3 and R4 preferably represent a hydrogen atom. In an advantageous embodiment, the substîtuents of the pair (Ri, R4) are identical and the substituents of the pair (R2, R3) are identical. In the preferred compounds of the invention, the substituents of the pair (Ri, R4) are identical and represent a (Ci-Cé)alkyl group, preferably a methyl group, whereas the substituents of the pair (R2, R3) are identical and represent a hydrogen atom or a halogen 10 atom, preferably a chlorine atom.

Advantageously, R₆ represents the group

More preferably, R₆ represents the group

ΙΟ

In the preferred compounds of the invention, R? represents a methyl group or a hydrogen atom. More preferably, R? represents a hydrogen atom.

Advantageously, Rg represents a -0-P(0)(0')(ORio) group in which Rto preferentially represents a hydrogen atom, a benzyl group or a methyl group. In another prefered embodiment of the invention, Rg represents a -O-SO₂-O‘ group. Preferably, Rg represents a 5-methyl-2-oxo-l,3-dioxoI-4-yl group; a -O-C(0)-CH3 group; a -O-C(O)-/Bu group; a -O-C(O)-CH₂-NH₂ group; a -O-C(O)-CH[CH(CHj)₂]-NH2 group; a -O-C(O)-O-CH₂CH₃ group; or a -O-C(O)-N(CH₂CH3)₂ group. Even more preferably, Rg represents a -0-P(0)(O )(OH) group.

Preferred compounds of the invention are:

- {4-[2-(4-{(55_a)-4-[(lR)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimÎdin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l-methylpiperazin- l-ium-1-yl{methyl hydrogen phosphate;

- benzyl {4-(2-(4-((55^)-4-(( l R)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyi)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-1 -methyIpiperazin-l -ium-1 -y l} methyl phosphate;

- {4-(2-(4-{(55_a)-4-[(lR)-I-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyI)thieno[2,3-i/]pyrimidtn-5-yl}-2-chloro3-inethylphenoxy)ethyl]-1 -methylpiperazin-1 -ium- l-yl}methyl methyl phosphate;

- {4-[2-(4-{(55_a)-4-[(lR)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yI}-2-chloro3-ethylphenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -yI}methyl hydrogen phosphate;

- {4-[2-(3-bromo-4-{(55a)-4-[(lR)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -y]}methyl hydrogen phosphate;

- benzyl {4-[2-(3-bromo-4-{(55a)-4-[(lR)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-y[]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-if|pyrimidin-5yl)-2-chlorophenoxy)ethyl]-l-methylpiperazin-1-ium-i-yl}methyl phosphate;

- {4-[2-(3-bromo-4-{(55_a)-4-(( l R)-1 -carboxy-2-(2-{ (2-(2-methoxyphenyl)pyrimidin-4-

U yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 -methyIpiperazin-1 -ium-l -yi}methyl methyI phosphate;

-X-[(55_a)-5-{3-chloro-4-[2-(4-{[(hydroxyphosphinato)oxy]rnethyl}-4methylpiperazin-4-ium-l-yl)ethoxy]-2-methylphenyl}-6-(4-fluorophenyl)thieno[2,3-i7] pyrimidin-4-yl]-2-{ [2-(2-methoxypheny l)pyrim idin-4-yl]methoxy }-D-phenylalanine;

- {4-[2-(4-{4-[(l.K)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-<Z]pyrimidin-5-yl}-2,6dichloro-3,5-dimethylphenoxy)ethyl]-1 -methylpîperazin-1 -ium-1 -yI}methyl hydrogen phosphate;

- {4-[2-(4-{4-[( 17Î)-1 -carboxy-2-(2- {[2-(2-methoxyphenyl)pyrim idin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-t(|pyrimidin-5-yl}-3,5dimethylphenoxy)ethyl]-1 -methylpîperazin-1 -ium-1 -yl} methyl hydrogen phosphate;

- {[2-(4-{(55_a)-4-(( 17?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-5-yl}-2-chloro-

3-methylphenoxy)ethyl](dimethyl)ammonio}methyl hydrogen phosphate;

- I -{4-[2-(4-{(55₀)-4-[(l 7?)-1 -carboxy-2-(2-{ [2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-t/]pyrimidin-5-yl]-2-chioro3-methylphenoxy)ethyl]-1 -methylpîperazin-1 -ium-1 -yI}ethyl hydrogen phosphate;

- l-{4-[2-(3-bromo-4-{(55_a)-4-[( l/ï)-l -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin20 4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-if]pyrimidin-5-yl}-2- chlorophenoxy)ethyl]-1 -methylpîperazin-1 -ium-1 -yl}ethyl hydrogen phosphate;

- {l -[2-(4-{(55_a)-4-[( ITÎ)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-4-methylpiperazin-1 -ium-1-yl{methyl hydrogen phosphate;

- {l-[2-(3-bromo-4-{(55_o)-4-[(l7î)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4y l]methoxy}pheny l)ethoxy]-6-(4-fl uorophenyl)thieno[2,3-i7jpyrim idin-5-yl}-2chlorophenoxy)ethyl]-4-methy Ipiperazin-1-ium-1-yl}methyl hydrogen phosphate;

- {4-[2-(4-{(55_α)-4-[( l /?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-(7)pyrimidin-5-yl}-2-chloro-

3-methylphenoxy)ethyI]-1 -methylpîperazin-1 -ium-1 -yl}methyl sulfate;

- l-[(acetyloxy)methyl]-4-[2-(4-{(55_a)-4-[(lR)-l-carboxy-2-(2-{(2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5y I }-2-chloro-3-methylphenoxy)ethyl]-1 -methylpiperazin-1 -ium;

- 4-[2-(4-{(55'_a)-4-[(l7î)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thîeno[2,3-</[pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l-{[(ethoxycarbonyl)oxy]methyl}-l -methylpiperazin-1 -ium;

- 4-[2-(4-{(55_a)-4-[(l/?)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidÎn-5-yl}-2-chloro3-methylphenoxy)ethyl]-l -{[(diethylcarbamoyl)oxy]methy l}-1 -methylpiperazin-1 -ium;

- 4-[2-(4-{(55_a)-4-[( l/?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidîn-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-1 -[(glycyloxy)methyl]-! -methylpiperazin-1 -ium;

- 4-(2-(4-{(55_a)-4-[( iR)-1 -carboxy-2-(2-{ [2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yI}-2-chloro-3methylphenoxy)ethyl]-1 -{l-[(diethylcarbamoyi)oxy]ethyl}-1 -methylpiperazin-1 -ium;

- 4-[2-(4-{ (5S_a)-4-[( lÆ)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l -methyl-1 -[(5-methyl-2-oxo-1,3-dioxol-4yl)methyl]piperazin-1 -ium;

- 4-[2-(4-{(5S^, _a)-4-[(I/î)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-r/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-1 -methy l-l -[(L-valyloxy)methyl]piperazin-1 -ium;

- 4-[2-(4-{(55_a)-4-[( ΙΛ)-1 -carboxy-2-(2-{[2-(2-methoxyphenyi)pyrimidin-4yl]methoxy} phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-y I} -2-chloro3-methylphenoxy)ethy I]-1 -{[(2,2-dimethylpropanoyl)oxy]methyl} -1 -methylpiperazinl-ium;

- I -[(acetyloxy)methyl]-4-[2-(3-bromo-4-{(55_a)-4-[( l R)-1 -carboxy-2-(2-{ [2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno [2,3-i/|pyrimidin-5-yI }-2-chlorophenoxy)ethyl]-1 -methylpiperazin-1 -ium;

- 4-[2-(3-brorno-4-{(55_a)-4-[(lA)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 -{[(ethoxycarbonyl)oxy]methyl} -1 -methylpiperazin-1 -ium;

- 4-[2-(3-bromo-4-{(5Sa)-4-[(IÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimtdin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/|pyrimidin-5-yl}-2chlorophenoxy)ethyl]-l-{((diethylcarbamoyl)oxy]methyl}-l-methylpiperazin-l-ium;

- 4-(2-(3-bromo-4-{(55'_fl)-4-[( lΛ)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 -[(glycyloxy)methyl]-1 -methy Ipiperazîn-l -ium;

- 4-[2-(3-bromo-4-{(55'_ii)-4-[( l R)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno(2,3-i/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 - {l -[(dîethylcarbamoy l)oxy]ethyl}-1 -methylpîperazin-1 -ium;

-4-[2-(3-bromo-4-{(55’_a)-4-[(l/?)-l-carboxy-2-(2-{(2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1-methyl-l-[(5-methyl-2-oxo-l,3-dioxo!-4-yl)methyl]piperazinl-ium;

- 4-[2-(3-bromo-4-{(5Sa)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidÎn-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-t/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]- l-methyl-1 -[(L-va!yloxy)methyl]piperazin-1 -ium;

- 4- [2-(3-bromo-4- {(55_fl)-4-[( l Λ)-1 -carboxy-2-(2- {[2-(2-methoxypheny l)pyrîm id i n -4yl]methoxy}phenyi)ethoxy]-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-l -{[(2,2-dimethylpropanoyl)oxy]methyl} -1 -methylpîperazin-1 ium.

Among the preferred compounds of the invention there may be mentioned:

- {4-(2-(4-((55(,)-4-(( l /?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yI]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-1 -methylpîperazin-1 -ium-1 -yl} methyl hydrogen phosphate;

- benzyl {4-[2-(4-{ (55’_a)-4-[( l /?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methyiphenoxy)ethy!]-1 -methylpîperazin-1 -ium-1 -yl} methyl phosphate;

- {4-[2-(4-{(55a)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-1 -methylpîperazin-1 -ium-1 -yl} methyl methyl phosphate;

I4

- (4-[2-(4-((55_a)-4-[( I Λ)-1 -carboxy-2-(2-{ [2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-5-yl}-2-chloro3-ethylphenoxy)ethyl]-l-methylpiperazin-l-ium-l-yl}methyl hydrogen phosphate;

- {4-[2-(3-bromo-4-{(55a)-4-[(U?)-l-carboxy-2-(2-{[2-(2-methoxyphenyI)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyi)thieno[2,3-<7]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 -methylpiperazin-l -ium-1 -yl}methyl hydrogen phosphate;

- benzyl {4-[2-(3-bromo-4-{(55_a)-4-[( ΙΛ)-1 -carboxy-2-(2-{ (2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5yl}-2-chlorophenoxy)ethyl]-1 -methylpiperazin-l-ium-l-yl}methyl phosphate;

- {4-[2-(3-bromo-4-{(55_a)-4-(( l /?)-1 -carboxy-2-(2-{(2-(2-methoxyphenyl)pyrimidin-4yl]methoxy)phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -yl}methyl methyl phosphate;

-A4(55_a)-5-{3-chioro-4-[2-(4-{((hydroxyphosphinato)oxy]methyl}-4methylpiperazin-4-ium-l-yl)ethoxy]-2-methylphenyi}-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanine;

- (4-(2-(4-{4-[( l /?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-5-yl}-2,6dichloro-3,5-dimethylphenoxy)ethyl]-1 -methylpiperazin-l-ium-1-yl}methyl hydrogen phosphate;

- {4-(2-(4-{4-[( l Λ)-1 -carboxy-2-(2-{ [2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-3,5dimethylphenoxy)ethyl]-1 -methylpiperazin-1 -ium-1-yl }methyl hydrogen phosphate;

- {[2-(4-{(55_a)-4-[( ΙΛ)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl](dimethyl)ammonio} methyl hydrogen phosphate;

- I -{4-[2-(4-{(55_a)-4-[( l /?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidîn-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2J-i/]pyrimidin-5-yl}-2-chloro-

3- methylphenoxy)ethyI]-1 -methylpiperazin-1 -ium-1 -yl}ethyl hydrogen phosphate;

- I -{4-[2-(3-bromo-4-{(55_a)-4-[( lX)-1 -carboxy-2-(2-{ [2-(2-methoxyphenyl)pyrimidin-

4- yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-l -methylpiperazin- l-ium-1 -yl }ethyl hydrogen phosphate;

- {l -[2-(4-{(55_a)-4-[( 17?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4- yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-4-methylpiperazin-l-ium-l-yl}methyl hydrogen phosphate;

- {l -[2-(3-bromo-4-{(5S'_a)-4-[( 17î)-l-carboxy-2-(2-{[2-(2-methoxyphenyi)pyrimidin-4yl]methoxy}phenyi)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2- chlorophenoxy)ethyl]-4-methylpiperazin-i-ium-I-yl}methyl hydrogen phosphate.

Preferred compounds of the invention are:

. {4-[2'(4-{(5S'₀)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrÎmidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -yljmethyl hydrogen phosphate;

- {4-[2-(3-bromo-4-{(5S_a)-4-[(lA)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/Ipyrimidin-5-yl}-2chlorophenoxy)ethyl]- i -methylpiperazin-1 -ium-l -yl}methyl hydrogen phosphate;

- {[2-(4-{(55_α)-4-[( lA)-1 -carboxy-2-(2-{ [2-(2-methoxyphenyl)pyrîmidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro-

3-methylphenoxy)ethyl](dimethyl)ammonio}methyl hydrogen phosphate.

The invention relates also to a process for the préparation of compounds of formula (l), which process is characterised in that there is used as starting material the compound of formula (ΙΓ):

Y are as defined for formula (I), and (II) wherein Ri, Ri, R3, R4, R5 and

Rô’ represents a -N(CHî)2 group or a 4-methyi-piperazinyl group,

wherein Ri, R₂, R3, R+, Rô’ and Y are as defined hereinbefore, and T represents a protecting group for the carboxylic acid function such as, for example,

I7 a p«ra-methoxybenzyl group, which is subjected to coupling with a compound of formula (IV):

wherein R.7 and Rs are as defined for formula (l), to yield the compound of formula (V):

wherein Rj, R2, R3, Ri, T and Y are as defined hereinbefore, and Râ is as defined in formula (I), which îs then subjected to a reaction deprotecting the carboxylic acid function, to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considered appropriate during the course of the process described above. some groups (hydroxy, amino...) of the starting reagents or of the synthesis intermediates can be protected. subsequently deprotected and functionalized, as required by the synthesis.

The compounds of formulae (II) and (IV) are either commercially available or can be obtaîned by the person ski lied in the art using conventional chemîcal reactions described in the literature.

Pharmacological study of the compounds of the invention has shown that they hâve proapoptotic properties. The ability to reactivate the apoptotic process in cancerous cells is of major therapeutic interest in the treatment of cancers and of immune and auto-immune diseases.

More especially, the compounds according to the invention will be usefül in the treatment of chemo- or radio-resistant cancers.

Among the cancer treatments envisaged there may be mentioned, without implying any limitation, treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

The présent invention relates also to pharmaceutical compositions comprising at least one compound of formula (I) in combination with one or more pharmaceutîcally acceptable excipients.

Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parentéral, nasal, per- or trans-cutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragées, sublingual tablets, sachets, paquets, capsules, glossettes, lozenges. suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.

The dosage varies according to the sex, âge and weight of the patient, the administration route, the nature of the therapeutic indication, or of any associated treatments, and ranges from 0.01 mg to l g per 24 hours in one or more administrations.

Furthermore, the présent invention relates also to the combination of a compound of formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, protéasome înhibitors, kinase inhibitors and antibodies, and also to pharmaceutical compositions comprising that type of combination and their use in the manufacture of médicaments for use in the treatment of cancer.

Advantageously, the présent invention relates to the combination of a compound of formula (T) with an EGFR inhibitor, and also to pharmaceutical compositions comprising that type of combination.

In another embodiment. the présent invention relates to the combination of a compound of formula (I) with a mTOR/PI3K inhibitor, and also to pharmaceutical compositions comprising that type of combination.

In a preferred embodiment, the présent invention relates to the combination of a compound of formula (I) with a MEK inhibitor, and also to pharmaceutical compositions comprising that type of combination.

Preferabiy, the présent invention relates to the combination of a compound of formula (I) with a HER2 inhibitor, and also to pharmaceutical compositions comprising that type of combination.

Advantageously, the présent invention relates to the combination of a compound of formula (I) with a RAF inhibitor, and also to pharmaceutical compositions comprising that type of combination.

In another embodiment, the présent invention relates to the combination of a compound of formula (I) with a EGFR/HER2 inhibitor, and also to pharmaceutical compositions comprising that type of combination.

In a preferred embodiment, the présent invention relates to the combination of a compound of formula (I) with a taxane, and also to pharmaceutical compositions comprising that type of combination.

In another embodiment, the present invention relates to the combination of a compound of formula (I) with a proteasome inhibitor, an immunomodulator or an alkylating agent, and also to pharmaceutical compositions comprising that type of combination.

The combination of a compound of formula (I) with an anticancer agent may be administered simultaneousiy or sequentially. The administration route is preferably the oral route, and the corresponding pharmaceutical compositions may allow the instantaneous or delayed release of the active ingrédients. The compounds of the combination may moreover be administered in the form of two separate pharmaceutical compositions, each containing one of the active ingrédients, or in the form of a single pharmaceutical composition, in which the active ingrédients are in admixture.

The compounds of the invention may also be used in combination with radiotherapy in the treatment of cancer.

Finally, the compounds of the invention may be linked to monoclonal antibodies or fragments thereof or linked to scaffold proteins that can be related or not to monoclonal antibodies.

Antibody fragments must be understood as fragments of Fv, scFv, Fab, F(ab')2, F(ab'), scFv-Fc type or diabodîes, which generally hâve the same specifïcity of binding as the antibody from which they are descended. According to the present invention, antibody fragments of the invention can be obtained starting from antibodies by methods such as digestion by enzymes, such as pepsin or papain, and/or by cleavage of the disulfide bridges by chemical réduction. In another manner, the antibody fragments comprised in the present invention can be obtained by techniques of genetic recombination likewise well known to the person ski lied in the art or else by peptide synthesis by means of, for example, automatic peptide synthesizers such as those supplied by the company Applied Biosystems, etc.

Scaffold proteins that can be related or not to monoclonal antibodies are understood to mean a protein that contains or not an immunoglobulin fold and that yîelds a binding capacity similar to a monoclonal antibody. The man skilled in the art knows how to select the protein scaffold. More particularly, it is known that. to be selected, such a scaffold should display several features as follow (Skerra, J. Mol. Recogn. 2000, 13, 167-I87): phylogenetîcally good conservation, robust architecture with a weil-known threedimensional molecular organization (such as, for example, crystallography or NMR), small size, no or only a low degree of post-translational modifications, easy to produce, express and purify. Such a protein scaffold can be, but without limitation, a structure selected from the group consisting in fibronectin and preferentially the tenth fîbronectin type III domain (FNfnlO), lipocalin, anticalin (Skerra, J. Biotechnol. 2001, 74, 257-75), the protein Z dérivative from the domain B of staphylococcal protein A, thioredoxin A or any protein with a repeated domain such as an “ankyrin repeat” (Kohl et ai. P NAS 2003, 100, 17001705), “armadillo repeat”, “leucine-rîch repeat” or “tetratricopeptide repeat”. There could also be mentioned a scaffold dérivative from toxins (such as, for example, scorpion, insect, plant or mollusc toxins) or protein inhibitors of neuronal nitric oxide synthase (PIN).

The following Préparations and Examples îllustrate the invention but do not limït it in any way.

General Procedures

Ail reagents obtained from commercial sources were used without further purification. Anhydrous solvents were obtained from commercial sources and used without further drying.

Flash chromatography was performed on ISCO CombiFlash Rf 200i with pre-packed silica-gel cartridges (RediSep® Ri Gold High Performance).

Thin layer chromatography was conducted with 5 x 10 cm plates coated with Merck Type 60 F254 silica-gel.

Microwave heating was performed in an Anton Parr MonoWave or CEM Discover® instrument.

Préparative HPLC purifications were performed on an Armen Spot Liquid Chromatography System with a Gemini-NX® ΙΟ μΜ Cl8, 250 mm x 50 mm i.d. column running at a flow rate of H8 mL min'¹ with UV diode array détection (210 - 400 nm) using 25 mM aqueous NH4HCO3 solution and MeCN as eluents unless specîfied 5 otherwise.

Analytîcal LC-MS: The compounds of the présent invention were characterized by high performance liquid chromatography-mass spectroscopy (HPLC-MS) on Agilent HP 1200 with Agilent 6140 quadrupole LC/MS, operating in positive or négative ion electrospray ionisation mode. Molecular weight scan range is 100 to 1350. Parallel UV détection was 10 done at 210 nm and 254 nm. Samples were supplied as a 1 mM solution in acetonitrile, or in tetrahydrofuran/HiO (1:1) with 5 pL loop injection. LCMS analyses were performed on two instruments, one of which was operated with basic, and the other with acîdîc eluents.

Basic LCMS: Gemini-NX, 3 pm, Cl8, 50 mm χ 3.00 mm i.d. column at 23 °C, at a flow rate of 1 mL min’¹ using 5 mM ammonium bicarbonate (Solvent A) and acetonitrile 15 (Solvent B) with a gradient starting from 100% Solvent A and finishing at 100%

Solvent B over various/certain duration of time.

Acidîc LCMS: ZORBAX Eclipse XDB-C18, 1.8 pm, 50 mm x 4.6 mm i.d. column at 40 °C, at a flow rate of 1 mL.min'¹ using 0.02 % v/v aqueous fournie acid (Solvent A) and 0.02% v/v fbrmic acid in acetonitrile (Solvent B) with a gradient starting from 100% 20 Solvent A and finishing at 100 % Solvent B over various/certain duration of time.

‘H-NMR measurements were performed on Bruker Avance 111 500 MHz spectrometer and Bruker Avance III 400 MHz spectrometer, using DMSO-dô or CDCfi as solvent. ‘H NMR data is in the form of delta values, given in part per million (ppm), using the residual peak of the solvent (2.50 ppm for DMSO-dô and 7.26 ppm for CDCh) as internai standard.

Splitting patterns are designated as: s (singlet), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet), br s (broad singlet), dd (doublet of doublets), td (triplet of doublets), dt (doublet of triplets), ddd (doublet of doublet of doublets).

Combination gas chromatography and low resolution mass spectrometry were performed on Agilent 6850 gas chromatograph and Agilent 5975C mass spectrometer using m χ 0.25 mm column with 0.25 pm HP-5MS coating and hélium as carrier gas. Ion source: EI⁺, 70 eV, 230 °C, quadrupole: 150 °C, interface: 300 °C.

HRMS were determined on a Shîmadzu IT-TOF, ion source température 200 °C, ESI +/-, ionizatîon voltage: (+/-)4.5 kV. Mass resolution min. 10000.

Elementary analyses were performed on a Thermo Flash EA 1112 Elemental Analyzer.

Example 1: {4-[2-(4-{(5S_e)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy|-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chIoro-

3- methylphenoxy)ethyl]-l-methylpiperazin-l-ium-l-yl}methyl hydrogen phosphate

Siep A: 4-methoxybenzyl (2R)-2-{[(5Sd-5-{3-chloro~2-methyl-4-[2-(4-meihylpiperazin-lyl)elhoxy]phenyl}-6-(4-fluoropheHyl)thieno[2,3-à]pyrimidîn-4-yl]oxy}-3-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate

1.75 g (27?)-2-{[(5S’_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-I-yl)ethoxy]phenyl}-

6-(4-fluorophenyl)thieno[2,3-ô/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid (2 mmol, 1 eq.; synthesized according to WO 2015/097123), 1.05 g triphenylphosphine (4 mmol, 2 eq.) and 0.5 mL

4- methoxybenzyl alcohol (4 mmol, 2 eq.) were dissolved in 20 mL dry toluene, then 0.92 g di-/er/-butyl azodicarboxylate (4 mmol, 2 eq.) was added over 3 minutes. The resulting mixture was stirred at 50 °C until no further conversion was observed. The reaction mixture was injected directly onto a preconditioned 120 g silica column, then it was purified by flash chomatography using ethyl acetate/méthanol (containing 1.2 % NFh) as eluent. to obtain a white crystal. 'H NMR (400 MHz. CDCfi): 8.63 (d, !H), 8.45 (s, 1H), 7.68 (dd. 1H), 7.59 (d. 1H), 7.45 (t, 1H), 7.28 (s. 1H), 7.21-7.13 (m, 5H), 7.10-7.04 (m, 2H), 6.99-6.80 (m, 7H). 6.24 (d, 1H), 5.68 (dd. 1H), 5.25-5.16 (m, 3H). 5.09 (d, 1H), 4.294.18 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.38 (dd, 1H), 2.96-2.89 (m, 2H), 2.69 (br s, 4H), 2.56 (dd. 2H), 2.46 (br s, 4H), 2.28 (s, 3H), 1.90 (s, 3H)

Step B: tert-butyl [4-[2-[2-chloro-4-[6-(4-flnorophenyl)-4-[(1 R)-2-[(4-methoxyphenyl) methoxy] -1 -[[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy]phenyl] methyl]-2-oxo~ ethoxy]-(5SJ-thieno[2,3-d]pyrim idin-5 -yl]-3-methyl -phenoxy] ethyl]-l~methyl-piperazin-1 ium-l-yl] methyl phosphate

249 mg 4-methoxybenzyl (27?)-2-{[(55_a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl )-6-(4-fiuorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{ [2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate (0.25 mmol, l eq.), 194 mg di-/erZ-butyl chloromethyl phosphate (0.75 mmol, 3 eq.), 112 mg sodium iodide (0.75 mmol, 3 eq.) and 62 mg NaHCCh (0.75 mmol, 3 eq.) were stirred in 3 mL dry acetone at room température ovemight (excluded from light). To the réaction mixture, 2 mL water was added and it was injected directly onto a RP18 column using acetonitrile / 5 mM NH4HCO3 as eluents with gradient method. After lyophilîzation, a white solid is obtained. ‘H NMR (400 MHz, CDCh): 8.64 (d, 1H), 8.46 (s, 1H), 7.68 (dd, 1H), 7.59 (d, 1H), 7.45 (t, 1H), 7.32 (d, 1H), 7.21-7.16 (m, 5H), 7.11-7.05 (m, 2H), 6.98 (t, 2H), 6.89-6.79 (m, 5H), 6.22 (d, 1H), 5.66 (dd. 1H), 5.20 (dd, 2H), 5.15 (dd, 2H), 5.08 (d, 1H), 4.26-4.16 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.70-3.65 (m, 2H), 3.38 (dd, 2H), 3.32 (br s, 1H), 3.19-3.09 (m, IH), 3.15 (s, 3H), 3.00 (t, 2H), 2.98-2.91 (m, 2H), 2.55 (dd, 1H), 1.90 (s, 3H), 1.87 (br s, 4H), 1.46 (s, 9H)

Step C: Example 1

To 150 mg rer/-butyl [4-[2-[2-chloro-4-[6-(4-fluorophenyl)-4-[(l A)-2-[(4-methoxyphenyl) methoxy]-l-[[2-[[2-(2-methoxyphenyl)pynmidin-4-yl]methoxy]phenyl]rnethyl]-2-oxoethoxy]-(5S^, _a)-thieno[2,3-d]pyrimidin-5-yl]-3-methyl-phenoxy]ethyl]-l-methyl-piperazinl-ium-l-yl]methyi phosphate (0.13 mmol, 1 eq.) dissolved in 4 mL dry dichloromethane, 0.5 mL trifluoroacetic acid (6.6 mmol, 50 eq.) was added and the mixture stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness, then it was purified by reversed phase chromatography using acetonitrile / 5 mM NH4HCO3 as eluents. After lyophilîzation, Example 1 is obtained as a white solid. HRMS calculated for C48H48CIFN6O10PS: 984.2485; found 471.1189 (M+2H)

Example 2: benzyl {4-[2-(4-{(5S'_e)-4-|(llî)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyI)ethoxy]-6-(4-fluorophenyl)thieno[23-4]pyriniidin-5yl}-2-chIoro-3-methylphenoxy)ethyl]-l-methylpiperazin-l-ium-l-yl}methyl phosphate

Step A: benzyl [4-(2-{2-chloro-4-[6-(4-fluorophenyl)-4-{[(2R)-l-[(4-methoxybenzyl)oxy]~

3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-l-oxopropan-2-yl]oxy} -(53a)-thieno[2,3~à]pyrimidin~5~yl]~3-methylphenoxy}ethyl)~l-methylpiperazin~l~ium-Iyl]methyl phosphate

995 mg 4-methoxybenzyl (27?)-2-{[(5S^, _a)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyI)thîeno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(210 methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoate (l mmol, l eq.) and 392 mg dibenzyl chloromethyl phosphate (1.2 mmol, 1.2 eq.) were stirred in 5 mL dry acetonitrile at 80 °C until no further conversion was observed. The reaction mixture was injected directly onto a preconditioned 80 g silica column, then it was purified by fash chomatography using ethyl acetate/methanol (containing l.2% NH3) as eluent. Product

I5 was obtained as an off-white crystal. 'H NMR (500 MHz, DMSO-dô): 8.66 (d, IH), 8.54 (s, IH), 7.52 (d, IH), 7.49 (dd, IH), 7.45 (tm, IH), 7.34-7.2 (m, 5Η), 7.29 (m, 2 H), 7.24 (d. IH), 7.22 (m. 2H), 7.19 (m, IH), 7.15 (m, 2H), 7.14 (m, IH), 7.12 (d, IH), 7.04 (m,

IH), 7.02 (tm, IH), 6.88 (d, 2H), 6.74 (t, IH), 6.21 (d, IH), 5.55 (dd, IH), 5.23 (d, IH), 5.17 (d, IH), 5.10 (d, IH), 5.01 (d, IH), 4.86 (d, 2H), 4.75 (d, 2H), 4.26-4.14 (m, 2H), 3.74 (s, 3H), 3.72 (s, 3H), 3.38-3.22 (m, 4H), 3.22-2.54 (m, 2 H), 2.96-2.74 (br s, 4H), 2.93 (s,

3H), 2.87 (t, 2H), I.84 (s, 3H)

Step B: Example 2

435 mg benzyl [4-(2-{2-chloro-4-[6-(4-fluorophenyl)-4-{[(2/Î)-l-[(4-methoxybenzyl)oxy]3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-l-oxopropan-2-yl]oxy}

-(5S_a)-thieno[2,3-i/]pyrimidin-5-yl]-3-methylphenoxy}ethyl)-l-methylpiperazin-l-iurn-lyl]methyl phosphate (0.36 mmol, l eq.) and 560 pL trifluoroacetic acid (7.28 mmol, 20 eq.) were stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using acetonitrile / 5 mM NH4HCO3 as eluents. After lyophilîzation,

Example 2 was obtained as a white solid. HRMS calculated for C55H53CIFN6O10PS: 1074.2954; found 538.1565 (M+2H)

In the following Examples 3 and 4, the procedure is as in Example 1, using the appropriate chlorîde dérivative of formula (IV) and the appropriate thienopyrimidine compound of formula (H).

Example 3: {4-[2-(4-{(5S'_a)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyI)thieno[2,3-</]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l-methylpiperazin-l-ium-l-yl}methyl methyl phosphate

Example 4: {4-[2-(4-{(5S_a)-4-[(lJÎ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-iZ]pyrimidin-5-yl}-2-chloro-

3- ethylphenoxy)ethyl]-l-methylpiperazin-l-ium-l-yl} methyl hydrogen phosphate

Example 5: {4-[2-(3-bromo-4-{(55_e)-4-|(l/ï)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2_T3-r/]pyrimidin-5yl}-2-chlorophenoxy)ethyl]-l-methylpiperazîn-l-ium-I-yI} methyl hydrogen phosphate

S te p A: 4-meihoxybenzyl (2R)-2-{[(5Sa)-5-{3-bromo-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl}-6-(4-fluorophenyl)thieno[2,3-à]pyriniidin-4-yl]oxy}-3-(2-{[2-(2inethoxyphenyl)pyrim idin-4-yl] methoxy} phenyl)propanoate

1.75 g (2/?)-2-{[(55'_iJ)-5-{3-bromo-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl}-

6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)propanoic acid (2 mmol, 1 eq.; synthesized according to WO 2015/097123), 1.05 g triphenylphosphine (4 mmol, 2 eq.) and 0.5 mL

4- methoxybenzyl alcohol (4 mmol, 2 eq.) were dissolved in 20 mL dry toluene, then 0.92 g di-/err-butyl azodicarboxylate (4 mmol, 2 eq.) was added over 3 minutes. The resulting mixture was stirred at 50 °C until no further conversion was observed. The reaction mixture was injected directly onto a preconditioned l 20 g silica column. then it was purified by flash chomatography using ethyl acetate/methanol (containing I.2 % NH3) as eluent, to obtain a white crystal. 'H NMR (400 MHz, CDCh): 8.63 (d, IH), 8.45 (s, IH), 7.68 (dd, IH), 7.59 (d, IH), 7.45 (t, IH), 7.28 (s, IH), 7.2I-7.13 (m, 5H), 7.10-7.04 (m, 2H), 6.99-6.80 (m, 7H), 6.24 (d, IH). 5.68 (dd, IH), 5.25-5.16 (m. 3H), 5.09 (d. IH), 4.294.18 (m, 2H), 3.88 (s, 3H). 3.81 (s, 3H), 3.38 (dd. IH), 2.96-2.89 (m, 2H), 2.69 (br s, 4H), 2.56 (dd. 2H), 2.46 (br s, 4H), 2.28 (s, 3H), 1.90 (s, 3H)

Step B: tert-butyl [4-[2-[2-bromo-4-[6-(4-fluorophenyl)-4-[( 1 R)-2-[(4-methoxyphenyl) methoxy]~l~[[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxyjphenyl] melhyl]-2-oxoethoxy]-(5Sa)-thierio[2,3-à]pyrimidin-5-yl]-3-methyl-phenoxy]ethyl]-l-methyl-piperazin-lium-l-yl] methyl phosphate

265 mg compound of Step A above (0.25 mmol, 1 eq.), 194 mg di-terz-butyl chloromethyl phosphate (0.75 mmol, 3 eq.), 112 mg sodium iodide (0.75 mmol, 3 eq.) and 62 mg NaHCCh (0.75 mmol, 3 eq.) were stirred in 3 mL dry acetone at room température ovemight (excluded from light). To the reaction mixture. 2 mL water was added and ît was injected directly onto a RP 18 column using acetonitrile ! 5 mM NH4HCO3 as eluents with gradient method. After lyophilization, a white solid is obtained. ^lH NMR (400 MHz, CDCI3): 8.64 (d, IH), 8.46 (s, IH), 7.68 (dd, IH), 7.59 (d, IH), 7.45 (t, IH), 7.32 (d, IH), 7.21-7.16 (m, 5H), 7.11-7.05 (m, 2H), 6.98 (t, 2H), 6.89-6.79 (m, 5H), 6.22 (d, IH), 5.66 (dd, IH), 5.20 (dd. 2H), 5.15 (dd, 2H), 5.08 (d, IH), 4.26-4.16 (m, 2H), 3.88 (s, 3H), 3.81 (s, 3H), 3.70-3.65 (m, 2H), 3.38 (dd, 2H), 3.32 (br s, IH), 3.19-3.09 (m, IH), 3.15 (s, 3H), 3.00 (t, 2H), 2.98-2.91 (m, 2H), 2.55 (dd, IH), 1.90 (s, 3 H), 1.87 (br s, 4H), 1.46 (s, 9H)

Step C: Example 5

To 150 mg compound of Step B above (0.13 mmol, I eq.) dissolved in 4 mL dry dichloromethane, 0.5 mL trifluoroacetic acid (6.6 mmol, 50 eq.) was added and the mixture stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness, then it was purified by reversed phase chromatography using acetonitrile / 5 mM NH4HCO3 as eluents. After lyophilization. Example 5 was obtained. HRMS calculated for C47H44CIFN6O10PS: 1048.1433; found 525.0791 (M+2H)

Example 6: benzyl {4-[2-(3-bromo-4-{(55_a)-4-[(lA)-l-carboxy-2-(2-{[2-(2-methoxy phenyl)pyrimidin-4-yllmethoxy}phenyi)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidin-5-yl}-2-chlorophenoxy)ethyl]-l-methylpiperazin-l-ium-l-yl}methyl phosphate

Step A: benzyl [4-(2-{3-bromo-2-chloro-4-[6-(4-fluorophenyl)-4-{[(2R)-l-[(4methoxybenzyl)oxy]-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-loxopropan-2-yl]oxy}thieno[2,3-à]pyrimidin-5-yl]phenoxy}ethyl)-1 -methylpiperazin-I-iuml-yl] methyl phosphate

318 mg of compound obtained în Step A of Example 5 (0.30 mmol, 1 eq.) and 147 mg dibenzyl chloromethyl phosphate (0.45 mmol. 1.5 eq) were stirred in 1.5 mL dry acetonitrile at 70 °C until no further conversion was observed. The reaction mixture was injected directly onto a preconditioned 80 g silica column, then it was purified by flash chomatography using ethyl acetate/methanol (containing 1.2 % NH3) as eluent. Product of Step A was obtained as white crystals. MS: M+H = 1260.6

Step B: Example 6

To the solution of 275 mg compound of Step B above (0.218 mmol, 1 eq.) in 3.5 mL dichloromethane, 334 pL trifluoroacetic acid was added and the réaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was concentrated and the crude product was purified by flash chromatography using ethyl acetate/methanol (containing 1.2 % NH3) as eluent. This product was then purified by reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and MeCN as eluents. After lyophilization Example 6 was obtained as a white solid. HRMS calculated for CîjHsoBrCIFNôOioPS: 1138.1903; found 570.1018 (M+2H)

Example 7: {4-[2-(3-bromo-4-{(5S_a)-4-[(li)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl|methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[23-iZ]pyrim!din-5yl}-2-chIorophenoxy)ethyl|-l-methylpiperazin-l-ium-l-yl}methyl methyl phosphate

[n the Example 7, the procedure is as in Example l, using the appropriate chloride dérivative of formula (IV) and the appropriate thienopyrimidine compound of formula (II).

Example 8:7V-[(55₀)-5-{3-chloro-4-[2-(4-{[(hydroxyphosphinato)oxy|methyl}-4methylpiperazin-4-ium-l-yI)ethoxy]-2-methylphenyl}-6-(4-fluorophenyl)thieno[2,3-J] pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalanine

SlepA: 6-[odo-3}A-thieno[2,3-à]pyrimidin-4-one

A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and reflux condenser was charged with the solution of 433 mL acetic acid, 13 mL sulfuric acid and 87 mL water. 69.3 g 3/7-thieno[2,3-c/]pyrimidin-4-one (0.46 mol), 51.9 g periodic acid (0.23 mol) and 104 g iodine (0.41 mol) were added to the stirred solution, which was heated to 60 °C for 1 hour. The resulting suspension was cooled to room température, filtered off, washed with a mixture of acetic acid and water (5:1) and then with dîethyl ether. The resulting beige crystalline solid was air dried. 'H NMR (500 MHz, DMSO-dô) δ: 12.57 (br s, 1 H), 8.09 (s, 1 H), 7.65 (s, 1 H)

Step B: 4-Chloro-6-iodo-thieno[2,3-d]pyrimidine

A 1 L round bottomed flask equipped with mechanical stirrer, thermometer, reflux condenser and a CaCL-tube was charged with 113 mL phosphorous oxychloride and 35 mL W-dimetliylaniline (0.29 mol). 75.54 g compound of Step A above (0.27 mol) was added to the mixture in portions during 5 minutes. The reaction mixture was stirred at 105 °C for 1 hour. The resulting suspension was cooled to 10 °C, filtered and washed with hexane. The crude product was added to ice water and stirred for 10 minutes, filtered off, washed with cold water, dîethyl ether and air dried. Beige crystalline solid was obtained. Ή NMR (400 MHz, DMSO-d₆) δ: 8.89 (s, 1H), 7.98 (s, 1H)

Sien C: 5-Bromo-4-chloro-6-iodo-thieno[2,3-d]pyrimidine

A 2 L round bottomed flask equipped with mechanical stirrer, thermometer and a bubbler was charged with 600 mL acetonitrile. 84.9 g compound of Step B above (0.29 mol), 50.9 g A-bromosuccinimide (0.29 mol) and 8.5 mL tetrafluoroboric acid dîethyl ether complex were added. The reaction mixture was stirred at room température for 16 hours. Further 22.9 g (0.12 mol) /V-bromosuccinimide was added to the mixture in three portions. After cooling the suspension to 0 °C and stirring for further l hour the precipitate was filtered off, washed with acetonitrile and air dried. The product was obtained as beige crystalline solid. Ή NMR (500 MHz. DMSO-d₆) δι 8.88 (s, IH)

Step D: 5-Bromo-4-chloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidine

75.08 g compound of Step C above (200 mmol), 53.63 g 2-(4-fluorophenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane (240 mmol), 130 g césium carbonate (400 mmol), 2.245 g Pd(OAc)2 (lOmmol) and 8.50 g 2-di-te/7-butylphosphino-2',4',6'-triisopropylbiphenyl (20 mmol) were placed in a 2 L flask. 600 mL tetrahydrofuran and 200 mL water were added, and then stirred ovemight at 70 °C under argon atmosphère. Tetrahydrofuran was evaporated, and then the product was collected by filtration. The crude product was sonicated in 250 mL acetonitrile and filtered again. Then 5-bromo-4-chloro-6-(4fluorophenyl)thieno[2,3-i/jpyrimidine was crystaiized from éthanol / tetrahydrofuran (2: l). Ή NMR (400 MHz, DMSO-d₆) δ: 9.02 (s, IH), 7.80-7.77 (m, 2H), 7.47-7.43 (m, 2H)

Step E: (2R)-2-[[5-Bromo-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino]-3-(2hydroxyphenyl)propanoic ac îd l eq. of compound of Step D above, 2 eq. of (2Æ)-2-amino-3-(2-hydroxyphenyl)propanoic acid and 3 eq. K2CO3 were mixed in dimethyl sulfoxide ( IO mL/mmol) and stirred at 50 °C until no further conversion was observed. The mixture was then diluted with water, acidified with IM HCl solution (to pH = I, or to pH = 6 in the presence of a basic amino group) and extracted with ethyl acetate, or the precipitate formed after acidification was isolated by filtration. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 and acetonitrile as eluents to give (2R)2-[[5-bromo-6-(4-fluorophenyl)thieno[2,3-t(|pyrimidin-4-yl]amino]-3-(2-hydroxyphenyI) propanoic acid.

Ή NMR (400 MHz, DMSO-d₆) δ: 12.90 (br s, IH), 9.65 (br s, IH), 8.41 (s, IH), 7.70 (m, 2H). 7.45-7.34 (m, 3H), 7.18 (dd, IH), 7.04 (td, IH), 6.80 (d, IH), 6.72 (t, IH), 4.96 (m, IH), 3.31 (dd, IH), 3.08 (dd. IH)

MS (M+H): 488.0

St en F: (4-Bromo-2-chloro-phenoxy)-trimethyl-silane

20.8 g 4-bromo-2-chloro-phenol (100 mmol) was dissolved in 150 mL dry tetrahydrofuran then 24.2 g hexamethyldisilazane (150 mmol) was added. The reaction mixture was stirred at 85 °C under argon atmosphère for l .5 hours then concentrated under reduced pressure. The resulted crude product was used without further purification. 'H NMR (200 MHz, CDC h) δ: 7.49 (d, IH), 7.23 (dd. IH), 6.75 (d, IH), 0.26 (s, 9H)

Step G: 4-Bromo-2~chloro-3-methyl-phenot mL n-butyl lithium solution (120 mmol, 2.5 M in hexanes) was added dropwise to a solution of 12.I g dry diisopropylamine (120 mmol) in 250 mL dry tetrahydrofuran at -78 °C under argon atmosphère. The mixture was stirred for 30 minutes at the same température then 28.0 g compound of Step F above (100 mmol) was added dropwise. After 2.5 hours, 21.3 g methyl iodide (150 mmol) was added dropwise then the cooling bath was removed and the mixture was stirred ovemight. The reaction was quenched with I00 mL NHiOH solution and 200 mL NH4CI solution then extracted with ethyl acetate. The organic phase was dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The resulting dark mass was refluxed with pure hexane several times (150-150 mL aliquots) and decanted leavîng a black tar behind. The combined organic phases were concentrated under reduced pressure affording 19.0 g crude product, which was used without further purification. ’H NMR (200 MHz, CDCb) δ: 7.32 (d, l H), 6.76 (d, IH), 5.62 (s, lH), 2.49 (s, 3H)

Step H: (4-Bromo-2-chloro-3-methyl-phenoxy)-trimethyl-silane

20.8 g hexamethyldisilazane (129 mmol) was added to the solution of 19.0 g compound of Step H above (86.0 mmol) in 150 mL dry tetrahydrofuran. The mixture was stirred at 85 °C under areon balloon for l .5 hours and then concentrated under reduced pressure. The obtained product was used without further purification. ’H NMR (200 MHz, CDCh) δ:

7.30 (d, IH), 6.63 (d, IH), 2.50 (s, 3H), 0.28 (s, 9H)

Step I: 2-Chloro-3-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phénol

A solution of 25.2 g compound of Step H above (86.0 mmol) in 250 mL dry tetrahydrofuran was cooled to -78 °C under argon and then 38 mL n-butyl lithium solution (94.6 mmol, 2.5M in hexanes) was added dropwlse. After 5 minutes, 19.2 g 2-îsopropoxy4,4,5,5-tetramethyl-l,3,2-dioxaborolane (103 mmol) was added dropwise. The cooling bath was removed and the mixture was slowly allowed to warm up to room température. Then the mixture was added to 200 mL NHtCI solution and extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and passed through a pad of silica gel using hexane and ethyl acetate as eluents. The crude product was recrystallized from a mixture of ethyl acetate and hexane to obtaîn 2-chloro-3-methyl-

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. 'H NMR (500 MHz, DMSO-d^) δ: 10.40 (s, IH). 7.42 (d, IH), 6.80 (d. IH), 2.49 (s, 3H), 1.27 (s, 12H)

Step J: l-[2-[2-Chloro-3-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2yl)phenoxy]ethyl]-4-methyl-piperazine

10.0 g compound of Step l above (37.2 mmol), 8.7 g 2-(4-methylpiperazin-l-yl)ethanol (60.3 mmol) and 15.8 g triphenylphosphine (60.3 mmol) were dissolved in 100 mL dry toluene and then 27 mL diethyl azodicarboxylate (60.3 mmol, 40 % solution in toluene) was added dropwise. The mixture was stirred at 50 °C under argon until no further conversion was observed. The volatiles were evaporated under reduced pressure and 100 mL diethyl ether was added. The precipitated white crystals were filtered off and washed with diethyl ether. The filtrate was concentrated under reduced pressure and purified via flash chromatography using chloroform and methanol as eluents. The resulting light brown oil was crystallized from hexane to give l -[2-[2-chloro-3-methyl-4-(4,4,5,5tetramethyl- 1,3,2-dioxaborolan-2-yl)phenoxy]ethyl]-4-methyl-piperazine as an off-white solid. ‘H NMR (500 MHz, DMSO-d₆) δ: 7.56 (d, IH), 6.99 (d, IH), 4.15 (t, 2H), 2.72 (t, 2H), 2.51 (s, 3H), 2.50 (br s, 4H), 2.29 (br s, 4H), 2.13 (s, 3H), 1.29 (s, 12H)

Step K: (2R)-2-[[(5S₃)-5-[3-Chloro-2-methyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fl uorophenyl)thieno[2,3-d]pyrim idin-4-yl] amino]-3-(2hydroxyphenyljpropanoic acid eq. of compound of Step E above and 3 eq. of compound of Step J above were dissolved in dioxane:water 2:1 mixture (lOmL/mmol), then 2 eq. CS2CO3, 5 mol% Pd(OAc)2 and 0.2 eq. tri-tert-butylphosphonium tetrafluoroborate were added and the mixture was stirred at 120 °C in microwave reactor under nitrogen until no further conversion was observed. The mixture was neutralized with IM HCl solution and extracted with dichloromethane. The combined organic phases were dried over NaiSOj, filtered and the filtrate was concentrated in vacuo. The crude product was purified via préparative reversed phase chromatography using 0.1 % aqueous trifluoroacetic acid solution and acetonitrile as eluents to give (2A)-2-[[5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl) propanoic acid as a mixture of diastereomers. The mixture was separated via flash chromatography using HILIC eluents. The earlier eluting diastereoisomer was collected as (2À)-2-[[(57î_a)5-[3-chloro-2-methyl-4-[2-(4’methylpiperazin-l-yl)ethoxy]phenyl]-6-(4fluorophenyl)thieno[2,3-i/|pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl)propanoic acid. MS (M+H): 676.2

The later eluting diastereoisomer was collected as (27?)-2-[[(55^, _a)-5-[3-chloro-2-methyl-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno [2,3-i/]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl)propanoic acid. MS (M+H): 676.2

Step L: Ethyl (2R)-2-[[(5S>a)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)elhoxy] phenyl]-6-(4-fluorophenyl)thieno[2,3-à]pyrimidin-4-yl] amino]-3-(2-hydroxyphenyl) propanoate

4.51 g of (2A)-2-[[(5S_fl)-5-[3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyl) propanoic acid (6.67 mmol) was dissolved in 85 mL 1.25M HCl in éthanol and stirred at 40 °C overnight. The mixture was then cautiously diluted with NaHCCL solution and extracted with dichloromethane. The combined organic phases were dried over NaiSO-t, filtered and concentrated in vacuo. The crude product was purified via flash chromatography using dichloromethane and methanol as eluents to obtaîn ethyl (2R)-2-[[(5S^, _fl)-5-[3-chloro-2-rnethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino]-3-(2-hydroxyphenyi)propanoate.

‘H NMR (500 MHz, DMSO-d₆) Ô: 9.49 (s, IH), 8.40 (s, IH), 7.34 (d, IH), 7.27-7.21 (m, 3H), 7.20-7.14 (m. 2H), 7.00 (td, IH), 6.71 (dd, IH), 6.60 (td, IH), 6.39 (dd, IH), 5.03 (d, IH), 4.92 (m, IH), 4.26 (t, 2H), 4.03 (m, 2H), 3.03 (dd, IH), 2.78 (t, 2H), 2.54 (br, 4H), 2.36 (dd, IH), 2.30 (br, 4H), 2.12 (s, 3H), 1.83 (s, 3H), I.IO (t, 3H)

HRMS calculated for C37H39CIFN5O4S: 703.2395; found 704.2450 (M+H)

Step M: (E)-4-(Dimethylamino)-l, /-dimethoxy-but-3-en-2-one

502.1 g l,l-dimethoxypropan-2-one (4.25 mol) and 506.4 g l.l-dimethoxy-AÇV-diinethylmethanamine (4.25 mol) were mixed in a 2 L flask and stirred at 105 °C for 3 hours. The formed methanol was removed continuously via distillation. When methanol formation stopped (at 65 °C head température) the reaction mixture was vacuum distilled (decreasing the pressure slowly to 30 mbar) to remove side products and unreacted starting materials. The crude product was distilled at 0.1 mbar. Fractions were collected between 107-118 °C head température (bath température 160-165 °C) to give a yellow oil. *H NMR (500 MHz. DMSO-dé) δ: 7.59 (d. IH), 5.17 (d, IH), 4.42 (s, IH), 3.25 (s, 6H), 3.09 (s, 3H), 2.78 (s, 3H)

Step N: 4-(Dimethoxymethyl)-2-(2-melhoxyphenyl)pyrimidine

To the mixture of 1.2 eq. of 2-methoxybenzamidine acetic acid sait and 1 eq. of compound of Step M above in dry methanol (0.5 mL/mmol), 1.2 eq. sodium methoxide was added portionwise and the mixture was stirred at 75 °C until no further conversion was observed. The reaction mixture was cooled and concentrated under reduced pressure. Water was added to the residue. and it was extracted with dichloromethane. The combined organic layers were dried over MgSCU, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to give 4-(dimethoxymethyl)-2-(2-rnethoxyphenyl)pyrirnidine. 'H NMR (400 MHz, DMSO-dâ) δ: 8.93 (d, IH), 7.55-7.44 (m, 3H), 7.16 (d, IH), 7.06 (m, IH), 5.31 (s, 1 H), 3.76 (s, 3H), 3.37 (s, 6H)

Step O: [2-(2-Methoxyphenyl)pyrimidin-4-yl]methanol

261 mg compound of Step N above (l.O mmol) was dîssolved in 2 mL 4M HCl solution (in dioxane), then 2 mL water was added and this mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to 0 °C, then 320 mg NaOH (8.0 mmol) was added portionwise. The pH was adjusted to 8 using 10 % K2CO3 solution, then 76 mg sodium borohydride (2.0 mmol) was added and the mixture was stirred for 30 minutes at 0 °C. The reaction mixture was diluted with 5 mL water and extracted with ethyl acetate. The combined organic phases were dried over Na₂SC>4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to give [2-(2methoxyphenyl)pyrimidin-4-yl]methanol. ‘H NMR (400 MHz. DMSO-dô) Ô: 8.84 (d, IH), 7.50-7.42 (m, 3H), 7.14 (d. IH), 7.03 (m, IH), 5.66 (t, IH), 4.58 (d, 2H), 3.75 (s, 3H)

Step P: N-f(5'Sa)-5-{3-Chloro-2-meîhyl-4-[2-(4-methylpiperazin-l-yi)ethoxy]phenyl}-6-(4fluorophenyl)thieno[2,3-à]pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy} -D-phenylalanine l eq. of compound of Step L above, 2 eq. of compound of Step O above, and 3 eq. triphenylphosphine were dîssolved in dry toluene (7 mL/mmol) under nîtrogen atmosphère, then 3 eq. di-rerr-butyl azodicarboxylate was added at room température. Then the mixture was stirred at 50 °C until no further conversion was observed. The volatiles were removed in vacuo and the residue was purified via flash chromatography using heptane and ethyl acetate as eluents.

I eq. of the formed ester dérivative was dîssolved in tetrahydrofuran (15 mL/mmol) then 10 eq. lithium hydroxide monohydrate and water (I5 mL/mmol) were added. The mixture was stirred at room température until no further conversion was observed. The pH was adjusted to 6 with l M HCl solution, then the mixture was diluted with brine, extracted with dichloromethane. The organic layer was dried over Na₂SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 25 mM aqueous NH4HCO3 solution and acetonitrile as eluents to yield .'V-[(55'_Ci)-5-{3-chloro-2-methyl-4-[2-(4-methylpiperazin-l-yl)ethoxy] phenyl}-6-(4-fluorophenyl)thieno[2,3-t/]pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}-D-phenylalanine. HRMS calculated for C47H45CIFN7O5S: 873.2875, found: 437.6498 (M+2H)

Step O: 4-methoxybenzyl N-/^-(5§a)-5-{3-chloro-2-methyl-4-[2-(4-niethylpiperazin-lyl)ethoxy]phenyl}-6-(4-flnorophenyl)thieno[2,3-ù]pyrimidin-4-yl]-2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}-D-phenylalaninate

1677 mg compound of Step P above (1.92 mmol, l eq.), l.5l g triphenylphosphine (5.76 mmol, 3 eq.) and 796 mg 4-methoxybenzyl alcohol (5.76 mmol, 3 eq.) were dîssolved in 20 mL dry toluene, then L33 g di(teri)butyl azodicarboxylate (5.76 mmol, 3 eq.) was added in one portion. The resulting mixture was stirred at 50 °C until no further conversion was observed. The reaction mixture was concentrated and the crude product was purified by flash chomatography using ethyl acetate/methanol (containing 1.2 % NH3) as eluent. Product of Step Q was obtained as off-white crystals. HRMS calculated for C55H53CIFN7O6S: 993.3450; found 497.6814 (M+2H)

Step R: 4-methoxybenzyl N-/(5Sa)-5-{4-[2-(4-{[(benzyloxy)phosphinato]oxy}-4methylpiperazin-4-ium-l-yl)ethoxy]-3-chloro-2-methylphenyl}-6-(4fluorophenyl)thieno[2,3-à]pyrimidin-4-yl]-2-{[2-(2-melhoxyphenyl)pyrimidin-4yl]methoxy}-D-phenylalaninate

300 mg compound of Step Q above (0.301 mmol, 1 eq.) and 148 mg dibenzyl chloromethyl phosphate (0.451 mmol, 1.5 eq.) were stirred in 1.5 mL dry acetonitrile at 40 °C until no further conversion was observed. The reaction mixture was injected directly onto a precondiotioned 24 g silica column, then it was purified by flash chomatography using ethyl acetate/methanol (containing 1.2 % NH3) as eluent. Compound of Step R was obtained as off-white crystals. HRMS calculated for C63H62CIFN7O10PS: 1193.3689; found 597.6928 (M+2H)

Step S: Example 8

To the solution of 100 mg compound of Step R above (0.0837 mmol) in 840 pL dichloromethane, 152 pL 33 % HBr in acetic acid was added and it was stirred at 0 °C until no further conversion was observed. The reaction mixture was concentrated, purified by flash chomatography using ethyl acetate/methanol (containing 1.2 % NH3) as eluent.

Then the resulted product was purified by reversed phase chromatography using acetonitrile / 5mM NH4HCO3 as eluents. After lyophilization, Example 8 was obtained as a white solid. HRMS calculated for C4gH48BrCIFN7O9PS: 983.2645; found 492.6377 (M+2H)

Example 9: {4-[2-(4-{4-[(lJf)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy}phenyl)ethoxyl-6-(4-fIuorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2,6-dichloro3,5-dimethylphenoxy)ethyl]-I-methylpiperazin-l-ium-l-yl}methyI hydrogen phosphate

Step A: 4-Bromo-2,6-dichlofo-3,5-dimethyl-phenol

ΙΟ 30.16 g 4-bromo-3,5-dimethyl-phenol (150 mmol) was dissolved in a mixture of 75 mL l,2-dichloroethane and 75 mL acetonitrile, then 40.06 g A-chlorosuccinimide (300 mmol, 2.0 eq.) was added portionwise and the mixture was stirred at room température until no further conversion was observed. Reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane, washed with water and brine.

I5 The organic layer was dried over NazSCU and concentrated under reduced pressure and used in the next step without further purification. ‘H NMR (400 MHz. DMSO-d&): 10.10 (s, l H), 2.46 (s, 6H)

Step B: l-Bromo-3,5-dichloro-4-methoxy-2,6-dunethyl-benzene

To a solution of 26.0 g compound of Step A above (96.3 mmol, 1.0 eq.) and 26.60 g 20 K2CO3 (192.6 mmol, 2.0 eq.) in 300 mL acetonitrile, 6.6 mL methyl iodide (105.9 mmol,

1.1 eq.) was added and the mixture was stirred at room température until no further conversion was observed. The solids were filtered off and the filtrate was concentrated under reduced pressure. The crude product was dissolved in dichloromethane, washed with water and brine. The organic layer was dried over Na^SCL and concentrated under reduced 25 pressure and used in the next step without further purification. 'H NMR (400 MHz, DMSO-dfi): 3.78 (s, 3H), 2.49 (s. 6H)

Step C: 2-(3,5-Dîchloro-4-methoxy-2,6-dime thyl-phenyl)-4,4,5,3-tetramethyl-1,3,2dioxaborolane

10.0 g compound of Step B above (35.2 mmol, 1.0 eq.) was dlssoived in 360 mL dry tetrahydrofuran under nitrogen and was cooled to -78 °C with dry îce-acetone. 23.2 mL rt-butyl lithium (L6M in hexanes) (37.0 mmol, 1.05 eq.) was added and the mixture was stirred for 15 minutes, then 8.6 mL 2-isopropoxy-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (42.24 mmol, 1.2 eq.) was added and the mixture was allowed to warm up to room température. It was quenched with brine, extracted with dichloromethane, dried over Na?SO4, fïltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 2-(3,5dichloro-4-methoxy-2,6-dimethyl-phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane. 'H NMR (400 MHz, DMSO-d₆): 3.81 (s, 3 H), 2.33 (s, 6H), 1.34 (s, 12H)

Step D: Ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)lhiophene-3-carboxylate

3.92 g ethyl 4-bromothiophene-3-carboxylate (16.68 mmol, 1.0 eq.) and 9.9 g compound of Step C above (30.0 mmol, 1.8 eq.) were dîssolved in 140 mL dioxane, then 10.87 g CS2CO3 (33.36 mmol, 2.0 eq.) dîssolved in 40 mL water was added. Then 590 mg bis(di/er/-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) (0.83 mmol, 0.05 eq.) was added, and the mixture was stirred under nitrogen at reflux température until no further conversion was observed. Then it was diluted with dichloromethane and brine. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over NajSOj, fïltered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethylphenyl)thiophene-3-carboxylate.

Ή NMR (400 MHz, DMSO-d₆): 8.53 (d, 1H), 7.47 (d, IH), 4.02 (q, 2H), 3.83 (s, 3H), 1.95 (s, 6H), 1.00 (t, 3H)

HRMS (M+NH₄)⁺ = 376.0538

Step E: Ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenylj-2,3-diiodo-thiophene-3carboxylate

2.65 g compound of Step D above (7.38 mmol, l.O eq.) was dîssolved in 75 mL acetonitrile, then 2.2 mL fluoroboric acid diethyl ether complex ( 16.23 mmol, 2.2 eq.) and

3.65 g jV-iodosuccinimide (16.23 mmol, 2.2 eq.) was added and the mixture was stirred at room température until no further conversion was observed. Reaction mixture was concentrated under reduced pressure, and the crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain ethyl 4-(3,5-dichloro-

4-methoxy-2,6-dimethyl-phenyl)-2,5-diîodo-thiophene-3-carboxylate. ’H NMR (400 MHz, DMSO-dé): 3.98 (q, 2H), 3.84 (s. 3 H), 1.92 (s, 6H), 0.84 (t, 3H)

Step F: Ethyl 4-(3,5-dichloro~4-methoxy~2,6-dimethyl-phenyl)-5-iodo-thiophene-3carboxylate

5.29 g compound of Step E above (8.66 mmol, L0 eq.) was dîssolved in 90 mL dry tetrahydrofuran, then cooled to -78 °C under argon atmosphère. 6.7 mL ïsopropyl magnésium chloride lithium chloride complex (L3M in tetrahydrofuran) (8.66 mmol, l.Oeq.) was added and the mixture was stirred at -78 °C for 30 minutes. Then saturated aqueous NH4CI was added and the mixture was extracted with ethyl acetate. The organic layer was dried over NaaSCh and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-iodo-thiophene-3-carboxylate. ¹H NMR (400 MHz, DMSO-d₆): 8.71 (s, 1H), 4.01 (q, 2H), 3.86 (s, 3H), 1.89 (s, 6H), 0.99 (t, 3H)

Step G: Ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-fluorophenyl)thiophene-3-carboxylate

4.20 g compound of Step F above (8.66 mmol, 1.0 eq.) and 1.82 g 4-fluorophenylboronic acid (13.00 mmol, 1.5 eq.) were dîssolved in 80 mL dioxane, then 5.64 g CS2CO3 (17.32 mmol, 2.0 eq.) dîssolved in 20 mL water was added. Then 500 mg tetrakis(triphenylphosphine)palladium(0) (0.43 mmol, 1.15 eq.) was added, and the mixture was stirred under nitrogen at 80 °C until no further conversion was observed. Then it was dîluted with dichloromethane and brine. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over NaiSOj, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain ethyl 4-(3,5dichloro-4-methoxy-2,6-dimethyl-pheny[)-5-(4-fluorophenyl)thiophene-3-carboxylate.

Ή NMR (400 MHz, DMSO-d₆): 8.58 (s, IH), 7.22-7.10 (m, 4H), 4.03 (q, 2H), 3.82 (s, 3H), L92 (s, 6H), l.OO (t, 3H) HRMS (M+H)⁺ = 453.0498

Step H: Ethyl 4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-fluorophenyl)-2-nitrothiophene-3-carboxylate

l.97g compound of Step G above (4.34 mmol, l.O eq.) was dissolved in 40 mL dry acetonitrile, then 576 mg nitronium tetrafluoroborate (4.34 mmol, LO eq.) was added and the mixture was stirred at room température until no further conversion was observed. Then it was diluted with dichloromethane and brine. After phase séparation the aqueous phase was extracted with dichloromethane. The organic layers were combined and dried over NaiSOj, filtered and concentrated under reduced pressure. The crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain ethyl

4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-fluorophenyl)-2-nitro-thiophene-3carboxylate. Ή NMR (400 MHz, DMSO-dô): 7.37-7.33 (m, 2H), 7.32-7.26 (m, 2H), 4.14 (q, 2H), 3.82 (s, 3H), 2.06 (s, 6H), 0.88 (t, 3H)

Step I: Ethyl 2-amino-4-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-5-(4-fluorophenyl)thiophene-3-carboxylate

I.85 g compound of Step H above (3.71 mmol, LO eq.) was dissolved in a mixture of 90 mL acetic acid and 18 mL water, then 2.43 g zinc dust (37.1 mmol, 10 eq.) was added portionwise and the mixture was stirred at room température until no further conversion was observed. Reaction mixture was concentrated under reduced pressure, and the crude product was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain ethyl 2-amino-4-(3,5-dichIoro-4-methoxy-2,6-dimethyl-phenyl)-5-(4fluorophenyl)thiophene-3-carboxylate.

Ή NMR (400 MHz, DMSO-d₆): 7.73 (s, 2H), 7.12-7.06 (m, 2H), 7.02-6.97 (m, 2H), 3.863.80 (m, 2H), 3.80 (s, 3H), 2.01 (s, 6H), 0.72 (t, 3H)

HRMS (M+H)⁺ = 456.0598

Step J: 5-(3,5-Dichloro-4-methoxy-2_r6-dimethyl-phenyl)-6-(4-fluorophenyl)-3}3thieno[2,3-d]pyrimidin-4-one

I.IO g compound of Step I above (2.35 mmol, l.O eq.) was dissolved in 20 mL formamide and it was stirred at 150 °C until no further conversion was observed. Then it was poured onto water and the precipitated product was collected by filtration to give 5-(3,5-dichloro-

4-methoxy-2,6-dimethyI-phenyl)-6-(4-fluorophenyl)-3/7-thieno[2,3-iZ|pyrimidin-4-one.

' H NMR (400 MHz, DMSO-d₆): 12.53 (br s, l H), 8.18 (s, l H), 7.23-7.16 (m, 4H), 3.84 (s, 3H), L96 (s, 6H)

HRMS (M+H)⁺ = 449.0289

Step K: 4-Chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethyl-phenyl)-6-(4~flnorophenyl)thieno[2,3-d]pyrimidine

700 mg compound of Step J above (1.56 mmol, L0 eq.) was dissolved in 6 mL phosphorous oxychloride and it was stirred at 90 °C until no further conversion was observed. Reaction mixture was concentrated under reduced pressure, then to the crude product icy water was added and it was sonicated for 10 minutes. The precipitated product was collected by filtration to give 4-chloro-5-(3,5-dichloro-4-methoxy-2,6-dimethylpheny 1)-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidine.

H NMR (400 MHz, DMSO-de): 9.02 (s, IH), 7.38-7.26 (m, 4H), 3.86 (s, 3H), 1.99 (s, 6H) HRMS (M+H)⁺ = 466.9954

Step L: 2,6-Dichloro-4-[4-ehloro-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-5-yl]-3,5dinieîhyl-phenol and 4-[4-bronio-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-5-yl]-2,6dichloro-3,5-dimethyl-phenol

To a stirred solution of 700 mg compound of Step K above (1.50 mmol, LO eq.) in 15 mL dichloromethane, 3.0 mL boron tribromide (IM in dichloromethane) (3.0 mmol, 2.0 eq.) was added at 0 °C and the mixture was allowed to warm up to room température and it was stirred until no further conversion was observed. The mixture was quenched with saturated aqueous NH-jCi and extracted with dichloromethane. The combined organic phases were dried over NajSOj and concentrated under reduced pressure. The residue was purified via flash chromatography using heptane and ethyl acetate as eluents to obtain 2,6-dichloro-4[4-chloro-6-(4-fluorophenyl)thieno[2,3-t/]pyrimidin-5-yl]-3,5-dimethyl-phenol and 4-[4bromo-6-(4-fluorophenyl)thieno[2.3-i/]pyrimidin-5-yl]-2,6-dichloro-3,5-dimethyl-phenol as a 37:63 mixture of products.

Ή NMR (400 MHz, DMSO-d₆): 10.14 (br s, IH), 9.01 (s, IH), 7.40-7.23 (m, 4H), 1.95 (s, 6H) and 10.14 (br s, IH), 8.93 (s, IH), 7.40-7.23 (m, 4H), 1.93 (s, 6H)

HRMS (M+H)⁴ = 452.9800 and 496.9287

Step M: 4-Chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-â]pyrimidine and 4-bromo-5-[3,5dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4jliiorophenyl)thieno[2,3-à]pyrimidine

300 mg mixture of 2,6-dichloro-4-[4-chloro-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5yl]-3,5-dimethyl-phenol and 4-[4-bromo-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-5-yl]2,6-dichloro-3,5-dimethyl-phenol (0.62 mmol), 286 mg 2-(4-methylpiperazin-l-yl)ethanol (1.98 mmol, 3.0 eq.) and 520 mg triphenyl phosphine (1.98 mmol, 3.0) were dissolved in 10 mL dry toluene, then 460 mg di-zerz-butyl azodicarboxylate (1.98 mmol, 3.0 eq.) was added. The mixture was stirred at 50 °C under nitrogen until no further conversion was observed. The volatiles were evaporated under reduced pressure and the crude intermédiare was purified via flash chromatography using ethyl acetate and methanol as eluents to obtain 4-chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1 -yl)ethoxy]phenyl] -6-(4-fluorophenyl)thieno[2,3-i/]pyrimidine and 4-bromo-5-[3,5-dichloro-2,6-dimethyl-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidine as a 35:65 mixture of products.

Ή NMR(400 MHz. DMSO-d₆): 9.02 (s, IH), 7.40-7.22 (m, 4H), 4.11 (t, 2H), 2.78 (t. 2H), 2.63-2.20 (m, 8H), 2.17 (br s, 3H), 1.98 (s, 6H) and 8.94 (s. IH), 7.40-7.22 (m, 4H), 4.11 (t, 2H), 2.78 (t, 2H), 2.63-2.20 (m, 8H), 2.15 (br s, 3H), l .98 (s, 6H)

HRMS (M+H)⁴ = 579.0968 and 623.0455

Step N: Ethyl (2R)-2-[5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-lyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-à]pyrimidin-4-yl]oxy-3-[2-[[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

200 mg mixture of 4-chloro-5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-l-yi) ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-J]pyrimidine and 4-bromo-5-[3,5-dichloro2,6-dimethyl-4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidine (0.33 mmol, I.O eq.), 2ll mg ethyl (2Æ)-2-hydroxy-3-[2-[[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate (0.52 mmol, 1.58 eq.) and 202 mg CS2CO3 (0.62 mmol, 1.88 eq.) was dissolved in 5 mL /er/-butanol and the mixture was stirred at 70 °C until no further conversion was observed. It was diluted with ethyl acetate and then it was washed with brine. The organic layer was dried over Na2SC>4, fïltered and concentrated under reduced pressure and purified via flash chromatography using ethyl acetate and methanol as eluents to obtain ethyl (2Æ)-2-[5-[3,5-dichloro-2,6dimethyl-4-[2-(4-methylpiperazin-l-yI)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-r/] pyrimidin-4-yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl] propanoate. MS: (M+H) = 951.0

Step O: (2R)-2-[5-[3,5-Dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-1 yl)ethoxy]phenyl]-6-(4-fliiorophenyl)thieno[2,3-d]pyrimidiri-4-yl]oxy-3-[2-[[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid

200 mg of compound of Step N above was dissolved in 5 mL dioxane-water 1:1 and 145 mg lithium hydroxide monohydrate (3.45 mmol) was added. The mixture was stirred at room température until no further conversion was observed. Then it was diluted with brine, neutralized with 2M HCl, extracted with dichloromethane, dried over Na2SC>4, fïltered and concentrated under reduced pressure. The crude product was purified via préparative reversed phase chromatography using 5 mM aqueous NH4HCO3 solution and acetonitrile to obtain (2R)-2-[5-[3,5-dichloro-2,6-dimethyl-4-[2-(4-methylpiperazin-Iyl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3<(]pyrimidin-4-yl]oxy-3-[2-[[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoic acid. HRMS calculated for C48H45N6O6FSCI2: 922.2482, found: 462.1310 (M+2H)

Step P: (4-Methoxyphenyl)methyl (2V.)-2-[5-[3,5-dichloro-2,6-dimethyl-4-[2-(4methylpiperazin-1 -yl)ethoxy]phenyl]-6-(4-fl uorophenyl)thieno[2,3-d]pyrimidin-4-yl] oxy-3[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate

400 mg compound of Step O above (0.433 mmol, 1 eq.), 341 mg triphenylphosphine (1.30 mmol, 3.0 eq.) and 180 mg 4-methoxybenzyl alcohol (1.30 mmol, 3.0 eq.) were dissolved in 5 mL dry toluene, then 300 mg di(ter/)buty! azodicarboxylate (1.30 mmol, 3.0 eq.) was added in one portion. The resulting mixture was stirred at 50 °C until no further conversion was observed. The reaction mixture was concentrated, the crude product was purified by flash chromatography using dichloromethane/methanol (containing 1.2 % NHj) as eluent to obtain (4-methoxyphenyl)methyl (27?)-2-[5-[3,5-dichloro-2.6-dimethyl-

4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yl]oxy-3-[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]propanoate. MS: (M+H)= 1043.2

Step O: Benzyl [4-[2-[2,6-dichloro-4-[6-(4-fluorophenyl)-4-[(lB.)-2-[(4methoxyphenyl)methoxy]-1 -J[2-[[2-(2-methoxyphenyl)pyrimidin-4yl] methoxyjphenyl] methyl]-2-oxo-ethoxy]thieno[2,3-à]pyrimidin-5-yl]-3,5-dimethylphenoxy]ethyl] -1 -methyl-piperazin- 1-i uni-1 -yl] methyl phosphate

428 mg compound of Step P above (0.62 mmol, 1.5 eq.) were stirred in 4 mL dry acetonitrile at 40 °C until no further conversion was observed. The reaction mixture was injected directly onto a preconditioned 24 g silîca column, then it was purified by flash chomatography using ethyl acetate/methanol (containing 1.2% Nfh) as eluent to give benzyl [4-[2-[2,6-dichloro-4-[6-(4-fluorophenyl)-4-[( 1 Æ)-2-[(4-methoxyphenyl)methoxy]l-[[2-[[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy]phenyl]methyl]-2-oxo-ethoxy]thieno [2,3-</]pyrimidin-5-y l]-3,5-dimethyl-phenoxy]ethy I]-1 -methyl-piperazin-1 -ium-1 -yl] methyl phosphate. MS: (M+H)= 1243.2

Step R: Exaniple 9

To the solution of 230 mg compound of Step P above (0.185 mmol) in 3 mL dichloromethane, 110 pL 33 % HBr in acetic acid was added and it was stirred at 0 °C until no further conversion was observed. The reaction mixture was concentrated to dryness and the resulted product was purified by reversed phase chromatography using acetonitrile / 25 mM NH4HCO3 as eluents. After lyophilization Example 9 was obtained as a white solid. HRMS calculated for C49H48 ChFNéOioPS: 1032.2251, found; 517.1213 (M+2H)

Example 10: {4-[2-(4-{4-[(lff)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyriniidin-4-yl| methoxy)phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/| pyrimidin-5-yl}-3,5-dîmethyl phenoxy)ethyl|-l-mcthylpiperazin-l-ium-l-yl}methyl hydrogen phosphate

In the Example 10, the procedure is as in Example 1, using the appropriate chloride dérivative of formula (IV) and the appropriate thienopyrimidine compound of formula (II).

Example 11: {[2-(4-{(5S_fl)-4-[(17î)-l-carboxj'-2-(2-{I2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro-

3- methyIphenoxy)ethyl](dimethyl)ammonio}methyl hydrogen phosphate

Step A: 4-methoxybenzyl (2R)-2-{[(5Sa-5-{3-chlaro-4-[2-(iiimethyliinimo)ethoxy-]-2methylphenyl}-6-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}-3-(2-{[2-(2melhoxyphenyi)pyrimidin-4-yl]methoxy}pheriyl)propanoate

928 mg (27?)-2-{[(5S_a)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl}-6-(4fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)propanoic acid (1.13 mmol, 1 eq.; synthesized according to WO 2015/097123), 889 mg triphenylphosphine (3.39 mmol, 3 eq.) and 468 mg

4- methoxybenzyl alcohol (3.39 mmol, 3 eq.) were dîssolved in 12 mL dry toluene, then 781 mg di(/er/)butyl azodîcarboxylate (3.39 mmol. 3 eq.) was added in one portion. The resulting mixture was stirred at 50 °C until no further conversion was observed. The reaction mixture was concentrated and the crude product was purified by flash chromatography using ethyl acetate/methanol (containing 1.2 % NH3) as eluent. Product of Step A was obtained as off-white crystals. HRMS calculated for C52H47CIFN5O7S: 939.2869; found 470.6511 (M+2H)

Step B: Benzyl [(2-{2-chloro-4-[6-(4-fluorophenyl)-4-{[(2R)-l-[(4~methoxybenzyl)oxy]-3(2-{[2-(2-methoxyphenyl)pyrinüdin-4-yl]methoxy}phenylEl-oxopropan-2-yl]oxy}-(5'S>_!s)thîeno[2,3 -d]pyrimidin-5-yl]-3-methylphenoxy}ethyl) (dimethyl)ammonio] methyl phosphate

282 mg compound of Step A above (0.300 mmol, l eq.) and 147 mg dibenzyl chloromethyl phosphate (0.450 mmol, Ï.5 eq.) were stirred in 1.5 mL dry acetonitrile at 40 °C untii no further conversion was observed. The reaction mixture was injected directly onto a precondiotioned 24 g silica column, then it was purified by flash chomatography using ethyl acetate/methanol (containing 1.2 % NH3) as eluent. Compound of Step B was obtained as off-white crystals. HRMS calculated for CôoHsôCIFNsOhPS: 1139.3107; found 570.6613 (M+2H)

Step C: Example l1

To the solution of 110 mg compound of Step B above (0.0964 mmol) in ImL dichloromethane, 175 pL 33 % HBr in acetic acid was added and it was stirred at 0 °C untii no further conversion was observed. The reaction mixture was concentrated, purified by flash chomatography using ethyl acetate/methanol (containing 1.2 % NH3) as eluent. Then the resulted product was purified by reversed phase chromatography using acetonitrile ! 5mM NH4HCO3 as eluents. After lyophîlization, Example 11 was obtained as a white solid. HRMS calculated for OilhiBrCIFNiOioPS: 929.2062; found 465.6087 (M+2H)

In the following Examples 12 to 16, the procedure is as in Example I, using the appropriate chloride dérivative of formula (IV) and the appropriate thienopyrimidine compound of formula (II).

Example 12; l-{4-|2-(4-{(55_fl)-4-[(lR)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidÎn-5yl}-2-chloro-3-methylphenoxy)ethyl|-l-methylpiperazin-l-ium-l-yl}ethyl hydrogen phosphate

Example 13: l-{4-[2-(3-bromo-4-{(55_fl)-4-|(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyI)ethoxy]-6-(4-fluorophenyl)thieno[23-i/]pyimidiii-5yI}-2-chlorophenoxy)ethyl]-i-methylpiperazin-l-ium-l-yl}ethyl hydrogen phosphate

Example 14: {l-|2-(4-{(55_fl)-4-[(li)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl|methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl]-4-methylpiperazin-l-ium-l-yl]methyl hydrogen phosphate

Example 15: {l-[2-(3-bromo-4-{(5S_a)-4-[(lfl)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)ethoxy|-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-5y|}-2-chlorophenoxy)ethyl]-4-methylpiperazin-l-ium-l-yl}methyl hydrogen phosphate

Example 16: {4-[2-(4-{(55_a)-4-[(l/?)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyI)ethoxy]-6-(4-fluorophenyl)thieno[2,3-if]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl]-l-methylpiperazin-l-ium-l-yl}methyl sulfate

Example 17: l-[(acetyloxy)methyl]-4-[2-(4-{(55_a)-4-|(l/f)-l-carboxy-2-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl) thieno|2,3-//]pyrimidin-5-yl}-2-chloro-3-methylphenoxy)ethyl]-l-methylpiperazin-lium trifluoroacetate

Step A: l-[(acetyloxy)methyl]-4-(2-{2-chloro-4-[6-(4~fluorophenyl)-4-{[(2R)-1 -[(4methoxybenzyl)oxy]-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-loxopropan-2-yl]oxy}-(5S>a)-thieno[2,3-à]pyrimidin-5-y}]-3-methylphenoxy}ethy'l)-lmethylpiperazin-l-ium trifluoroacetate

To the solution of 149 mg compound obtained in Step A of Example l (0.150 mmol, l eq.) and 33 mg chloromethyl acetate (0.300 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 22 mg sodium iodide (0.15 mmol, LO eq.) was added and the reaction mixture was stirred at 70 °C until no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/H₂O (0.5 mL/L) as eluents. Product of Step A was obtained as trifluoroacetate sait. MS: Μ = 1067.2

Step B: Example 17

To the solution of 73 mg compound of Step A above (0.062 mmol, I eq.) in 4 mL dichloromethane, 300 pL trifluoroacetic acid was added and the reacion mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HjO (0.5 mL/L) as eluents. After lyophilization, Example 17 was obtained as a white solid. HRMS calculated for CsoH-içClFNôOgS: 947.3000; found 947.3001 (M)

Example 18: 4-[2-(4-{(5S’_a)-4-|(lR)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimÎdin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l-{[(ethoxycarbonyl)oxy]methyI}-l-methylpiperazin-l-ium

Step A: 4-(2-{2-chloro-4-[6-(4-fluorophenyl)-4-{[(2R)-l-[(4-methoxybenzyl)oxy]-3-(2-([2(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-l-oxopropan-2-yl]oxy}-(5Sdlhieno[2,3-àjpyrimidin-5-yl]-3-melhylphenoxy} ethyi)-l-{[(ethoxycarbonyl)oxy] methyl}-!methylpiperazin-1 -ium trifluoroacetate

To the solution of 200 mg compound obtained in Step A of Example 1 (0.201 mmol, 1 eq.) and 56 mg ethyi chloromethyl carbonate (0.402 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 30 mg sodium iodide (0.201 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70°C until no further conversion was observed. The réaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/EhO (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. HRMS calculated for C59H59CIFN6O10S: 1097.3680; found 1097.3694 (M)

Step B: Example 18

To the solution of 162 mg compound of Step A above (0.134 mmol, 1 eq.) in 4 mL dichloromethane, 300 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température untii no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acîd/acetonitrile (0.5 mL/L) and trifluoroacetic acid/FhO (0.5 mL/L) as eluents. After lyophilization, Example 18 was obtained as a white solid. HRMS calculated for C51H51CIFN6O9S: 977.3105; found 977.3122 (M)

Example 19: 4-[2-(4-{(55_fl)-4-[(lR)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyriniidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l-{[(diethylcarbamoyl)oxy]methyl}-l-methylpïperazin-l-ium trifluoroacetate

Step A: 4-(2-{2-chloro-4-[6-(4-fluorophenyl)-4-{[(2R.)-l-[(4-methoxybenzyl)oxy]-3-(2-{[2(2-methoxyphenyl)pyrimidin-4-yl/ methoxyjphenyl) -1 -oxopropan-2-yl] oxy}-(5 SJ thieno[2,3-d]pyrim idin-5-yl]-3-methylphenoxy}ethyl)-l - {[(diethylcarbamoyl)oxy]melhyl} 1 -methylpiperazin-1 -ium trifluoroacetate

To the solution of 200 mg compound obtained in Step A of Example 1 (0.201 mmol. 1 eq.) and 67 mg chloromethyl ?/,jV-diethylcarbamate (0.402 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 30 mg sodium iodide (0.201 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70 °C untii no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HïO (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. HRMS calculated for C61H64CIFN7O9S: 1124.4153; found 1124.4209 (M)

Step B: Example 19

To the solution of 192 mg compound of Step A above (0.155 mmol. 1 eq.) in 4 mL dichloromethane, 300 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonîtrile (0.5 mL/L) and trifluoroacetic acid/FbO (0.5 mL/L) as eluents. After lyophilization, Example 19 was obtained as a white solid. HRMS calculated for C53H56CIFN7O8S: 1004.3578; found 1004.3579 (M)

Example 20: 4-[2-(4-{(5S^, _o)-4-[(Hf)-l-carboxy-2-(2-{f2-(2-methoxyphenyl)pynmidin-4yl]methoxy}phenyl)ethoxy|-6-(4-fluorophenyl)thieno[2,3-if|pyrimîdin-5-yI}-2-chloro3-methylphenoxy)ethyl]-l-[(glycyloxy)methyl|-l-methylpiperazin-l-ium

In the Example 20, the procedure is as in Example 1, using the appropriate chloride dérivative of formula (IV) and the appropriate thienopyrimidine compound of formula (II). The obtained compound is quatemary ammonium sait in which counterions can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate. tosylate, triflate, or the like.

Example 21: 4-|2-(4-{(55_a)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno|2,3-</]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl|-l-{l-|(diethylcarbamoyl)oxy]ethyl}-l-methylpiperazin-l-ium trifluoroacetate

Step A: 1-chloroethyl N.^l-diethylcarbamate

To the solution of 1.828 g diethylamine (25 mmol, 1.0 eq.) in tetrahydrofuran, 3.574 g 1-chloroethyl carbonochloridate (25 mmol, LO eq.) was added dropwise at -78 °C, then pyridine was added dropwise at -78 °C. Reaction mixture was stirred at this température for 30 minutes, then it was let to warm to room température slowly (3 hours) and it was stirred ovemight. The raction mixture was concentrated, the crude product was diluted with

5I mL dichloromethane then it was washed with 50 mL IN HCl aqueous then two times with 50 mL brine. Organic layer was dried over MgSOj, it was filtered, the filtrate was concentrated under reduced pressure to give l-chloroethyl AQV-diethylcarbamate as light brown oil. 'H NMR (400 MHz, CDCh): 6.64 (q, IH), 3.34 (m, 4H), I.83 (d, 3H), LI7 (t, 6H).

Step B: 4-(2~{2-chloro-4-[6-(4-fluorophenyl)-4-{[(2R)-l~[(-l-methoxybenzyl)oxy]-3-(2-{[2(2-methoxyphenyl)pyrimidin-4-yl] methoxy}phenyl)-!-oxopropan-2-yl]oxy}-(5S_a)thieno[2,3-à]pyrimidm-5-yl]-3-methylphenoxy}ethyl)-l-{ l-[(diethylcarbamoyl)oxy] ethyl}1 -methylpiperazin-1 -tiirn trifluoroacetate

To the solution of 250 mg compound obtained in Step A of Example 1 (0.251 mmol, 1.0 eq.) and 225 mg compound of Step A above (1.26 mmol, 5.0 eq.) in 5 mL acetonitrile, 75 mg sodium iodide (0.50 mmol, 2.0 eq.) was added and it was stirred at 45 °C for 45 minutes. The reaction mixture was cooled, filtered, then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acîdÆLO (0.5 mL/L) as eluents. Compounds of Step B were obtained as trifluoroacetate salts of the diastereomers (diastereomers were not separated). MS: Μ = 1138.4

Step C: Example 21

To the solution of 81 mg compounds of Step B above (0.0647 mmol, 1 eq.) in 5 mL dichloromethane, 800 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HîO (0.5 mL/L) as eluents. After lyophiiization, Example 21 was obtained as a white solid (diastereomers were not separated). HRMS calculated for C54H58CIFN7O8S: 1018.3735; found 509.6925 (M+H)²⁺

Example 22: 4-[2-(4-{(5S,₎)-4-[(lJ?)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l-methyl-l-[(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl] piperazin-l-ium trifluoroacetate

Step A: 4-(2-{2-chloro-4-[6-(4-fluoropheryl)-4-{[(2R)-l-[(4-methoxybenzyl)oxy]-3-(2-{[2(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-l-oxopropan-2-yl]oxy}-(5'Sdthieno[2,3-à]pyrimidin-5-yl]-3-methylphenoxy}ethyl)-l-methyl-1 -[(5-methyl-2-oxo-1,3dioxol-4-yl)methyl]piperazin-l-ium trifluoroacetate

To the solution of 348 mg compound obtained in Step A of Example 1 (0.350 mmol, 1 eq.) and 104 mg 4-(chloromethyl)-5-methyl-i,3-dioxol-2One (0.700 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 52 mg sodium iodide (0.35 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70 °C until no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HiO (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. MS: Μ = 1107.2

Step B: Example 22

To the solution of 250 mg compound of Step A above (0.205 mmol, 1 eq.) in 8 mL dichloromethane, 600 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/LLO (0.5 mL/L) as eluents. After lyophilization, Example 22 was obtained as a white solid. HRMS calculated for C52H49CIFN6O9S: 987.2949; found 987.2961 (M)

Example 23: 4-[2-(4-{(5S_fl)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy|-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l-methyl-l-[(L-valyloxy)methyl]piperazin-l-iiim

In the Example 23, the procedure is as in Example 1, using the appropriate chloride dérivative of formula (IV) and the appropriate thienopyrimidine compound of formula (II). The obtained compound is a quatemary ammonium sait in which counterions can be selected from bromide, chloride, iodide, acetate, tri fl uoro acetate, benzoate, mesylate, tosylate, triflate, or the like.

Example 24: 4-[2-(4-{(55_a)-4-|(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy]phenyl)ethoxy]-6-(4-fluorophenyl)thieno|2,3-i/]pyrimidin-5-yl}-2-chloro3-methylphenoxy)ethyl]-l-{[(2,2-dimethylpropanoyI)oxy]methyl}-l-methylpiperazin1-ium trifluoroacetate

Step A: 4-(2-{2-chloro-4-[6-(4-fluorophenyl)-4-{[(2B,)-1 fl(4anethoxybenzyl)oxy]-3-(2-{[2(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-l-oxopropan-2-yl]oxy}-(5S_a)thieno[2,3-à]pyrimidin-5-yl]-3-methylphenoxy}elhyl)-1-{[(2,2dimethylpropanoyl)oxy]methyl}-l-methylpiperazin-l-ium trifluoroacetate

To the solution of 249 mg compound btained in Step A of Example 1 (0.250 mmol, I eq.) and 75 mg chloromethyl 2,2-dimethylpropanoate (0.500 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 37 mg sodium iodide (0.25 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70 °C until no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/H₂O (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. HRMS calculated for C61H63CIFN6O9S: 1109.4044; found 1109.4040 (M)

Step B: Example 24

To the solution of 216 mg compound of Step A above (0.177 mmol. I eq.) in 8 mL dichloromethane, 600 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acîd/H₂O (0.5 mL/L) as eluents. After lyophilization, Example 24 was obtained as a white solid. HRMS calculated for C53H55CIFN6O8S: 989.3469; found 989.3480 (M)

Example 25: l-[(acetyloxy)methyl]-4-[2-(3-bromo-4-{(5S^, _a)-4-[(12î)-l-carboxy-2-(2-{[2(2-methoxyphenyl)pyrimidin-4-yi]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl) thieno[2,3-if]pyrimidin-5-yl}-2-chlorophenoxy)ethyl]-l-methylpiperazin-l-ium trifluoroacetate

Step A: l-[(acetyloxy)methyl]-4-(2-{3-bromo-2-chloro-4-[6-(4-fluorophenyl)-4-{[(2RJ-1[(4-methoxybenzyl)oxy]-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-loxopropan-2-yl]oxy}-(5^<S₃)-^thieno[2,3-d]pyrimidiri-5-yl]phenoxy}ethyl)-}-methylpipera:inl-ium trifluoroacetate

To the solution of 212 mg compound obtained in Step A of Example 5 (0.20 mmol, l eq.) and 43 mg chloromethyl acetate (0.40 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 30 mg sodium iodide (0.20 mmol, L0 eq.) was added and the reaction mixture was stirred at 70 °C until no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HiO (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. MS: Μ = 1131.0

Step B: Example 25

To the solution of 105 mg compound of Step A above (0.0842 mmol, 1 eq.) in 4 mL dichloromethane, 300 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HîO (0.5 mL/L) as eluents. After lyophilization, Example 25 was obtained as a white solid. HRMS calculated for CisTUBrCIFNéOsS: 1011.1948; found 1011.1949 (M)

Exampie 26: 4-[2-(3-bromo-4-{(5S_a)-4-[(17f)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl|methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[23-i/lpynmidin-5yl}-2-chlorophenoxy)ethylJ-l-{[(ethoxycarbonyi)oxy]methyl}-l-methylpiperazin-lium trifluoroacetate

Step A: 4-(2-{3-bromo-2-chloro-4-[6-(4-fluorophenyl)-4-{[(2R)-I-[(4methoxybenzyl)oxy]-3-(2- {[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-l oxopropan-2-yl]oxy}-(5?>3)-thieno[2,3-â]pyriniidin-5-yl]phenoxy}ethyl)-I{[(ethoxycarbonyl)oxy]methyl}-l-methylpiperazin-l-ium trifluoroacetate

To the solution of 252 mg compound obtained in Step A of Example 5 (0.20 mmol, l eq.) and 55 mg ethyl chloromethyl carbonate (0.40 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 30 mg sodium iodide (0.20 mmol, l.O eq.) was added and the reaction mixture was stirred at 70 °C until no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/FbO (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. HRMS calculated for CssHsôBrCIFNôOwS: H6L2629 found H6L2674 (M)

Step B: Example 26

To the solution of 240 mg compound of Step A above (0.188 mmol, l eq.) in 4 mL dichloromethane, 300 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HjO (0.5 mL/L) as eluents. After lyophilization, Example 26 was obtained as a white solid. HRMS calculated for C₅oH48BrClFN₆09S: 1041.2054; found 1041.2049 (M)

Example 27: 4-[2-(3-bromo-4-{(55_a)-4-[(l/î)-l-carboxy“2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl]methoxy}phenyi)ethoxy]-6-(4-fluorophenyi)thieno[23-</]pynmidin-5yl}-2-chlorophenoxy)ethyl|-l-{[(dÎethylcarbamoyl)oxy]methyl}-l-methylpiperazin-lium trifluoroacetate

Step A : 4-(2-{3-bromo-2-chloro-4-[6-(4-flttorophenyl)-4-{[(2R)-l-[(4methoxybenzyl)oxy]-3- (2-{[2-(2-methoxyphenyl)pyrimidin-4-yl] methoxy}phenyl)-loxopropan-2-yi]oxyf-(5Sp-thieno[2,3-d]pyrimidin-5-yl]phenoxy}ethylpi{[(diethylcarbamoyl)oxy]methyl} -1 -methylpiperazin-1-ium trifluoroacetate

To the solution of212 mg compound obtained in Step A of Example 5 (0.20 mmol, 1 eq.) and 66 mg chloromethyl MA-diethylcarbamate (0.40 mmol, 2.0 eq.) ïn 2 mL dry acetonitrile, 30 mg sodium iodide (0.20 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70 °C untii no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HzO (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. HRMS calculated for CfioHôiBrCIFNvChS; 1188.3102; found 1188.3101 (M)

Step B: Example 27

To the solution of 208 mg compound of Step A above (0.160 mmol, 1 eq.) in 4 mL dichloromethane, 300 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température untii no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HîO (0.5 mL/L) as eluents. After lyophilization, Example 27 was obtained as a white solid. HRMS calculated for C52H53B1-CIFN7O8S: 1068.2527; found 1068.2514 (M)

Example 28: 4-[2-(3-bromo-4-{(5S_e)-4'[(lJï)-l-carboxy-2-(2-{[2-(2-methoxyphei]yl) pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyI)thieno[23'i/]pyrimidin-5yl}-2-chlorophenoxy)ethyl]-l-[(glycyloxy)methyl]-l-methylpiperazin-l-ium

In the Example 28, the procedure is as in Example l, using the appropriate chloride dérivative of formula (IV) and the appropriate thienopyrimidine compound of formula (II). The obtained compound is a quatemary ammonium sait in which counterions can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate. mesylate, tosylate, triflate, or the Iike.

Example 29: 4-[2-(3-bromo-4-{(5S_fl)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxy^rphenyl) pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[23-rf] pyrimidin-5yI}-2-chlorophenoxy)ethyI]-l-{l-[(diethylcarbamoyl)oxy|ethyl}-l-methylpiperazin-lium trifluoroacetate

Step A: 4-(2-{3-bromo-2-chloro-4-[6-(4-fluorophenyl)-4-{[(2R)-l-[(4methoxybenzyl)oxy]-3-(2-{[2-(2-methoxyphenyl)pyrimidm-4-yl]methoxy}phenyl)-loxopropan-2-yl]oxy} - (5Sa)-thieno[2,3-dJpyrimidi n-5-yl]phenoxy} ethyl)-!-{![(diethylcarbamoyl)oxy]ethyl}-1 -methylpiperazin-1-ium trifluoroacetate

To the solution of 250 mg compound obtained in Step A of Example 5 (0.236 mmol, 1.0 eq.) and 212 mg compound obtained in Step A of Example 21 (1.18 mmol, 5.0 eq.) in 5 mL acetonitrile, 71 mg sodium iodide (0.471 mmol, 2.0 eq.) was added and it was stirred at 45 °C for 45 minutes. The reaction mixture was cooled, filtered, then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrîle (0.5 mL/L) and trifluoroacetic acid/HiO (0.5 mL/L) as eluents. Compounds of Step A were obtained as trifluoroacetate salts of the diastereomers (dîastereomers were not separated). MS: (M+H)²⁺ =602.8

Step B: Example 29

To the solution of 51 mg compounds of Step A above (0.0387 mmol, 1 eq.) in 5 mL dichloromethane, 800 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonîtrile (0.5 mL/L) and trifluoroacetic acid/HiO (0.5 mL/L) as eluents. After lyophilization. Example 29 was obtained as a white solid (diastereomers were not separated). HRMS calculated for (^HâsBrCIFNîOeS: 1082.2683; found 541.6396 (M+H)²⁺ and 541.6389 (M+H)²⁺

Example 30: 4-[2-(3-bromo-4-{(5S_a)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl) pyrimidin-4-yl|methoxy}phenyl)ethoxy|-6-(4-fluorophenyl)thieno[2,3-i/] pyrimidin-5yl}-2-chlorophenoxy)ethyl]-l-methyl-l-[(5-methyl-2-oxo-l,3-dioxol-4-yl)methyl| pîperazin-l-ium trifluoroacetate

Step A: 4-(2-{3-bromo-2-chloro-4-[6-(4-fhtorophenyl)-4-{[(2R)-l-[(4methoxybenzyl)oxy]-3-(2-{[2-(2-methoxyphenyl)pyrimidm-4-yl]methoxy}phenyl)-loxopropan-2-yl]oxy}-(53^)-thieno[2,3-à]pyrimidin-5-yl]phenoxy}ethyl)-l-methyl-l-[(5methyl-2-oxo-1,3-dioxol-4-yl)methyl]piperazin-1 -ium trifluoroacetate

To the solution of 212 mg compound obtained in Step A of Example 5 (0.200 mmol, 1 eq.) and 59 mg 4-(chloromethyl)-5-methyl-l,3-dioxol-2-one (0.40 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 30 mg sodium iodide (0.20 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70 °C until no further conversion was observed, The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/FhO (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. HRMS calculated for Csç^BrClFNôOioS: 1171.2473; found 1171.2461 (M)

Step B: Example 30

To the solution of 225 mg copound of Step A above (0.175 mmol, i eq.) in 8 mL dichloromethane, 600 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HzO (0.5 mL/L) as eluents. After lyophilîzation, Example 30 was obtained as a white solid. HRMS calculated for C₅iH4ôBrClFN₆O9S: 105l.l897; found 105U891 (M)

Example 31: 4-[2-(3-bromo-4-{(5S_fl)-4-[(ltf)-l-carboxy-2-(2-n2-(2-methoxyphenyl) pyrimidin-4-yl] methoxy] phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-rf| pyrimidin-5yl]-2-chlorophenoxy)ethyl]-l-methyI-l-[(L-valyloxy)methyl]piperazin-l-ium

In the Example 31, the procedure is as in Example 1, using the appropriate chloride dérivative of formula (IV) and the appropriate thienopyrimidine compound of formula (II). The obtained compound is a quatemary ammonium sait in which counterions can be selected from bromide, chloride, iodide, acetate, trifluoroacetate, benzoate, mesylate, tosylate, triflate, or the like.

Example 32: 4-[2-(3-bromo-4-{(5S_n)-4-[(l/î)-l-carboxy-2-(2-{[2-(2-rnethoxyphenyl) pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5yl]-2-chlorophenoxy)ethyll-l-{[(2,2-dimethylpropanoyl)oxy]methyl}-l-methyl pîperazin-l-iiim trifluoroacetate

Step A: 4-(2-{3-bromo-2-chloro-4-[6-(4-fluorophenyl)-4~{[(2R)-l-[(4methoxybenzyl)oxy]-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)-loxopropan-2-yl]oxy't-(5SA-thieno[2,3-6]pyrimidin-5-yl]pherioxy}ethyl)-l-{[(2,2dimelhylpropanoyl)oxy]methyl}-!-methylpiperazin-l-iunt trifluoroacetate

To the solution of 212 mg compound obtained in Step A of Example 5 (0.200 mmol, 1 eq.) and 60 mg chloromethyl 2,2-dimethylpropanoate (0.40 mmol, 2.0 eq.) in 2 mL dry acetonitrile, 30 mg sodium iodide (0.20 mmol, 1.0 eq.) was added and the reaction mixture was stirred at 70 °C until no further conversion was observed. The reaction mixture was purified by reversed phase chromatography using trifluoroacetic acid/acetonîtrile (0.5 mL/L) and trifluoroacetic acid/HiO (0.5 mL/L) as eluents. Compound of Step A was obtained as trifluoroacetate sait. HRMS calculated for CôoHôoBrClFNôOçS: 1173.2993; found H 73.2994 (M)

Step B: Example 32

To the solution of 215 mg compound of Step A above (0.167 mmol, I eq.) in 8 mL dichloromethane, 600 pL trifluoroacetic acid was added and the reaction mixture was stirred at room température until no further conversion was observed. The reaction mixture was evaporated to dryness then it was purified by reversed phase chromatography using trifluoroacetic acid/acetonitrile (0.5 mL/L) and trifluoroacetic acid/HjO (0.5 mL/L) as eluents. After lyophilization, Example 32 was obtained as a white solid. HRMS calculated for C₅2H₅2BrClFN6O₈S: 1053.2418; found 1053.2405 (M)

Depending on their electronic charge and the pH in solution. Examples 1, 4, 5 and 8 to 15 10 can exist as four ionic forms (zwitterionic, dianionic, anionic or cationic); Examples 2, 3, 6 and 7 can exist as three forms (zwitterionic, anionic or cationic); and Examples 16 to 32 can exist as two forms (zwitterionic or cationic).

PHARMACOLOGICAL STUDY

EXAMPLE A: Inhibition of Mcl-1 bv the fluorescence polarisation technique

The relative binding potency of each compound was determined via Fluorescence Polarisation (FP). The method utiiised a Fluorescein labelled ligand (Fluorescein-pAlaAhx-A-REIGAQLRRMADDLNAQY-OH; mw 2,765) which binds to the Mcl-1 protein (such that Mcl-1 corresponds to the UniProtKB® primary accession number: Q07820) leading to an increased anisotropy measured in milli-polarisation (mP) units using a reader. The addition of a compound which binds competitively to the same site as the ligand will resuit in a greater proportion of unbound ligand in the System indicated by a decrease in mP units.

An 11 point serial dilution of each compound was prepared in DMSO and 2 μΐ transferred into fiat bottomed, low binding, 384-well plate (final DMSO concentration 5 %). 38 μΙ of buffer (10 mM 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid [HEPES], 150 mM NaCl, 0.05 % Tween 20, pH 7.4), containing the Fluorescein labelled ligand (final concentration 1 nM) and Mcl-1 protein (final concentration 5 nM) was then added.

Assay plates were incubated -2 hours at room température before FP was measured on a Biomek Synergy2 reader (Ex. 528 nm, Em. 640 nm, Cut off 510 nm) and mP units calculated. The binding of increasing doses of test compound was expressed as a percentage réduction in mP compared to a window established between ‘5 % DMSO only’ and ‘100% inhibition* controls. Il-point dose response curves were plotted with XL-Fit software using a 4-Parameter Logistic Model (Sigmoidal Dose-Response Model) and the inhibitory concentrations that gave a 50 % réduction in mP (IC50) were determined. Results are presented in Table 1 below.

The results show that the compounds of the invention inhibit interaction between the Mcl-1 protein and the fluorescent peptide described hereinbefore.

EXAMPLE B: /» vitro cvtotoxicitv

The cytotoxicity studies were carried out on the H929 multiple myeloma tumour line.

The cells are distrîbuted onto microplates and exposed to the test compounds for 48 hours.

The cell viability is then quantified by a colorimétrie assay, the Microculture Tétrazolium Assay (Carmichael et al. Cancer Res. 1987, 47, 936-942).

The results are expressed in IC50 (the concentration of compound that inhibits cell viability by 50 %) and are presented in Table l below.

The results show that the compounds of the invention are cytotoxic.

Table 1: ICso of Mcl-1 inhibition (fluorescence polarisation test) and of cvtotoxicitv for H929 cells

	ICm(M)McM FP	IC» (Μ) MTT H929		ICm(M)McI-I FP	IC» (M) MTT H929
Example 1	1.03E-09	2.84E-08	Example 17	I.12E-09	2.15E-09
Example 2	9.48E-10	1.09E-08	Exampie 18	9.48E-10	1.74E-09
Example 3	ND	ND	Example 19	1.2E-09	1.64E-06
Example 4	ND	ND	Example 20	ND	ND
Example 5	I.06E-09	5.54E-08	Example 21	1.96E-09	7.04E-08
Example 6	ND	ND	Example 22	9.48E-10	2.23E-09
Example 7	ND	ND	Example 23	ND	ND
Example 8	9.48E-IÛ	2.29E-07	Example 24	1.04E-09	2.52E-09
Example 9	ND	ND	Example 25	1.07E-09	1.95E-09
Example 10	ND	ND	Example 26	9.48E-10	2.29E-09
Example 11	1.06E-09	3.93E-08	Example 27	I.17E-09	1.9E-06
Example 12	ND	ND	Example 28	ND	ND
Exampie 13	ND	ND	Example 29	1.36E-09	1.36E-07
Example 14	ND	ND	Example 30	9.48E-10	2.81E-09
Example 15	ND	ND	Example 31	ND	ND
Example 16	ND	ND	Example 32	1.77E-09	2.11E-09

ND: not determined

EXAMPLE C: Quantification of the cleaved form of PARP in vivo

The ability of the compounds of the invention to induce apoptosis, by measurîng cleaved PARP levels, is evaluated in a xenograft model of AMO-l multiple myeloma cells.

5.10⁶ AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SCID 5 strain). 12 to 14 days after the graft, the animais are treated by intraveinous routes with the varions compounds. After treatment. the tumour masses are recovered and lysed, and the cleaved form of PARP is quantified in the tumour lysâtes.

The quantification is carrîed out using the “Meso Scale Discovery (MSD) ELISA platform” test, which specifically assays the cleaved form of PARP. It is expressed in the form of an IO activation factor corresponding to the ratio between the quantity of cleaved PARP in the tumors from treated mice divided by the quantity of cleaved PARP in the tumors from untreated mice.

The results show that the compounds of the invention are capable of inducing apoptosis in AMO-i tumour cells in vivo.

EXAMPLE D: Anti-tumour activity in vivo

The anti-tumour activity of the compounds of the invention is evaluated in a xenograft model of AMO-l multiple myeloma cells.

IxlO⁷ AMO-l cells are grafted sub-cutaneously into immunosuppressed mice (SCID strain). 6 to 8 days after the graft. when the tumour mass has reached about 150 mm³, the 20 mice are treated with the various compounds in a daily schedule (5-day treatment). The tumour mass is measured twice weekly from the start of treatment.

The results obtained using ΔΤ/C ratio (i.e. qualification parameter of the activity of a product, which is defined as the ratio tumour volume of the treated group / tumour volume of the untreated control group) show that the compounds of the invention induce a 25 prolonged and significant complété tumour régression after the treatment period.

EXAMPLE E: Solubilitv test

Method l: Sample solutions (around 16.7 mg/ml) in propylene glycol were diluted with Z water (30 % propylene glycol). Then, samples were shaked for 72 hours at room température. After the shakîng period, samples were centrîfuged, then the lîquid phase was fïltered and analyzed using HPLC coupled to UV détection. To détermine the actual concentration a 5-poînt calibration curve was established.

For instance, in these conditions, the solubility of the compound of Example l was significantly increased (> 4907 μΜ) compared to (2/?)-2-{[(5S_a)-5-{3-chloro-2-methyl-4[2-(4-methylpiperazin-l-yl)ethoxy]phenyl)-6-(4-fluorophenyI)thieno[2,3-</]pyrimidin-4yl]oxy )-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy)phenyl)propanoic acid (63.3 μΜ) disclosed in WO 2015/097123.

Method 2: Samples (40 mg/mL) were diluted in aqueous phosphate buffer (67.7 mM, with pH adjusted at 7.4) used for in vivo studies. Samples were shaked at room température, then fïltered. The solubilized fraction was quantifïed by LC-MS-MS analysis.

In these conditions, compounds of Example l and Example 11 showed hîgh solubility (>35 mg/mL) which are more soluble compared to (2R)-2-{[(5S'₀)-5-{3-chloro-2-methyl4-[2-(4-methylpiperazin-l-yl)ethoxy]phenyl)-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-4yl]oxy)-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)propanoic acid and (27?)-2-{ [(55^)-5-{3-chloro-4-[2-(dimethylamino)ethoxy]-2-methylphenyl)-6-(4fluorophenyl)thieno[2,3-i/]pyrimidÎn-4-yl]oxy}-3-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy)phenyl)propanoic acid, respectively, disclosed in WO 2015/097123.

EXAMPLE F: Pharmaceutical composition: Tablets

1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 32...........5g

Wheat starch............................. 20g

Maîze starch.................................................................................................. 20g

Lactose..............................................................................................................................30g

Magnésium stéarate............................................................................................................2g

Silica....................................... I g

Hydroxypropylcellulose.......................... 2 g

Claims (15)

CLAIMS wherein:
1. - 1 -[(acetyloxy)methyl]-4-[2-(4-{(55_a)-4-[( 17?)-1 -carboxy-2-(2- {[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy} pheny l)ethoxy]-6-(4fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro-3-methylphenoxy)ethyl]-lmethylpiperazin-1 -ium;

   - {1 -[2-(3-bromo-4- {(55'_a)-4-[( 1 /?)-1 -carboxy-2-(2- {[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy(phenyl)ethoxy]-6-(4fluorophenyl)thieno[2,3-<7]pyrimidin-5-yl(-2-chlorophenoxy)ethyl]-4methylpiperazin-1-ium-1-yl (methyl hydrogen phosphate;
2. . {[2-(4-{(5S_e)-4-[(l/?)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyI)ethoxy]-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl](dimethyl)ammonio}methyl hydrogen phosphate;

   . i-{4-[2-(4-{(5S_o)-4-[(l/f)-l-carboxy-2-(2-{[2-(2-melhoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-if]pyrimidm-5-yl}-2chloro-3-methylphenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -yl} ethyl hydrogen phosphate;

   . i -{4-[2-(3-bromo-4-{(55_e)-4-[( 1 Λ)-1 -carboxy-2-(2- {[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4nuorophenyl)thieno[2,3-t/]pyrimidin-5-yl}-2-chlorophenoxy)ethyl]-lmethylpiperazin-1-ium-1-yl (ethyl hydrogen phosphate;

   _ {] -(2-(4-{(5S_o)-4-[( 17?)-1 -carboxy-2-(2-{ [2-(2-methoxyphenyl)pyrimidin-4yl]methoxy(phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl]-4-methylpiperazin-1 -ium-1 -yl}methyl hydrogen phosphate;

   2. Compound of formula (I) according to claim l, wherein Y represents an oxygen atom.
3. 3. Compound of formula (I) according to claim l, wherein at least one of the groups selected from R₂, R₃ and R4 does not represent a hydrogen atom.
4. - 4-[2-(3-bromo-4-{(55_i,)-4-[(l7î)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 - {[(2,2-dimethylpropanoyl)oxy]methyl} -1 -methylpiperazinl-ium.

   - 4-[2-(3-bromo-4- {(5S_o)-4-(( l R)-1 -carboxy-2-(2- {[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-r/]pyrimidin-5-yl}-2chiorophenoxy)ethyl]-1 -methyl-1 -[(L-valyloxy)methyl]piperazin-1 -ium;

   - 4-[2-(3-bromo-4-{(55'_ÎI)-4-[(l/î)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 -methyl-1 -| (5-methyl-2-oxo-1,3-dioxol-4yl)methyl]piperazin-1 -ium;

   - 4-[2-(3-bromo-4-{(5S_ü)-4-[(l/î)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidtn4-yl]methoxy}phenyi)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-l-{ l-[(diethylcarbamoyl)oxy]ethyl}-l-methylpiperazin-lium;

   - 4-[2-(3-bromo-4-{(5.S^, ₀)-4-[(l7î)-l-carboxy-2-(2-{[2-(2-melhoxyphenyl)pyrimidin4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-l-[(glycyloxy)methyl]-l-methylpiperazin-1-ium;

   - 4-[2-(3-bromo-4- {(55^)-4-(( l R)-1 -carboxy-2-(2-{ [2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)ethoxy]-6-(4-fluoroplienyl)thieno[2,3-i/]pyrimÎdÎn-5-yl}-2chlorophenoxy)ethyl]-1 - {[(diethylcarbamoyl)oxy]methyl} -1 -methylpiperazin-1 ium;

   - 4-[2-(3-bromo-4-{(5S_fl)-4-[(l7?)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin4-yl(methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-L/]pyrimidin-5-yl}-2chlorophenoxy)ethyl]-1 - {[(ethoxycarbonyl)oxy]methyl} -1 -methylpiperazin-1 -ium;

   - 4-(2-(4-((55(,)-4-(( l R)-1 -carboxy-2-(2- {[2-(2-methoxyphenyî)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chloro-3-methyiphenoxy)ethyl]-l-{[(2,2-dimethylpropanoyl)oxy]methyl}-lmethylpiperazin-1 -ium;

   - I -[(acetyloxy)methyl]-4-(2-(3-bromo-4- {(55_a)-4-[(l À)-1 -carboxy-2-(2- {[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chlorophenoxy)ethyl]-lmethylpiperazin-l -ium;

   - 4-[2-(4-{(5S’_o)-4-[(l7?)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)elhoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl]-l-methyl-l-[(L-valyloxy)methyl]piperazin-l-ium;

   - 4-[2-(4-{(5S_c)-4-[(l7?)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyI)thieno[2,3-iZ]pyrimidin-5-yl}-2chloro-3-methylphenoxy ) ethyl ] -1 -methyl-1 -[(5-methyl-2-oxo-1,3-dioxol-4yl)methyl]piperazin-1 -ium;

   - 4-[2-(4-{(5S_iI)-4-[(l/î)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}pheny])ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl]-1 -{l -[(diethylcarbamoyl)oxy]ethyl} -1 methylpiperazin-! -ium;

   - 4-(2-(4- {(5S_a)-4-[( l Λ)-1 -carboxy-2-(2- {[2-(2-methoxyphenyl )pyrimidin-4yl]methoxy)phenyi)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl]-1 -[(glycyloxy)methyl]-1 -methylpiperazin-1 -ium;

   - 4-[2-(4- {(5Sa)-4-[( l /?)-1 -carboxy-2-(2- {[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno(2,3-c/)pyrimidin-5-yl)-2chloro-3-methy lphenoxy)ethyl]-1 -{[(diethylcarbarnoyl)oxy]methyl} -1 methylpiperazin-1 -ium;

   - 4-[2-(4-{(55'_a)-4-[(17?)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-(/]pyrimidin-5-yl}-2 chloro-3-methylphenoxy)ethyl]-1 - {[(ethoxycarbonyl)oxy]methyl}-1 methylpiperazin-1 -ium;

   . {4-(2-(4-{(55_a)-4-[( 17?)-1 -carboxy-2-(2- {[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy(phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i7]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -yl (methyl sulfate;

   - (4-(2-(4-(4-(( 1 /?)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-<7]pyrimidin-5-yl}-2,6dichloro-3,5-dimethylphenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -yl (methyl hydrogen phosphate;

   7l _ {4_[2-(4-{4-[( l /?)-1 -carboxy-2-(2- {[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-5-yl}-3,5dimethylphenoxy)ethyl]-l -methylpiperazin-1 -ium-1 -yl} methyl hydrogen phosphate;

   - {4-[2-(3-bromo-4-{(55_fl)-4-((l/?)-l-carboxy-2-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy(phenyl)ethoxy]-6-(4fluorophenyl)thieno[2,3-i7]pyrimidin-5-yl} -2-chlorophenoxy)ethyl]-1 methylpiperazin-l-ium-l-yl (methyl methyl phosphate;

   - A^r-[(5S₀)-5-(3-chloro-4-[2-(4-{[(hydroxyphosphinato)oxy]methyl}-4methylpiperazin-4-ium-1 -y l)ethoxy]-2-methylphenyl} -6-(4fluorophenyl)thieno[2,3-i/]pyrimidin-4-yl]-2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}-D-phenylalanine;

   - {4-[2-(3-bromo-4-{(5S_a)-4-[(lÀ)-l-carboxy-2-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}pheny!)ethoxy]-6-(4fluorophenyI)thieno[2,3-c/]pyrimidin-5-yl} -2-chlorophenoxy)ethyl]-lmethylpiperazin-l-ium-l-yl(methyl hydrogen phosphate;

   - benzyl {4-[2-(3-bromo-4-{(55_fl)-4-[(l7î)-l-carboxy-2-(2-{[2-(2methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4fluorophenyl)thieno[2,3-t/]pyrimidin-5-yl} -2-chlorophenoxy)ethyl]-1 methylpiperazin-1 -ium-1 -yl} methyl phosphate;

   . {4-(2-(4-{(55^)-4-(( l Λ)-1 -carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy(phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-c/]pyrimidin-5-yl}-2chloro-3-ethylphenoxy)ethyI]-1 -methylpiperazin-1 -ium-1 -yl}methyl hydrogen phosphate;

   . {4-(2-(4-((5^)-4-(( l R)-1 -carboxy-2-(2- {[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-iluorophenyl)thieno[2,3-i/]pyrimîdin-5-yl}-2chloro-3-methylphenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -yl (methyl methyl phosphate;

   - {4-[2-(4-{(5S'_£J)-4-[(lÆ)-l-carboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-</]pyrimidin-5-yl}-2chloro-3-methylphenoxy)ethyl]-l-methylpiperazin-l-ium-l-yl}methyl hydrogen phosphate;

   - benzyl {4-(2-(4-{(5SJ-4-[( l Æ)-l -carboxy-2-(2- {[2-(2-methoxyphenyl)pyrimidin4-yl]methoxy}phenyl)ethoxy]-6-(4-fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2chioro-3-methylphenoxy)ethyl]-1 -methylpiperazin-1 -ium-1 -yl}methyl phosphate;

   4. Compound of formula (I) according to claim l, wherein R| represents a linear or branched (Ci-C₆)alkyl group or a halogen atom.
5. 5 to yield the compound of formula (I), which may be purified according to a conventional séparation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional séparation technique, it being understood that at any moment considérée! appropriate during the course of the

   5 methylphenoxy)ethyl](dimethyl)ammonio} methyl hydrogen phosphate.

   17. Process for the préparation of a compound of formula (I) according to claim 1, characterised in that there is used as starting material the compound of formula (H):

   wherein R|, R₂, R3, Ri, R5 and Y are as defined for formula (I), and R<f represents

   5. Compound of formula (I) according to claim 1, wherein R₂ represents a halogen atom, a hydroxy group, a linear or branched (CrC₆)alkoxy group.

   5 ♦ Y represents a -NH- group or an oxygen atom, ♦ R] represents a linear or branched (Ci-C&)alkyl group, a linear or branched (Cz-Côjalkenyl group, a linear or branched (C2-C₆)alkynyl group, a linear or branched (Cj-C₆)alkoxy group, a -S-(C_rC₆)alkyl group, a linear or branched (Ci-C₆)polyhaloalkyl group, a hydroxy group, a hydroxy(Ci-C₆)alkyl group, a
6. 6. Compound of formula (I) according to claim 1, wherein R₃ and R4 represent a hydrogen atom.
7. 7. Compound of formula (I) according to claim 1, wherein the substituents of the pair (Ri, R4) are identical and the substituents of the pair (FU. R3) are identical.
8. 8. Compound of formula (I) according to claim l, wherein R₍, represents the group
9. 9. Compound of formula (l) according to claim l, wherein R₍, represents the group
10. 10 process described above, some groups (hydroxy, amino...) of the starting reagents or of the synthesis intennediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

    18. Pharmaceutical composition comprising a compound of formula (I), according to any one of daims 1 to 16, or an addition sali thereof with a pharmaceutically acceptable 15 acid or base in combination with one or more pharmaceutically acceptable excipients.

    19. Pharmaceutical composition according to claim 18 for use as pro-apoptotic agents.

    η

    20. Pharmaceutical composition according to claim 19 for use in the treatment of cancers and of auto-immune and immune System diseases.

    21. Pharmaceutical composition according to claim 20 for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, maiignant haemopathies, myelomas, ovarian cancer, nonsmall-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

    22. Use of a pharmaceutical composition according to claim 18 in the manufacture of médicaments for use as pro-apoptotic agents.

    23. Use of a pharmaceutical composition according to claim 18 in the manufacture of médicaments for use in the treatment of cancers and of auto-immune and immune System diseases.

    24. Use of a pharmaceutical composition according to claim 18 in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, maiignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

    25. Compound of formula (I), according to any one of daims 1 to 16, or an addition sait thereof with a pharmaceutically acceptable acid or base, for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, maiignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

    26. Use of a compound of formula (I), according to any one of daims 1 to 16, or an addition sait thereof with a pharmaceuticaîly acceptable acid or base, in the manufacture of médicaments for use in the treatment of cancers of the bladder, brain, breast and utérus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, 5 malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

    27. Combination of a compound of formula (I), according to any one of daims l to 16, with an anti-cancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, protéasome inhibitors, kinase inhibitors and antibodies.

    I0

    28. Pharmaceutical composition comprising a combination according to claim 27 in combination with one or more pharmaceuticaîly acceptable excipients.

    29. Combination according to claim 27 for use in the treatment of cancers.

    30. Use of a combination according to claim 27 in the manufacture of médicaments for use in the treatment of cancers.

    10 a -N(CH₃)₂ group or a 4-methyI-piperazinyl group.

    which is subjected to a reaction protecting the carboxylic acid fonction to yield the compound of formula (III):

    wherein R], R₂, R3, R4, R/,' and Y are as defined hereinbefore, and T represents a protecting group for the carboxylic acid function.

    which is subjected to coupling with a compound of formula (IV):

    (IV) wherein R7 and R_s are as defined for formula (I), to yield the compound of formula (V):

    wherein Ri, R2, R3, R-s. T and Y are as defined hereinbefore, and R<, is as defined in claim l, which is then subjected to a reaction deprotecting the carboxylic acid function,

    10. Compound of formula (I) according to claim 1, wherein R7 represents a methyl group or a hydrogen atom.

    10 cyano group, -NR₉R₉’, -Cyi or a halogen atom, ♦ R-2, R3 and R4 independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (Cj-C₆)alkyl group, a linear or branched (C2-C6)alkenyl group, a linear or branched (C2-Cô)alkynyl group, a linear or branched (Ci-Côjpolyhaloalkyl, a hydroxy group, a hydroxy(C|-C₆)alkyl group,

    15 a linear or branched (Ci-C₆)alkoxy group, a -S-(Ci-C₆)alkyl group, a cyano group, a nitro group, -alkyl(Co-C6)-NR₉R₉’, -O-alkyl(C|-C₆)-NR₉R₉’, -C(O)-OR₉, -O-C(O)-R₉, -C(O)-NR₉R₉’, -NR₉-C(O)-R₉’, -NR₉-C(O)-OR₉’,

    -alkyl(C|-C₆)-NR₉-C(O)-R₉’, -SO₂-NR₉R₉’, -SO₂-aIkyl(Cj-C₆), ♦ Rj represents a hydrogen atom, ♦ R₆ represents the group

    ♦ R? represents a hydrogen atom or a linear or branched (Ci-Cé)alkyl group, ♦ R_s represents a -O-P(O)(O')(O) group, a -O-P(O)(O')(OR_l0) group, a -0-P(0)(ORio)(ORio’) group, a -O-SO₂-O' group, a -O-SO₂-OR_l0 group, -Cy₂, a -O-C(O)-R₉ group, a -O-C(O)-OR9 group or a -O-C(O)-NR9R</ group;

    ♦ R₉ and R₉’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Céjalkyl group or a linear or branched amino(Ci-C₆)alkyl group, ♦ Rio and Rio’ independently of one another represent a hydrogen atom, a linear or branched (Ci-Côjalkyl group or an arylalkyl(C]-C6) group, ♦ Cyi and Cy₂ independently of one another, represent a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group.

    it being possible for the ammonium so defined to exist as a zwitterionic form or to hâve a monovalent anionic counterion, it being understood that:

    - “aryl” means a phenyl or naphthyl group, “heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10 ring members, having at least one aromatic moiety and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, “cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, and containing from l to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring Systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, to be substituted by from l to 4 groups selected from linear or branched (C|-C₆)alkyl, linear or branched (Cj-Câjalkenyl group, linear or branched (C₂-C₆)alkynyl group, linear or branched (Ci-Cfi)alkoxy, (Ci-Cô)alkyl-S-, hydroxy, oxo (or jV-oxide where appropriate), nitro, cyano, -C(O)-OR’, -O-C(O)-R’, -C(O)-NR’R”, -NR’R”, -(C=NR’)-OR”, linear or branched (Ci-Côjpolyhaloalkyl, trifluoromethoxy or halogen, it being understood that R’ and R” independently of one another represenl a hydrogen atom or a linear or branched (Ci-C₆)alkyl group, and it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceuticaîly acceptable acid or base.
11. 11. Compound of formula (I) according to claim 1, wherein Rx represents a -0-P(0)(0')(ORio) group in which Rio represents a hydrogen atom, a benzyl group or a methyl group.
12. 12. Compound of formula (1) according to claim 1, wherein Rs represents a 5-methyl-2-oxo-l,3-dioxol-4-yl group; a -O-C(O)-CH₃ group; a -O-C(O)-/Bu group; a -O-C(O)-CH₂-NH₂ group; a -O-C(O)-CH[CH(CH₃)₂]-NH₂ group; a -0-C(O)-O-CH₂CH₃ group; or a -O-C(O)-N(CH₂CH₃)₂ group.

    15
13. 13. Compounds according to claim 1, which are:
14. 14. A compound according to claim 1, which is {4-(2-(4-((55^)-4-((1/^)-1 -carboxy-2-(2{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}pheny])ethoxy]-6-(4fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl} -2-chloro-3-methylphenoxy)ethyl]-1 methylpiperazin-1-ium-1-yl (methyl hydrogen phosphate.

    15. A compound according to claim 1, which is {4-[2-(3-bromo-4-{(55’_a)-4-[(l/?)-lcarboxy-2-(2-{[2-(2-methoxyphenyl)pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chlorophenoxy)ethyl]-lmethylpiperazin-1-ium-1-yl}methyl hydrogen phosphate.

    16. A compound according to claim 1, which is {[2-(4-{(5S^, _a)-4-[(l/î)-l-carboxy-2-(2-{[2(2-methoxyphenyI)pyrimidin-4-yl]methoxy}phenyl)ethoxy]-6-(4fluorophenyl)thieno[2,3-i/]pyrimidin-5-yl}-2-chloro-3-
15. 15 31. Compound of formula (1), according to any one of daims 1 to 16, for use in the treatment of cancers requiring radiotherapy.