OA16962A - New phosphate derivatives, their preparation process and the pharmaceutical compositions which contain them. - Google Patents

Abstract

Compounds of formula (I): wherein X, Y, A1, A2, Ra, Rb, Rc, Rd, R3, R4, T and R5 are as defined in the description. Medicines.

Description

The present invention relates to novel phosphate derivatives, their preparation process and the pharmaceutical compositions which contain them.

The compounds of the present invention are new and exhibit very advantageous pharmacological and pharmacokinetic characteristics for their use in the field of apoptosis and cancerology.

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

Apoptotic cell death involves morphological changes, such as nucleus condensation, DNA fragmentation, as well as biochemical phenomena, such as the activation of caspases that will degrade key structural components of the cell for induce its disassembly and death. Regulation of the process of apoptosis is complex and involves the activation or suppression of several intracellular signaling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647656).

Deregulation of apoptosis is involved in certain pathologies. Increased apoptosis is linked to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and ischemia. Conversely, deficiencies in the performance of apoptosis play an important role in the development of cancers and their drug resistance, autoimmune diseases, inflammatory diseases and viral infections. Thus, escape from apoptosis is one of the phenotypic signatures of cancer (Hanahan D. 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 many types of cancer, such as colorectal cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, cancer bladder, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, follicular lymphoma, myeloma ... The overexpression of anti-apoptotic proteins of the Bcl-2 family is involved in tumorogenesis, in resistance to chemotherapy and in

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-2 clinical prognosis of cancer patients. There is therefore a therapeutic need for compounds which inhibit the anti-apoptotic activity of proteins of the Bcl-2 family.

The compounds of the present invention in addition to their novelty, exhibit pharmacological and pharmacokinetic properties allowing them to be used in pathologies involving an apoptosis defect, such as for example in the treatment of cancer, autoimmune diseases and the immune system.

The present invention relates more particularly to a phosphate compound of formula (1):

in which :

♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they cannot simultaneously represent two carbon atoms or two nitrogen atoms, ♦ At and A ₂ together with the atoms which carry them form a optionally substituted heterocycle Het, aromatic or not, consisting of 5, 6 or 7 members, and which may contain, in addition to the nitrogen represented by X or by Y, one to 3 heteroatoms chosen independently from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question can be substituted by a group representing an atom

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-3 of hydrogen, a linear or branched alkyl (CpCe) group or a -C (O) -O-Alk group in which Alk is a linear or branched (C ₂ -Ce) alkyl group, or else, Ai and A ₂ represent, independently of one another, a hydrogen atom, a linear or branched polyhaloalkyl (Ci-Ce), a linear or branched alkyl (Ci-Ce) group or a cycloalkyl, ♦ T represents a hydrogen atom, a linear or branched (C1-C6) alkyl optionally substituted with one to three halogen atoms, a (C | -C4) -NRiR ₂ alkyl group, or a (C | -C4) -OR6 alkyl group, ♦ Ri and Rj represent, independently of one another, a hydrogen atom or a linear or branched (C 1 -C 6) alkyl group, or else R 1 and R ₂ together with the nitrogen atom which carries them form a heterocycloalkyl, ♦ R ₃ represents a linear or branched alkyl (C ₁ -C 6), linear or branched (C ₂ -C ₆ ) alkenyl, linear or branched (C ₂ -Ce) alkynyl, cycloalkyl, cycloalkyl (C ₃ -C | o) alkyl (Ci -This) linear or branched, heterocycloalkyl, aryl or heteroaryl, it being understood that one or more carbon atoms of the preceding groups, or of their optional substituents, can (wind) be deuterated (s), ♦ R4 represents an aryl, heteroaryl, cycloalkyl or alkyl group (C | -Ce) linear or branched, it being understood that one or more carbon atoms of the preceding groups, or of their optional substituents, can be deuterated, ♦ R5 represents a hydrogen or halogen atom , a linear or branched (C | -Ce) alkyl group, or a linear or branched (Ci-C) alkoxy group, ♦ R6 represents a hydrogen atom or a linear or branched (C | -C6) alkyl group, ♦ R _a , Rb, Rc and Rj represent independently of each other R7, a halogen atom, a linear or branched (Ci-C-) alkoxy group, a hydroxy group, a linear or branched polyhaloalkyl (CpCe) group, a group trifluoromethoxy, -NR7R7 ', nitro, R7-CO-alkyl (C ₀ -C6) -, R7-CO-NH-alkyl (Co-C6) -, NR7R7'-CO-al kyl (Co-C6) -, NR7R7'-CO-alkyl (Co-C ₆ ) -0-, R7-SO2-NH-alkyl (C ₀ -C ₆ ) -, R7-NH-CO-NH-alkyl ( Co-C6) -, R7-0-CO-NH-alkyl (Co-Ci) -, a heterocycloalkyl group, or the substituents of one of the couples (R _a , R _b ), (Rb, Rc) or (Rc, Rd) together with the carbon atoms which carry them form a ring

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-4 consists of 5 to 7 members, which may contain from one to 2 heteroatoms chosen from oxygen and sulfur, it being also understood that one or more carbon atoms of the previously defined ring may (wind) be deuterated or substituted by one to 3 groups chosen from halogen or linear or branched alkyl (C i-Ce), ♦ R7 and R? ' independently of one another hydrogen, alkyl (Cj-alkyl) linear or branched, alkenyl (C ₂ -This) -straight or branched alkynyl (C ₂ -CO) -straight or branched alkyl, aryl or a heteroaryl, or else Rj and R7 'form together with the nitrogen atom which carries them a heterocycle consisting of 5 to 7 members, the compound of formula (I) being such that at least one of the carbon atoms which it constitute is substituted by one of the following phosphate groups: -OPO (OM) (OM '), -OPO (OM) (O'M | ⁺ ), -OPO (O'M | ⁺ ) (O'M2 ⁺ ) , -ΌΡΟ (Ο -) (Ο ·) Μ3 ²⁺ ,

-OPO (OM) (O [CH ₂ CH ₂ O] _n CH ₃ ), or -OPO (O'M | ⁺ ) (O [CH2CH2O] nCH3), wherein M and M 'independently represent one of the 'another a hydrogen atom, a linear or branched (Ci-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a cycloalkyl or a heterocycloalkyl, both consisting of 5 to 6 members, while Mi ⁺ and M2 ⁺ independently of each other represent a pharmaceutically acceptable monovalent cation, M ₃ ²⁺ represents a pharmaceutically acceptable divalent cation and n is an integer between! and 5,>

Being heard that :

- By aryl is meant a phenyl, naphthyl, biphenyl or indenyl group,

- By heteroaryl is meant any mono or bi-cyclic group consisting of 5 to 10 members, having at least one aromatic part, and containing from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen (including quaternary nitrogen),

- By cycloalkyl is meant any non-aromatic, mono or bi-cyclic carbocyclic group containing 3 to 10 members,

- By heterocycloalkyl is meant any non-aromatic mono or bicyclic group, fused or spiro, consisting of 3 to 10 members, and containing 1 to 3

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-5heteroatoms chosen from oxygen, sulfur, SO, SO ₂ or nitrogen, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and alkyl, alkenyl, alkynyl, alkoxy groups which may be substituted with 1 to 3 groups chosen from alkyl (Ci -Ce) linear or branched optionally substituted, 5 spiro (C ₃ -C ₆ ), linear or branched (C | -C6) alkoxy optionally substituted, (C | -C6) alkyl-S-, hydroxy, oxo (or Λ ^ -oxide where appropriate), nitro, cyano, -COOR ', -OCOR *, NR'R, linear or branched polyhaloalkyl (Cj-Ce), trifluoromethoxy, (Ci-CeJalkylsulfonyl, halogen, optionally substituted aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl optionally substituted by one or more halogen atoms or 10 alkyl groups, it being understood that R 'and R ”represent, independently of one another, a hydrogen atom or an alkyl group (C | -Ce) linear or branched optionally substituted, the Het group defined in formula (I ) which may be substituted with one to three groups selected from linear or branched (C 1 -C 6) alkyl, hydroxy, linear or branched (C 1 -Ce) alkoxy, NRi'Ri ”, or halogen, it being understood that R 1 and R 1 "have the same definitions as the groups R * and R" mentioned above, its enantiomers and diastereomers, as well as its addition salts with an acid or with a pharmaceutically acceptable base.

Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane sulfonic, camphoric, etc ...

Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

Among the preferred compounds of the invention are the compounds of formula (1) for which R4 represents a phenyl substituted in the para position by a group of formula

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-6-ΟΡΟ (ΟΜ) (ΟΜ '), -ΟΡΟ (ΟΜ) (Θ'Μι ⁺ ), -OPO (O'Mt ⁺ ) (O'M2 ⁺ ), -ΌΡΟ (Ο ·) (Ο *) Μ3 ²⁺ , -OP0 (0M) (0 [CH2CH ₂ 0] _n CH ₃ ), or -OPO (OW) (O [CH ₂ CH ₂ O] _n CH ₃ ), in which M and M 'independently represent the one of the other a hydrogen atom, a linear or branched alkyl (Ct-Ce) group, a linear or branched (C ₂ -Cé) alkenyl group, a linear or branched (Q-C6) alkynyl group, a cycloalkyl or heterocycloalkyl, both of which are 5 to 6 membered, while M | ⁺ and M2 ⁺ independently of one another represent a pharmaceutically acceptable monovalent cation, M3 ²⁺ represents a pharmaceutically acceptable divalent cation and n is an integer between 1 and 5, it being understood that the phenyl group can be optionally substituted by one or more halogen atoms.

The compounds of formula (1) in which R4 represents a phenyl or a pyrimidin-5-yl group, both substituted in the para position by a group of formula -OP0 (0'M | ⁺ ) (0'M ₂ ⁺ ), and more particularly still by a group of formula -ΟΡ0 (0 · Ν3 ⁺ ) (0 · Νη ⁺ ), are preferred.

Advantageously, X represents a carbon atom and Y represents a nitrogen atom. More advantageously still, the group:

represents a 5,6,7,8-tetrahydroindolizine, an indolizine or a dimethylated pyrrole.

Preferably, T represents a methyl, (morpholin-4-yl) methyl or 3- (morpholin-4-yl) propyl group.

In the preferred compounds of the invention, R _a and R <j each represent a hydrogen atom and (Rb, Rc) together with the carbon atoms which bear them form a 1,3-dioxolane group, a group 1, 4-dioxane, or else Ra, Rc and Rj each represent a

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-7 atom of hydrogen and Rb represents hydrogen or halogen.

In another embodiment of the invention, R _a and R <i each represent a hydrogen atom, Rb represents a halogen atom and Rc a methoxy group.

Alternatively, Ra, Rb and Rj each advantageously represent a hydrogen atom and Rc represents a NR7R7'-CO-alkyl (Co-C6) -0- group, and more preferably still Rc represents a 2-oxo-2- ( piperidin-1-yl) ethoxy.

Furthermore, R ₃ advantageously represents a group chosen from phenyl, 1 / 7indole, 177-pyrrolo [2,3-6] pyridine, pyridine, 1 // - pyrazole, 177-pyrroIe, and 2,3-dihydro-1 / 7pyrrolo [2,3-6] pyridine, these groups optionally comprising one or more substituents chosen from linear or branched (C1-C6) alkyl (and more preferably methyl), cyano, or trideuteriomethyl.

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

- 4 - [{[3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (17 /) yl] carbonyl} -l, 3-benzodioxol-5 -yl) -5,6,7,8-tetrahydroindolizin-lyl] carbonyl) (phenyl) amino] phenyl disodium phosphate,

4 - [{[5- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) yljcarbonyl} ph eny 1) -1,2 -dimethyl-1 77-pyrrol-3-yl] carbonyl} (pyridin-4yl) amino] phenyl disodium phosphate,. 4 - ({[5- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1/7) yljcarbonyl} phenyl) -1,2 -diméthyI-l 77-pyrrol-3-yI] carbonyl} [1 - (trideuteriomethyl) 177-pyrazol-4-yl] amino) disodium phenyl phosphate,

- 4 - [{[5- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1 //) yljcarbonyl} phenyl) -1, Disodium 2-dimethyl-1 J7-pyrrol-3-yl] carbonyl} (5-cyano-1,2-dimethyIl / 7-pyrrol-3-yl) amino] phenyl phosphate,

- 4 - [{[5- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1 //) yljcarbonyl} phenyl) -1, Disodium 2-dimethyl-1 // - pyrrol-3-yl] carbonyl} (5-cyano-1 -methyl-1 Hpyrrol-3-yl) amino] phenyl phosphate,

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4 - [{[5- (5-chloro-2 - ([(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1 //) yl] carbonyl} phenyl) -l , 2-dimethyl-1 // - pyrrol-3-yl] carbonyl} (1-methyl! -L // - pyrazol-

4-yl) amino] pheny! disodium phosphate,

4 - [(5-cyano-1,2-dimethyl! -L // - pyrro! -3-y!) {[5- (5-fluoro-2 - ([(3S) -3- (morpholin-4y ! methyl) -3,4-dihy droisoqui no! in-2 (12 /) - yl] carbonyl} pheny 1) -1,2-dimethyl 1-1 // pyrrol-3-y!] carbonyl} amino] phenyl disodium phosphate,

4 - [{[5- (5-fluoro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquino! In-2 (1 //) yl] carbonyl} phenyl) -l, 2-dimethylI-1 // - pyrrol-3-yl] carbonyl} (1-methyl-1 // pyrazol-4-yl) amino] phenyl phosphate, their enantiomers and diastereomers, as well as their salts of addition to a pharmaceutically acceptable acid or base.

The pharmacokinetic study of the phosphate compounds of formula (I) showed that they were converted in vivo into compounds of formula (Γ) characterized in that the phosphate function was metabolized into a hydroxy function. The compounds of formula (I) therefore behave as prodrugs of compounds of formula (Γ) of the following formula:

NOT

O in which:

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-910 ♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they cannot simultaneously represent two carbon atoms or two nitrogen atoms, ♦ A | and A ₂ together with the atoms which carry them form an optionally substituted heterocycle Het, aromatic or not, consisting of 5, 6 or 7 members, and which may contain, in addition to the nitrogen represented by X or by Y, one to 3 heteroatoms independently chosen from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-Cg) alkyl group or a -C (O) group -O-Alk in which Alk is a linear or branched (C | -Ce) alkyl group, or alternatively, Ai and A ₂ represent, independently of one another, a hydrogen atom, a polyhaloalkyl (C | -Ce ) linear or branched, a linear or branched (Cj-Cé) alkyl group or a cycloalkyl, ♦ T represents a hydrogen atom, a linear or branched (C | -Cé) alkyl optionally substituted with one to three halogen atoms , an alkyl group (Ci-C ₄ ) -NR | R ₂ , or an aIkyl (Ci-C ₄ ) -OR group, ♦ Ri and Rî represent independent em one from the other a hydrogen atom or a linear or branched alkyl group (Ci-Ce), or else R 1 and R 2 form with the nitrogen atom which carries them a heterocycloalkyl, ♦ R 1 represents a group linear or branched (Ci-Cé) alkyl, linear or branched (C ₂ -C ₆ ) alkenyl, linear or branched (Cî-Cè) alkynyl, cycloalkyl, cycloalkyl (C3-Cio) linear or branched (Ci-Ce) alkyl, heterocycloalkyl, aryl or heteroaryl, it being understood that one or more carbon atoms of the preceding groups, or of their possible substituents, can (wind) be deuterated (s), ♦ R ₄ represents an aryl, heteroaryl, cycloalkyl or alkyl group ( Ci-Cé) linear or branched, it being understood that one or more carbon atoms of the preceding groups, or of their possible substituents, can (wind) be deuterated (s), ♦ Rj represents a hydrogen or halogen atom , a linear or branched (C | -Ce) alkyl group, or a linear or branched (C 1 -C) alkoxy group, ♦ Re represents an atom hydrogen or a linear or branched (Ci-C ₆ ) alkyl group,

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-ίο- ♦ R ", Rb, Rc and R <j represent independently of each other R7, a halogen atom, a linear or branched alkoxy group (Cj-Ce), a hydroxy group, a polyhaloalkyl group (C | -Ce) linear or branched, a trifluoromethoxy group, -NR7R7 *, nitro, R7-CO-alkyl (Co-C ₆ ) -, R7-CO-NH-alkyl (Co-C6) -, NR7R7 * -CO-alkyl (C ₀ -C ₆ ) -, NR7R7 * -CO-alkyl (C ₀ -C ₆ ) -O-, R ₇ -SO ₂ -NH-alkyl (C ₀ -C ₆ ) -, R7-NH-CO- NH-alkyl (Co-C6) -, R7-0-CO-NH-alkyl (Co-C6) -, a heterocycloalkyl group, or the substituents of one of the couples (Ra, Rb), (Rb, Rc ) or (Rc.Rd) together with the carbon atoms which carry them form a ring consisting of 5 to 7 members, which may contain from one to 2 heteroatoms chosen from oxygen and sulfur, it being also understood that one or more carbon atoms of the previously defined cycle can be deuterated or substituted with one to 3 groups chosen from halogen or linear or branched (C | -Ce) alkyl, ♦ R7 and R7 * independently represent one of the other hydrogen, linear or branched (Ci-C6) alkyl, linear or branched (C ₂ -C $) alkenyl, linear or branched (C ₂ -C ₆ ) alkynyl, aryl or heteroaryl, or indeed R7 and R7 * together with the nitrogen atom which carries them form a heterocycle consisting of 5 to 7 members, it being understood that:

- By aryl is meant a phenyl, naphthyl, biphenyl or indenyl group,

- By heteroaryl is meant any mono or bi-cyclic group consisting of 5 to 10 members, having at least one aromatic part, and containing from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen (including quaternary nitrogen),

- By cycloalkyl is meant any non-aromatic, mono or bi-cyclic carbocyclic group containing 3 to 10 members,

- By heterocycloalkyl is meant any non-aromatic mono or bicyclic, fused or spiro group, consisting of 3 to 10 members, and containing from 1 to 3 heteroatoms chosen from oxygen, sulfur, SO, SO2 or nitrogen, aryl and heteroaryl groups, cycloalkyl and heterocycloalkyl thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups which may be substituted by 1 to 3

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-11groups chosen from optionally substituted linear or branched (C1-C6) alkyl, spiro (C3-C6), linear or branched (C 1 -C ₆ ) alkoxy optionally substituted, (Cj-C ^ alkyl-S-, hydroxy, oxo (or W-oxide where appropriate), nitro, cyano, -COOR ', -OCOR *, NR'R ”, linear or branched polyhaloalkyl (C1-C6), trifluoromethoxy, (C1-C6alkylsulfonyl, halogen, optionally substituted aryl , heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl optionally substituted by one or more halogen atoms or alkyl groups, it being understood that R 'and R ”represent, independently of one another, a hydrogen atom or a optionally substituted linear or branched (Ci-C6) alkyl group, the Het group defined in formula (Γ) possibly being substituted with one to three groups chosen from linear or branched (C | -C6) alkyl, hydroxy, (C | -Ce) linear or branched, NRi'Ri ”, or halogen, it being understood that R | 'and Ri have the same definitions as the groups R 'and R mentioned above, their enantiomers and diastereomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

The compounds of formula (Γ) possess pro-apoptotic properties and therefore exhibit major therapeutic interest in the treatment of cancers, autoimmune diseases and the immune system. In the present invention, it has been shown that by administering the phosphate compounds of formula (1), the in vivo exposure of compounds of formula (Γ) is optimized. Indeed, the solubility of the compounds of formula (I) is much higher than that of the compounds of formula (Γ). Therefore, the use of the compounds of formula (1) for the manufacture of pharmaceutical compositions is particularly advantageous from the pharmaceutical point of view.

The invention also extends to the process for preparing the compounds of formula (I), characterized in that the starting product of the compound of formula (II) is used:

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in which R _a , Rb, Rc and R <j are as defined in formula (Γ), compound of formula (II) which is subjected to a Heck reaction, in aqueous or organic medium, in the presence of a catalyst with palladium, a base, a phosphine and the compound of formula (III):

(III) in which the groups A], A ₂ , X and Y are as defined in formula (Γ) and Alk represents a linear or branched (C | -Ce) alkyl, to obtain the compound of formula (IV) :

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in which Ai, A2, X, Y, R _a , Rb, Rc and Rj are as defined in formula (Γ) and Alk is as defined above, compound of formula (IV) in which the aldehyde function is oxidized to acid carboxylic acid to form the compound of formula (V):

Afk

(V) in which Ai, A2, X, Y, R _a , R _b , R “and R <t are as defined in formula (Γ) and Alk is as defined above,

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-14compound of formula (V) which then undergoes peptide coupling with a compound of formula (VI):

(VI) in which T and R5 are as defined in formula (P), to result in the compound of formula (VII):

Alk

(VID in which Ai, A ₂ , X, Y, R _a , Rb, Rc, Rj. T and R; are as defined in formula (P) and Alk is as defined above, compound of formula (VII) whose ester function is hydrolyzed to yield the carboxylic acid or the corresponding carboxylate, which can be converted into an acid derivative such as acyl chloride or the corresponding anhydride, before being coupled with an amine NHR3R4, in which Rj and R4 have the same meaning as in formula (P), before being subjected to the action of a pyrophosphate, phosphonate or phosphoryl derivative under basic conditions, the compound thus obtained being able to be optionally hydrolyzed or hydrogenolysed, to yield the compound of formula (I),

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-15compound of formula (I) which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with an acid or with a pharmaceutically acceptable base and from which the isomers according to a conventional separation technique, it being understood that at any time deemed opportune during the process described above, certain groups (hydroxy, amino, etc.) of the reagents or synthesis intermediates can be protected and then deprotected for the needs of the synthesis.

The compounds of formulas (II), (III), (VI), as well as the amine NHR3R4, are either commercial or accessible to a person skilled in the art by conventional chemical reactions described in the literature.

More specifically, the phosphate compounds of formula (I) according to the invention will be useful in the treatment of chemo-resistant or radiation-resistant cancers, as well as in hematologic malignancies and small cell lung cancer.

Among the cancer treatments envisaged there may be mentioned, without being limited thereto, the treatment of cancers of the bladder, brain, breast, uterus, chronic lymphoid leukemia, colorectal cancer, cancer of the esophagus , liver, lymphoblastic leukemias, non-Hodgkin lymphomas, melanomas, hematologic malignancies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer and lung cancer with small cells. Among non-Hodgkin's lymphomas, there may be mentioned more preferably follicular lymphomas, mantle cell lymphomas, diffuse large B-cell lymphomas, small lymphocytic lymphomas and B-cell lymphomas of the marginal zone.

A subject of the present invention is also the pharmaceutical compositions containing at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention, there may be mentioned, more particularly those which are suitable for oral, parenteral, nasal or per

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-16 or transcutaneous, rectal, perlingual, ocular or respiratory and in particular simple or sugar-coated tablets, sublingual tablets, sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels , and drinkable or injectable ampoules.

The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments and ranges between 0.01 mg and 1 g per 24 hours in one or more takes.

Furthermore, the present invention also relates to the association of a compound of formula (1) with an anticancer agent chosen from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors, or antibodies, as well as pharmaceutical compositions containing this type of combination and their use for the manufacture of medicaments useful in the treatment of cancer.

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

The following Preparations and Examples illustrate the invention and do not limit it in any way.

Preparation 1: Acid 6- [1- (methoxycarbonyI) -5,6,7,8-tetrahydro-3-lndolizinyI] -

13-benzodioxole-5-carboxylic

Stage A t 1-Formyl-2-piperidine carboxylic acid

To a solution of 40 g of a racemic mixture of 2-piperidine carboxylic acid (0.310 mmol) in 300 ml of formic acid placed at 0 ° C, is added dropwise 200 ml (2.15 mmol) of acetic anhydride. The whole is then stirred at room temperature overnight. Then, the reaction medium is cooled to 0 ° C, hydrolyzed by the addition of 250 mL of water, and stirred for half an hour at 0 ° C before being concentrated to dryness. The oil thus obtained is taken up in 200 ml of methanol and then concentrated to dryness. The title product is obtained in the form of an oil with a yield of 98%. It is used

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-17directly, without further purification, for the next step.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 13.0 (m, 1H OH); 8.0-8.05 (2s, 1H aldehyde); 4.9-4.5 (2d, 1H a of N and COOH); 4.1-2.6 (m. 2H to a of N); 2.2-1.2 (m, 6H piperidine)

IR: v: -OH: 2000-3000 cm- ¹ acid; v:> C = O 1703 cm ^-1 wide band

Stage B15,6,7,8-Methyl tetrahydro-1-indolizine carboxylate

To a solution of 10 g of carboxylic acid obtained in Stage A (63.6 mmol) in 65 mL of dichloroethane are successively added 13.4 g of tosyl chloride (70.4 mmol), 11.5 mL of 2- Methyl chloroacrylate (113.5 mmol), then, dropwise, 17.8 mL of A 2 A 3 M triethylamine (127.2 mmol). The reaction medium is then brought to reflux for 1 h 30 min. It is then placed at room temperature, then 5 mL of methyl 2chloroacrylate (48.9 mmol) and, dropwise, 9 mL of W./V.JV-triethylamine (64 mmol) are added. The whole is heated at reflux overnight.

The environment reacts! is then diluted with methylene chloride, washed successively with a 1 M HCl solution, a saturated aqueous solution of NaHCO ₃ , then with brine until a neutral pH is obtained. The organic phase is then dried over MgSO ₄ , filtered, concentrated to dryness, and purified by chromatography on silica gel (heptane / AcOEt gradient). The title product is obtained in the form of an oil.

1 H * NMR δ (400 MHz; CDCl ₃ ; 300 ° K): 6.55-6.40 (d, 2H, tetrahydroindolizine); 3.91 (t, 3H methyl ester); 3.78 (s, 3H tetrahydroindolizine); 3.08 (t, 2H, tetrahydroindolizine);

1.95-1.85 (m, 4H, tetrahydroindolizine)

IR: v:> C = O 1692 cm ⁴ ester

Stage C: 3- (6-Formyl-l, 3-benzodioxol-5-y!) - 5,6,7,8-tetrahydro-l-indolizine carboxylate methyl

To a solution of 6.4 g of the ester obtained in Stage B (35.7 mmol) in 12 mL of Nfldimethylacetamide, 12.3 g of 6-bromo-1,3-benzodioxo! E-5carbaldehyde (53 , 6 mmol), 7 g of potassium acetate (71.4 mmol), then the whole is stirred under argon for 20 minutes. 1.3 g of palladium catalyst are then added

DUPLICATE

- 18dichlorobis (triphenylphosphine) palladium (II) (PdCl ₂ (PPhj) ₂ ) (1.8 mmol). The reaction medium is then heated at 130 ° C. for one hour before adding 139 μL of H ₂ O thereto. Heating is maintained at this same temperature overnight. The medium is allowed to return to ambient temperature, then it is diluted with AcOEt. Animal charcoal 5 (25 g per g of product) is added and the whole is stirred at room temperature for 1 hour, then filtered. The organic phase is then washed with water, dried over magnesium sulfate and concentrated to dryness. The crude product thus obtained is purified by chromatography on silica gel (heptane / AcOEt gradient). The title product is obtained in the form of an oil.

1 H NMR: δ (400 MHz; dmso-d6; 353 ° K): 9.65 (s, 1H, H aldehyde); 7.3-7.15 (2s, 2H, aromatic H); 6.45 (s, 1H tetrahydroindolizine); 6.20 (s, 2H methylenedioxy); 3.70 (s, 3H methyl ester); 3.5-4.0 (m, 2H tetrahydroindolizine); 3.05 (m, 2H tetrahydroindolizine); 1.85 (m, 4H tetrahydroindolizine)

IR: v:> C = O 1695 cm * ¹ ester; v:> C = O 1674 cm ' ¹

Stage D: 6- [1- (methoxycarbonyl) -5,6,7,8-tetrahydro-3-indolizinylJ-1,3benzodioxole-5-carboxylic acid

A solution is prepared containing 3.37 g of the compound obtained in Stage C (10.3 mmol) in

9.3 mL of acetone and 8.8 mL (80.24 mmol) of 2-methyl-2-butene, which is placed at 0 ° C. 9.3 mL of an aqueous solution containing a mixture of 3.3 g of sodium chlorite (NaClO ₂ ) (36.05 mmol) and 3.6 g of sodium dihydrogenphosphate monohydrate is added dropwise. (NaH ₂ PO 4) (25.75 mmol). The whole is then stirred at room temperature for 7 hours. Then, the reaction medium is concentrated in order to remove the acetone. The solid thus obtained is filtered, washed with water and then dried under vacuum at 40 ° C. overnight. The title product is obtained as a solid, which is used hereinafter without further purification.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 12.10 (m, 1H, H carboxylic acid); 7,406.88 (2s, 2H, aromatic H); 6.20 (s, 1H, H tetrahydroindolizine); 6.18 (s, 2H, H methylenedioxy); 3.70 (s, 3H, methyl ester); 3.55 (t, 2H tetrahydroindolizine); 3.00 (t, 2H tetrahydroindolizine); 1.80 (m, 4H, H tetrahydroindolizine)

DUPLICATE

-19IR: v: -OH: 3000-2000 cm- ¹ acid; v:> C = O 1686-1676 cm * ¹ ester + acid; v:> C = C <1608 cm ' ¹

Preparation ______ 2: 2- [1- (methoxycarbonyl) -5,6,7,8-tetrahydro-3indolizinyljbenzoic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C by 2-bromo-benzaIdehyde.

Preparation 3: 6-] 1- (Methoxycarbonyl) -3-indoIzinyl] -13 * benzodioxole-5carboxylic acid

Stage A: 1- (carboxymethyl) -1, 2-dihydropyridinium bromide

To a solution of 16.2 mL of pyridine (200 mmol) in 120 mL of ethyl acetate is added portionwise 27.8 g (200 mmol) of bromoacetic acid. The whole is then stirred at room temperature overnight. The precipitate thus obtained is filtered, then washed with cold ethyl acetate. After drying, the title product is obtained in the form of a powder which is used directly for the next step.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 9.15 (d, 2H, H aromatic pyridine); 8.7 (t, 1H, aromatic H); 8.25 (t, 2H, aromatic H); 5.65 (s, 2H, H CH2COOH) IR: v: C = O: 1732 cm- ¹ ; -OH acid: 2800 cm ' ¹

Stage B: Methyl 1-Indolizlnecarboxylate

To a suspension of 6.55 g of the pyridinium salt obtained in Stage A (30 mmol) in 240 20 mL of toluene, 16.7 mL of methyl acrylate (150 mmol), 4.2 mL of triethylamine are successively added. (30 mmol), then in portions 20.9 g of MnOl (240 mmol). The whole is then heated at 90 ° C for 3 hours. After cooling, the reaction medium is filtered through a celite cake and concentrated to dryness. The title product is then isolated by purification on silica gel (heptane / AcOEt gradient: 0-10%) in the form of an oil which crystallizes in the cold.

DUPLICATE

-20RMN * H: δ (300 MHz; dmso-d6; 300 ° K): 8.5 (d, 1H, H indolizine); 8.05 (d, 1H, H indolizine); 7.6 (s, 1H, H, indolizine); 7.15 (m, 2H, H indolizine); 6.85 (m, 1H, H indolizine); 4.25 (q, 2H, -C (O) CH ₂ CH ₃ ); 1.35 (t, 3H, -C (O) CH ₂ CH ₃ )

IR v: C = O ester: 1675 cm- ¹ ; C = C aromatics: 1634 cm ' ¹

Stage C: 6- [1- (methoxycarbonyl) -3-indolizinyll-l, 3-benzodioxole-5-carboxylic acid The procedure is carried out according to the protocol described in Steps C and D of Preparation 1.

Preparation 4: 4-ChIoro-2- [4- (ethoxycarbonyl) -1, 5-diinethyl-1H-pyrrOl-2yljbenzoic acid

Stage A: ethyl 1,2-Dimethyl-1H-pyrrole-3-carboxylate

Has a solution of 10 g of ethyl 2-methyl-1/7-pyrrole-3-carboxylate (65.3 mmol) and 8.95 mL (130.6 mmol) of methyl iodide in 70 mL of dimethylformamide placed at 0 ° C., 2.61 g (65.3 mmol) of 60% sodium hydride are added in three portions. The whole is then stirred at 0 ° C for 1 hour. Then, the reaction medium is hydrolyzed by the addition of 420 mL of ice-cold water. The reaction medium is then diluted with ethyl acetate, washed successively with 0.1 M HCl solution, saturated aqueous LIICl solution, then brine. The organic phase is then dried over MgSO4, filtered, concentrated to dryness, and purified by chromatography on silica gel (petroleum ether / AcOEt gradient).

1 H NMR: 6 (400 MHz; dmso-d6; 300K): 6.65 (d, 1H pyrrole); 6.3 (bd, 1H pyrrole); 4.1 (bq, 2H, OCH ₂ CHj); 3.5 (s, 3HN-pyrrole); 2.4 (s, 3H pyrrole); 1.5 (bt, 3H OCH ₂ CH ₃ ) IR: v:> C = O: 1688 cm- ¹ ; v: COC: 1172 cm ' ¹

Stage B, 5- (5-Chloro-2-formylphenyl) -l, 2-dimethyl-1H-pyrrole-3-carboxylate

To a solution of 10.5 g of the compound obtained in Stage A (62.8 mmol) in 65 mL of N, N · dimethylacetamide, 15.2 g of 2-bromo-4-chlorobenzaldehyde (69 mmol) are added successively, 12.3 g of potassium acetate (125.6 mmol), then the whole is stirred under argon for 20 minutes. 2.2 g of palladium catalyst PdChfPPhjh (3.14 mmol) are then added. The reaction medium is then heated to 130 ° C. overnight. We leave it

DUPLICATE

-21milieu return to room temperature, then diluted with dichloromethane. Animal charcoal (30 g) is added and the whole is stirred at room temperature for 1 hour, then filtered. The organic phase is then washed with water, dried over magnesium sulfate and concentrated to dryness. The crude product thus obtained is purified by chromatography on silica gel (petroleum ether / AcOEt gradient). The title product is obtained as a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 9.8 (s, 1H, formyl); 7.91-7.69-7.61 (aromatic d, 3H); 6.5 (s, 1H pyrrole); 4.2 (q, 2H, OCH ₂ CH ₃ ); 3.4 (s, 3H, CHj-N-pyrrole); 2.55 (s, 3H pyrrole); 1.28 (t, 3H, OCH ₂ CH ₃ )

Stage C; 4-Cltloro-2- [4- (ethoxycarbonyl) -1, 5-dimethyltyi-1H-pyrro! -2-yl / benzoic acid

A solution is prepared containing 12.85 g of the compound obtained in Stage B (42 mmol) and 35.7 mL (336 mmol) of 2-methyl-2-butene in a mixture consisting of 20 mL of acetone and 20 mL of tetrahydrofuran. 200 mL of an aqueous solution containing a mixture of 13.3 g of sodium chlorite (NaClO ₂ ) (147 mmol) and 14.5 g of sodium dihydrogenphosphate monohydrate (NaH ₂ PO4 ') are added dropwise. H ₂ O) (105 mmol). The whole is then stirred vigorously at room temperature for 7 hours. Then, the reaction medium is concentrated in order to remove the acetone. Ethyl acetate is added and the organic phase is washed with water, then concentrated to dryness. The residue is then taken up in a minimum of ethyl ether. The solid thus obtained is filtered, washed with ether and then dried under vacuum at 40 ° C. overnight. The title product is obtained in the form of a solid, which is used for the following without further purification.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 13 (m, 1H COOH),; 7.85-7.6-7.4l (d, dd, df, 3H, H aromatics); 6.3 (s, 1H, H pyrrole); 4.15 (q, 2H, OCH ₂ CH ₃ ); 3.25 (s, 3H, CH ₃ N-pyrrole); 2.5 (s, 3H, CH ₃ -pyrrole); 1.25 (t, 3H, OCH ₂ CH ₃ )

IR: v: -OH: 3100-2500 cm- ¹ acid; v:> C = O: 1681 cm ' ¹ ester + acid

Preparation S: 6- [4- (ethoxycarbony)) - 1 ^ -dimétbyl-1H-pyrrol-2-yl | -13benzodioxole-5-carboxylique

The procedure of Preparation 4 is carried out, replacing 2-bromo-4DUPLICATA • 22.

chlorobenzaldehyde used in Stage B by 6-bromo-l, 3-benzodioxole-5-carbaldehyde.

Preparation 6; 4-Fluoro-3-methoxy-2- [4- (ethoxycarbonyl) -l, 5-dimethyll // - py rro 1-2-y I] benzoic acid

The procedure is carried out according to the method of Preparation 4, replacing the 2-bromo-4chlorobenzaldehyde used in Stage B by 2-bromo-4-fluoro-3-methoxybenzaldehyde.

Preparation 7: 4-Fluoro-2- | 4- (ethoxycarbonyl) -1, 5-dimethyl-1f / -pyrrol-2yl] benzoic acid

The procedure is carried out according to the method of Preparation 4, replacing the 2-bromo-4chlorobenzaldehyde used in Stage B with 2-bromo-4-fluorobenzaldehyde.

Preparation 8 7- | 4- (Methoxycarbonyl) -1, 5-dimethyl-1/7-pyrrol-2-yI] -23dihy d ro-1,4-benzodio xin e-6-carboxy liquid acid

The procedure of Preparation 4 is carried out by replacing in Stage A the ethyl 2-methyl-1Hpyrrole-3-carboxylate with methyl 2-methyl-lZ7-pyrrole-3-carboxylate, as well as 2-bromo- 4-chlorobenzaldehyde used in Stage B by 7-bromo-2,3-dihydro-1,4benzodîoxi ne-6-carbaldehy de.

Preparation 9; 5-Benzyloxy-2- (1-methoxycarbonyl-5,6,7,8-titrahydroindolizin- acid

3-yl) benzoic

Stage A: methyl 3- (4-Ben ^ 'loxy-2-formyl-phenyl) -5,6,7,8-tetrahydroindolizine-1-carboxylate

5-Benzy) oxy-2-bromo-benzaldehyde (12.3 g, 42.2 mmol) is introduced into a flask in the presence of potassium acetate (8.3 g; 84.2 mmol) and 120 mL of dimethylacetamide. After degassing under argon, dichlorobis (triphenylphosphine) palladium (II) (1.04 g, 1.5 mmol) is added, then the mixture is degassed under argon before being heated at 100 ° C. for 16 h. After returning to ambient temperature, the reaction medium is poured into 200 ml of ethyl acetate, filtered through Celite, washed with water, then with brine. The combined aqueous phases are extracted with ethyl acetate. The organic phases are

DUPLICATE

-23séchées over sodium sulfate, filtered and concentrated under reduced pressure. The residue obtained is purified by chromatography on silica gel in order to obtain the title product.

Stage B: 5-Benzyloxy-2- (1-methoxycarbonyl-5,6,7,8-tetrabydroindolizin-3yl) benzoic acid

To a solution of the compound obtained in Stage B (4.63 g, 11.89 mmol) in 300 mL of acetone is added 2-methyl 1-2-butene (6.31 mL, 59 mmol). A solution of sodium dihydrogen phosphate monohydrate (6.56 g, 47.6 mmol) and sodium chlorite (2.69 g, 23.8 mmol) in 40 mL of water is then poured dropwise while maintaining the temperature. below 20 ° C. After 30 min of stirring at room temperature, the mixture is acidified with a 2M HCl solution, then decanted. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and evaporated to dryness to give the expected compound.

Preparation Γ î (3LS) -3- (4-Morpholinylmethyl) -1,23 »4-tetrahydroisoquinoline

Stage A: (3S) -3- (4-Morpliolinylcarbonyl) -3,4-dihydro-2 (1H) -isoquinoline carboxylate benzyl

To a solution of 5 g of (3S) -2 - [(benzyloxy) carbonyl] -l, 2,3,4-tetrahydro-3isoquïnolinecarboxylic acid (16 mmol) in 160 ml of dichloromethane are added 1.5 ml of morpholine (17.6 mmol), then 9 mL of 77.77, jV-triethylamine (64 mmol), 3.3 g of 1ethyl-3- (3'-dimethyl aminopropyl) -carbodiimide (EDC) (19.2 mmol ), and 2.6 g of hydroxybenzotriazole (HOBT) (19.2 mmol). The reaction medium is stirred at room temperature overnight, then it is poured into an aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase is then dried over magnesium sulfate, then filtered and evaporated to dryness. The crude product thus obtained is then purified by chromatography on silica gel (dichloromethane / methanol gradient). The product is obtained in the form of a foam.

1 H NMR: δ (400 MHz; dmso-d6; 353 ° K): 7.30 (m, 5H benzyl); 7.15 (aromatic m, 4H); 5.2-5.0 (m, 3H, 2H benzyl, 1H dihydroisoquinoline); 4.75-4.5 (2d, 2H

DUPLICATE

-24dihydroisoquinoline); 3.55-3.3 (m, 8H morpholine); 3.15-2.9 (2dd, 2H dihydroisoquinoline)

IR: v:> C = O: 1694; 1650cm ' ¹

Stage B: (3S) -3- (4 ~ MorphoHnylmethyl) ~ 3,4-dihydro ~ 2 (1H) -isoquinoline carboxylate benzyl

To a solution of 5.3 g of the product obtained in Stage A (13.9 mmol) in 278 mL of tetrahydrofuran are added 14 mL of borane-dimethylsulfide (BHî-MeîS) complex (27.8 mmol) at room temperature. The whole is heated for 4 hours at 80 ^g C. It is allowed to return to room temperature, then 7 ml (14 mmol) of BH ₃ -Me2S are added. The reaction medium is again heated to 80 ° C. for 2 hours. The tetrahydrofuran is then evaporated off, then methanol is slowly added, then 5.6 ml of 5M hydrochloric acid (27.8 mmol). The mixture is stirred at ambient temperature overnight, then at 80 ° C. for 1 hour. A saturated aqueous solution of NaHCO _{3 is then added} to the reaction medium at 0 ° C. until a pH = 8 is reached, then extraction is carried out with ethyl acetate. The organic phase is then dried over magnesium sulfate, then filtered and evaporated to dryness. The title product is obtained in the form of an oil.

1 H NMR: δ (400 MHz; dmso-d6; 353 ° K): 7.43-7.30 (solid, 5H benzyl); 7.19 (aromatic m, 4H); 5.16 (m, 2H, 2H benzyl); 4.79-4.29 (d, 2H dihydroisoquinoline); 4.58 (m, 1H dihydroisoquinoline); 3.50 (m, 4H morpholine); 3.02-2.80 (dd, 2H dihydroisoquinoline); 2.42-2.28 (solid, 5H, 4H morpholine, 1H morpholine); 2.15 (dd, 1H morpholine)

IR: v:> CH: 2810 cm- ¹ ; v:> C = O: 1694 cm- ¹ ; v:> COC <: 1114 cm '¹;v:> CH-Ar: 751; 697 cm ' ¹

Stage C: (3S) -3- (4-Morpholirtylmélhyl) ~ l, 2,3,4-tetraltydroisoquinolÎne

To a solution of 4.9 g of the compound of Stage B (13.4 mmol) in 67 mL of ethanol is added 0.980 g of palladium dihydroxide (20% by mass) at room temperature. The reaction medium is placed under 1.2 bar of hydrogen at room temperature for 4 hours. It is then passed through a Wathman filter, then the palladium is rinsed several

DUPLICATE

-25times with ethanol. The filtrate is evaporated to dryness. The title product is obtained in the form of an oil.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 7.12-7.0 (solid, aromatic 4H); 3.92 (s, 2H tetrahydroisoquinoline); 3.60 (t, 4H morpholine); 2.98 (m, 1H tetrahydroisoquinoline); 2.68 (dd, 1H tetrahydroisoquinoline); 2.5-2.3 (solid, 8H, 1H tetrahydroisoquinoline, 6H morpholine, 1HNH)

IR: v:> NH: 3322 cm- ¹ ; v:> COC <: 1115 cm '';v:> CH-Ar: 742 cm ''

Preparation 2 ': (3Æ) -3-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

Stage A: 13S) -2 - [(4-Methylphenyl) sulfonyl-1,2,3,4-tetrahydroisoquinolin-3-yl} methyl 4-methylbenzenesulfonate

To a solution of 30.2 g of [(3S) -l, 2,3,4-tetrahydroisoquinolin-3-yl] methanol (185 mmol) in 750 mL of dichloromethane are successively added 91.71 g of tosyl chloride ( 481 mmol), then, dropwise, 122.3 mL of MMAMriethylamine (740 mmol). The reaction medium is then stirred at room temperature for 20 h. It is then diluted with dichloromethane, washed successively with a 1M HCl solution, a saturated aqueous solution of NaHCO 3, then brine until neutral. The organic phase is then dried over MgSO ₄ , filtered, concentrated to dryness. The solid obtained is then dissolved in a minimum volume of dichloromethane, then cyclohexane is added until a precipitate forms. This precipitate is then filtered off and washed with cyclohexane. After drying, the title product is obtained in the form of crystals.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 7.75 (d, 2H, aromatic Hs, ortho O-tosyl);

7.6 (d, 2H, aromatic Hs, ortho N-tosyl); 7.5 (d, 2H, aromatic Hs, meta O-tosyl); 7.3 (d, 2H, aromatic Hs, meta N-tosyl); 7.15-6.9 (m, 4H, aromatic Hs, tetrahydro isoquinoline); 4.4-4.15 (dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 4.25 (m, 1H, aliphatic H, tetrahydroisoquinoline); 4.0-3.8 (2dd, 2H, aliphatic Hs, CH ₂ -O-tosyl); 2.7 (2dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.45 (s, 3H, O-SO ₂ -Ph-CHj); 2.35 (s, 3H, MSO ₂ -Ph- CH ₃ )

IR: v: -SO ₂ : 1339-1165 cm ' ¹

DUPLICATE. -26 Stage B: (3R) ~ 3-Methyl-2 - [(4-methylphenyl) sutfonylf-l, 2,3,4-tetrahydroisoqubtoline

To a suspension of 8.15 g (214.8 mmol) of L1AIH4 in 800 mL of methyl zm-butyl ether (MTBE), 101.2 g of the ditosylated derivative obtained in Stage A (214.8 mmol) in solution are added. in 200 mL of MTBE. The whole is then heated at 50 ° C for 2 hours. Allowed to cool and stand at 0 ° C, then add, dropwise, 12 mL of 5M NaOH solution. The whole is stirred at room temperature for 45 minutes. The solid thus obtained is then filtered off, washed with MTBE then with dichloromethane. The filtrate is then concentrated to dryness. We then obtain the title product in the form of a solid

NMR H: δ (400 MHz; dmso-d6; 300 ° K): 7.70 (d, 2H, aromatic Hs, ortho Ύ-tosyl);

7.38 (d, 2H, aromatic Hs, mixed JV-tosyl); 7.2-7.0 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.4 (m, 2H, aliphatic H, tetrahydroisoquinoline); 4.3 (m, 1H, aliphatic H, tetrahydroisoquinoline); 2.85-2.51 (2dd, 2H, aliphatic Hs, tetrahydro isoquinoline); 2.35 (s, 3H, / V-SO1-Ph-CH ₃ ); 0.90 (d, 3H, tetrahydroisoquinoline-CH ₃ ) IR ·. v: -SO ₂ : 1332-1154 cm ' ¹

Stage C: (3R) -3-Methyl-I, 2,3,4-tetrahydroisoqubtoline

To a solution of 31.15 g (103.15 mmol) of the monotosylated derivative obtained in Stage B in 500 mL of anhydrous methanol is added 3.92 g (161 mmol) of magnesium turnings by scoop. The whole is stirred in the presence of ultrasound for 96 hours. The reaction medium is then filtered and the solid is washed several times with methanol. The filtrate is then concentrated to dryness. After purification by chromatography on silica gel (dichloromethane / EtOH / NH4OH gradient), the title product is obtained in the form of an oil.

1 H NMR: δ (400 MHz; dmso-d6; 300 ^Q K): 7.05 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 3.90 (m, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.85 (m, 1H, aliphatic H, tetrahydroisoquinoline); 2.68-2.4 (2dd, 2H, aliphatic Hs, tetrahydro isoquinoline); 1.12 (d, 3H, tetrahydroisoquinoline-CH ₃ ); 2.9-2.3 (m, broad, 1H, HN (tetrahydroisoquinoline))

IR: v: -NH: 3248cm * ¹

DUPLICATE

-27 Stage D: (3R) -3-methyl-1,2,3,4-tetrahydroisoqiiinoline hydrochloride

To a solution of 14.3 g (97.20 mmol) of the compound obtained in Stage C in 20 mL of anhydrous ethanol is added, dropwise, 100 mL of a solution of 1 M hydrochloric ether. The whole is stirred at room temperature for 1 hour, then filtered. The crystals thus obtained are washed with ethyl ether. After drying, the title product in the form of crystals.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 9.57 (m, broad, 2H, NH ₂ ⁺ (tetrahydro isoquinoline); 7.22 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.27 (s, 2H, aliphatic H, tetrahydroisoquinoline); 3.52 (m, 1H, aliphatic H, tetrahydroisoquinoline); 3.03-2.85 (2dd, 2H, aliphatic H, tetrahydroisoquinoline); 1.39 ( d, 3H, tetrahydro isoquinoline-CH ₃ )

IR: v: -NH ₂ ⁺ : 3000-2300 cm- ¹ ; v: -CH aromatic: 766 cm ' ¹

Preparation 3 *: i3 /? Î-3-f3-fMon) holin-4-vl) DroDvll-U3.4-tetrahv (ÎroÎsoquinoline

Stage A: {(3S) -2 - [(4-Methylphértyl) sulfoitylJ-l, 2,3,4-telrahydroisoquîrtolin-3-yl} methyl 4-methylbenzèrtesiilfonate

The process is identical to that of Stage A of Preparation 2 ’.

Stage B 12- (i3R) -2-l ('4-Methvlphénvl) sidfbnvU-l, 2,3,4-tetrahydroîsoqubtolin-3yl} methyl) -3- (morpholin-4 ~ yl) -3 ~ tert- oxopropanoate butyl

To a suspension of 1 g of NaH (60%) (25.08 mmol) in 30 mL of MTBE is added dropwise a solution of 5 g of Zeri-butyl 3-morpholino-3-oxopropanoate (21.81 mmol) in 20 mL of anhydrous MTBE. This suspension is stirred at room temperature for 1 h, then the compound obtained in Stage A is added in the form of a powder. The whole is stirred at 60 ° C for 30 hours. A solution of 100 mL of a saturated aqueous solution of ammonium chloride is added. This solution is extracted with dichloromethane. The organic phase is then dried over MgSCh, filtered and concentrated to dryness. After purification by chromatography on silica gel (dichloromethane / MeOH gradient), the expected product is obtained in the form of an oil.

DUPLICATE

-28RMN * H (500 MHz, dmso-d6) δ ppm: 7.63 / 7.59 (2d, 2H); 7.3 / 7.26 (2d, 2H); 7.13 (m, 2H); 7.09 / 6.97 (2t, 2H); 4.64 / 4.55 / 4.36 / 4.28 (2AB, 2H); 4.25 / 4.11 (2m, 1H); 3.81 (m, 1H); 3.73-3.48 (m, 4H); 3.57-3.32 (m, 4H); 2.51 (m, 2H); 2.32 / 2.31 (2s, 3H); 1.88 / 1.79 (2m, 2H); 1.39 / 1.38 (2s, 9H)

IR (ATR) cm ′ ¹ : v:> C = O: 1731 (ester); v:> C = O: 1644 (amide); v: -SO2: 13341156; v:> COC <: 1115; γ:> CH-Ar: 815-746-709

Stage C; 2 - ({(3R) -2 - [(4-methylphenyl) sulfonylJ-l, 2,3,4-tetrahydroisoquîno! In-3yljméthyI) -3- (morpholin-4-yl) -3 ~ oxopropanoic acid

To a solution of 9.5 g (17.97 mmol) of the compound obtained in Stage B in 40 mL of dioxane is added dropwise 20 mL of a solution of 4M hydrochloric acid in dioxane. The whole is stirred at room temperature for 48 hours, then the solution is concentrated to dryness. After drying, the expected product is obtained in the form of an oil.

1 H NMR (400 MHz, dmso-d6) δ ppm: 12.75 (m, 1H); 7.6 (2 * d, 2H); 7.3 (2 * d, 2H); 7.1 / 6.95 (2 * m, 4H); 4.7-4.2 (d, 2H); 4.25 / 4.12 (2 * m, 1H); 3.9-3.3 (m, 9H); 2.55 (d, 2H); 2.3 (2 * s, 3H); 1.8 (t, 2H).

IR (ATR) cm ′ ¹ : v: -OH: 3500 to 2000; v:> C = O: 1727 (acid); v:> C = O: 1634 (amide); v: -SO2: 1330-1155

Stage D t 3 - {(3R) -2 - [(4-Methylplienyl) sulfonylJ-l, 2,3,4-tetrahydroÎsoquino! In-3-yl} -l (morphoHn ~ 4-yl) propan ~ J ~ one

To a solution of 7.80 g (16.51 mmol) of the compound obtained in Stage C in 100 mL of DMSO, 1.16 g (19.83 mmol) of solid sodium chloride is added, then 5 mL of solid sodium chloride is added dropwise. 'water. The whole is stirred at 130 ° C. for 1 h, then the solution is concentrated to ³ A. The reaction medium is then diluted with dichloromethane, washed successively with a saturated aqueous solution of lithium chloride, then with brine. The organic phase is then dried over MgSCh, filtered and concentrated to dryness. After purification by chromatography on silica gel (cyclohexane / ethyl acetate gradient), the expected product is obtained in the form of an oil.

DUPLICATE

-29RMN ’H (400 MHz, dmso-d6) δ ppm: 7.65 (d, 2H); 7.3 (d, 2H); 7.15 / 7 (2m, 4H); 4.6 (d, 1H); 4.25 (d, 1H); 4.2 (m, 1H); 3.5 (m, 4H); 3.4 (2m, 4H); 2.6 (2 dd, 2H); 2.35 (s, 3H); 2.3 (m, 2H); 1.5 (quad, 2H)

IR (ATR) cm ' ¹ : v:> C = O: 1639; v: -SO2: 1331-1156; γ:> CH-Ar: 815-675

Stage E; (3R) -2 - [(4-Methylphenyl) sulfony! J-3- [3- (morpholin-4-yl) propylJ-l _t 2,3,4 ~ tetrahydroisoquinoline

To a solution of 6.0 g (14.0 mmol) of the compound obtained in Stage D in 60 ml of MTBE and 14 ml of dichloromethane, 1.06 g (28 mmol) of LAH is added per portion over 5 minutes. The whole is stirred at room temperature for 15 h. 1.5 ml of water are added dropwise and the mixture is stirred for 15 min. Then, 1.5 ml of 5 M sodium hydroxide are added dropwise and the mixture is stirred for 15 min. The reaction medium is then diluted with MTBE and dichloromethane. Then, the suspension is filtered and the precipitate is washed with MTBE and dichloromethane. The organic phase is then dried over MgSOj, filtered, and concentrated to dryness. After purification by chromatography on silica gel (dichloromethane / EtOH / NH4OH gradient), the expected product is obtained in the form of an oil.

¹ H NMR (400 MHz, dmso-d6) δ ppm: 7.68 (d, 2H); 7.32 (d, 2H); 7.1 (solid, 4H); 4.65 / 4.23 (AB, 2H); 4.2 (m, 1H); 3.55 (t, 4H); 2.7 / 2.6 (ABx, 2H); 2.35 (s, 3H); 2.25 (t, 4H); 2.2 (t, 2H); 1.4 / 1.3 (2m, 4H).

IR (ATR) cm ¹ : v: -SO2: 1333-1158

Stage F: (3R) -3- [3- (Morpholin-4-yl) propylJ-I, 2,3,4-tetrahydroisoquinoline

To a solution of 1.50 g (3.62 mmol) of the derivative obtained in Stage E in 20 ml of anhydrous methanol is added 2.0 g (82.3 mmol) of magnesium turnings by scoop. The whole is stirred in the presence of ultrasound for 96 h. The reaction medium is then filtered, the solid is washed several times with methanol, and the filtrate is concentrated to dryness. After purification by chromatography on silica gel (dichloromethane / EtOH / NH4OH gradient), the expected product is obtained in the form of an oil.

DUPLICATE

-30RMN ’H (400 MHz, dmso-d6) δ ppm: 7.3 (d, 2H); 7.1 (t, 2H); 7.1 (d + t, 3H); 7 (d, 2H); 3.9 (s, 2H); 3.55 (t, 4H); 2.75 (m, 1H); 2.72 / 2.45 (dd, 2H); 2.35 (t, 4H); 2.25 (t, 2H); 1.6 (m, 2H); 1.45 (m, 2H)

IR (ATR) cm * ': v:> NH2 + / NH +: 3500-2300; v:> C-O-C <: 1115

High resolution mass (ESI + -ÎFIA / HR):

Molecular formula: C _{) 6} H ₂₄ N ₂ O [M + H] ⁺ calculated: 261.1961 [M + H] ⁺ measured: 261.1959

Preparation 4 *: (3Jî) -3- (4-Mo rpholiny Imé thy 1) -1,2,3,4-tetrahydroisoquin olin e

The procedure is carried out according to the process of Preparation 1 ', replacing the (3S) -2 [(benzyloxy) carbonyl] -1, 2,3,4-tetrahydro-3-isoquinoIinecarboxylic acid used in Stage A by the (3Æ) acid ) -2 - [(benzyloxy) carbonyl] -1, 2,3,4-tetrahydro-3-isoquinolinecarboxylic.

Preparation 1 ”: 4 - {[fôrt-Butyl (dimethyl) silyl] oxy) -jV-phenylaniline

To a solution of 12 g of 4-anilinophenoI (64.7 mmol) in 200 mL of acetonitrile are added at room temperature 6.7 g of imidazole (97.05 mmol) and 11.7 g of tertbutyl (chloro) dimethylsilane (77.64 mmol). The whole is stirred at 70 ° C for 4 hours. Then, the reaction medium is poured into water and extracted with ether. The organic phase is then dried over magnesium sulfate, then filtered and evaporated to dryness. The crude product thus obtained is then purified by chromatography on silica gel (petroleum ether / dichloromethane gradient). The title product is obtained in the form of a powder.

H NMR: δ (400 MHz; dmso-d6; 300 ° K): 7.84 (s, 1H NH); 7.17 (t, 2H aniline); 6.98 (d, 2H phenoxy); 6.94 (d, 2H aniline); 6.76 (d, 2H phenoxy); 6.72 (t, 1H aniline); 0.95 (s, 9H / erf-butyl); 0.15 (s, 6H dimethyl)

IR: v:> NH: 3403 cm ¹ ;> Ar: 1597 cm ⁴

DUPLICATE

-31Preparation 2 ”t jV- (4 - ([/ eri-Butyl (dimethyl) silyl] oxy} phenyl) -l-methyl-1 // - indol-5amine

The procedure of Preparation 5 ”is carried out by replacing the 4-bromo-1-methyl-1Hpyrazole used in Stage B by 5-bromo-1-methyl-1H-indole.

Preparation 3 ”: ΛΓ- (4- {[fert-Butyl (dimethyl) silyl] oxy} phenyl) -l-methy] -lWpyrrolo [23-5] pyridin-5-amine

The procedure is carried out according to the method of Preparation 5 ”, replacing the 4-bromo-1-methyl-1Hpyrazole used in Stage B by 5-bromo-1-methyl! -1 // - pyrrolo [2,3 - &] pyridine (obtained according to a protocol in the literature: Heterocycles, 60 (4), 865,2003).

IR: v: -NH-: 3278 cm 2; v: -C = C- aromatics: 1605 cm * ¹

Preparation 4 **: jV- (4 - {[terr-ButyI (dimethyI) silyl] oxy} phenyI) pyridin-4-anrine

The procedure of Preparation 5 ”is carried out by replacing the 4-bromo-1-methyl-1Hpyrazole used in Stage B by 4-bromopyridine.

IR: v -NH-: 3200 and 2500 cm * ¹ ; v -Si-O-: 902 cm ^-1 ; v -Si-C-: 820 cm ' ¹

Preparation 5 ”; JV- (4 - {[fert-ButyI (dimethyl) silyl] oxy} phenyl) "l-methyl-1HpyrazoM-amine

Stage A. · 4 - {[tert-Butyl (dimethyl) silylJoxy} an 'dine

The title compound is obtained from 4-aminophenol in THF in the presence of imidazole and / er / -butyl (chloro) dîmethylsilane according to the protocol described in the literature (S. Knaggs et al, Organic ά Biomolectdar Chemistry , 3 (21), 4002-4010; 2005).

1 H NMR: δ (400 MHz; dmso-d6; 300K): 6.45-6.55 (dd, 4H, aromatic Hs); 4.60 (m, 2H, NH ₂ -Ph); 0.90 (s, 9H, Si (CH ₂ ) ₂ CH (CH ₃ ) ₂ ); 0.10 (s, 6H, Si (CH ₂ ) ₂ CH (CH ₃ ) ₂ ) IR: v: -NH ₂ ⁺ : 3300-3400 cm ' ¹

DUPLICATE

-32 Stage B; N-] 4-hert-Butv! (Dimethvl} silvUoxvphénvl] -l-methvl-Dvrazol-4-amine

To a solution of 30.8 g (0.137 mol) of the compound of Stage A in 525 mL of anhydrous toluene, 29.8 g of sodium ierr-butoxide (0.310 mol), 4.55 g of Pd ₂ (dba) are successively added. ₃ (also called tris (dibenzylideneacetone) dipalladium (0)) (4.96 mmol), 4.81 g of 2-di-teri-butylphosphino-2 ', 4', 6'-tri-isopropyl-l, r- biphenyl (9.91 mmol) and 12.8 mL of

4-Bromo-1-methyl-1 H-pyrazole (0.124 mol). The whole is degassed under argon for 30 min and then heated to reflux for 3 h. Leave to cool. The reaction medium is concentrated to dryness, then taken up in dichloromethane, filtered through Celite, then again concentrated to dryness. The residue is then purified by chromatography on silica gel (CH ₂ Cl ₂ / AcOEt gradient) to provide the expected product in the form of a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 7.55 (s, 1H, pyrazole); 7.23 (s, 1H, pyrazole); 7.18 (broad s, 1H, NH ₂ -Ph); 6.64 (m, 4H, aromatic H); 3.77 (s, 3H, CH3-pyrazole); 0.90 (s, 9H, Si (CH ₂ ) ₂ CH (CHj) ₂ ); 0.12 (s, 6H, Si (CH ₂ ) ₂ CH (CH ₃ ) ₂ )

IR: v -NH ⁺ : 3275 cm- ¹ ; v Ar and C = N: 1577 el 1502 cm- ¹ ; v -Si-C-: 1236 cm- ¹ ; v -Si-O-: 898 cm- ¹ ; v -Si-C-: 828.774 cm ' ¹

Preparation 6 ”: JV- {4 - [(feri-ButyIdimethylsilyl) oxyJphenyl} -l-trideuteriomethyl-1Hpyrazol-4-amine

Stage A t 4-Bromo-1-trideuteriomethyl-1 H-pyrazole

4-Bromo-1 H-pyrazole (9.05 g, 61.6 mmol) is added portionwise to a suspension of sodium hydride (60% in oil) (2.83 g, 70.8 mmol) ) in tetrahydrofuran (90 mL) cooled in an ice bath. After removing the ice bath, the solution is stirred at room temperature for 0.5 h. This is again cooled in an ice bath and riodomethane (5.0 mL, 80.3 mmol) is added. The solution is stirred at room temperature for 19 h. The suspension is then concentrated. The evaporation residue is triturated with fortz-butylmethyl ether (90 mL) and filtered. The filtrate is concentrated in vacuo to obtain the expected compound in the form of an oil.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm: 7.37 (s, 1H); 7.43 (s, 1H)

DUPLICATE

-33 Stage B: N-f4-l (tert-BiitvldîméthybUvl) oxvlphenyll-I-trideuteriomethyl-1H-pyrazol-4 amine

4-Bromo-1-trideuteromethyl-1H-pyrazole (9.6 g, 58.5 mmol), 4 - [(/ erfbutyldimethylsilyl) oxy] aniline (14.4 g, 64.6 mmol) and toluene (150 mL) are added in a 500 mL three-necked flask. The solution is degassed with nitrogen for 15 minutes, then sodium / erf-butoxide (11.4 g, 0.12 mol), 2-di- / erf-butylphosphino-2 ', 4', 6 'triisopropylbiphenyl (0.77 g, 1.81 mmol) and tris (dibenzylideneacetone) dipalladium (0) (1.64 g, 1.79 mmol) are successively added. The suspension is heated to 85 ° C for

1.5 hrs. The reaction mixture is then cooled to room temperature and water (270 mL) is added. The mixture is stirred for 30 minutes. Then we add

Celite (30 g) and the suspension is filtered through a bed of Celite. The phases of the filtrate are separated and the aqueous phase is extracted with ethyl acetate (3 x 200 mL). The combined organic phases are dried with sodium sulfate and filtered. The product is purified by chromatography on silica gel (ethyl acetate / heptane gradient). The product obtained is recrystallized from heptane (80 mL) to obtain the expected compound.

1 H NMR (400 MHz, CDCl 3) δ ppm: 0.16 (s, 6H); 0.97 (s, 9H); 4.92 (s, 1H); 6.61-6.73 (m, 4H); 7.25 (s, 1H); 7.36 (s, w H)

* ³ C NMR (100 MHz, CDClj) δ ppm: -4.37; 18.28; 25.86; 38.67 (seven, V _C -d = 21.0 Hz); 115.12; 120.73; 123.76; 126.52; 134.74; 141.07; 148.43

MS (ESI): [M + H] ⁺ 307.08

Preparation 7 ”: 4- ({4 - [(tert-Buty ldimethylsilyl) oxy] phenyl} am ino) -l, 5-dimethylI / Z-pyrrole-2-carbonitrile

Stage A - 4-Bromo-1,5-dimethyl-1 H-pyrro-2-carbonitrile

A solution of bromine (6.58 mL, 0.13 mol) in acetic acid (60 mL) is added dropwise using an addition funnel in a solution of 1,5-dimethyl -1Hpyrrole-2-carbonitrile (15.0 g, 0.12 mol) in acetic acid (300 mL). The whole is stirred at room temperature for 24 hours. The reaction mixture is then poured into a beaker containing 300 mL of water. The solid formed is filtered off and rinsed with water.

DUPLICATE

-34Then, it is solubilized in dichloromethane (300 mL) and the organic phase is washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo to give the expected product in the form of a solid.

1 H NMR (CDCh) δ ppm: 2.25 (s, 3H); 3.67 (s, 3H); 6.74 (s, 1H)

Stage B; 4 - ({4 - [(tert ~ Biityldimethylsilyl) oxyJplienyl} amino) -l, 5-dimethyll-lli-pyrrole-2carbonîtrile

A solution of the compound of the previous stage (1.5 g, 7.53 mmol), of 4 - [(ter / butyldimethylsilyl) oxy] aniline (2.02 g, 9.04 mmol), of sodium ZerZ-butoxide ( 1.45 g, 15.06 mmol) and 2-di-zerZ-butylphosphino-2 ', 4', 6'-triisopropylbiphenyl (0.13 g, 0.30 mmol) in toluene (20 mL) is purged with nitrogen. Tris (dibenzylideneacetone) dipalladium (0) (0.28 g, 0.30 mmol) is added, then the reaction mixture is heated to 90 ° C until the reaction is complete (followed by TLC). The heating is stopped and the mixture is allowed to come to room temperature. Water (75 mL) is added and the mixture is extracted with ethyl acetate (3 x 75 mL). The combined organic phases are washed with brine and then concentrated. The crude product is purified by flash chromatography on silica gel (ethyl acetate / heptane gradient). The product thus obtained is dissolved in hot heptane and allowed to precipitate with stirring at room temperature, then at 0 ° C. The solid is filtered off and the operation is repeated on the filtrate to give the expected compound in the form of a solid.

1 H NMR (400 MHz, CDCl 3) δ ppm: 0.15 (s, 6H); 0.97 (s, 9H); 2.13 (s, 3H); 3.66 (s, 3H); 4.68 (broad s, 1H); 6.49 (d, J = 8.5Hz, 2H); 6.64 (s, 1H); 6.66 (d, J = 8.7Hz, 2H) ¹³ C NMR (100 MHz, CDCl) δ ppm: 4.34; 9.72; 18.30; 25.88; 32.94; 101.27; 114.37;

114.70; 116.41; 120.73; 124.52; 131.23; 141.54; 148.27

MS (ESI +): [M + H] ⁺ measured: 342.3

Preparation 8 ”: 4 -] (4 - {] ZerZ-Butyl (dimethyl) silyl] oxy) phenyl) amino] -l-methyl-1 // pyrrole-2-carbonitrile

DUPLICATE

-35 Stage A: 1-Methyl-1H-pyrrole-2-carbonitrile

Ν, ΛΓ-dimethylformamide (3 mL) and 1,4-diazabicyclo [2.2.2] octane (0.49 g, 4.3 mmol) are added to a solution of pyrrole-2-carbonitrile (4 g, 43 , 4 mmol) in dimethylcarbonate (56 mL). The solution is stirred at 90 ° C for 15 h, then heated at 110 ° C for 8 h. The mixture is cooled to room temperature, then ethyl acetate (80 mL) is added. The phases are separated and the organic phase is washed with water (2 x 80 mL) and a 1 M aqueous solution of hydrochloric acid (1 x 80 mL). The combined aqueous phases are extracted again with ethyl acetate (1 x 80 mL). The combined organic phases are washed with brine (1 x 80 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to obtain the expected product as a liquid.

1 H NMR (400 MHz, CDCl 3) δ ppm: 3.78 (m, 2H); 6.12-6.18 (m, 1H); 6.74-6.82 (m, 1H)

Stage B: 4-Bromo-1-methyl-1H-pyrrole-2-carbonitrile

ΛΓ-Bromosuccinimide (6.2 g, 34.9 mmol) is added to a solution of 1-methyl-1 // pyrrole-2-carbonitrile (3.7 g, 34.9 mmol) in NN-dimethylformamide ( 150 mL). The solution is stirred for 15 h at room temperature. A further quantity of Nbromosuccinimide (2.0 g, 11 mmol) is added and the mixture is stirred for 3 h. The product is purified by chromatography on silica gel (AcOEt / heptane gradient) to obtain the expected product in the form of a solid.

1 H NMR (400 MHz, CDCl 3) δ ppm: 3.77 (s, 3H); 6.75 (d, J = 1.7Hz, 1H); 6.80 (d, J =

1.7 Hz, 1 H)

Stage C. · 4-f (tert-Butvldimethvlsllyl) oxylphértyl} amino) -l-methyl-1H-pyrrole-2carbortitrile

Nitrogen is allowed to bubble for 5 minutes in a solution of 4-bromo-1-methyl-1Hpyrrole-2-carbonitrile (2.82 g, 15.2 mmol) and 4 - [(fert-butyldimethylsilyl) oxy] aniline (4.08 g, 18.3 mmol) in toluene (55 mL). Sodium ierf-butoxide (2.92 g, 30.4 mmol), tris (dibenzylideneacetone) epalladium (0) (556 mg, 0.6 mmol) and 2-di-teriDUPLICATA

-36butylphosphmo-2 ', 4', 6'-triisopropylbiphenyl (255 mg, 0.6 mmol) are then added to the reaction mixture. The medium is stirred for 1 h at 80 ° C. under nitrogen. The suspension is then cooled to room temperature and filtered through Celite. The Celite pad is then rinsed with ethyl acetate. The filtrate is washed with water and then with brine. The organic phase is dried over magnesium sulfate, filtered and concentrated in vacuo. The product is purified twice by chromatography on silica gel (AcOEt / heptane gradient), then by trituration in heptane to obtain the expected product in the form of a solid.

1 H NMR (400 MHz, CDCl ₃ ) δ ppm: 0.16 (s, 6H); 0.97 (s, 9H); 3.73 (s, 3H); 6.57 (d, J, 1.9Hz, 1H); 6.64-6.66 (m, 1H); 6.70 (s, 4H)

^1J C NMR (100 MHz, CDCl 3) δ ppm: -4.48; 18.17; 25.72; 35.46; 103.01; 113.56; 113.69; 115.92; 119.55; 120.67; 129.04; 139.94; 148.85

MS (ESI +): [M + H] ⁺ 328.25

The amines NHR3R4 in which R3 and R4 represent, independently of one another, an aryl or heteroaryl group are obtained according to the methods described in the literature (Surry DS et al., Chemical Science, 201), 2,27-50, Charles MD et al., Organic Letters, 2005, 7, 3965-3968). The reaction for protecting the hydroxy function of 4anilinophenol described in Preparation 1 ”can be applied to various secondary amines NHR3R4 (as defined above), comprising one or more hydroxy functions, when these are commercially available. Alternatively, the secondary amines comprising at least one hydroxy substituent can be synthesized directly in a protected form, i.e. from reagents whose hydroxy function has been protected beforehand. Among the protective groups, / er / -butyl (dimethyl) silyloxy and benzyloxy are particularly preferred.

Among the NHR3R4 amines comprising a hydroxy substituent which are used to synthesize the compounds of the invention, there may be mentioned: 4- (4-toluidino) phenol, 4- (4chloroanîlino) phenoi, 4- (3-fluoro- 4-methylanilino) phenol, 4- [4 (trifluoromethoxy) anino] phenol, 4- [4-hydroxyanilino] phenol, {4 - [() - methyl-1Hindol-6-yl) amino] phenyl} methanol, 4- (2,3-dihydro-1 // - indol-6-ylamino) phenol, 4 [(1 -methyl-2,3-dîhydro-1 W-indol-6-yl) amino] phenol, 4 - [(1 -methyl-1 H-indol-6DUPLICATA

-37yl) amino] phenol, 4 - [(1-methyl-1/7-indol-6-yl) amino] cyclohexanol, 4 - [(l-methyl1,2,3,4-tetrahydro-6-quinolinyl ) amino] phenol, 4 - [(4-methyl-3,4-dihydro-2 // - 1,4benzoxazin-7-yl) amino] phenol, 4- [4- (diethylamino) anilino] phenol, 4- (2,3-dihydrol // - inden-5-ylamino) phenol, 4 - [(l-methyl] -l // - indazol-5-yl) amino] phenol, 4 - ((Γ5 methyl -r, 2'-dihydrospiro [cyclopropane-1,3'-indol] -5'-yl) amino] phenol, 4 - ((1,3,3trimethyl-2,3-dihydro-1 // - indol- 5-yl) amino] phenol, 4- [4-methoxy-3 (trifluoromethyl) anilino] phenol, 4-] 4- (methylsulfanyl) -3 (trifluoromethyl) anilino] phenol, 2-fluoro-4- [ (1-methyl-1H-indoI-5-yl) amino] phenol, 4 * [(1 -ethyl-1 Zf-indol-5-yl) amino] phenol, 4 - [(1 -ethyl 1 -2 , 3 -di hydro-1 // - indol-510 yl) amino] phenol, 4 - [(1-isopropyl-2,3-dihydro-1/7-indol-5-yl) amino] phenol, 4 (butylamino) phenol, 3 -] (1-methyl-l / Aindol-5-yl) amino] -l-propanol, 4 - [(l-methyll / 7-indol-5-yl) amino] -l -butanol, 4 -] (3-fluoro-4-methylphenyl) amino] phenol, 4 - ((3chloro-4-methylphenyl ) amino] phenol, 4 - [(4-fluorophenyl) amîno] phenol, 4 -] (1 -methyl- \ Hpyrrolo [2,3-to] pyridin-5-yl) amino] phenol, 4 - [(4- fluorophenyl) amïno] phenol, 4 - ((215 fluorophenyl) amino] phenol, 4 -] (3-fluorophenyl) amino] phenol, 4 - [(2,4-difluorophenyl) amînojphenol, 4 - [(3,4-difluorophenyl ) amino] phenoI, 3 -] (4-hydroxyphenyl) amino] benzonitrile, 4 -] (3-methoxyphenyl) amino] phenol, 4 -] (3,5-difluorophenyl) amino] phenol, 4 [(3-methylphenyl) amino] phenol, 4 - [(4-hydroxyphenyl) amino] benzonitrile, 4 - ((3chlorophenyl) amîno] phenol, 4- (pyrimidin-2-ylamino) phenol, 4 - [(cyclobutylmethyl) 20 aminojphenol, 2 - [( 4-hydroxyphenyl) amino] benzonitri! E, 4- {[(1 -methyl-1 // - pyrazol-4yl) methyl] amino} phenol, 4 -] (cyclopropylmethyl) amino] phenol, 4 - {((l- methyl-17Zpyrazol-3-yl) methyl] amino} phenol, 4- (but-2-yn-1-ylamino) phenol, 4- (pyrazin-2-ylamino) phenol, 4- (pyridin-2-ylamino) phenol , 4- (pyridazin-3-ylamino) phenol, 4- (pyrimidin-5ylamino) phenol, 4- (pyridin-3-ylamino) phenol, 4 - [(3,5-difluoro-4-methoxyphenyl) 25 aminojphenol, 4 - (pyridin-4-ylamino) p henol, 4 - [(3-fluoro-4-methoxyphenyl) amîno] phenol, 2- (phenylamino) pyrimidin-5-ol, 5 - [(4-hydroxyphenyl) amino] -2-methoxy benzonitrile, 4 - {[3 - (trifluoromethyl) phenyl] amîno} phenol.

The hydroxy function (s) of the secondary amines listed above is (are) protected beforehand by a suitable protective group before any coupling to an acid derivative of the compound of formula (VII) as defined in previous general process.

DUPLICATE

-38Example 1. 4 - [{[3- (6 - {[(3S) -3- (Morpholin-4-ylmethyl) -3,4-dihydroisoquinolin2 (1H) -yl] carbonyI} -1, 3-benzodÎoxol- 5-yI) -5,6,7,8-tetrahydroindolÎzin-lyl) carbonyl} (phenyl) aminojphenyl phosphate disodium

Stage A. 3- (6 - (((3S) -3- (4-Morph olirtylmethyl) -3,4-dihydro-2 (1 H) -isoquinolinyl) carbonyl] -l, 3-benzodioxo! -5- methyl yl} -5,6,7,8-tetrahydro-l-indolizine carboxylate To a solution of 2 g of the compound of Preparation 1 (5.83 mmol) in 20 mL of dichloromethane is added at room temperature 5, 5 mL of ΛζΛζΛΓ-triethylamine (6.96 mmol), 2.12 g of the compound of Preparation Γ (6.96 mmol), then 0.94 g of hydroxybenzotriazole (HOBT) and 1.34 g of l- ethyl-3- (3'-dimethylaminopropyl) carbodiimide (EDC) (6.96 mmol). The reaction medium is then stirred at room temperature for 1 night, then it is poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic phase is then dried over magnesium sulphate, then filtered and evaporated to dryness. The crude product thus obtained is then purified by chromatography on silica gel (heptane / AcOEt gradient). of the title is obtained in the form of an oil.

¹ H NMR: δ (500 MHz; dmso-d6; 300 ° K): 7.2-6.9 (m, 4H, aromatic Hs); 7.04-7.037.00 (m, 1H, aromatic H); 6.85 (m, 1H, aromatic H); 6.35-6.26-6.06 (m, 1H, H tetrahydroindolizine); 6.15-6.12 (m, 2H, H methylenedioxy); 5.06-4.84 (m, 1H, H dihydroisoquinoline); 4.86-4.17 (m, 2H, H dihydroisoquinoline); 3.65-3.6-3.55 (m, 3H, H methyl ester); 3.43-4.26 (m, 2H, H tetrahydroindolizine); 3.58-3.5 (m, 4H, H morpholine); 2.37-3.05 (m, 4H, 2H dihydroisoquinoline, 2H tetrahydroindolizine); 1,682.56 (m, 4H, H morpholine); 1.4-2.0 (m, 4H, H tetrahydroindolizine)

IR: v; > C = O 1695 cm * ¹ ester; v:> C = O 1625 cm * ¹ amide; v:> COC <1214-1176-1115 cm- ¹ ; > CH-Ar 772-744 cm * ¹

Stage B: 3- [6-1 (3S) -3- (MorpliolÎnomethyl) -3,4-dihydro-1H-isoqidno! Ine-2-carbonyl / -l, 3benzodioxol-S-ylJ-5,6,7, Lithium 8-tetrahydro-l-indolizine carboxylate

To a solution of 4.6 g of the compound of Stage A (8.26 mmol) in 24 mL of dioxane is added a solution of lithium hydroxide (675 mg, 16.1 mmol). The assembly is placed in a microwave oven at 140W, 100 ° C for a period of 2h30. The reaction medium

DUPLICATE

-39 is then filtered and evaporated. The solid thus obtained is dried at 40 ° C. in an oven in the presence of P ₂ Oj.

¹ H NMR: δ (400 MHz; dmso-d6; 353 ° K): 6.7-7.15 (solid, 6H, aromatic Hs); 6.21 (s, 1H, aromatic H); 6.03 (s, 2H, H methylenedioxy); 4.0-5.0 (solid, 3H dihydroisoquinoline); 3.4-3.6 (solid, 3H tetrahydroindolizine, 3H morpholine); 2.5-3.1 (solid, 4H, 2H tetrahydroindolizine, 2H morpholine); 1.5-2.4 (solid, 10H morpholine) IR: v:> C = O 1567 wide cm * 'acetate; v: 1236cm * ¹

Stage C: N- (4 - {[tert-Butyl (dimethyl) sily! [Oxy} pheny!) - 3- {6 - [((3S) -3- (4-morplio! Iny!

methyl) -3,4-diliydro-2 (lH) ~ isoquinolinyl) carbony! [- l, 3-benzodioxol-5-yl} -N-plienyl5,6,7,8-tetrahydro-l-indofizine carboxamlde

To a solution of 2.6 g of the compound of Stage B (4.73 mmol) in 47 mL of dichloromethane are added, dropwise, 1.2 mL of oxalyl chloride (14.2 mmol) at 0 ° vs. The reaction medium is stirred at room temperature for 11 hours, then coevaporated several times with dichloromethane. The product thus obtained is suspended in 37 mL of dichloromethane, then added to a solution of 2.1 g of the compound obtained in Preparation 1 ”(7.1 mmol) in 10 mL of dichloromethane in the presence of 0.6 mL of pyridine (7.1 mmol). The whole is stirred at room temperature overnight.

The reaction medium is concentrated, purified by chromatography on silica gel (dichloromethane / methanol gradient). The title product is obtained in the form of a foam.

NMR ¹ !! : δ (500MHz; dmso-d6; 300 ° K): 6.9-7.3 (aromatic 9H); 6.88 (aromatic 2H); 6.72-6.87 (aromatic 2H); 6.64 (aromatic 2H); 6.13 (2H methylenedioxy); 5.05-4.74 (1H dihydroisoquinoline); 4.25-4.13 (2H dihydroisoquinoline); 3.44-3.7 (4H morpholine); 3.62-3.52 (2H tetrahydroindolizine);

3.0-2.6 (4H, 2H tetrahydroindolizine, 2H dihydroisoquinoline); 2.54-1.94 (6H morpholine); 1.91-1.53 (4H tetrahydroindolizine); 0.92 (9H ferf-butyl); 0.17 (6H dimethyl)

IR: v:> C = O: 1632 cm * ¹ ; v:> COC <: 1237 cm * ¹ ; v: -If-OC-: 1035 cm '; -If-C-:

910 cm * ¹ ; > CH-Ar: 806 cm * '

DUPLICATE

-40 Stage D; N- (4-Hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1H) -isoquinolinyl) carbonylJ-1,3-benzod! Oxol- hydrochloride 5-yl / -N-phenyl-5,6,7,8tetrahydro-1-indolizine carboxamide

0.646 g (11.5 mmol) of potassium hydroxide dissolved in 8 mL of methanol is added to a solution of 1.9 g of the compound obtained in Stage C (2.3 mmol) in 4 mL of methanol. The whole is stirred at room temperature for 30 min. The reaction medium is then diluted in dichloroméihane and washed successively with a 1M HCl solution, a saturated aqueous solution of saturated NaHCCh, then brine until a neutral pH is reached. The organic phase is then dried over magnesium sulfate, filtered and evaporated. The crude product thus obtained is purified by chromatography on silica gel (dichloromethane / methanol gradient). The solid is then dissolved in dichloromethane and 2 mL of 1M hydrochloric ether is added. The whole is stirred for 1 hour, then evaporated to dryness. The hydrochloride thus obtained is dissolved in a water / acetonitrile mixture until complete solubilization, then is lyophilized.

Elemental microanalysis: (% theoretical: measured)% C = 69.11: 68.95; % H = 5.8: 5.46; % N = 7.5: 7.51; % Cl- = 4.74: 4.48

Optical rotation: (a) d ²⁰ “+ 50.8 ° (c = 9 mg / mL, MeOH)

Stage E: 4 - [{[3- (6 - {[(3S) -3- (Morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) yljcarbonyl} -l, 3-benzodioxol-5- yl) -5,6,7,8-tetrahydrolndolizin-l-yljcarbonyl} (ph enyl) amlnojphenyl phosphate dibenzyl

To a suspension of 82 mg of sodium hydride (2.06 mmol) in 10 mL of anhydrous THF is added in portions and at 0 ° C 700 mg of the compound of Stage D. After 30 minutes of stirring at 0 ° C and 30 min at ambient temperature, the tetrabenzyl pyrophosphate is added at 0 ° C. and the reaction medium is stirred overnight at ambient temperature. After evaporation of the solvent, the reaction crude is diluted with dichloromethane (30 mL), washed with a saturated aqueous solution of NaHCO ₃ , then with brine. The organic phase is then dried over MgSOi, filtered, concentrated to dryness, and purified by chromatography on silica gel (gradient CH1Cfe / MeOH). The title product is then obtained in the form of a solid.

DUPLICATE

-41RMN ‘11: δ (500 MHz; DMSO-d6; 300K): 7.34 (m, 10H, phenyl); 7.30-6.71 (m, 15H, aryl); 6.06 (s, 1H, methylenedioxy); 5.30-4.97 (m, 1H, pyrrole); 5.11 (m, 4H, benzyl): 5.03-3.64 (m, 1H, THIQ tertiary); 4.91-4.09 (m, 2H, C-secondary THIQ); 3.99-3.48 (m, 2H, C-secondary THIQ); 3.54-3.44 (m, 4H, morpholine); 2.89-2.65 (m, 3H, C-secondary THIQ); 2.51-1.87 (m, 4H, Csecondary TH1D); 2.36-1.85 (m, 2H, C-secondary THIQ); 1.91-1.45 (m, 4H, CsecondaryTHID)

Stage F: 4 - [{f3- (6 - {[(3S) -3- (Morpholin-4-ylmethyl) -3,4-dihydroisoqulnolin-2 (1H) yl] carbonyl} -l, 3-benzodioxol-5 -yl) -5,6,7,8-tetraliydroindolizin-1-yljcarbonyl} (phenyl) aminojphenyl disodium phosphate

To a solution of the product obtained in Stage A (505 mg; 0.52 mmol) in methanol (10 mL) is added 50 mg of Pd (OH) ₂ , then the reaction medium is placed under a hydrogen atmosphere (1 bar) for 5h. After filtration of the catalyst and concentration to dryness, the reaction crude is dissolved in methanol (5 mL) and treated with 0.95 mL of IM sodium hydroxide. The solvents are then evaporated off and the reaction crude is purified by chromatography on an OASIS® phase (Acetonitrile / H ₂ O gradient) to obtain a white solid.

Elemental microanalysis.

%VS % H %we ° / oNa Calculated 61.87 4.95 6.71 5.51 Find 61.45 4.46 6.61 5.38

IR: v: -C = O: 1628 cm · *; v: COC: 1234 cm * ¹ ; v: P = O: 115 cm * ¹ ; v: P-0: 985 cm * ¹ ; v: CH-Ar: 876 cm ' ¹

High resolution ground (ES1 +):

Molecular formula: C “Hu N4 Na ₂ O9 P [M + H] + calculated: 835.2479 [M + H] + measured: 835.2467

DUPLICATE

-42Example 2. 4 - [{[3- (6 - {[(3Æ) -3-Methyl-3,4-dihydroisoquinolin-2 (l / f) -yl] carbonyl} 13-benzodioxol-5-yl) - 5,6,7,8-tetrahydroindolizin-1-yl] carbonyl} (phenyl) amino] phenyl disodium phosphate

Stage A: N ~ (4-Hydroxyphenyl) -3- (6 - {[(3R) -3 ~ methyl-3,4-dihydroisoquinolin-2 (1H) y!] Carbonyl} -l, 3-benzodioxol-5- yl) -N-ph ény! -5,6,7,8-tetrahydroindolizine ~ l -carboxamide The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing in Stage A the product of Preparation 1 'by that of Preparation 2', it being understood that the product thus obtained is not subjected to a salification step in the presence of hydrochloric ether.

Elemental microanalysis: (% theoretical. · Measured)% C = 74.86: 74.88; % H = 5.64: 5.31; % N = 6.72: 6.78

Stage B - 4 - [{[3- (6 - {[(3R) -3-Methyl-3,4-dihydroisoquinolin-2 (1H) -ylJcarbony!} - 1,3benzodioxol-5-yl) -5,6 , 7,8-tetrahydroindolizin-1-ylJcarbonyl} (plienyl) aminoJphenyl disodium phosphate

The procedure is carried out according to a protocol similar to that described in Stages E and F of Example I.

High resolution ground (ES1 +):

Molecular formula: C18Hi6NjOgP [M + H] ⁺ calculated: 706.2313] M + H] + measured: 706.2324

Example 3.4 - [(1-Methyl-1H-indol-5-yl) | [3- (2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (lf7) -yl | ^ca rbonyl} pheny 1) -5,6,7,8-tetrahydroindolizin-1-yl] carbonyl) amino] phenyl disodium phosphate

Stage A: 3- {5-Cliloro-2 - [((3S) -3- (4-morpholiny! Methyl) -3,4-dihydro2 (1H) -isoquinolinyl) carbonyl / phenyl} -N- (4 -ltydroxypheny!) - N- (1-methyl-1H-indol-5-yl) 5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure is carried out according to a protocol similar to that described in Stages A-D of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of

DUPLICATE

-43 Preparation 2, and on the other hand the compound of Preparation Γ "used in Stage C by that of Preparation 2".

Elemental microanalysis:

%VS ° / oH %NOT % cr Calculated 68.04 5.72 8.82 4.91 Find 67.84 5.46 8.64 5.21

Optical rotation: (a) d ²⁰ ~ + 55.9 ° (c - 7 mg / mL, MeOH)

Stage B ΐ 4 - [(1-Methyl-1H-indol-5-yl) {[3- (2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4diliydroisoquinolin-2 (1H) -ylJcarbonyl} phenyl) -5,6,7,8-tetrahydroindolizln-l ~ ylJ carbonyl} disodium aminojphenylphosphate

The procedure is carried out according to a protocol similar to that described in Stages E and F of Example 1.

High resolution ground (ESI +);

Molecular formula: C45H44N $ Na2O7P [M-2Na + 3H] ⁺ calculated: 800.3208 [M-2Na + 3H] + measured: 800.3211

Example 4. 4 - [{[3- (6 - {[(3 / î) -3-Methyl-3,4-dihydroisoquinolin-2 (1H) * yl] <rerbonyl} 13-benzodioxol-5-yl) Indolizin -l-yl] carbonyl} (1-methyl-1H-pyrroloI23'è | pyridin-5yl) amino] phenyl disodium phosphate

Stage A: N- (4-Hydroxyphenyl) -3- (6 - [[(3R) -3-methyl-3,4dihydroisoquinolin-2 (1H) -y! Jcarbonyl} -l, 3-benzodioxol-5- hydrochloride yl) -N- (1-methyl-1Hpyrrolo [2,3-bjpyridin ~ 5-y!) indo! izine-1-carboxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1 by replacing, on the one hand, the compounds of Preparation 1 and Γ used in Stage A 'by the compounds of Preparations 3 and 2', and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 3”.

DUPLICATE

-44Elemental microanalysis ΐ (% theoretical: measured)% C = 69.14: 70.09; % H = 4.81: 4.55; % N = 9.83: 10.09; % C1-M, 98: 3.26

Stage B: 4 - [{[3- (6 - {[(3R) -3-Methyl-3 _t 4-dîhydroisoquinolin-2 (lH) -ylJcarbonyl} -l, 3benzodioxol-5-yl) indolizin ~ l-ylJcarbonyl ) (l-methyl ~ lH ~ pyrrolo [2,3-bjpyridin-5ytyaminojphenylphosphate diethyl

To a suspension of the compound obtained in Stage A (1.5 mmol) in 10 mL of anhydrous CH2Cl2 is added triethylamine (0.42 mL; 3 mmol), then diethylcyanophosphonate (0.24 mL; 1.65 mmol) dropwise at room temperature. After stirring overnight at room temperature, the reaction medium is diluted with CH2Cl2, washed with a saturated aqueous solution of NaHCO3, then with brine. The organic phase is then dried over MgSO ₄ , filtered, concentrated to dryness, and purified by chromatography on silica gel (gradient ClhCh / MeOH). The title product is then obtained in the form of a solid.

Stage C: 4 - [{[3- (6 - {[(3R) ~ 3-Methyl-3,4-dîhydroisoquinolïn-2 (1H) -ylJcarbonyl} -l, 3benzodioxol-5-yl) indolizin ~ l-ylJcarbonyl } (l-methyl-1H-pyrrolo [2,3-b] pyrldin-5yl) amlnojphenyl disodium phosphate

To a solution of the product obtained in Stage B (0.78 mmol) in CH2Cl2 (12 mL) is added 0.4 mL of trimethylsilyl bromide (3 mmol) dropwise at room temperature. The reaction medium is stirred for 5 h, then a solution of Na ₂ COj (580 mg) in water (4 mL) is slowly added at 0 ° C. After 30 min of stirring, the reaction medium is concentrated to dryness, diluted with anhydrous methanol (25 mL), and μ-filtered. The filtrate is dried and purified by chromatography on an OASIS® phase (acetonitrile / H ₂ O gradient).

High resolution mass (ESI +) t

Molecular formula: C ₄ 5H ₄₄ N5Na ₂ O7P [M-2Na + 3H] ⁺ calculated: 800.3211 [M-2Na + 3H] + measured: 800.3201

DUPLICATE

-45Example 5. 4 - [{(3- (6 - {[(3ZÏ) -3-Methyl-3,4-dihydroisoquinolin-2 (li /) ^_ yllc ^ar bonyI} - 1,3-benzodioxol-5-yl ) indolizin-1-yl | carbonyl} (pyridin-4-yl) amino] pheny | disodium phosphate

Stage A; N- (4-Liydroxyphenyl) -3- (6 - {/ (3R) -3-methyl-3,4dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3-benzodioxol-5-yl) - hydrochloride N- (pyrîdin-4-yl) indolizin1-carboxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compounds of Preparation 1 and Γ used in Stage A by the compounds of Preparations 3 and 2 ′, and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 4”.

Elemental microanalysis: (% theoretical: measured)% C = 69.24: 69.12; % H = 4.74: 4.23; % N = 8.5: 8.45; % Cl- = 5.38: 5.2

Stage B; 4 - [{[3- (6- {J (3R) -3-Methyl-3,4-dihydroisoqiiinolin-2 (1H) -ylJcarbonyl} -l, 3benzodioxol-5-yl) indolizin-1-yl / carbonyl} diethyl (pyridin-4-yl) amIrto / phenyl phosphate

To a suspension of 950 mg of the compound obtained in Stage A (1.5 mmol) in 10 mL of anhydrous CH2Cl2 is added triethylamine (0.42 mL; 3 mmol), then the diethylcyanophosphonate (0.24 mL; 1, 65 mmol) dropwise at room temperature. After stirring overnight at room temperature, the reaction medium is diluted with CH2Cl2, washed with a saturated aqueous solution of NaHCO3, then with brine. The organic phase is then dried over MgSOj, filtered, concentrated to dryness, and purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH gradient). The title product is then obtained in the form of a solid.

1 H NMR: δ (500 MHz; DMSO-d6; 300K): 8.5-8.0 (m, 5H); 7.2-7.1 (m, 1H); 6.85-6.65 (m, 1H); 7.3-6.8 (m, 10H); 6.25-6.10 (brs, 1H); 6.2 (brs, 2H); 5.1-3.7 (6d, 2H); 4.7-3.8 (m.1H); 4.15 (m, 4H); 3.0-1.7 (m, 2H); 1.25 (m, 6H); 0.85-0.24 (m, 3H)

DUPLICATE

-46Stad C: 4 - [{[3- (6 - {[(3R) -3-Methyl-3,4-dihydroisoquinolin-2 (1H) -ylJcarbonyl} -l, 3benzodioxol'5-yl) indolizin-1- yiJcarbony!} (pyridin-4-yl) aminojphenyl phosphate dtsodium

To a solution of the product obtained in Stage B (591 mg; 0.78 mmol) in CH2Cl2 (12 mL) is added 0.4 mL of trimethylsilyl bromide (3 mmol) dropwise at room temperature. The reaction medium is stirred for 5 h, then a solution of Na ₂ COj (580 mg) in water (4 mL) is slowly added at 0 ° C. After 30 min of stirring, the reaction medium is concentrated to dryness, diluted with anhydrous methanol (25 mL), and μ-filtered. The filtrate is dried and purified by chromatography on an OASIS® phase (acetonitrileÆ ^ O gradient).

1 H NMR: 6 (500 MHz; D ₂ O; 300K): 8.23-7.98 (m, 2H, pyridyl); 7.01-6.97 (m, 2H, pyridyl); 7.88-7.80 (m, 1H, indolizine); 7.18-6.57 (m, 13H, aromatics THIQ + aryl + indolizine + phenol); 6.17-6.15 (m, 1H, indolizine): 5.96 (m, 2H, methylenedioxy); 4.61-3.76 (m, 1H, C temieire THIQ); 4.16 (m, 2H, Csecondary THIQ); 2.86-2.31 (m, 2H, C-secondary THIQ); 0.94-0.76 (m, 3H, Cprimary THIQ)

IR: v: -C = O: 1620 cm ⁴ ; v: COC: 1218 cm ⁴ ; v: P = O: 1107 cm ⁴ v: P-0: 981 cm ⁴ v: CH-Ar: 881-741 cm ⁴

High resolution mass (ESI +):

Molecular Formula: C38H29N4Na ₂ OeP [M-2Na + 3H] ⁺ Calculated: 703.1952 [M-2Na + 3H] + Measured: 703.1951

Example 6.4 - [{[3- (6 - {[(3S) -3- (Morpholin-4-ylmethyl) -3,4-dîhydroisoquînolin2 (17 /) - yl] carbonyl) -13-benzodioxol-5- yl) -5,6,7,8-tetrahydroindolizin-lyl] carbonyl} (phenyl) aminojphenyl dibenzyl phosphate

We proceed according to the protocol described in Stages A-E of Example L

H NMR: δ (500 MHz; DMSO-d6; 300K): 7.34 (m, 10H, phenyl); 7.30-6.71 (m, 15H, aryl); 6.06 (s, 1H, methylenedioxy); 5.30-4.97 (m, 1H, pyrrole); 5.11 (m, 4H, benzyl);

DUPLICATE

-475.03-3.64 (m, 1H, THIQ tertiary); 4.91-4.09 (m, 2H, CsecondaryTHIQ); 3.99-3.48 (m, 2H, C-secondary THIQ); 3.54-3.44 (m, 4H, morpholine); 2.89-2.65 (m, 3H, C-secondary THIQ); 2.51-1.87 (m, 4H, C-secondary THID); 2.36-1.85 (m, 2H, C-secondary THIQ); 1.91-1.45 (m, 4H, CsecondaryTHID)

Example 7, 4 - [{[3- (6 - {[(3R) -3-Methyl-3,4-dihydroisoquinolin-2 (1/7) -yl] carbonyl} 13-benzodioxol-5-yl) indolizin- 1-yl] carbonyl} (pyridin-4-yl) amino] phenyl phosphate diethyl

The procedure is carried out according to the protocol described in Steps A and B of Example 5.

NMR ‘H: δ (500 MHz; DMSO-d6; 300K): 8.5-8.0 (m, 5H); 7.2-7.1 (m, 1H); 6.85-6.65 (m, 1H); 7.3-6.8 (m, 10H); 6.25-6.10 (brs, 1H); 6.2 (brs, 2H); 5.1-3.7 (6d, 2H); 4.7-3.8 (mJH); 4.15 (m, 4H); 3.0-1.7 (m, 2H); 1.25 (m, 6H); 0.85-0.24 (m, 3H)

Example 8. 4 - [{[3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroi8oquinolin-2 (17 /) - yl] carbonyl} -13-benzodioxol- hydrochloride 5-yl) -5,6,7,8tetrahydroindolizin-1-yl] carbonyl} (phenyl) amino] phenyl dihydrogen phosphate

To a solution of the product obtained in Stage E of Example I (500 mg; 0.51 mmol) in methanol (10 mL) are added 100 mg of Pd (OH) ₂ , then the reaction medium is placed under an atmosphere of 'hydrogen (1 bar) for 5 h. After filtration of the catalyst and concentration to dryness, the reaction crude is immediately purified by chromatography on C18 phase (acetonitrile / H ₂ O + 0.2% HCl gradient) to obtain a solid.

High resolution ground (ESI +);

Molecular Formula: C43H43N4O9P [M + H] ⁺ Calculated: 791.2846 [M + H] ⁺ Measured: 791.2852

Example 9 4 - [{[5- (5-Ch! Oro-2 - {[(3Æ) -3-methyl! -3,4-dihydroisoquinolin-2 (lZ /) yl] carbonyl} phenyl) -l, 2-dimethyl-1 / f-pyrrol-3-y! | Carbon!} (Pyridin-4y!) Amino] phenyl disodium phosphate

DUPLICATE

-48 Stage A: 5- (5-ch! Oro-2 - {[(3R) -3-methyl! -3,4-diliydroisoquino! In-2 (1H) yl] carbonyl} phenyl) -N- ( 4-hydroxyphenyl) -1, 2-dimethyl-N- (pyridin-4-yl) '1H-pyrrole-3carboxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compounds of Preparation 1 and 1 'used in Stage A by the compounds of Preparations 4 and 2', and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 4”.

Elemental microanalysis: (% theoretical: measured)% C = 66.99: 66.88; % H = 5.14: 5.28; % N = 8.93: 8.87; % CI- = 5.65: 4.98

High resolution mass (ESI +):

Molecular Formula: C3SH32CIN4O3 [M + H] ⁺ Calculated: 591.2157 [M + H] ⁺ Measured: 591.2178

Stage______B: 4 '[{[5- (5-Chloro-2 - {[(3R) -3-methyl! -3,4-dihydroisoquinolin-2 (1H) ylJcarbonyI} phenyl) -l, 2-dimethyl-1H- pyrrol-3-ylJcarbony! J (pyridin-4-y!) amino] phenyl disodium phosphate

The procedure is carried out according to a protocol similar to that described in Stages B and C of Example 4.

Example 10. 4 - [{[14-Dimethyl-5- (6 - {[(3S) -3- (moq) holin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1 //) - ylIcarbonyl} -13 -benzodioxol-5-yl) -l // - pyrrol-3yl] carbonyl} (1-methyl-1jff-pyrrolo [23-6] pyridin-5-yl) amino] phenyl phosphate

Stage A: N- (4-Hydroxyphenyl) -I, 2-dimethyl! -N- (1-methyl! -LHpyrro! O [2,3-b] pyridin-5-yl) -5- (6- hydrochloride) {[(3S) -3- (morpholin-4-ylmethyl!) - 3,4-dihydroisoquinolin2 (1H) -yl] carbonyl} -l, 3-benzodioxol-5-yl) -lH-pyrrole-3-carboxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 5, and on the other hand the compound of Preparation I ”used in Stage C by that of Preparation 3”.

DUPLICATE

-49 Elemental microanalysis: (% measured (theoretical))% C = 66.41 (66.62); % H = 5.08 (5.59); % N = 10.85 (10.84); % Cl- = 4.68 (4.57)

Stage B14 - [{[1,2-Dimethyl-5- (6 - {[(3S) -3- (morpho! In-4-ylmethyl) -3,4dihydroisoqitinolin-2 (1H) -ytfcarbonyl) -l, 3 -benzodioxol-5-yl) -lH-pyrrol-3yl] carbonyl} (1-methyl-1H-pyrrolo [2,3-bJpyridin-5-yl) aminojph enyl phosph ate of disodium

The procedure is carried out according to a protocol similar to that described in Steps B and C of Example 4.

Example 11, 4- | {[1,2-Dimethyl-5- (6- {| (35) -3- (morpholin'4-ylmethyl) -3,4dihydroisoquinolin-2 (177) -yl] carbonyl} -13 * benzodioxol-5-yl) -l / -pyrrol-3yl | carbonyl} (l-methyl-l // - pyrazol-4-yl) amino | disodium phenyl phosphate

Stage A N- (4-Hydroxyphenyl) -1, 2-dimethyl-N- (1-methyl-1H-pyrazol ~ 4yl) ~ 5- (6 - {[(3S) ~ 3- (morpholin-4) hydrochloride -ylmetltyl) -3,4-dihydroisoquinolin-2 (1H) -yljcarbony!} - 1,3benzodioxol-5-yl) -lH-pyrrole-3-carboxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation [used in Stage A by the compound of Preparation 5, and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 5”.

Elemental microanalysis: (% measured (theoretical))% C = 64.25 (64.59); % H = 5.4 (5.7); % N = 11.41 (11.59); % Cl- = 4.93 (4.89)

Stage B: 4-ffil.2-Dimethvl-5- (6-ff (3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoqulno! In-2 (1H) -y! Jcarbonyl) -l, 3 -benzodioxo! -5-yl) -lH-pyrrol-3-yljcarbonyl) (I-methyl-1H-pyrazol-4-yl) amino] phenylphosphate

The procedure is carried out according to a protocol similar to that described in Stages E and F of Example 1.

IR (cm ¹ ): v; C = O: 1628; v: (phosphate; ether): 1238,1143,1113,985; γ:> CH Ar: 740

DUPLICATE

-50 Elemental microanalysis:

%VS % H %NOT Calculated 57.64 4.84 10.34 Find 56.62 4.54 10.14

High resolution mass (ESI + - / FIA / HR);

Molecular formula: CjHîClNeNaiOQP [M-Na + Hf calculated: 791.2565 [M-Na + H] ⁺ measured: 791.2564

Example 12. 4 - [{[I3-Dimethyl-5- (6 - {[(3Æ) -3- [3- (niorpholin-4-yl) propyl] -3,4dihydroisoquinoIin-2 (lZ /) - yl] carbonyl} -13-benzodioxol-5-yl) -IH-pyrrol-3yl] carbonyl} (1-methyl-1J7-pyrrolo [23 * è] pyridin-5-yl) amino] plienyl phosphate

Stage A: N- (4-Hydroxyphenyl) -1, 2-dlmethyl-N- (1-methyl ~ 1H · pyrrolo [2,3-bJpyrîdin-5-yl) -5- (6 - {[(3R) hydrochloride ) -3- [3- (morpholin-4-yl) propyl] -3,4dihydroisoquinolin-2 (1H) -yljcarbonyl} -l, 3-benzodÎoxol-5-yl) -lH-pyrrole-3-carboxamide The procedure is a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compounds of Preparation l and l used in Stage A by the compounds of Preparations 5 and 3 ', and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 3”.

Elemental microanalysis: (% measured (theoretical))% C = 67.63 (68.06); % H = 5.27 (5.95); % N = 10.08 (10.13); % Cl- = 4.53 (4.27)

High resolution ground (ESI +);

Molecular Formula: C35H32CIN4O3 [M + H] ⁺ Calculated: 793.3708 [M + H] ⁺ Measured: 793.3704

DUPLICATE

-51Stage B: 4 - [{[1,2-Dimethyl-5- (6 ~ {[(3R) -3- [3- (morpholin ~ 4-yl) propyl] -3,4dihydroisoqulnolin-2 (1H) - yl] carbonyl} -1, 3-benzodioxol-5-yl) -lH-pyrrol-3yl] carbonyl} (1-methyl-1H-pyrrolo [2,3-bJpyridin-S-yl) disodium aminoJpltenyl phosphate

The procedure is carried out according to a protocol similar to that described in Stages E and F of Γ Example 1.

Unless otherwise indicated, the compounds of the following Examples are synthesized according to the process of Example 1 using: (i) the appropriate acid obtained according to one of Preparations 1 to 9 and (ii) the appropriate tetrahydroisoquinoline derivative obtained according to one of Preparations 1 'to 4', as well as in Stage C: (iii) the adequate NHRjRi amine (a non-exhaustive list is proposed for Preparations 1 ”i 8”).

Example 13. 4 - [{[5- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1W) -yl [carbonyl} phenyl) -l Disodium, 2-dimethyl-1 / f-pyrrol-3yl [carbonyl) (pyridin-4-y |) amino] phenyl phosphate

Stage A: 5- (5-chloro-2 - {[(3S) -3- (morpholin ~ 4-yimetliyl) -3,4dihydroisoquinolin ~ 2 (lH) -ylJcarbonylJpltenyl) ~ N ~ (4-hydroxyphenyl) - hydrochloride l _t 2-dimellyl-N (pyridin-4-yl) -lH-pyrrole-3-carboxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 4, and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 4”. The product obtained is finally subjected to a salification step in the presence of 1M hydrochloric acid in ether. After filtration and lyophilization in an acetonitrile / water mixture, the expected compound is obtained.

High resolution mass (ESI +) t

Molecular formula: C39H38CIN5O4 [M + H] ⁺ calculated: 676.2685 [M + HJ * measured: 676.2684

DUPLICATE

-52stage B; 4 - [{[5- (5-Chloro-2 - {[(3S) -3- (morpltolin-4 ~ ylmethyl) ~ 3,4-diltydroÎsoquinolin2 (1H) -yl] carbonyl} ph enyl) 1,2 -dim ethyl lII-pyrrol-3-yljcarbonyl} (pyridin -4yl) amino / disodium phenyl phosphate

The procedure is carried out according to a protocol similar to that described in Steps B and C of Example 16.

^3l P NMR (500 MHz, D ₂ O) δ ppm: -0.05

IR (cm ⁴ ): v: C = O: 1631; v: (phosphate; ether): 1243,1136,1112, 982; γ:> CH Ar: 883, 745

Elemental microanalysis:

% C% H% N

Calculated 58.54 4.66

8.75

Found 58.23 4.51

8.76

High resolution mass (ESI +):

Molecular Formula: C ₃ 9H ₃ 7ClNîNa ₂ O7p [M-Na + 2H] ⁺ calculated: 778.2168 [M-Na + 2H] ⁺ measured: 778.2169

Example 14. 4 - [{[5- (5-Fluoro-4-methoxy-2 - {[(3S> 3- (morpholin-4-yIniethyl) -3,4dihydroisoquinolÎn-2 (lZ /) - yllcarbony!} Phenyl ) -l, 2-diniethyl-1/7-pyrrol-3yl] carbonyl} (1-methyl-1 // - pyrazol-4-yl) amino] phenyl phosphate

Example 15. 4 - [{[5- (5-Fluoro-2 - {[(35) -3- (morpholin-4-y! Methy!) - 3 _t 4dihydroisoquinolin-2 (l //) - y!] carbonyl} phenyl) -1, 2-dimethyl-lI7-pyrrol-3-yllcarbonyl} (l-methyl-l // - pyrazol-4-yl) amino] phenyl disodium phosphate

Stage A: 5- (5-Fluoro-2 - [[(3S) -3- (morpltolin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1H) -yl] carbonyl} plienyl) -N- (4) hydrochloride -liydroxyplienyl) -l, 2-dimethyl-N- (lmethyl ~ lH-pyrazol-4 ~ yl) ~ l H-pyrrole-3-carboxamlde

The procedure is carried out according to a protocol similar to that described in Stages A-D of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of

DUPLICATE

-53the Preparation 7, and on the other hand the compound of Preparation 1 used in Stage C by that of Preparation 5 ". The product obtained is finally subjected to a salification step in the presence of hydrochloric ether in ether. After filtration and lyophilization in an acetonitrile / water mixture, the expected compound is obtained.

Elemental microanalysis: (% measured (theoretical))% C = 65.69 (65.28); % H = 5.38 (5.77); % N = 11.18 (12.02); % Cl- = 5.61 (5.07)

Stage B: 4 - [{[5- (5-Fluoro-2 - {[(3S) -3- (morpholin ~ 4-ylmethyl) -3,4-dihydroisoquinolin2 (1H) -ylJcarbonyl} phenyl) -l, 2 -dintethyl-1H-pyrrol-3-ylJcarbonyl} (1-methyl-1H-pyrazol4-yl) disodium aminoJphenyl phosphate

The procedure is carried out according to a protocol similar to that described in Steps B and C of Example 16.

³¹ P NMR (400/500 MHz, CD ₃ OD) δ ppm: -0.5

IR (cm ' ¹ ): v: C = O: 1628; v: (phosphate; ether): 1238,1114,983

Elemental microanalysis:

%VS % H %NOT Calculated 58.02 4.87 10.68 Find 59.03 4.98 10.14

High resolution ground (ES1 +):

Molecular Formula: C ₃ gH ₃ 8FN6Na2O7P [M-2Na + 3H] ⁺ calculated: 743.2752 [M-2Na + 3Hf measured: 743.2760

Example 16. 4 - [{| 1 ^ -Dimethyl-5- (7 - ([(aS) -3 - ("norpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1W) -yl] carbonyl} -23 -dihydro-1,4-benzodioxin-6-yl) -l // - pyrrol-

3-yl] carbonyl} (1-methyl-1H-pyrazol-4-yl) amino] phenyl disodium phosphate

Stage A: N- (4-hydroxyphenyl) -I, 2-dimethyl-N- (1-methyl-1H-pyrazol ~ 4yl) -5- (7 - {[(3S) -3- (niorpliolin ~ 4) hydrochloride -ylmethyl) -3,4-dihydrolsoqulnolin-2 (lH) -yl] carbonyl} -2.3 · dihydro-1,4 ~ benzodioxln-6-yl) -lH-pyrrole-3-carboxamlde

DUPLICATE

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 8, and on the other hand the compound of Preparation 1 "used in Stage C by that of Preparation 5". The product obtained is finally subjected to a salification step 5 in the presence of 1M hydrochloric ether in ether. After filtration and lyophilization in an acetonitrile / water mixture, the expected compound is obtained.

Elemental microanalysis: (% theoretical: measured)% C = 64.99: 64.67; % H = 5.86: 5.67; % N = 11.37: 11.27; % Cl- = 4.8: 4.71

High resolution mass (ES / +):

OJ Crude formula: C40H43N6O6 [M + H] ⁺ calculated: 703.3236 [M + H] ⁺ measured: 703.3239

Stage B: Ν, Ν, Ν ', Ν'-Tetramethylphosphorodiamidate of 4 - [{[1,2 ~ dimethyl-5- (7 - ([(3S) -3 (morpholin-4-ylmethyl) -3,4- dihydroisoquinolin-2 (1H) -ylJcarbonyl} -2,3-dihydro-1,415 benzodioxin-6-yl) -lH-pyrroI-3-ylJcarbony!} (1-methyl-1H-pyrazol-4-yl) aminoJphenyl

To a solution of 125 mg of the compound of Stage A (0.18 mmol) in dichloromethane (6 mL) is added 55 pL of diazabicyclo [5.4.0] undec-7-ene (DBU; 0.36 mmol), then 33 µL of bisdimethylaminophosphoryl chloride (0.19 mmol) and 2 mg of 4-dimethylamino-pyridine (0.02 mmol). The reaction is left under stirring for 15 hours, diluted in dichloromethane then in a saturated aqueous solution of sodium carbonate. The aqueous phase is extracted with dichloromethane, then the organic phases are combined, washed with water, with brine and dried over magnesium sulfate. After evaporation of the solvents, the crude reaction is used directly in the next step.

Stage C. 4 - [{[1,2-Dimethyl-5- (7 - ([(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydro isoquinolin-2 (1H) -ylJcarbonylJ- 2,3-dlhydro-1,4-benzodioxin-6-yl) -lH-pyrrol-3-ylJ carbonyI} (l-methyl! -LH-pyrazol-4-yl) disodium aminoJphenylphosphate

To a solution of 125 mg of the Stage B compound (0.15 mmol) in a 1: 1 mixture of acetonitrile and water (5 mL) are added 4 mL of trifluoroacetic acid dropwise

DUPLICATE

-55 drop. After 20 hours of stirring at room temperature, the reaction medium is evaporated to dryness while maintaining the temperature of the water bath below 40 ° C., then the residue is treated with a solution of sodium carbonate (95 mg; 0.9). mmol) in water (4 mL). After stirring for 2 hours at room temperature, the reaction medium is evaporated to dryness and then 6 mL of anhydrous ethanol are added. The solid is filtered off, and the filtrate is concentrated to dryness, then purified on an OASIS® phase (acetonitrile / water gradient).

^3, P NMR (500 MHz, D ₂ O) δ ppm: 0.9

IR (cm ' ¹ ): v: C = O: 1623; v; (phosphate; ether): 1235, 1162,1115, 1065, 985; γ:> CH Ar: 745

High resolution ground (ESI +);

Empirical formula: C4oH4iNiNa ₂ 09P [M-2Na + 3H] ⁺ calcd: 783.2902 [M-2Na + ⁺ 3HL measured: 783.2907

Example 17. 5 - [{[5- (5-Fluoro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,415 dihydroisoquino! In-2 (1 //) - yl] carbonyl} phenyl ) -l, 2-dimethyl-1/7-pyrrol-3yl] carbonyl} (pyridin-4-yl) amino] pyrimidin-2-yl disodium phosphate

Example 18. 5 - [{[5- (5-Chloro-2 - {[(3iS) -3- (morpholiii-4-ylmethyl) -3,4dihydrolsoquinolin-2 (177) -yl] carbonyl} pheny!) - 1,2 * diniethyl-1ZZ-pyrro] -3yl] carbonyl} (pyridIN-4-yl) amino] pyrimidin-2-yl disodium phosphate

Example 19. 4 - ({[5- (5-Chloro-2 - {[(35) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1/7) -yl] carbony |} phenyl ) -l, 2-dimethyl-lfZ-pyrrol-3yl] carbonyl} [l- (trideuteriomethyl) -lf / -pyrazol-4-yl] amino) disodium phenyl phosphate

Stage A: 5- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3.425 dihydroisoquinolîn ~ 2 (1H) -yl] carbonyl} phenyl) -N- (4- hydrochloride) hydroxyphenyl) ~ 1,2-dimethyl ~ N- [l (tridetitériomethyl) -] H-pyrazol ~ 4-ylJ-IH-pyrrole ~ 3-carboxamide

DUPLICATE

The procedure is carried out according to a protocol analogous to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 4, and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 6”. The product obtained is finally subjected to a salification step 5 in the presence of 1M hydrochloric ether. After filtration and lyophilization in an acetonitrile / water mixture, the expected compound is obtained.

Elemental microanalysis (% theoretical. · Measured)% C = 63.51: 63.41; % H = 5.63, 5.42; % N = 11.69: 11.61; % C1M, 93: 4.85

High resolution ground (ESI + - / FIA / HR, ESI- / FIA) î

Molecular formula: C ₃ g H36 Cl Dj Ne O4 [M + H] ⁺ calculated: 682.2982 [M + H] ⁺ measured: 682.2986

Stage B: 4 - ({[5- (5-Ch! Oro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin2 (1H) -ylJcarbonyl} phenyl) -l , 2-dimethyl-1H-pyrrol-3-ylJcarbonyl} [1- (trideuteriomethyl) 15 1 H-pyrazol-4-yl] amlno) disodium phenylphosphate

The procedure is carried out according to a protocol similar to that described in Steps B and C of Example 16.

³¹ P NMR (500 MHz, D ₂ O) δ ppm: 4.8

IR (cm *): v: C = O: 1626; v: (phosphate; ether): 1243, 1141,1115, 982; γ:> CH Ar: 880, 831

High resolution mass (ESI / FIA / HR and MS / MS);

Crude formula: Cjg H35 Cl Dj Né Na ₂ O7 P [M + Hf calculated: 806.2285 [M + H] ⁺ measured: 806.2280

DUPLICATE

-57Example 20. 4 - [{[5- (5-Chloro-2 - {[(35) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1 //) - yl] carbonyl} phenyl ) -13-dimethyl-1 // - pyrrOl-3 'yl] carbonyl) (5-cyano-13-dimethyl-1H-pyrrol-3-yl) amino] phenyl disodium phosphate

Stage A: 5- (5-chloro-2 - {[(3S) ~ 3- (morpholin-4-ylmethy!) - 3,4dihydroisoquinolin-2 (1H) -ylJcarbonyljphenyl) -N- (5-cyano- hydrochloride) 1,2-dimethyl-1H-pyrrol-3-yl) N- (4-hydroxyphenyl) -l, 2-dimethyl-1H-pyrrole-3-carboxamlde

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 4, and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 7”. The product obtained is finally subjected to a salification step in the presence of 1M hydrochloric ether. After filtration and lyophilization in an acetonitrile / water mixture, the expected compound is obtained.

1 H NMR (500 MHz, dmso-d6) δ ppm: 11.2 (bs, 1H); 9.39 (bs, 1H); 7.83 (d, 1H); 7.54 (d, 1H); 7.33 (s, 1H); 7.14 (m, 2H); 7 (m, 2H); 6.8 (d, 2H); 6.62 (d, 2H); 6.57 (bs, 1H); 5.26 (s, 1H); 5.26 (m, 1H); 4.64 / 4.03 (AB, 2H); 4.01 / 3.92 (2m, 4H); 3.75 / 3.43 / 3.15 / 3.02 (4m, 4H); 3.59 (s, 3H); 3.3 / 3.15 (2m, 2H); 2.97 (s, 3H); 2.69 / 2.52 (dd + d, 2H); 2.06 (s, 3H); 1.91 (s, 3H)

Elemental microanalysis: (% theoretical: measured)% C = 65.34: 65.50; % H = 5.62: 5.15; % N = 11.15: 10.84; % Cl- = 4.70: 4.44

High resolution ground (ESI +);

Molecular formula: C ₄ i Η> ι Cl Nô O ₄ [M + Hf calculated: 717.2952 [M + H] ⁺ measured: 717.2951

Stage B: 4 - [{[5- (5-Chloro-2 - {[(3S) -3- (morplto! In ~ 4-y! Methyl) -3,4-dihydroisoquinolin2 (1H) -ylJcarbonyl) phenyl) -l, 2-dimethyl-lH-pyrrol-3-yiJcarbonyl) (5-cyano-1,2-dimethyllH-pyrro! -3 ~ y!) disodium aminoJphenylphosphate

DUPLICATE

The procedure is carried out according to a protocol similar to that described in Steps B and C of Example 16.

³¹ P NMR (500 MHz, dmso-d6) δ ppm: 3.7

IR (cm * ¹ ): v: -CN: 2210 cm- ¹ ; v: C = O: 1623; v: (phosphate; ether): 1227, 1133,1110,

982; γ:> CHAr: 884-741

Elemental microanalysis:

%VS % H <7oN Calculated 58.54 4.79 9.99 Find 58.75 4.71 10.18

High resolution mass (ESI + - / FIA / HR);

Molecular formula: C41 H40 Cl Born Na ₂ O ₇ P [M-2Na + H] ⁺ calculated: 797.2614 [M-2Na + Hf measured: 797.2618

Example 21. 4 - [{[5- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1 //) - yl [carbonyl} phenyl) Disodium-1,2-dimethyl-1 // - pyrrol-3yl] carbonyl} (5-cyano-1-methyl-1H-pyrroI-3-yl) amino] phenyl phosphate

Stage A: 5- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1H) -yl] carbonyl} phenyl) -N- (5) hydrochloride -cyano-1-methyl-1H-pyrrol-3-yl) -N (4-hydroxyphenyl) -l, 2-dintethyl-III-pyrro! e-3-carboxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 4, and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 8”. The product obtained is finally subjected to a salification step in the presence of 1M hydrochloric ether. After filtration and lyophilization in an acetonitrile / water mixture, the expected compound is obtained.

Elemental microanalysis: (% theoretical: measured)% C = 64.95: 65.09; % H = 5.45: 5.20; % N = 11.36: 11.26; % Cl- = 4.79: 4.62

DUPLICATE

-59 High resolution mass (ESI / +).

Molecular formula: C40 H39 Cl Ne O ₄ [M + H] ⁺ calculated: 703.2794 [M + H] * measured: 703.2789

Stage B; 4 - [{[5- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylntethyl) -3,4-dihydroisoquinolin2 (1H) -yl [carbonyl} phenyl) -l, 2- disodium dimethyl-1H-pyrrol-3-ylfcarbonyl} (5-cyano-1-methyl-1Hpyrrol-3-yl) amlnojphenylphosphate

The procedure is carried out according to a protocol similar to that described in Steps B and C of Example 16.

³¹ P NMR (500 MHz, dmso-d6) δ ppm: 4.5

IR (cm ' ¹ ): v: -CN: 2215 cm'¹; v: C = O 1626; v: (Phosphate; ether): 1227, 1141,1112, 982; γ:> CH Ar: 826-742

High resolution mass (ESI + - / FIA / HR);

Molecular Formula: C40 H ₃ g Cl Ne Na ₂ O7P [M-2Na + 3H] ⁺ calculated: 783.2457 [M-2Na + 3H] ⁺ measured: 783.2462

Example 22. 4 - [{| 3- (6 - {[(3R) -3- (Morpholin-4-ylinethyl) -3,4-dihydroisoquinolin2 (1ZO-yl [carbonyl} -13-benzodioxol-5-yl) -5,6,7,8-tetrahydroindolizin-lyl] carbonyl} (phenyl) amino] phenyl disodium phosphate

Stage A: N- (4-Hydroxyphenyl) -3- {6 - [((3R) -3- (4-morpholinylmethyl) 3,4-dihydro-2 (1H) -isoquinolÎnyl) carbonyl [-l, 3 hydrochloride -benzodioxol-5-yl} -N-phenyl-5,6,7,8tetrahydro-l-indolizine carboxamide

The procedure is carried out according to a protocol similar to that described in Stages A-D of Example 1, replacing the compound of Preparation Γ used in Stage A by the compound of

Preparation 4 ’. The solid is then dissolved in dichloromethane and 2 mL of 1M hydrochloric ether is added. The whole is stirred for 1 hour, then evaporated to dryness. The hydrochloride thus obtained is dissolved in a water / acetonitrile mixture until

DUPLICATE

-60 total solubilization, then is lyophilized.

Elemental microanalysis:

% C% H% N% cr

Calculated 69.11 5.80

7.50 4.74

Found 68.89 5.23

7.41 4.62

Optical rotation ΐ (a) d ^{20 =} - 45.1 ° (c = 9 mg / mL, MeOH)

Stage B: 4 - [{[3- (6 - {[(3R) -3- (Morpholin-4-ylntethyl) -3,4-dihydroisoquinolin-2 (1H) ytfcarbonyl} ~ 1,3 ~ benzodioxol-5- yl) -5,6,7,8-tetraltydroindolizÎn ~ l-yl] carbonyl} (phenyl) amïnojpfténylphosphate de disodium

We proceed according to a protocol similar to that described in Stages B and C of Example 16.

^3, P NMR (400/500 MHz, dmso-d6) δ ppm: 2.6

Elemental microanalysis;

% C% H% N

Calculated 61.87 4.95

6.71

Found 61.33 4.93

7.14

High resolution ground (ES1 + - / FIA / 1IR).

Molecular formula: C43 H41 N4 Na O9P [M-2Na + H] ⁺ calculated: 791.2840 [M-2Na + H] ⁺ measured: 791.2845

Example 23. 4 - [(1-Methyl-23-dihydro-1 / f-pyrrolo [23-è] pyridin-5-yl) {[3- (2 - {[(1S) -3 (morphoIin-4- ylmethyl) -3,4-dihydroisoquinolm-2 (lZ /) - yl] carbonyl} -4- [2-oxo-2 (piperidin-1-yl) ethoxy] phenyl) -5,6,7,8-tetrahydroindolÎzin- I-yl] carbonyl) amino] phenyl disodium phosphate

DUPLICATE

-61Stage A: 3-l4-Benzvloxv-2 - [(3S) -3- (morpliolinomethvl) -3.4- <lilivdro-1H-isoaiiinoline-2carbonyl] phenyl] -5,6,7,8-tetrahydroindolizine-l-carboxylate methyl

To a solution of 14.19 g (35.0 mmol) of the compound obtained in Preparation 9 in 200 mL of dimethylformamide, are added successively 4 - [[(3S) -1,2,3,4tetrahydroisoquinolin-3-yl ] methyl] morpholine (Preparation 1 *; 8.13 g; 35.0 mmol), hydroxybenzotriazole (6.15 g; 45.5 mmol), 1-ethyl-3- (3'-dimethyl aminopropyl hydrochloride) ) -carbodiimide (6.70 g; 45.5 mmol) and triethylamine (21.95 mL; 0.16 mol). The whole is then stirred overnight at room temperature. The reaction medium is then poured into 400 mL of ethyl acetate, then washed successively with a saturated aqueous solution of NaHCO 3, water and brine. The combined aqueous phases are extracted with ethyl acetate. The resulting organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The product obtained is purified by chromatography on silica gel to provide the title compound.

¹ H NMR (500 MHz, dmso-d6, 300K) δ ppm: 7.5-7.3 (m, 5H); 7.38 (d, 1H); 7.2-6.9 (m, 4H); 7.15 (dd, 1H); 6.9 (d, 1H); 6.35 / 6.25 / 6.08 (3 * s, 1H); 5.21 / 5.12 (3 * s, 2H); 5.09 / 4.85 / 3.7 (3 * m, 1H); 4.9-3.8 (8 * d, 2H); 4.2-3.4 (m, 2H); 3.65 / 3.6 / 3.55 (3 * s, 3H); 3.6-3.4 (m, 4H); 3-2.4 (m, 2H); 2.9-1.8 (6 * dd, 2H); 2.5-1.95 (4 * m, 4H); 2.35-1.7 (6 * m, 2H); 2-1.45 (6 * m, 4H)

Stage B: 3- [4-Benzyloxy-2 - [(3S) -3- (morpliolinomethyl) -3,4-dihydro-1HÎsoquinoline ~ 2-carbonyljphenyl] ~ 5,6,7,8-tetrahydroindolizine-l ~ carboxylic acid

To a solution of 12.7 g (20 mmol) of the compound obtained in the preceding stage in 40 mL of dioxane are added 40.1 mL of a 1 M aqueous solution of LIIOH. The whole is heated at 100 ° C. for 1 m. night. The reaction medium is poured into water, then extracted with ethyl ether. The ethereal phase is extracted again once with water. The combined aqueous phases are acidified to pH 4 by adding powdered citric acid, then extracted with dichloromethane. The dichloromethane phase is washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The title product is obtained in the form of a meringue.

1 H NMR (500 MHz, dmso-d6.300K) δ ppm: 11.35 (bs, 1H); 7.5-7.3 (m, 5H); 7.38 (m, 1

DUPLICATE

-62H); 7.2-6.9 (m, 4H); 7.15 (m, 1H); 6.9 (m, 1H); 6.31 / 6.25 / 6.1 (3 * s, 1H); 5.22 / 5.2 / 5.15 (3 * s, 2H); 5.1 / 4.82 / 3.7 (3 * m, 1H); 4.85-3.8 (8 * d, 2H); 4.2-3.4 (m, 2H); 3.6-3.45 (m, 4H); 3-2.3 (m, 2H); 2.9-1.8 (m, 2H); 2.5-1.9 (6 * m, 4H); 2.35-1.8 (6 * m, 2H); 1.9-1.3 (m, 4H)

Stage C; 3- [4-Benzy! Oxy-2 - [(3S) -3- (morpho! Inomethy!) - 3,4-dihydro-1H-isoquinoline-2carbonylJphenylj-N- [4- [tert-butyl (dimethyl) silyiJoxyphenylJ -N- (I-methylpyrrolo [2,3b] pyridin-5-yl) -5,6,7,8-tetrahydroindolizine ~ l-carboxamide

The acid obtained in Stage B (9 g, 11.8 mmol) is dissolved in 90 mL of 1.2dichloroethane. 1.9 mL of 1-chloro-N, A ^r , 2-trimethylpropenylamine (14 mmol) is added thereto.

After 3 hours of stirring at room temperature, 90 mL of toluene and 4.62 g of N- [4- [ier / butyl (dimethyl) silyl] oxyphenyl] -l-methyl-1 // - pyrrolo [2,3 -i>] pyridin-5-amine (Preparation 3 ”, 13 mmol) are added. The reaction medium is heated at 110 ° C. for 20 h. After returning to ambient temperature, the reaction medium is washed with brine, dried over Na ₂ SO 4, filtered and concentrated to dryness. The residue obtained is purified by chromatography on silica gel (dichloromethane / ethanol gradient) to yield the expected product.

1 H NMR (500 MHz, dmso-d6, 300K) Ô ppm: 7.95 / 7.8 / 7.75 (3 * d, 1H); 7.68 / 7.65 / 7.4 (3 * d, 1H); 7.4 / 7.3 (2 * d, 1H); 7.25-6.8 (m, 9H); 7.05 / 6.9 (2 * m, 1H); 7-6.6 (3 * dl, 2H); 6.9 (m, 1H); 6.75-6.45 (3 * dl, 2H); 6.7 (m, 1H); 6.3 (2 * d, 1H); 5.15-4.95 (m, 220H); 5.15 / 5.1 / 4.8 (3 * s, 1H); 4.95 / 4.6 / 3.5 (3 * m, 1H); 4.9-3.7 (8 * d, 2H); 3.8-3.3 (3 * m, 2

H); 3.75 / 3.7 / 3.5 (3 * s, 3H); 3.45 / 3.3 (2 * m, 4H); 3-2.5 (3 * m, 2H); 3-2.3 (m, 2H); 2.41.75 (5 * m, 4H); 2.25 - 1.7 (6 * m, 2H); 1.75-1.3 (m, 4H); 0.7 (bs, 9H); 0.1 (m, 6H)

Stage D: N-f4-ftert-Butvl (dimethvl) silvlloxvphénvl} -3-f4-hydroxy-2-f (3S) -3- (morpholino métliy!) - 3,4-dihydro-lH-isoquinoline-2-carbonyljphenylJ -N- (1-methylpyrrolo [2,325 bJpyridin-5-y1) -5,6,7,8-tetrahydroindoHzine-1-carboxamide

To a solution in 100 mL of ethanol of 8.88 g (8.4 mmol) of the compound obtained in Stage C is added 0.9 g of 10% Pd / C under bubbling argon. The reaction mixture is placed under 1.2 bar of hydrogen at room temperature for 15 h. The catalyst is filtered off and the solvent evaporated off under reduced pressure to provide the title compound.

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-63RMN * H (500 MHz, dmso-d6, 300K) δ ppm: 8.06 / 7.92 / 7.87 (3 * d, 1H); 7.75 / 7.5 / 739 (3 * d, 1H); 7.5 (m, 1H); 7.28-6.9 (m, 5H); 6.87 / 6.7 (2 * m, 2H); 6.76 (m, 1H); 6.75 / 6.67 / 6.62 (3 * m, 2H); 6.67 / 6.46 (m, 1H); 6.4 / 6.36 (2 * m, 1H); 5.19 / 5.13 / 4.9 (3 * sl,

H); 5.06 / 4.7 / 3.6 (3 * m, 1H); 4.97 / 4.2 / 4.15 / 4.07 (4 * m, 2H); 4.87 / 4.81 (bs, 1H); 3.86 / 3.56 / 3.39 (3 * m, 2H); 3.78 / 3.57 (2 * m, 3H); 3.59 / 3.44 (2 * m, 4H); 2.96-2.61 (2 * m,

H); 2.88 / 2.6 (2 * m, 2H); 2.59-1.81 (m, 6H); 1.87-1.42 (m, 4H); 0.89 (s, 9H); 0.12 (m, 6H)

Stage E; N- [4- [tert-Butyl (dimethyl) sllyl] oxyphenyl] -N- (1-methylpyrrolo [2,3-bJpyrldln-5yl) -3- [2 - [(3S) -3- (morpholinomethyl) -3 , 4-dihydro-1H-isoquinolhie-2-carbonylJ-4- [2-cxo2- (l-plperldyl) etlioxyJp! Enylj-5,6,7,8-tetrahydrolndolizlne-l-carboxamlde

The compound of Stage D (3.0 g, 2.9 mmol) is dissolved in 100 mL of toluene. To this are added 1.53 g (5.8 mmol) of triphenylphosphine and 0.62 g (4.3 mmol) of 2-hydroxyl- (1-piperidyl) ethanone. The mixture is heated to 50 ° C., then 1.01 g (4.3 mmol) of di-reri-butyl azodicarboxylate is added. The reaction medium is stirred at 50 ° C. for 1 h then left to return to ambient temperature before adding 1 ml of trifluoroacetic acid. After stirring overnight at room temperature, the mixture is washed successively with water, a saturated solution of NaHCO ₃ and a brine solution. The combined aqueous phases are extracted with ethyl acetate. The resulting organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel (dichloromethane / ethanol 98/2) to yield the expected compound.

1 H NMR (500 MHz, dmso-d6, 300K) δ ppm: 8.06 / 7.92 / 7.87 (3 * d, 1H); 7.75 / 7.51 / 7.4 (3 * d, 1H); 7.49 (2 * d, 1H); 7.29-6.89 (m, 5H); 6.93 (m, 1H); 6.88 / 6.7 (m, 2H); 6.75 / 6.67 (m, 1H); 6.75 / 6.68 / 6.59 (3 * m, 2H); 6.4 / 6.36 (2 * m, 1H); 5.2 / 5.16 / 4.92 (3 * m, 1H); 5.06 / 4.69 / 3.58 (3 * m, 1H); 4.97 / 4.25 / 4.16 / 4.03 (4 * d, 2H); 4.89 / 4.81 (2 * m, 2H); 3.79 / 3.59 (2 * m, 3H); 3.59 / 3.43 / 3.4 (3 * m, 6H); 3.58 / 3.43 (2 * m, 4H); 3.03-2.61 (m, 2H); 2.97-2.65 (m, 2H); 2.57-1.74 (m, 6H); 1.89-1.3 (m, 10H); 0.89 (2sl, 9H); 0.11 (m, 6H)

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-64 Stage F; N- (4-Hydroxyphenyl) -N- (1-methylpyrrolo [2,3-bJpyridin-5-yl) -3- [2 - [(3S) -3 (morph olinomethyl) -3,4-dihydro-1 H -isoquinolin e-2-carbon! J-4- [2-oxo-2- (Ipiperidyl) ethoxyjph enylJ-5,6,7,8-tetrahydroindolizine ~ 1-carboxamide

Has a solution in 30 mL of tetrahydrofuran of the compound obtained in Stage E (2.92 g,

2.9 mmol) is added a solution of IM tetrabutylammonium fluoride (3.14 mL, 3 mmol) in tetrahydrofuran at room temperature. After 5 minutes with stirring, the reaction medium is poured into a 50/50 mixture of ethyl acetate and a saturated aqueous solution of NaHCO 3. The decanted organic phase is washed with water, then with brine. The combined aqueous phases are extracted with ethyl acetate. The resulting organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel (dichloromethane / ethanol / ammonia gradient) to yield the title compound.

1 H NMR (500 MHz, dmso-d6, 300K) δ ppm: 9.4 (m, OH); 8.1-7.8 (3 * d, 1H); 7.7-7.3 (2 * m, 1H); 7.5 / 7.4 (2 * m, 1H); 7.3-6.9 (m, 4H); 7.2 (m, 1H); 6.9 (m, 1H); 6.8-6.5 (m, 2H); 6.7-6.5 (m, 2H); 6.7 (m, 1H); 6.4 (m, 1H); 5.3-5 (m, 1H); 5.1 / 4.7 / 3.6 (3 * m, 1H); 5-3.6 (m, 2H); 5-3.6 (m, 2H); 4.8 (m, 2H); 3.8-3.6 (m, 3H); 3.6 / 3.4 (m, 2H); 3.4 (m, 6H); 3.1-2.5 (m, 2H); 2.9-1.9 (m, 2H); 2.5-1.7 (m, 4H); 1.8-1.4 (m, 6H); 1.6-1.3 (m, 4H)

Stage G: N- (4-Hydroxyphenyl) -N- (1-methyl'2,3-dihydropyrrolo [2,3'bJpyridin-5-yl) -3- [2 '[(3S) -3- (morpholinomethyl) -3,4-dihydro-1H-isoquinoline-2-carbonyl] -4- [2-oxo-2- (l ~ piperyl) ethoxy] phenylj-5 _f 6,7,8-tetrahydroirtdolizine-l-carboxamide

To a solution in 20 mL of acetic acid of the compound obtained in Stage F (2.0 g, 2.2 mmol) is added 0.71 g (11 mmol) of sodium cyanoborohydride. After 14 h of stirring at room temperature, 0.36 g (5.5 mmol) of sodium cyanoborohydride is added, then the reaction mixture is heated at 50 ° C for 3 h before a second addition of 0.1 eq of cyanoborohydride sodium to complete the reaction in 30 min at 50 ° C. The acetic acid is evaporated off under reduced pressure, then the residue is taken up in dichloromethane and washed with a saturated aqueous solution of NaHCO 3, water and brine. The combined aqueous phases are extracted with dichloromethane. The resulting organic phases are dried over sodium sulfate, filtered and concentrated under

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-65 reduced pressure. The crude product obtained is purified by chromatography on silica gel (dichloromethane / ethanol / ammonia gradient) to yield the title compound in the form of a meringue.

1 H NMR (500 MHz, dmso-d6, 300K) δ ppm: 9.3 (bs, 1H); 7.5 / 7.4 / 7.3 (3 * m, 1H); 7.2 / 6.7 (2 * m, 1H); 7.2 (m, 1H); 7.1-6.8 (m, 4H); 6.9 / 6.7 (m, 1H); 6.9 (m, 1H); 6.8-6.5 (m, 2H); 6.7-6.5 (m, 2H); 5.3-5.1 (2 * d, 1H); 5.1 / 4.7 / 3.6 (3 * m, 1H); 4.9 / 4.2-3.5 (2 * m, 1H); 4.9 / 4.2-3.5 (2 *. 1H); 4.9-4.8 (m, 2H); 3.6 / 3.4 (2 * m, 4H); 3.4 / 3.3 (m, 2H); 3.4 (m, 6H); 3.1-2.5 (m, 4H); 3-2.4 (m, 2H); 2.8 / 2.6 (m, 3H); 2.6-1.7 (m, 6H); 1.9-1.3 (m, 10H)

Stage H: N- (4-hydroxyphenyl) ~ N- (1-methyl ~ 2,3-di / tydropyrrolo [2 _t 3b [pyridin-5-yl) -3- [2 - [(3S) -3 hydrochloride - (morpholinomethyl) -3,4-dihydro ~ 1H-isoquinotine-2 ~ carbony! j-4- [2-oxo-2- (l-pÎperidyl) ethoxyJplienylJ-5,6,7,8-tetraliydroindoiizine-Icarboxamide

The base obtained in Stage G (0.60 g, 0.69 mmol) is dissolved in acetonitrile, then salified with 0.7 ml (0.7 mmol) of an IN HCl solution. The solution is filtered, frozen and then lyophilized to provide the title hydrochloride in the form of a powder.

Elemental microanalysis: (% theoretical: measured)% C = 68.02: 68.06; % H = 6.49: 6.21; % N = 10.89: 10.87; % C1 = 4.14: 3.94

High resolution ground (ES1 +) t

Molecular Formula: C51 H57 N7 O6 [M + H] ⁺ Calculated: 864.4445 [M + H] ⁺ Measured: 864.4443

Stage I: 4-l (1-Methyl-2,3-dihydro-1H-pyrrolo [2,3-b] pyridin-5-yl) [l3- (2 - {[(3S) -3 (morpltolin-4 -ylmetltyl) -3,4-di! iydroisoquinolÎn-2 (III) -ylJcarbony!} - 4- [2-oxo-2 (pipérldin-l ~ y!) ethoxyjpheny!) '5,6,7,8-tetrahydroindolizin -1-yl] carbonyl} amino [disodium phenyl phosphate

The procedure is carried out according to a protocol similar to that described in Steps B and C of Example 16.

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-66IR (cm * ¹ ): v: C = O: 1625; v: (phosphate; ether): 1229, 1138,1115, 982; γ:> CH Ar: 88O748-745

Elemental microanalysis

%VS % H %NOT Calculated 62.00 5.71 9.92 Find 61.45 5.53 9.96

High resolution ground (ESI +).

_Molecular formula: C ₅ i Η _ΐ8 N ₇ Na ₂ O9 P [M-2Na + 3H] ⁺ calculated: 944.4106 [M-2Na + 3H] ⁺ measured: 944.44116

Example 24. 4 - [{[5- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1 //) - yl [carbonyl} phenyl) -l, 2-dimethyl-1H-pyrrol-3yl] carbonyl) (l-methyl-1H-pyrazol-4-yl) amino] phenyl phosphate

Stage A: 5- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) ~ 3,4dihydroisoquinolin-2 (1H) -yI / carbonyl} phenyl) -N- (4) hydrochloride -hydroxyphenyl) -l, 2-dimethyl-N- (lmethyl-1H-pyrazol-4-yl) -lH-pyrrole-3-carboxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 4, and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 5”. The product obtained is finally subjected to a salification step in the presence of hydrochloric ether in ether. After filtration and lyophilization in an acetonitrile / water mixture, the expected compound is obtained.

Elemental microanalysis: (% theoretical: measured)% C = 63.77: 62.83; % H = 5.63: 5.83; % N = 11.74: 11.29; % CI- = 4.95: 5.42

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-67Stade B: 4 - [{[5- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) ~ 3,4 ~ diliydroisoquinolin2 (lH) -ylJcarbonyl} phenyl) -l, Disodium 2 ~ dimethyl-1H-pyrrol-3-ylJcarbonyl} (l-methyl-1H-pyrazol4-yl) amino] phenylphosphate

The procedure is carried out according to a protocol similar to that described in Steps B and C of Example 16.

IR (cm ' ¹ ): v: C = O: 1625; v: (phosphate; ether): 1241,1146,1112,983

Elemental microanalysis:

%VS % H %NOT Calculated 56.83 4.77 10.46 Find 56.82 4.58 10.43

Mass haunts resolution (ES1 +):

Molecular formula: C _3g H _3g Cl Ne Na ₂ O7 P [M-2Na + 3H] ⁺ calculated: 759.2457 [M-2Na + 3H] ⁺ measured: 759.2465

Example 25. 4 - [(5-Cyano-1,2-dlmethyl-1W-pyrro! -3-y!) {[5- (5-nuoro-2- {| (3.S) -3 (morpholÎn- 4-ylmethy!) - 3,4-dihydroisoquino! In-2 (l / 7) -y!] Carhony!} Pheny!) - 1,2dîmethyl-1 J7-pyrrol-3-yl] carhonyl} amino] phenyl phosphate of disodium

Stage A: jV- (5-cyano-1,2-dimethyl-1W-pyrro! -3-yl) -5- (5-nuoro-2 {[(3S) -3- (morpholin-4-ylmethyl) hydrochloride ) -3,4-dihydroisoquinolin-2 (l / 7) -yl] carhonyl} pheny!> JV- (4-hydroxyphenyl) -l, 2-dimethy! -LH-pyrrole-3-carhoxamide

The procedure is carried out according to a protocol similar to that described in Stages AD of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 7, and on the other hand the compound of Preparation 1 ”used in Stage C by that of Preparation 7”. The product obtained is finally subjected to a salification step in the presence of hydrochloric ether in ether. After filtration and lyophilization in an acetonitrile / water mixture, the expected compound is obtained.

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-68 High resolution mass (ESI / FIA / HR and MS / MS) t

Molecular formula: C41 H41 F Born O4 [M + H] ⁺ calculated: 701.3246 [M + H] ⁺ measured: 701.3282

Stage B: 4 - [(5-Cyano-13-dÎmethyl-1 / f-pyrrol'3-yl) {[5- (5-nuoro-2 - {((35) -3 (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} phenyl) -l, 2dimethyl-1 // - pyrrol-3-yllcarbonyl} amino] phenyl disodium phosphate

We proceed according to a protocol similar to that described in Stages B and C of Example 16.

^3, P NMR (400/500 MHz, CD3OD) δ ppm: -0.5

IR (cm * ¹ ): v: -CN: 2211 cm * ¹ ; v: C = O: 1629; v: (phosphate; ether): 1236, 1114.984

Elemental microanalysis:

%VS % H %NOT Calculated 59.71 4.89 10.19 Find 60.09 4.95 9.88

High resolution mass (ESI +) î Crude formula: C41H40 F Nô Naî O7P [M-2Na + 3H] ⁺ calculated: 781.2909 [M-2Na + 3H] ⁺ measured: 781.2898

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-69PHARMACOLOGICAL AND PHARMACOKINETIC STUDIES

For the sake of clarification, in all that follows, compounds of formula (Γ) will be referred to as "drug of Example x" from which they are derived. For example, N- (4hydroxyphenyl) -3- (6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (I //) - isoquinolinyl) carbonyl] - The 3′benzodioxol-5-yl} -iV-pheny] -5,6,7,8-tetrahydro-1 -indolizine carboxamide will be referred to as "drug of Example I".

EXAMPLE A1: Induction of caspase activity in vivo by the compounds of formula (I ’)

The capacity of the compounds of formula (Γ) to activate caspase 3 is evaluated in an RS4 leukemia cell xenograft model; 11.

1.10 ⁷ RS4 cells; 11 are grafted subcutaneously in immunosuppressed mice (SCID strain). 25 to 30 days after the transplant, the animals are treated orally with the different compounds. Sixteen hours after the treatment, the tumor masses are recovered, lysed and the caspase 3 activity is measured in the tumor lysates.

This enzymatic measurement is carried out by measuring the appearance of a fluorigenic cleavage product (DEVDase activity, Promega). It is expressed in the form of an activating factor corresponding to the ratio between the two caspase activities: that for the treated mice divided by that for the control mice.

The A ^r - (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1 //) isoquinolinyl) carbonyl] -l, 3- benzodioxol-5-yl} -jV-phenyl-5,6,7,8-tetrahydro-I-indolizine carboxamide (also called the drug of Example I) was tested. At a dose of 100 mg / kg po, the caspase activation factor in vivo is 29.3.

The results obtained show that the compounds of formula (Γ) are capable of inducing apoptosis in RS4; 11 tumor cells in vivo.

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EXAMPLE A2 Quantification of the cleaved form of caspase 3 in vivo induced by the compounds of formula (Γ).

The capacity of the compounds of formula (Γ) to activate caspase 3 is evaluated in an RS4 leukemia cell xenograft model; 11.

1.10 ⁷ RS4 cells; 11 are grafted by the subcutaneous route in immunosuppressed mice (strain SC1D). 25 to 30 days after the transplant, the animals are treated orally with the different compounds. After the treatment, the tumor masses are recovered, lysed and the cleaved (activated) form of caspase 3 is quantified in the tumor lysates.

This quantification is carried out using the “Meso Scale Discovery (MSD) ELISA platform” assay which specifically assays the cleaved form of caspase 3. It is expressed in the form of an activation factor corresponding to the ratio between the quantity of caspase 3 cleaved in the treated mice divided by the amount of caspase 3 cleaved in the control mice.

The results show that the compounds of formula (Γ) are capable of inducing apoptosis in RS4; 11 tumor cells in vivo.

Table 1: Caspase activation factors (cleaved caspase 3 MSD test in tumors of treated mice versus control mice) in vivo, after oral treatment

Compound tested Dose (mg / kg) Sampling time Activation factor +/- H.E.M. Drug from example 13 12.5 2h 24.5 +/- 7.5 Drug from example 19 12.5 2h 13.5 +/- 1.2 Drug from example 20 12.5 2h 52.0 +/- 8.6 Drug from example 21 12.5 2h 22.6 +/- 2.4 Drug from example 24 25 2h 45.7 +/- 2.0 Drug example 25 12.5 2h 38.7 +/- 10.7 Drug from example 15 25 2h 29.8 +/- 4.0

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EXAMPLE A3: Quantification of the cleaved form of caspase 3 in vivo induced by the compounds of formula (I).

The ability of the compounds of formula (1) to activate caspase 3 is evaluated in an RS4; 11 leukemia cell xenograft model according to the protocol presented in Example A2.

Table 2: Caspase activation factors (caspase 3 cleaved MSD test in tumors of treated mice versus control mice) in vivo, after oral treatment

Compound tested Dose (mg / kg) Sampling time Activation factor + / S.E.M. Example 13 12.5 2h 58.6 +/- 4.6 Example I 50 2h 21.2 +/- 1.3 Example 19 12.5 2h 27.5 +/- 3.5 Example 20 12.5 2h 62.1 +/- 3.4 Example 21 25 2h 55.2 +/- 6.2 Example 24 25 2h 60.5 +/- 4.5 Example 25 12.5 2h 61.8 +/- 8.9 Example 15 25 2h 12.1 +/- 1.1

EXAMPLE B: Solubility of the compounds of formula (I)

The solubility of compounds of formula (I) was measured in water and compared to that of 10 compounds of formula (Γ).

Specifically, the 4 - [{[3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin2 (1 //) - yl] carbonyI) -l, 3- benzodioxol-5-yl) -5,6,7,8-tetrahydroindolizin-1-yl] carbonyl} (phenyl) aminojphenyl phosphate (also called compound of Example I) was tested and compared to / V- ( 4-hydroxyphenyl) -3- (6 - [((3S) -3- (4-morpholinyImethyl) -3,415 dihydro-2 (1 //) - isoquinolinyl) carbonyl] -l, 3-benzodioxol-5-yl) - A / -phenyl-5,6,7,8tetrahydro-1-indolizine carboxamide (also called the drug of Example 1).

The solubility of the compound of Example 1 in water is greater than or equal to 10 mg / mL (12.6 mM) while that of the associated drug is only 40 pg / mL (56.2 μΜ). The solubilities of the compounds were also measured in a medium buffered at pH.

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-72physiological (see Table 3).

Table 3; Solubilities in aqueous medium (buffer solution: 033 M phosphate, pH = 7 _t 4) of the compounds of formula (I) and of the compounds of formula fl ¹ ) associated, measured at four concentrations; ΙΟμΜ, 20ρΜ, 50μΜ and ΙΟΟμΜ

Compound tested Solubility at ΙΟμΜ Solubility at 20μΜ Solubility at 50 μΜ Solubility at ΙΟΟμΜ Example 19 Soluble Soluble Soluble Soluble Drug from Example 19 Soluble Soluble Soluble Insoluble Example 20 Soluble Soluble Soluble Soluble Drug from Example 20 Soluble Insoluble Insoluble Insoluble Example 25 Soluble Soluble Soluble Soluble Drug from Example 25 Soluble Soluble Insoluble Insoluble Example 1 Soluble Soluble Soluble Soluble Drug from example 1 Insoluble Insoluble Insoluble Insoluble

The results show that the compounds of formula (I) are much more soluble than the compounds of formula (P). Only the compounds of formula (I) show solubilities greater than or equal to ΙΟΟμΜ.

EXAMPLE C; In vivo conversion of compounds of formula (I)

The pharmacokinetic profile of the phosphate derivatives of formula (I) is evaluated in a lipid formulation and in aqueous solution in female SCID mice. It is compared to the pharmacokinetic profile of compounds of formula (Γ) in a lipid formulation.

Specifically, 4 - [{[3- (6 - {[(3S) -3- (morphoIin-4-ylmethyl) -3,4-dihydroisoquinolin2 (l /) - yl] carbonyl} -l, 3-benzodioxoI -5-yI) -5,6,7,8-tetrahydroindolizin-1-yl] carbonyI} (phenyl) aminojphenyl phosphate (also referred to as the compound of Example I) was tested and compared to 2V- (4 -hydroxyphenyl) -3- (6 - [((3S) -3- (4-morpholinyl methyl) -3,4dihydro-2 (I /) 'Îsoquinolinyl) carbonyl] -l, 3-benzodioxol-5-yl} - A ^r -phenyl-5,6,7,8tetrahydro-1-indolizine carboxamide (also called the drug of Example 1).

Lipid formulation of the compound of Example 1

The compound of Example 1 is prepared in an anhydrous ethanol / polyethylene glycol 300 / water (10/40/50, v / v / v) mixture intended for p.o. administration. The study is

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-73 carried out on 2 groups of SCID mice in which the compound of Example 1 is administered under the following conditions:

- Group 1: 3 mg / kgp.o. (gavage, 10 mL / kg),

- Group 2: 25 mg / kgp.o. (gavage, 10 mL / kg).

Blood samples are taken at the following times (3 samples per animal and 3 animals for each time): 0.25 h, 0.5 h, 1 h, 2 h, 6 h and 24 h after oral administration.

Aqueous formulation of the compound of Example 1

The compound of Example 1 is also administered orally in aqueous medium in SCID mice under the following conditions:

- Group I: 30 mg / kgp.o. in solution in 1 mM sodium carbonate (gavage, 10 mL / kg),

- Group 2: 100 mg / kgp. o. in water (gavage, 10 mL / kg).

Blood samples are taken at the following times (3 animals for each time and 1 sample per animal): 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h and 24 h after administration oral.

Whatever the formulation of the compound of Example I, the blood thus collected is centrifuged and the plasma is transferred to tubes containing 1 M hydrochloric acid. The concentrations in the plasma of the phosphate derivative (prodrug) and of its Hydroxylated homolog (drug) are determined simultaneously using a liquid chromatography technique coupled with mass spectrometry detection (TFC-LCMS / MS). The limit of detection for each of the two entities is 0.5 ng / mL.

Lipid drug formulation of the compound of Example 1

The drug of Example 1 is prepared in an anhydrous ethanol / polyethylene glycol 300 / water (10/40/50, v / v / v) mixture intended for oral administration. The study is carried out on several groups of mice SCID in which the drug of Example 1 is administered under the following conditions:

- Group 1: 3 mg / kgp.o. (gavage, 10 mL / kg),

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-74- Group 2: 30 mg / kgp.o. (gavage, 10 mL / kg),

- Group 3: 25 mg / kgp.o. (gavage, 10 mL / kg).

- Group 4: 100 mg / kgp.o. (gavage, 10 mL / kg).

Blood samples are taken at the following times (3 animals for each time and 3 samples per animal for groups 1-2 or 1 sample per animal for groups 3 and 4):

- po: before administration then 0.25 h, 0.5 h, 0.75 h, 1 h, 2 h, 4 h, 6 h, 8 h, 16 h and 24 h after oral administration at 3 and 30 mg / kg,

- po: at 0.5 h, 2 h, 6 h, 16 h and 24 h after oral administration at 25 mg / kg and 0.5 h, 1 h, 2 h, 6 h, 16 h, 30 h and 48 h after oral administration at 100 mg / kg.

The plasmas of the blood samples collected after administration of the lipid formulations of the drug of the compound of Example 1 are analyzed by liquid chromatography coupled with detection by mass spectrometry. The drug limit of quantification of the compound of Example 1 is less than or equal to 0.5 ng / mL.

A non-compartmental pharmacokinetic analysis is carried out on the mean values of the plasma concentrations of the compounds tested. The results are shown in Tables 4 and 5 below.

The results show that whatever the dose (from 3 to 100 mg / kg) and the vehicle (formulation of lipid or aqueous type), the prodrug of formula (I) is rapidly and predominantly converted in vivo into the corresponding drug of formula (Γ) (see table 4). Plasma exposure of the prodrug (C _max , AUC) is low compared to that of the corresponding drug. The results also show that the plasma concentration of the drug thus measured (after administration of the prodrug) is equivalent or even greater than that measured after direct administration of the drug by the oral route (see Table 5).

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-75 Table 4

Compound administered Compound measured Example 1 Drug of ('Example 1 Example 1.3 mg / kg p.o. Lipid formulation Cma ”(ng / mL) —16 Tnux (h) = 0.25 AUC, (ng.h / mL) = 5 Cmw (ng / mL) = 342 T ™, (h) = 0.25 AUC, (ng.h / mL) = 314 Example 1.25 mg / kg p.o. Lipid formulation C ™, (ng / mL) = 244 T ™ Jh> 0.25 AUC, (ng.h / mL) = 92 C ™, (ng / mL) = 6204 T ™ _x (hh0.5 AUC, (ng.h / mL) = 20952 Example 1.30 mg / kg p.o. Aqueous formulation C _m „(ng / mL) = 391 Wh) - 1.0 AUC, (ng.h / mL) = 879 Cm ”, (ng / mL) = 11967 Troxx (h> 0.5 AUC, (ng.h / mL) 49416 Example 1.100 mg / kg p.o. Aqueous formulation C _mM (ng / mL) = 359 T _m „(h) = 2.0 AUC, (ng.h / mL) = 797 Cmix (ng / mL) = 28066 Tro „(h) = 2.0 AUC, (ng.h / mL) = 168478

Table 5

Compound administered Compound measured Drug from Example 1 Drug of Example 1.3 mg / kgp.o. Lipid formulation Cmax (ng / mL) - 295 T _mBX (h) = 0.25 AUC, (ng.h / mL) = 225 Drug of Example 1.25 mg / kgp.o. Lipid formulation Cmax (ng / mL) = 5070 T _ma x (h) = 2.0 AUC, (ng.h / mL) = 20400

DUPLICATE

Drug of Example 1.30 mg / kg p.o. Lipid formulation C _m ax (ng / mL) »8580 Tmaxih ^ 1.0 AUC, (ng.h / mL) = 24200 Drug of Example 1.100 mg / kg p.o. Lipid formulation C _max (ng / mL) = 25878 Tmax (h) ~ 0.5 AUC, (ng.h / mL) = 148,046

Specifically, p.o. administration of the prodrug in an aqueous vehicle achieves your equivalent plasma drug concentrations in excess of those obtained after direct p.o. administration of the drug in a lipid vehicle. The prodrug therefore offers ease of formulation compared to the corresponding drug, in particular in aqueous medium, which is very advantageous from the perspective of clinical development. Indeed, as shown in Example D, the drug of Example 1 is difficult to formulate in an aqueous medium.

Aqueous formulation of the compounds of Examples 20 and 25

The compounds of Examples 20 and 25 are administered orally in aqueous medium in SCID mice, under the following conditions:

- Group 1: 3 mg / kg p.o. in solution in 1 M sodium carbonate (gavage, 10 mL / kg),

- Group 2: 25 mg / kgp.o. in solution in 1 M sodium carbonate (gavage, 10 mL / kg),

Blood samples are taken at the following times (3 animals for each time): 0.25 h, 0.5 h, 1 h, 2 h, 6 h and 24 h after oral administration.

The blood thus collected is centrifuged and the plasma is transferred to tubes containing 1 M hydrochloric acid. The plasma concentrations of the phosphate derivative (prodrug) and its hydroxylated homologue (drug) are simultaneously determined using a technique of liquid chromatography coupled with detection by mass spectrometry (TFC-LC-MS / MS). The limit of quantification for each of the two entities is 0.5 ng / mL.

DUPLICATE

-77 Lipid Drug Formulation of Compounds of Examples 20 and 25

The drugs of Examples 20 and 25 are prepared in a mixture of polyethylene glycol 300 / ethanol / phosal 50PG (30/10/60, v / v / v) intended for administration by the p.o. route in SCID mice, under the following conditions:

- Group l: 3 mg / kg p.o. (gavage, 10 mL / kg),

- Group 2: 25 mg / kgp.o. (gavage, 10 mL / kg).

Blood samples are taken at the following times (3 animals for each time): 0.25 h, 0.5 h, 1 h, 2 h, 6 h and 24 h after oral administration.

The blood thus collected is centrifuged and the plasma is transferred to tubes containing 1M hydrochloric acid. The plasma concentrations of the drug are determined using a liquid chromatography technique coupled with mass spectrometric detection (TFC-LC-MS / MS). The limit of quantification is 0.5 ng / mL.

A non-compartmental pharmacokinetic analysis is performed. The average results are shown in Tables 6,7,8 and 9 below.

Table 6, Example 20

Compound administered Compounds measured Example 20 Drug from Example 20 Example 20.3 mg / kg p.o. Aqueous formulation Cmax (ng / mL) = BLQ T _ma x (h) = ND AUCt (ng.h / mL) = ND C _mM (ng / mL) = 56 Tmax (h) = 1.0 AUC _t (ng.h / mL) = 51 Example 20.25 mg / kgp.o. Aqueous formulation Cmax (ng / mL) ”127 T _max (h) = 0.25 AUC ₍ (ng.h / mL) = 106 Cmax (ng / mL) = 3701 Tmax (h) = 1.0 AUC _t (ng.h / mL) = 8724

ND: not determined

DUPLICATE

-78BLQ: below the limit of quantification

Table 7, Example 20

Compound administered Compound measured PE Drug Example 20 PE drug Example 20.3 mg / kgp.o. Lipid formulation Cmax (ng / mL) = 39 T _m „(h) = 1.0 AUC _t (ng.h / mL) = 55 PE drug example 20.25 mg / kgp.o. Lipid formulation c _max (ng / mL) = 5524 Tmax (h) “2.0 AUC, (ng.h / mL) = 10172

Table 8, Example 25

Compound administered Compounds measured Example 25 PE Drug Example 25 Example 25.3 mg / kg p.o. Aqueous formulation C _max (ng / mL) = 17 Tmax (h) = 1.0 AUQ (ng.h / mL) = 14 C _max (ng / mL) = 29 Tmax (h) ⁼ 1.0 AUC, (ng.h / mL) = 31 Example 25.25 mg / kgp.o. Aqueous formulation Cmax (ng / mL) = 106 T _m ax (h) ⁼ 1.0 AUCt (ng.h / mL) = 114 Cmax (ng / mL) = 2232 T _m ax (h) = 1.0 AUC, (ng.h / mL) = 3965

DUPLICATE

-79 Table 9, Example 25

Compound administered Compound measured Drug of {'Example 25 Example drug 25.3 mg / kg p.o. Lipid formulation C _max (ng / mL) = 33 Tmax (h) - 1.0 AUC, (ng.h / mL) = 37 Drug of Example 25.25 mg / kgp.o. Lipid formulation Cmax (ng / mL) = 3004 Tmax (h) ⁼ 1.0 AUCt (ng.h / mL) = 5704

The results show that whatever the dose (of 3 and 25 mg / kg), the prodrugs of formula (I) are rapidly and mainly converted in vivo into corresponding drugs of formula (Γ) (see tables 6, 7, 8 and 9). The plasma exposures of the prodrugs (Cmax, AUC) are low compared to the exposures of the corresponding drugs. The results also show that the plasma concentrations of the drugs thus measured (after administration of the prodrugs) are equivalent to those measured after direct administration of the drugs by the oral route (see Tables 7 and 9).

EXAMPLE D: In vivo pharmacokinetic profile of the compounds of formula (I *)

The pharmacokinetic profile of / V- (4-Hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinyl methyl) -3,4-dihydro-2 (1W) -Îsoquinolinyl) carbonyl] - l, 3-benzodioxol-5-yl} -N-phenyl5,6,7,8-tetrahydro-l-indolizine carboxamide (also referred to as the drug of Example I) was also evaluated in a lipid and aqueous formulation in the Wistar rat .

The drug of Example 1 is prepared in aqueous suspension in hydroxyethylcellulose at 1% (w / v) in water and compared to a lipid formulation consisting of a mixture of anhydrous ethanol / polyethylene glycol 400 / phosal 50PG (10 / 30/60, v / v / v). Both formulations are administered orally to male rats

Wistar (3 rats / formulation) at a dose of 100 mg / kg p.o (gavage, 10 mL / kg).

DUPLICATE

-80 Blood samples are taken at the following times from each animal (3 animals / time): 0.25 h, 0.5 h, 0.75 h 1 h, 2 h, 4 h, 8 h and 24 h after the oral administration.

The concentrations of the compound tested are determined in the plasma after extraction followed by liquid chromatography coupled with detection by mass spectrometry.

The limit of quantification is 0.1 ng / mL. The results are presented in the table below:

Table 10

Compound administered Compound measured Drug from Example 1 Drug of Example 1.100 mg / kg p.o Aqueous formulation Cmax (ng / mL) ⁼ 816 AUC _t (ng.h / mL) = 3480 Drug of Example 1.100 mg / kg p.o Lipid formulation Cmax (ng / mL) = 5070 AUC _t (ng.h / mL) - 42900

The results show that the lipid formulation allows much better plasma exposure of the drug of Example 1 than the aqueous formulation.

EXAMPLE E i In vitro test on human Caco-2 cells.

The cellular passage from A to B (Apical to Basolateral) of the phosphate derivatives of formula (I) and of the compounds of formula (Γ) (corresponding drugs) is studied on human Caco-2 cells. Each compound is deposited apically at 1 or 3 μΜ (in duplicate), then incubated for 120 min.

DUPLICATE

-81Several samples were taken during the experiment;

- Apical: just after the deposit (t = 0) and at 120 min

- Basolateral: at the end of the experience (120 min)

The concentrations of the phosphate derivative (prodrug) and / or its hydroxyated homologue (drug) are determined by liquid chromatography coupled with detection by mass spectometry (LC-MS / MS). The limit of quantification for each of the two entities is 2 ng / mL.

The apparent permeability (P _app ) and the absorbed fraction (F _a bs) predicted in humans are calculated for the prodrug, for the drug after incubation of the prodrug and for the drug after incubation of the drug (Hubatsch et al, Nat Protoc. 2007; 2 (9), 2111-2119).

The yield of the experiment, which corresponds to the ratio (in percentage) of the total amount of compound found at the end of the experiment versus that incubated, is also calculated.

The results have been collated in Table 11. They show that the prodrugs of the compounds of formula (I) are strongly degraded during the experiment (experiment yields <1.5%), thus leading to the formation of the drugs. associated in significant proportions.

Finally, the absorbed fraction predicted in humans for drugs formed after incubation of prodrugs is similar to that obtained after incubation of drugs.

Table 11

Compound administered Compounds measured Example 1 Drug from Example 1 Example 1 P _app (ÎO * cm / s) = 0.01 F _abs (%) = ND Efficiency (%) = 0 P _app (10 ^ό cm / s) = 0.83 Fabs (%) = 71 Yield (%) = 42

DUPLICATE

P drug Example 1 Pepp (10 * cm / s) = 0.65 F _abî (%) = 67 Yield (%) = 37 Example 4 Drug from Example 4 Example 4 P _B pp (10 ^ cm / s) = 0.33 F _abs (%) = ND Efficiency (%) = 1.3 P app (10 * cm / s) = 0.43 F _abs (%) = 69 Efficiency (%) = 38 Drug from Example 4 Ρ, ρρ (10 ^ 0111/8) = 0.21 F _abs (%) = 46 Efficiency (%) = 20 Example 5 Drug from Example 5 Example 5 P.pp (10 ^ cm / s) = 0.26 F _abs (%) = ND Yield (%) = 1.2 P7pp (10- * cm / s) = 2.3 F _abs (%) = 86 Efficiency (%) = 78 Drug from Example 5 Papp (10 * cm / s) = 0.7 F _abs (%) = 68 Efficiency (%) = 34 Example 20 Drug from Example 20 Example 20 P _app (10 ^- * cm / s) = 0 F _abs (° / o) = ND Efficiency (%) = 0.94 P _a pp (10 * cm / s) = 0.16 F _abs (%) = 16 Efficiency (%) = 100 Drug from Example 20 P _ap p (10 ^ cm / s) = 0.29 F _abs (%) = 25 Efficiency (%) = 91 Example 21 Drug from Example 21 Example 21 Ρ _β ρρ (1 θ '* cm / s) = 0 F _abs (%) = ND Efficiency (%) = 0.83 P.pptlO ⁴ 'cm / s) = 0.21 F _abî (%) = 19 Efficiency (%) = 100

DUPLICATE

Drug from Example 21 P _arP (l0 ^ cm / s) = 0.27 F _abs (%) = 24 Efficiency (%) = 82 Example 25 Drug from Example 25 Example 25 P ^ ÔÔ ^ cÎÏVsj ^ Ô F _abs (%) = ND Yield (%) = 33 PapJlÔ * cm / s) = 0 ^ 22 F _abs (%) = 20 Yield (%) = 48 Drug from Example 25 P _app (10 ** cm / s) - 0.49 F _abs (%) = 40 Efficiency (%) = 100

ND: not determined

EXAMPLE F: Anti-tumor activity in vivo.

The anti-tumor activity of the compounds of the invention is evaluated in an RS4 leukemia cell xenograft model; 11.

1.10 ⁷ RS4 cells; 11 are grafted subcutaneously in immunosuppressed mice (SCID strain). 25 to 30 days after the transplant, when the tumor mass has reached about 150 mm ³ , the mice are treated orally with the different compounds in 2 different schedules (daily treatment for five days per week for two weeks, or two treatments with week for two weeks). Tumor mass is measured twice a week from the start of treatment.

The compounds of the invention exhibit oral antitumor activities in the RS4; 11 leukemia model (acute lymphoblastic leukemia). The results obtained show that the compounds of the invention are capable of inducing significant tumor regression.

DUPLICATE

-84EXAMPLE G; Pharmaceutical composition t Tablets

1000 tablets containing 5 mg of a compound chosen from Examples 1 to 25 ............ 5g

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

Corn starch............................................... .................................................. ..... 20g

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

Magnesium stearate ............................................... ............................................. 2g

Silica................................................. .................................................. ..................... 1g

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

DUPLICATE

Claims (18)

1. Phosphate compound of formula (I): in which : ♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they cannot simultaneously represent two carbon atoms or two nitrogen atoms, ♦ Ai and A2 together with the atoms which carry them form a heterocycle Het optionally substituted, aromatic or not, consisting of 5, 6 or 7 members, and which may contain, in addition to the nitrogen represented by X or by Y, one to 3 heteroatoms chosen independently from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Ci-C6) alkyl group or a C (O) -O-Alk group in which Alk is an alkyl group (Cj-Ce ) linear or branched, or, Al and A2 represent, independently of one another, a hydrogen atom, a linear or branched polyhaloalkyl (Cj-Cé), a linear or branched (Ci-C6) alkyl group or a cycloalkyl, ♦ T represents a hydrogen atom, a linear or branched alkyl (Cj-Ce) é optionally substituted by one to three halogen atoms, a group DUPLICATE (Ci-C ₄ ) -NR | R2 alkyl, or a (C | -C4) -OR “alkyl group, ♦ R | and R ₂ represent, independently of one another, a hydrogen atom or a linear or branched alkyl group (Cj-Ce), or else Rj and R ₂ together with the nitrogen atom which bears them form a heterocycloalkyl, ♦ R ₃ is alkyl (Cj-Ce) linear or branched, alkenyl (C ₂ -CO) -straight or branched alkynyl (C ₂ -C 6) -straight or branched alkyl, cycloalkyl, cycloalkyl (C ₃ -Cio) alkyl (C | -Ce) linear or branched, heterocycloalkyl, aryl or heteroaryl, it being understood that one or more carbon atoms of the preceding groups, or of their optional substituents, can be deuterated, ♦ R4 represents an aryl group , heteroaryl, cycloalkyl or linear or branched (C | -Ce) alkyl, it being understood that one or more carbon atoms of the preceding groups, or of their optional substituents, can be deuterated, ♦ R ₅ represents a hydrogen or halogen atom, a linear or branched (Ci-C ₆ ) alkyl group, or a linear (Cj-C6) alkoxy group or branched, ♦ R $ represents a hydrogen atom or a linear or branched (Ci-C6) alkyl group, ♦ R “, Rb, Rc and Rj represent independently of each other R ?, a halogen atom, a group linear or branched (C | -C ₆ ) alkoxy, a hydroxy group, a linear or branched polyhaloalkyl (Cj-Ce) group, a trifluoromethoxy group, -NR7R7 ', nitro, R7-CO-alkyl (Co-Ce) -, R7-CO-NH-alkyl (Co-Cé) -, NR7R ₇ '-CO-alkyl (Co-C ₆ ) -, NR7R7'-CO-alkyl (Co-C ₆ ) -0-, R7-S0 ₂ - NH-alkyl (Co-C ₆ ) -, R7-NH-CO-NH-alkyl (Co-C ₆ ) -, R ₇ -O-CO-NH-alkyl (CQ-C ₆ ) -, a heterocycloalkyl group, or else the substituents of one of the pairs (Ra, Rb), (Rb, Rc) or (Rc, R <i) together with the carbon atoms which carry them form a ring consisting of 5 to 7 members, which may contain from one to 2 heteroatoms chosen from oxygen and sulfur, it being also understood that one or more carbon atoms of the previously defined cycle can be deuterated or substituted by one to 3 groups chosen from halogen or linear or branched alkyl (Cj-Ce), ♦ R7 and R7 'represent, independently of one another, hydrogen, linear or branched (CiCé) alkyl, linear or branched (C ₂ -Ce) alkenyl, a linear or branched (C ₂ -C1) alkynyl, an aryl or a heteroaryl, or else R7 and R? ' form together DUPLICATE -87with the nitrogen atom which carries them a heterocycle consisting of 5 to 7 members, the compound of formula (I) being such that at least one of the carbon atoms which constitute it is substituted by one of the phosphate groups following: -OPO (OM) (OM '), -ΟΡΟ (ΟΜ) (Ο · Μ! ⁺ ), -OPO (O'Mi ⁺ ) (O'Mî ⁺ ), -ΟΡΟ (Ο ·) (Ο ·) Μ ₃ ²⁺ , -OPO (OM) (O [CH ₂ CH ₂ O] _n CH ₃ ), or -OPO (O'Mi ⁺ XO [CH2CH2O] nCH3), in which M and M are independently of each other a hydrogen atom, a linear or branched alkyl (Cj-Ce) group, a linear or branched (C2-Ce) alkenyl group, a linear or branched (C2-Ce) alkynyl group, a cycloalkyl or a heterocycloalkyl, both consisting of 5 to 6 membered members, while M / and M2 ⁺ independently of each other represent a pharmaceutically acceptable monovalent cation, M3 ²⁺ represents a pharmaceutically acceptable divalent cation and n is an integer between 1 and 5, being understood that: - By aryl is meant a phenyl, naphthyl, biphenyl or indenyl group, - By heteroaryl is meant any mono or bi-cyclic group consisting of 5 to 10 members, having at least one aromatic part, and containing from 1 to 4 heteroatoms chosen from oxygen, sulfur or nitrogen (including quaternary nitrogen), - By cycloalkyl is meant any non-aromatic, mono or bi-cyclic carbocyclic group containing 3 to 10 members, - By heterocycloalkyl is meant any non-aromatic mono or bicyclic group, fused or spiro, consisting of 3 to 10 members, and containing 1 to 3 heteroatoms chosen from oxygen, sulfur, SO, SO ₂ or nitrogen, aryl and heteroaryl groups , cycloalkyl and heterocycloalkyl thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups which may be substituted with 1 to 3 groups chosen from linear or branched (C1-C6) alkyl optionally substituted, spiro (C ₃ -C ₆ ), alkoxy ( C | -C ₆ ) linear or branched optionally substituted, (Ci-C ₆ ) alkyl-S-, hydroxy, oxo (or A-oxide where appropriate), nitro, cyano, -COOR ', -OCOR *, NR'R ”, linear or branched polyhaloalkyl (C | -Cè), trifluoromethoxy, DUPLICATE -88 (Cj-C6) alkylsulfonyl, halogen, optionally substituted aryl, heteroaryl, aryloxy, arylthio, cycloalkyl, heterocycloalkyl optionally substituted with one or more halogen atoms or alkyl groups, it being understood that R 'and R ”represent, independently l 'on the other, a hydrogen atom or a linear or branched alkyl group (C 1 -Ce) optionally substituted, the Het group defined in formula (I) possibly being substituted with one to three groups chosen from alkyl ( C | -Ce) linear or branched, hydroxy, linear or branched (Cj-C6) alkoxy, NRfRi ”, or halogen, it being understood that Rf and Rf * have the same definitions as the groups R 'and R mentioned above, its enantiomers and diastereoisomers, as well as its addition salts with a pharmaceutically acceptable acid or base. 2. Compound of formula (I) according to claim 1 wherein R4 represents a phenyl substituted in the para position by a group of formula -OPO (OM) (OM '), -OP0 (0M) (0'Mi ⁺ ), - OP0 (0'Mi ⁺ ) (0'M2 ⁺ ), -ΟΡΟ (Ο ·) (Ο ·) Μ3 ²⁺ , -OP0 (0M) (0 [CH ₂ CH ₂ 0] _n CH ₃ ), or -OP0 (0'Mf) (0 [CH ₂ CH ₂ 0] nCH ₃ ), in which M and M 'independently represent the of each other a hydrogen atom, an alkyl group (Cj-Co) linear or branched, an alkenyl group (C ₂ -This) -straight or branched alkynyl group (C ₂ -This) -straight or branched alkyl, cycloalkyl or heterocycloalkyl, both of which are 5 to 6 membered, while Mj ⁺ and M2 ⁺ independently of each other represent a pharmaceutically acceptable monovalent cation, M3 ²⁺ represents a pharmaceutically acceptable divalent cation and n is a number integer between 1 and 5, it being understood that the phenyl group can be optionally substituted by one or more halogen atoms. 3. A compound of formula (I) according to claim 1 in which R4 represents a phenyl substituted in the para position by a group of formula -OP0 (0'Na ⁺ ) (0'Na ⁺ ). 4. Compound of formula (I) according to one of claims 1 to 3 wherein X represents a carbon atom and Y represents a nitrogen atom. DUPLICATE 5 * Compound of formula (I) according to one of claims 1 to 3 wherein the group: represents a 5,6,7,8-tetrahydroindolizine, an indolizine or a dimethylated pyrrole. 6 "Compound of formula (I) according to one of claims 1 to 5 wherein T 5 represents a methyl, (morpholin-4-yl) methyl or 3- (morpholin-4yl) propyl group. 7. Compound of formula (I) according to one of claims 1 to 6 in which R 1 and Rd each represent a hydrogen atom and (Rb, R ") together with the carbon atoms which bear them form a group 1 , 3-dioxolane, a 1,4-dîoxane group, or alternatively R ,, R <and Rj each represents a hydrogen atom and Rb represents a hydrogen or a halogen. 8, A compound of formula (I) according to one of claims 1 to 6 wherein R, and Rd each represents a hydrogen atom, Rb represents a halogen atom and Rc a methoxy group. 15 9, A compound of formula (I) according to one of claims 1 to 6 wherein R ,, Rb and Rd each advantageously represents a hydrogen atom and R <represents an NR ₇ R7'-CO-alkyl (Co-C6) -O- group. JO. Compound of formula (I) according to one of claims I to 9 in which R3 advantageously represents a group chosen from phenyl, lH-indole, \ H20 pyrrolo [2,3-i »] pyridine, pyridine, ΙΗ-pyrazole, lH -pyrrole, and 2,3-dihydro-1H-pyrrolo [2,3ôjpyridine, these groups optionally comprising one or more substituents DUPLICATE -90 selected from linear or branched (C1-C11) alkyl, cyano, or trideuteriomethyl. 11. A compound of formula (1) according to claim I chosen from the following list: • 4 - [{[3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (l / 7) yl] carbonyl) -1,3-benzodioxol- 5-yl) -5,6,7,8-tetrahydroindolizin-1 yl] carbonyl} (phenyl) amino] phenyl phosphate, 4 - [{[5- (5-chloro-2 - {[(3S) - 3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1/7) y JJcarbonyl} phenyl) -l, 2-dimethyM H-pyrrol-3-yl] carbonyl) (pyridin-4yl) amino] disodium phenyl phosphate, • 4 - ({[5- (5-chloro-2 - {[(3S) -3- (morphoiin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (l / 7) y ljcarbony 1} pheny I) -1,2-dimélhy 1-1 H-pyrro 1-3-y I] carbony 1} [1 - (trideuteriomethy 1) lif-pyrazoI-4-yl] amino) phenyl disodium phosphate, • Ή {[5- (5-chIoro-2- {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) yljcarbonyl} pheny I) -1,2-dimethyl- 17f-pyrrol-3-yl] carbonyl) (5-cyano-1,2-dimethyll / f-pyrrol-3-yl) amino] phenyl phosphate, • 4 - [{[5 '(5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4'dihydroisoquinoIin-2 (1W) yl] carbonyl} phenyI) -l, 2-dimethybl / f'pyrrol-3-yl] carbonyl} (5-cyano-1-methyM / fpyrrol-3-yl) am disodium ino] phenyl phosphate, 4 - [{[5- (5-chloro-2- {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquino! in-2 (1H) yl ] carbonyl) phenyl) -1,2-dimethyl-1 H-pyrrol-3-yl] carbonyl} 0-methyl-1 H-pyrazol- Disodium 4-yl) amino] phenyl phosphate, - 4 - [(5-cyano-1,2-dimethyl-1 // - pynol-3-yl) {[5- (5-fluoro-2 - {[(3S) -3- (morpholin-4yIméthyI) - 3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} phenyl) -I, 2-dimethyl-1Hpyrrob3-yl] carbonyHamino] phenyl phosphate,. 4 - [{[5- (5-fluoro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1/7) yl] carbonyl) pheny!) - Disodium 1,2-dimethyl-1 // - pynol-3-yI] carbonyl) (1-methyl-1Hpyrazoi-4-yl) amino] phenyl phosphate, their enantiomers and diastereomers, as well as their addition salts with a acid or a pharmaceutically acceptable base. DUPLICATE -91IX Process for preparing the compounds of formula (I) according to Claim 1, characterized in that the starting product of the compound of formula (II) is used: in which R #, Rt>, R “and Ra are as defined in claim 1, 5 compound of formula (II) which is subjected to a Heck reaction, in aqueous or organic medium, in the presence of a palladium catalyst, a base, a phosphine and the compound of formula (III): ( III) in which the groups A 1, A ₂ , X and Y are as defined in claim 1 and Atk represents a linear or branched (Cj-Ce) alkyl, 10 to obtain the compound of formula (IV): DUPLICATE -92AJk \ in which A |, A ₂ , X, Y, R ”, Rb, Rc and R <j are as defined in claim 1 and Alk is as defined above, compound of formula (IV) in which the aldehyde function is oxidized in carboxylic acid for 5 form the compound of formula (V): wherein Ai, A ₂ , X, Y, R _a , Rb, Rc and Rj are as defined in claim I and Alk is as defined above, DUPLICATE -93 compound of formula (V) which then undergoes peptide coupling with a compound of formula (VI): where T and R; are as defined in claim 1, 5 to lead to the compound of formula (VII): Alk \ Rc in which A |, A2, X, Y, R _a , Rb, Rc, R <j, T and R 5 are as defined in claim 1 and Alk is as defined above, compound of formula (VII) of which the ester function is hydrolyzed to result in the carboxylic acid or the corresponding carboxylate, which can be converted into an acid derivative such as acyl chloride or the corresponding anhydride, before being coupled with an amine NHR3R4 , wherein R3 and Rj have the same meaning as in claim 1, before being subjected to the action of a pyrophosphate, phosphonate or phosphoryl derivative under basic conditions, the compound thus obtained being optionally hydrolyzed or hydrogenolysed. , to lead to the compound of formula (I), DUPLICATE -94compound of formula (I) which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with an acid or with a pharmaceutically acceptable base and from which the isomers according to a conventional separation technique, it being understood that at any time deemed appropriate during the process described above, certain groups (hydroxy, amino, etc.) of the reagents or synthesis intermediates can be protected and then deprotected for the needs of the synthesis. 13. Pharmaceutical composition containing a compound of formula (I) according to any one of claims 1 to 11 or one of its addition salts with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. 14. The pharmaceutical composition of claim 13 for use as a prodrug of a pro-apoptotic agent. 15. A pharmaceutical composition according to claim 13 for its use in the treatment of cancers, autoimmune diseases and the immune system. 16. Pharmaceutical composition according to claim 15 for its use in the treatment of cancers of the bladder, of the brain, of the breast, of the uterus, of chronic lymphoid leukemia, of colorectal cancer, of cancers of the esophagus, of the liver, lymphoblastic leukemias, non-Hodgkin lymphomas, melanomas, hematologic malignancies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. 1Z. Use of a pharmaceutical composition according to claim 13 for the manufacture of a medicament useful as a pro-apoptotic agent. 1 £ Use of a pharmaceutical composition according to claim 13 for the manufacture of a medicament for the treatment of cancers, autoimmune diseases and the immune system. DUPLICATE -9519. Use of a pharmaceutical composition according to claim 18 for the manufacture of a medicament for the treatment of cancers of the bladder, brain, breast, uterus, chronic lymphoid leukemia, colorectal cancer, cancer of the uterus. esophagus, liver, lymphoblastic leukemia, non-Hodgkin's lymphoma, melanoma, hematologic malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and cancer small cell lung. 20, A compound of formula (I) according to one of claims 1 to 11, or an addition salt thereof with a pharmaceutically acceptable acid or base, for its use in the treatment of cancers of the bladder, of the brain. , breast, uterine, chronic lymphoid leukemia, colorectal cancer, cancer of the esophagus, liver, lymphoblastic leukemia, non-Hodgkin's lymphoma, melanoma, hematologic malignancies, myeloma, cancer of ovarian, non-small cell lung cancer, prostate cancer and small cell lung cancer. 15 2L Use of a compound of formula (I) according to one of claims 1 to 11, or one of its addition salts with a pharmaceutically acceptable acid or base, for the manufacture of a medicament intended for the treatment of cancers of the bladder, brain, breast, uterus, chronic lymphoid leukemia, colorectal cancer, cancer of the esophagus, liver, lymphoblastic leukemia, non-Hodgkin's lymphoma, melanoma, blood disease malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. 21 Association of a compound of formula (I) according to any one of claims 1 to 11 with an anticancer agent chosen from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors or antibodies. 23. Pharmaceutical composition containing a combination according to claim 22 DUPLICATE -96in combination with one or more pharmaceutically acceptable excipients. Combination according to claim 22 for its use in the treatment of cancer. 2L Use of a combination according to claim 22 for the manufacture of a medicament useful in the treatment of cancer. 26, A compound of formula (I) according to any one of claims 1 to 11 for its use in combination with radiotherapy in the treatment of cancer.