OA17865A - New Indolizine derivatives, their preparation process and the pharmaceutical compositions which contain them. - Google Patents

Abstract

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

Description

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

The compounds of the present invention are new and exhibit very interesting pharmacological characteristics 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 of the bladder, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, follicular lymphoma, myeloma, prostate cancer ... The overexpression of antiapoptotic proteins of the Bcl-2 family is involved in tumorogenesis, in resistance to chemotherapy and in the clinical prognosis of cancer patients. So there is

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- 2 a therapeutic need for compounds which inhibit the anti-apoptotic activity of proteins of the Bcl-2 family.

The compounds of the present invention besides their novelty, exhibit proapoptotic 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 the compounds of formula (I):

(D 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, the Het part of the group

represents an optionally substituted ring, 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, being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, a linear or branched (Cj-Cê) alkyl group or a -C (O) -O-Alk group in which Alk is an alkyl group (C] -C6) linear or branched.

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- J - ♦ T represents a hydrogen atom, a linear or branched (Ci-C6) alkyl optionally substituted with one to three halogen atoms, a (C2-C4) -NR] R2 alkyl group, or an alkyl group (C | -C4) -OR6, ♦ R 1 and R 2 represent, independently of one another, a hydrogen atom or a linear or branched (C 1 -C 6) alkyl group, or else R | and R ₂ form with the nitrogen atom carrying them, a heterocycloalkyl, ♦ R3 represents an alkyl (Ci-alkyl) linear or branched, alkenyl (C ₂ -CO) -straight or branched alkynyl (C ₂ -CO) linear or branched, cycloalkyl, cycloalkyl (C3-Cio) linear or branched (Ci-C6) alkyl, heterocycloalkyl, aryl or heteroaryl, it being understood that one or more carbon atoms of the preceding groups, or of their possible substituents, can ( vent) be deuterated, ♦ R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (Ci-C6) alkyl group, it being understood that one or more carbon atoms of the preceding groups, or of their optional substituents, can (vent) be deuterated, ♦ R5 represents a hydrogen or halogen atom, a linear or branched (Ci-C6) alkyl group, or a linear or branched (Ci-C6) alkoxy group, ♦ R6 represents a hydrogen atom or a linear or branched (Ci-C6) alkyl group, ♦ R _a , R _b , R _c and R _d represent inde pendant from each other R ₇ , a halogen atom, a linear or branched (Ci-C6) alkoxy group, a hydroxy group, a linear or branched polyhaloalkyl (Ci-C6) group, a trifluoromethoxy group, -NR7R7 ', nitro, R ₇ -CO-alkyl (Co-Cô) -, R ₇ -CO-NH-alkyl (Co-Cô) -, NR ₇ R ₇ '-CO-alkyl (Co-Cô) -, NR ₇ R7' -CO-alkyl (C ₀ -C ₆ ) -O-, R ₇ -SO ₂ -NH-alkyl (C ₀ -C ₆ ) -, R ₇ -NH-CO-NH-alkyl (Co-C6) -, R ₇ -O-CO-NH-alkyl (C ₀ -C6) -, a heterocycloalkyl group, or the substituents of one of the couples (R _a , Rb). (Rb, Rc) or (R _c , 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 a or several carbon atoms of the previously defined cycle can be deuterated or substituted with one to 3 groups chosen from halogen or linear or branched (Cj-C6) alkyl, ♦ R ₇ and R ₇ 'independently represent the one from the other a hydrogen, an alkyl (C | DUPLICATA

-4Cg) linear or branched, a linear or branched (Cd-C ^) alkenyl, a linear or branched (Ct-C /,) alkynyl, an aryl or a heteroaryl, or else R7 and R ₇ 'form together with the nitrogen atom which carries them a heterocycle made up of 5 to 7 members.

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, fused or spiro group, consisting of 3 to 10 members, and containing from 1 to 3 heteroatoms chosen from oxygen and sulfur. SO. SO? or nitrogen, the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups which may be substituted with 1 to 3 groups chosen from linear or branched alkyl (C 1 -C 6) optionally substituted, spiro ( Ca-C6), linear or branched alkoxy (Cj-C6) optionally substituted, (C | -C6) alkyl-S-, hydroxy, oxo (or / V-oxide where appropriate), nitro, cyano, -COOR '. -OCOR ', NR'R ”, linear or branched polyhaloalkyl (Ci-C6), trifluoromethoxy, (C | C6) alkylsulfonyl, 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 linear (C | -C 6) alkyl group or branched optionally substituted, the Het part of the group defined in formula (I) possibly being substituted by one to three groups chosen from linear or branched (C | -C6) alkyl, hydroxy, linear or branched (Ci-C ₆ ) alkoxy , NRi'Ri ”, or halogen, it being understood that R / and Ri” have the same definitions as the groups R 'and R ”mentioned above,

DUPLICATE their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or 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 and tartaric acids. 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.

Advantageously, the group:

represents one of the following groups: 5,6,7,8-tetrahydroindolizine optionally substituted with an amino group; indolizine; 1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine optionally substituted with methyl; pyrrolo [1,2 - ″] pyrimidine. The groups

5,6,7,8-tetrahydroindolizine and indolizine are more particularly preferred.

In the preferred compounds of the invention, T represents a hydrogen atom, a methyl group (and more particularly a (TÜJ-methyl), a 2 (morpholin-4-yl) ethyl group, 3- (morpholin-4- yl) propyl, -CHz-OH, 2-aminoethyl, 2- (3,3difluoropiperidin-1-yl) ethyl, 2 - [(2,2-difluoroethyl) amino] ethyl or 2- (3-methoxyazetidinl-yl) ethyl .

Preferably, R _a and R _c each represent a hydrogen atom and (Rt> .R _c ) together with the carbon atoms which bear them form a 1,3-dioxolane group or a 1,4-dioxane group , or else R _a , R _c and R _d each represent a hydrogen atom and Rb represents a hydrogen, a halogen, a methyl or a methoxy, or alternatively R _a , Rb and Rd each represent a hydrogen atom and R _e represents a hydroxy or methoxy group. More preferably still, R _a and R _d each represent an atom

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-6d of hydrogen and (Rb, R _c ) together with the carbon atoms which carry them form a 1,3-dioxolane group, or else R _a , R _c and Rd each represent a hydrogen atom and Rb represents a halogen .

The preferred R 1 group is 4-hydroxyphenyl.

In the preferred compounds of the invention, Ra represents a linear (Cj-C6) alkyl, aryl or heteroaryl group, these last two groups possibly being substituted with one to three groups chosen from halogen, linear or branched (Cj-C6) alkyl. , linear or branched (CjC6) alkoxy, linear or branched cyano and heterocycloalkyl-alkyl (Cj-C6). More preferably still, Ra represents a heteroaryl group chosen from the following group: 1H-indole, 2,3-dihydro-1 // - indole, 1H-indazole, pyridine, 177-pyrrolo [2,36jpyridine, 1H-pyrazole, imidazo [1,2-a] pyridine, pyrazolo [1,5-c /] pyrimidine, [1,2,4] triazolo [1,5-a] pyrimidine, and l // - pyrazolo [3,4-6] pyridine, all of which may be substituted by a linear or branched (C1-C6) alkyl group.

The preferred compounds according to the invention are included in the following group:

- N- (4-hydroxyphenyl) -3- (6 - {[(3Æ) -3-methyl-3,4-dihydroisoquinolin-2 (l / -7) yl] carbonyl} -l, 3-benzodioxol-5- yl) -W- {l- [2- (morpholin-4-yl) ethyl] -l // - indol-5yl} -5,6,7,8-tetrahydroindolizine-1-carboxamide,

- W- (4-hydroxyphenyl) -3- (6 - {[(3S) -3- [2- (morpholin-4-yl) ethyl] -3,4dihydiOisoquinolin-2 (1H) -yl] carbonyl} -l , 3-benzodioxol-5-yl) - / V-phenyl-5,6,7,8tetraliydroindolizine-1-carboxamide,

- N- {3-fluoro-4- [2- (morpholin-4-yl) ethoxy] phenyl} -N- (4-hydroxyphenyl) -3- (6 {[(37?) - 3-methyI-3, 4-dihydroisoquinolin-2 (l / -7) -yl] carbonyl} -1.3-benzodioxol-5yl) indolizine-l-carboxamide,

- N- (4-hydroxyphenyl) -3- (6- {[(3Â) -3-methyl-3,4-dihydroisoquinolin-2 (127) yl] carbonyl} -l, 3-benzodioxol-5-yl) - / V- (pyridin-4-yl) indolizin-1-carboxamide.

- JV- (4-hydroxyphenyl) -3- (6- {[(3À) -3-methyl-3,4-dihydroisoquinolin-2 (1 H) yl] carbonyl} -l, 3-benzodioxol-5-yl) -N- (2-methylpyridin-4-yl) indolizin-lcarboxamide,

- A ^z - (4-hydiOxyphenyl) -3- (6 - {[(31?) - 3-methyl-3,4-dihydiOisoquinolin-2 (l / · /) yl] carbonyl} -l, 3-benzodioxol- 5-yl) -7V- (1-methyl-lff-pyriOlo [2,3-ô] pyridin-5yl) indolizine-1 -carboxamide,

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-7- ÎV- (4-hydroxyphenyl) -3- (6 - {[(3J?) - 3- [3- (morpholin-4-yl) piOpyl] -3,4dihydroisoquinolin-2 (17-7) -yl ] carbonyl} -l, 3-benzodioxol-5-yl) - / V-phenyl-5,6,7,8tetrahydroindolizine-1 -carboxamide,

- 7V- (2,6-dimethylpyridin-4-yl) -7V- (4-hydroxyphenyl) -3- (6 - {[(37?) - 3-methyl-3,4dihydroisoquinolin-2 (l / 7) - yl] carbonyl} -l, 3-benzodioxol-5-yl) indolizin-lcarboxamide,

- N- (4-hydroxyphenyl) -3- (6 - {[(3Æ) -3-inethyl-3,4-dihydroisoquinolin-2 (l #) yl] carbonyl} -l, 3-benzodioxol-5-yl) -? / - (pyridin-4-yl) -5,6,7,8-tetrahydroindolizine-

-carboxamide,

- 3- (5-ChloiO-2 - {[(3JÎ) -3-methyl-3,4-dihydiOisoquinolin-2 (1/7) -yl] carbonyl} phenyl) 7V '- (4-hydroxyphenyl) -7 / - (1 -methyl-1 Æ-pyrrolo [2,3-6] pyridin-5-yl) indolizin-1 carboxamide,

- N- (4-Hydroxyphenyl) -AA (2-methoxypyridin-4-yl) -3- (6 - {[(3Æ) -3-iiiethyl-3,4dihydiOisoquinolin-2 (177) -yl] carbonyl} -l , 3-benzodioxol-5-yl) indolizin-lcarboxamide, their enantiomers and diastereoisomers, as well as their addition salts with an acid or with a pharmaceutically acceptable base.

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:

Br O

^R c in which R _a . Rb, R _c and R _d are as defined in formula (I), a compound of formula (II) which is subjected to a Heck reaction, in aqueous or organic medium, in the presence of a palladium catalyst, of a base, a phosphine and the compound of formula (III):

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in which the groups X, Y and Het are as defined in formula (I), to obtain the compound of formula (IV):

in which R _a . Rb, R _c , Rd, X, Y and Het are as defined in formula (I), a compound of formula (IV) whose aldehyde function is oxidized to carboxylic acid to form the compound of formula (V):

in which R _a , R _b , R _c , Rd, X, Y and Het are as defined in formula (I),

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

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

in which R _a . Rb, R _c , Rd, T, R5. X, Y and Het are as defined in formula (I).

compound of formula (VII) in which the 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 d 'be coupled with an amine NHR3R1, in which R3 and R | have the same meaning as in formula (I), to lead to the compound of formula (I), compound of formula (I) which can be purified according to a conventional separation technique, which is converted, if desired, in its addition salts with an acid or with a pharmaceutically acceptable base and the isomers of which are optionally separated according to a conventional separation technique, it being understood that at any time deemed appropriate during the process described above.

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- 10certain groups (hydroxy, amino, etc.) of the synthesis reagents or intermediates can be protected and then deprotected for the needs of the synthesis.

More particularly, when one of the R3 or R4 groups of the amine NHR3R4 is substituted by a hydroxy function, the latter can be subjected beforehand to a protection reaction before any coupling with the carboxylic acid of the compound of formula (VII) , or with one of the corresponding acid derivatives, the resulting protected compound of formula (I) then undergoes a deprotection reaction, then is optionally converted into one of its addition salts with an acid or a base pharmaceutically acceptable.

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

Pharmacological study of the derivatives of the invention has shown that they have pro-apoptotic properties. The ability to reactivate the apoptotic process in cancer cells represents a major therapeutic interest in the treatment of cancers, autoimmune diseases and the immune system.

More particularly, the compounds according to the invention will be useful in the treatment of chirnio or radioresistant 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, mention may be made more preferably of follicular lymphomas, mantle cell lymphomas, diffuse large B-cell lymphomas, small lymphocytic lymphomas and B-cell lymphomas of the area

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- He's marginal.

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, mention may be made, more particularly, of those which are suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular single or sugar-coated tablets, sublingual tablets. , sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, skin 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 (I) 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.

Finally, the compounds of the invention may be linked to monoclonal antibodies or fragments thereof or may be linked to framework proteins which may or may not be related to monoclonal antibodies.

The term “antibody fragments” should be understood to mean fragments of the Fv, scFv, Fab, F (ab ') 2 type. F (ab '), scFv-Fc, or diabodies, which in general have the same binding specificity as the antibody from which they are derived. According to the present invention, the antibody fragments of

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The invention can be obtained from antibodies by methods such as digestion with enzymes such as pepsin or papain, and / or by cleavage of disulfide bonds by chemical reduction. In addition, the antibody fragments included in the present invention can be obtained by genetic recombination techniques also well known to those skilled in the art or by peptide synthesis by means of automatic peptide synthesizers for example, such as than those provided by the company Applied Biosystems etc ...

By framework proteins which may or may not be related to monoclonal antibodies is meant a protein which may or may not include an immunoglobulin folding and which delivers a binding capacity similar to that of a monoclonal antibody. Those skilled in the art know how to select the framework protein. More particularly, it is known that, to be selected, such a framework should have several characteristics as follows (Skerra A., J. Mol. Recogn. 13, 2000, 167-187): good phylogenetic conservation, a robust architecture with well known three-dimensional molecular organization (such as crystallography or NMR, for example), small size, little or no post-translational modification (s), ease of production, expression and purification. Such a framework protein may be, without limitation, a structure selected from the group consisting of fibronectin and preferably the tenth type III domain of fibronectin (FNfn10). lipocalin, anticalin (Skerra A., J. BiotechnoL, 2001, 74 (4): 257-75), protein Z derived from the B domain of protein A of staphylococci, thioredoxin A or any protein with a repeat domain such as an ankyrin repeat (Kohl et al., PNAS, 2003, vol. 100, no. 4, 1700-1705), an armadillo repeat, a leucine-rich repeat or a tetratricopeptide repeat. One could also mention a framework derived from toxins (such as toxins from scorpions, insects, plants or molluscs, for example) or inhibitory proteins of nitric oxide synthase (PIN).

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

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- 13 General procedures

All reagents and anhydrous solvents are commercial and were used without further purification or drying. Flash chromatography is performed on an ISCO CombiFIash Rf 200i apparatus with prepackaged cartridges filled with silica gel (SiliaSep ™ F60 (40-63pm), 60Â). Thin layer chromatographies were performed on 5 x 10 cm plates coated with Merck Type 60 F ™ silica gel. The microwave heating was carried out with a CEM Discover® SP device.

Analytical LC-MS

The compounds of the invention were characterized by high performance liquid chromatography coupled with mass spectrometry (HPLC-MS) either on an Agilent HP 1200 apparatus with rapid resolution coupled to a mass detector 6140 with multimodal source (interval m / z from 150 to 1000 atomic mass units or amu), or on an Agilent HP 1100 device coupled to a 1946D mass detector with an electrospray ionization source (m / z range from 150 to 1000 amu). The conditions and methods listed below are identical for both machines.

Detection: UV detection at 230, 254 and 270 nm.

Injection volume: 2pL

Mobile Phases: A - Water + 10 mMol I ammonium formate + 0.08% (v / v) formic acid at pH around 3.5.

B - 95% Acetonitrile + 5% A + 0.08% (v / v) formic acid

Method A (3.75 min; either positive ionization (pos) or positive and negative ionization (pos / neg))

Column: Gemini 5pm, Cl8, 30mm x 4.6mm (Phenomenex).

Temperature: 35 ° C.

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- 14Gradient:

Time (min) Solvent A (%) Solvent B (%) Debit (mL / min) 0 95 5 2 0.25 95 5 2 2.50 95 5 2 2.55 5 95 n J 3.60 5 95 n J 3.65 5 95 2 3.70 95 5 2 3.75 95 5 2

Method B (1.9 min; either positive ionization (pos) or positive and negative ionization (pos / neg))

Column: Gemini 5pm, C18, 30mm x 4.6mm (Phenomenex).

Temperature: 35 ° C.

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- 15 Gradient:

Time (min) Solvent A (%) Solvent B (%) Flow (mL / min) 0 95 5 1.1 0.12 95 5 1.1 1.30 5 95 1.1 1.35 5 95 1.7 1.85 5 95 1.7 1.90 5 95 1.1 1.95 95 5 1.1

Preparation 1: 6- [1- (methoxycarbonyI) -5,6,7,8-tetrahydro-3-indolizinyl | - 1,3-benzodioxole-5-carboxylic acid

Stage A: L-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 10,250 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 directly, without further purification, for the next step.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 13.0 (m. 1H OH); 8.0-8.05 (2s, 1H 15 aldehyde); 4.9-4.5 (2d, 1H oc of N and COOH); 4.1-2.6 (m, 2H to a of N); 2.2-1.2 (m, 6H piperidine)

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- 16IR: v: -OH: 2000-3000 cm- ¹ acid; v:> C = O 1703 cm ' ¹ wide band

Stage B: 5,6,7,8-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 dichloromethane are successively added 13.4 g of tosyl chloride (70.4 mmol).

11.5 mL of methyl 2-chloroacrylate (113.5 mmol), then, dropwise, 17.8 mL of N, N, A-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 A./VjV-triethylamine (64 mmol) are added. The whole is heated at reflux overnight.

The reaction medium is then diluted with methylene chloride, washed successively with IN HCl solution, saturated NaHCOa solution, then saturated NaCl solution until a neutral pH is obtained. The organic phase is then dried over MgSOd, 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: 8 (400 MHz; CDCl ₃ ; 300K): 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 ' ¹ ester

Stage C: 3- (6-Formyl-I, 3-benzodioxol-5-yl) -5,6,7,8-tetrahydro-1-indolizine carboxylate of methyl

To a solution of 6.4 g of the ester obtained in Stage B (35.7 mmol) in 12 mL of N, Ndimethylacetamide, 12.3 g of 6-bromo-1,3-benzodioxole-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 PdC12 (PPli3) 2 (1.8 mmol) are then added. 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 (2 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

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-17 Washed with water, dried over magnesium sulfate and concentrated to dryness. The crude product thus obtained is purified 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 Hs); 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:> 00 1695 cm- ¹ ester; v:> C = O 1674 cm ' ¹

Stage D: 6- [1 ~ (metlioxycarbonyl) -5,6,7,8-tetrahydro-3-indolizinyl] -l, 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 NaClO is added dropwise. (36.05 mmol) and 3.6 g of NajPOj (25.75 mmol). The whole is then stirred at room temperature for 7 hours. Then, the reaction medium is concentrated to remove acetone. The solid thus obtained is filtered, washed with water 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.

NMR‘H: δ (400 MHz; dmso-d6; 300K): 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 (ΐ, 2H tetrahydroindolizine); 1.80 (m, 4H, H tetrahydroindolizine)

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

Preparation 2: 2- [2 - (/ <? / T-butoxycarbonyl) -8- (methoxycarbonyl) -1,2,3,4tetrahydropyrro! O [1,2-fl] pyrazin-6-yI] -4- acid chIorobenzoic

DUPLICATE

- 18 Stage A; 1-tert-biityl 3-methyl 4-Formyl-1,3-piperazinedicarboxylate

To a solution of pentafluorophenol in 520 mL of anhydrous ether placed at 0 ° C, 49 g of 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide (286 mmol) are added successively in portions and 12 mL of formic acid (312 mmol). The whole is stirred at room temperature for 2 hours. Then added a mixture of 32 g of 1-ierAbutyl and 3-methyl 1,3-piperazinedicarboxylate (130 mmol) and 18 mL of triethylamine (130 mmol) dissolved in 520 mL of CH2Cl2. The whole is stirred overnight at room temperature. The reaction medium is hydrolyzed with an aqueous solution of HCl, IN and extracted with CH2Cl2. The organic phases are then combined, then washed with a saturated aqueous NaHCO 3 solution, then with a saturated aqueous NaCl solution until neutral. After drying over MgSO4, filtration and concentration to dryness, the product is isolated by chromatography on silica gel (petroleum ether / AcOEt gradient: 0-30%). The title product is obtained in the form of an oil.

IR: v: C = O: 1674-1745 cm ^-1 m / z (C12H20N2O5): 272.1 (M +); 295,121 (M + Na) ⁺ ; 567.253 (2M + Na) ⁺

Stage B: lithium 4- (tert-Butoxycarbonyl) -1-fonnyl-2-piperazinecarboxylate

To a solution of 28 g of the compound obtained in Stage A (103 mmol) in 515 mL of dioxane, 4.8 g of LiOH (113 mmol) dissolved in 100 mL of HO is added. The whole is stirred at room temperature for 4 h. The reaction medium is then concentrated to dryness, then coevaporated several times with ethyl acetate. The title product is obtained as a solid and is used directly for the next cyclization step.

¹³ C NMR: δ (500 MHz; dmso-d6; 300K): 46 (s, C piperazine); 42-38 (m, C piperazine); 58-53 (s, C piperazine); 28.5 (s, C 'Bu)

IR: v: C = O: 1650 cm- ¹ ; 2800 cm ' ¹

Stage C: 3,4-Dihydropyrrolo [1,2-a] pyrazine-2,8 (1H) -dicarboxylate of 2-tert-butyl and

8-methyl

To a suspension of 29 g of the compound obtained in Stage B (103 mmol) in 800 mL of dichloromethane, 24 g of tosyl chloride (124 mmol) are successively added. 12.6

DUPLICATE

- 19mL of methyl 2-chloroacrylate (124 mmol), then 35 mL of triethylamine (247 mmol). The whole is stirred at reflux for 2 hours. After cooling, the reaction mixture is diluted with ethyl acetate and the organic phase is washed with saturated NaCl solution until neutral. After drying over MgSCL, filtration and concentration to dryness. the title product is isolated by chromatography on silica gel (petroleum ether / AcOEt gradient: 0-20%) in the form of a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 6.8-6.43 (m, 2H, H pyrrole); 4.75-3.75 (m, 6H, H piperazine)); 3.73 (s, 3H, H COOCH3); 1.48 (s, 9H, H ^l Bu)

IR: v: C = O (conjugated ester): 1712 cm- ¹ ; C = O (carbamate): 1677 cm ' ¹

Stage_____D: 2- [2- (tert-butoxycarbonyl) -8- (methoxycarbonyl) -l, 2,3,4tetrahydropyrrolo [1,2-a] pyrazin-6-yl] -4-chlorobenzoic acid

The procedure is carried out according to the protocol described in Steps C and D of Preparation 1, replacing the

6-bromo-1,3-benzodioxole-5-carbaldehyde used in Stage C by 2-bromo-4chlorobenzaldehyde.

Preparation 3: 4-Chloro-2- [1- (methoxycarbonyl) -5,6,7,8-tetrahydro-3indolizinyl] benzoic acid

The procedure of Preparation 1 is carried out, replacing the 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C by 2-bromo-4-chlorobenzaldehyde.

Preparation 4: 7- [2- (terAbutoxycarbonyI) -8- (methoxycarbonyl) -1, 2,3,4tetrahydropyrrolo [1,2 - “] pyrazin-6-yl] -2,3-dihydro-1,4- acid benzodioxin-6-carboxylic

Stage A: 3,4-Dihydropyrrolo [1,2-a] pyrazine-2,8 (1H) -dicarboxylate of 2-tert-butyl and

8-methyl

The procedure is carried out according to the process described in Steps A-C of Preparation 2.

NMR "H:" (400 MHz; dmso-d6; 300K): 6.8-6.43 (m, 2H, H pyrrole); 4.75-3.75 (m. 6H.

H piperazine)); 3.73 (s, 3H, H COOCH3); 1.48 (s, 9H, H ^l Bu)

IR: v: C = O (conjugated ester): 1712 cm- ¹ ; C = O (carbamate): 1677 cm ' ¹

DUPLICATE

-20Stage _____ B: Acid 7- [2- (tert-butoxycarbonyl) -8- (methoxycarbonyl) -l, 2,3,4tetrahydropyrrolo [1,2-a] pyrazin-6-yl] -2,3- (lihydro-l , 4-benzodioxine-6-carboxylic

The procedure is carried out according to the protocol described in Steps C and D of Preparation 1, replacing the

6-bromo-1 J-benzodioxole-5-carbaldehyde used in Stage C by 7-bromo-2,3-dihydro-1,4-benzodioxine-6-carbaldehyde.

Preparation 5: 4-Chloro-2- [1- (methoxycarbonyl) -3-indolizinyI] benzoic acid

Stage A: 1- (carboxymethyl) -1, 2-hydropyridinium 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.

H NMR: δ (400 MHz; dmso-d6; 300K): 9.15 (d, 2H, H aromatic pyridine)); 8.7 (t. 1H, aromatic H); 8.25 (ΐ, 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-Indolizinecarboxylate

To a suspension of 6.55 g of the pyridinium salt obtained in Stage A (30 mmol) in 240 mL of toluene, 16.7 mL of methyl acrylate (150 mmol), 4.2 mL of triethylamine ( 30 mmol), then in portions 20.9 g of M11O2 (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.

1 H NMR: δ (300 MHz; dmso-d6; 300K): 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 )

DUPLICATE

-21 IR: v: C = O ester: 1675 cm- ¹ ; C = C aromatics: 1634 cm ' ¹

Stage C: 4-Chloro-2- [1- (methoxycarbonyl) -3-indolizinyl] benzoic acid

The procedure is carried out according to the protocol described in Steps C and D of Preparation 1, replacing the

6-bromo-1,3-benzodioxole-5-carbaIdehyde used in Stage C by 2-bromo-4chlorobenzaldehyde.

Preparation 6: 2- [2- (te / 7-butoxycarbonyI) -8- (methoxycarbonyl) -l, 2,3,4tetrahydropyrrolo [1,2-n] pyrazin-6-yI] -4-fluorobenzoic acid

The procedure is carried out according to the protocol described in Preparation 2, replacing the 2-bromo-4chlorobenzaldehyde used in Stage D by 2-bromo-4-fluorobenzaldehyde.

Preparation 7: 6- [2- (ta / 7-butoxycarbonyl) -8- (methoxycarbony 1) -1,2,3,4tetrahydropyrrolo [1,2-n] pyrazin-6-yl] -l, 3-benzodioxole acid -5-carboxylic

The procedure is carried out according to the protocol described in Preparation 2, replacing the 2-bromo-4chlorobenzaldehyde used in Stage D by 6-bromo-l, 3-benzodioxole-5-carbaldehyde.

Preparation 8: 6- [l '- (methoxycarbonyl) -5', 6'-dihydro-8'H-spiro [1,3-dioxoIane2,7'-indoIizin] -3'-yl] -l, 3- Acid benzodioxole-5-carboxylic

Stage A: Methyl 8-Formyl-1,4-dioxa-8-azaspiro [4.5] decane-7-carboxylate g of methyl 1,4-dioxa-8-azaspiro [4.5] decane-9-carboxylate (111 mmol ) are dissolved in 80 mL of ethyl acetate and 80 mL of dichloromethane. 26 g of (4-nitrophenyl) formate (155 mmol) are added and the whole is stirred at room temperature for 1 hour. The reaction medium is evaporated to dryness and taken up in ethyl acetate. The organic phase is then washed successively with a 1N NaOH solution, water and then with saturated NH4Cl solution until a neutral pH is reached. It is then dried over magnesium sulfate, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (heptane / ethyl acetate gradient). The title product is obtained in the form of an oil.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 8.15 (s, 1H, CHO); 5.0-4.75 (m. 1H, tertiary H); 4.3-3.7 (m, 5H, 4H ethylenedioxy + 1H aliphatic piperidine); 3.70 (s, 3H,

DUPLICATE

-22Me); 3.4-2.9 (2m, 1H, H aliphatic piperidine); 2.3-1.75 (m, 2H, H aliphatic piperidine); 1.7-1.5 (m, 2H, H aliphatic piperidine)

Stage B: 8-formyl-1,4-dioxa-8-azaspiro [4.5Jdecane-7-carboxylic acid [ue

15.25 g of the compound obtained in Stage A (62.7 mmol) is dissolved in 160 ml of dioxane. A solution of 125 mL of IM KOH is added dropwise and the whole is stirred at room temperature for 1 h. Then 125 mL of 1M HCl is added and the compound is extracted with dichloromethane. The organic phase is dried over MgSCU, filtered and concentrated to dryness. The title product is obtained in the form of a powder.

1 H NMR: δ (400 MHz; dmso-d6; 300K) 13.5-12 (m, 1H, OH); 8.1 + 8.0 (2s, 1H, CHO);

4.9 + 4.6 (2m, 1H, tertiary H); 4.0-3.8 (m, 4H, ethylenedioxy); 4.2 +3.7 (2ms. 1H, aliphatic H piperidine); 3.4 + 2.9 (2m, 1H, H aliphatic piperidine); 2.4-1.5 (m. 4H, H aliphatic piperidine)

IR: v: OH: 3500-2000 cm- ¹ ; -C = O (acid + aldehyde): 1731 + 1655 cm ' ¹

Stage C: 5 ', 6'-Dihydro-8' H-spiro [1,3-dioxolane-2,7'-iiidolizine] -l ’-carboxylate of methyl

To a solution of 13.5 g (62.7 mmol) of the acid obtained in Stage B in 380 mL of dichloromethane, 39.5 mL (238.4 mmol) of triethylamine are successively added, then by shoveling 12.5 g (65.6 mmol) of / wa-toluene sulfonyl chloride and 23.7 mL (238.4 mmol) of methyl chloroacrylate. The whole is stirred at 80 ° C for 18 hours. The reaction medium is then filtered through Celite. The filtrate is then washed with a saturated solution of NaHCO 3 and then with a saturated solution of NH 4 Cl. The organic phase is dried over MgSO4, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (heptane / ethyl acetate gradient). The product is obtained in the form of a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300K) 6.70 (d, 1H, pyrrol); 6.40 (d, 1H, pyrrole); 4.05 (ΐ, 2H, aliphatic H, piperidine); 4.00 (m, 4H, ethylenedioxy); 3.70 (s, 3H, methyl);

3.15 (s, 2H, H aliphatic piperidine); 2.05 (t, 2H, H aliphatic piperidine)

IR: v: -C = O (ester): 1689 cm ' ¹

DUPLICATE

-23Stade D: 3 '- (6-Formyl-l, 3-benzodioxol-5-yl) -5', 6'-dihydro-8'H ~ spiro [l, 3 ~ dioxolane-2,7'indolizinej-1 '-methylcarboxylate

The procedure is carried out according to Stage C of Preparation 1.

Stage E: Acid 6- [l '- (methoxycarbonyl) -S6'-dihydro-8'H-spiro [l, 3-dioxolane-2,7'indolizin] -3Lyl] M, 3-benzodiox () le-5 -carboxylic

The procedure is carried out according to the method of Stage D of Preparation 1.

Preparation 9: 6- [1- (Methoxycarbonyl) -3-indolizinyl] -1, 3-benzodioxole - 5carboxylic acid

The procedure is carried out according to the protocol described in Preparation 5, replacing the 2-bromo-4chlorobenzaldehyde used in Stage C by 6-bromo-l, 3-benzodioxole-5-carbaldehyde.

Preparation 10: 4-Methyl-2- [1- (methoxycarbonyl) -5,6,7,8-tetrahydro-3in d oliziny 1] b enzoic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing the 6-bromo-l, 3benzodioxole-5-carbaldehyde used in Stage C by 2-bromo-4-methylbenzaldehyde.

Preparation ______ 11: 2- [1- (methoxycarbonyI) -5,6,7,8-tetrahydro-3in d oliziny 1] b enzoic acid

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

Preparation 12: 6- [8- (methoxycarbonyI) pyrroIo [1,2 - “] pyrimidin-6-yl] -I, 3benzodioxole-5-carboxylic acid

Stage A: Methyl pyrrolo [1,2-a] pyrimidin-8-carboxylate

To a solution of 6.2 g of methyl 2-pyrimidin-2-ylacetate (40.75 mmol) in 250 mL of acetone is successively added 14.04 g (167 mmol) of powdered NaHCO3, 13.2 mL (203.75 mmol) of chloroacetaldehyde, then 3.54 g (40.75 mmol) of lithium bromide. The whole is heated at 60 ° C for 24 hours. The reaction medium is then concentrated to dryness, taken up in ethyl acetate, washed with water, dried over MgSO 4, filtered then

DUPLICATE

-24concentrated dry. The solid thus obtained is then purified by chromatography on silica gel (AcOEt). The expected product is obtained in the form of an oil.

Mass Spectrum:

Empirical Formula: C8H8N2O?

LC / MS: m / z - [M + H] ⁺ = 177

Stage B: Methyl 6- (6-Formyl-1,3-benzodioxol-5-yl) pyrrolo [1,2-a] pyrimidiiie-8-carboxylate

To a solution of 3.93 g of the compound obtained in Stage A (22.3 mmol) in 80 mL of anhydrous dimethylacetamide, is added 7.66 g (33.45 mmol) of 6-bromo-1,3-benzodioxole5- carbaldehyde and 4.4g (44.6 mmol) of potassium acetate. The whole is degassed under nitrogen for 15 min. Then 1.56 g (2.23 mmol) of PdCl ₂ (PPh3) 4 catalyst are added. The reaction medium is heated at 130 ° C. for 16 h under an inert atmosphere. After drying, the residue is taken up in dichloromethane, filtered through a celite cake and then the filtrate is washed with water, dried over MgSO4 and concentrated to dryness. The black solid is then chromatographed on silica gel (Cl-LCh / MeOH 5%). The expected product is obtained in the form of a solid.

Mass Spectrum:

Molecular formula: C17H12N2O3 LC / MS: m / z = [M + H] ⁺ = 325

Stage C: 6- [8- (methoxycarbonyl) pyrrolo [1,2-a] pyrimidm-6-yl] -l, 3-benzodioxole5-carboxylic acid

To a solution of 2.91 g (8.97 mmol) of the aldehyde obtained in Stage B in 140 mL of acetone cooled to 0 ° C, 2-methylbutene is added, then dropwise a mixture of 2, 8 g (17.94 mmol) of NaH ₂ PO4.2H ₂ O and 2.84 g (31.4 mmol) of NaC10 ₂ dissolved in 30 mL of water. The whole is stirred at room temperature for 4 h. The reaction medium is then concentrated under vacuum to remove the acetone, placed at 0 ° C. and then acidified to pH = 2-3 by adding 5N HCl solution dropwise. We observe the

DUPLICATE

-25forming a precipitate, which is filtered, washed with water, then with diethyl ether and dried in vacuo.

H NMR: δ (400 MHz; dmso-d6; 300K): 12.7 (m, 1H, COOH); 8.45 (aromatic d, 1H. H, H pyrrolo [1,2-a] pyrimidine); 8.19 (d, 1H, aromatic H, H pyrrolo [1,2ajpyrimidine); 6.9 (dd, 1H, aromatic H, H pyrrolo [1,2-a] pyrimidine); 7.51 (s, 1H, aromatic H); 7.21 (s, 1H, aromatic H); 7.07 (s, 1H, aromatic H); 6.2 (s, 2H, aliphatic Hs, O-CH2-O); 3.8 (s, 3H, aliphatic H, COOCH3)

IR: v -OH-: 3300-1800 cm- ¹ ; v -CO-: 1705 cm ' ¹ , v> C = C <: 1616 cm' ¹

Preparation 13: 4-Methoxy-2- [1- (inethoxycarbonyI) -5,6,7,8-tetrahydro-3in dolizinyl] b enzoic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing the 6-bromo-1.3benzodioxole-5-carbaldehyde used in Stage C by 2-bromo-4-methoxybenzaldehyde.

Preparation 14: 5-Methoxy-2- | 1- (methoxycarbonyl) -5,6,7,8-tetrahydro-3indolizinylbenzoic acid

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

Preparation 15: 7- [1- (Methoxycarbonyl) -5,6,7,8-tetrahydro-3-indoIizinyl] -2,3dihydro-1,4-benzodioxin-6-carboxylic acid

The procedure of Preparation 1 is carried out, replacing the 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C by 7-bromo-2,3-dihydro-1,4benzodioxine-6-carbaldehyde.

Preparation 16: 2- [1- (methoxycarbonyl) -3-indoIizinyl] benzoic acid

The procedure is carried out according to the method of Preparation 5, replacing the 2-bromo-4chlorobenzaldehyde used in Stage C by 2-bromo-benzaldehyde.

DUPLICATE

-26 Preparation 17: 4-Fluoro-2- [1- (methoxycarbonyl) -3-indolizinyl] benzoic acid

The procedure is carried out according to the method of Preparation 5, replacing the 2-bromo-4clilorobenzaldehyde used in Stage C by 2-bromo-4-fluorobenzaldehyde.

Preparation 18: 4-Fluoro-2- [1- (methoxycarbonyl) -5,6,7,8-tetrahydro-3indolizinyl] benzoic acid

The procedure of Preparation 1 is carried out by replacing the 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C by 2-bromo-4-fluorobenzaldehyde.

Preparation 1 ': (37î) -3-methyl-1,2,3,4-tetrahydroisoquinoline hydrochloride

Stage A: {(3S) -2 - [(4-Methylphenyl) sulfonyl] -l, 2,3,4-tetrahydroisocpiinolin-3-yl} methyl

4-methylbenzenesulfonate

To a solution of 30.2 g of [(35) -1,2,3,4-teti'ahydroisoquinolin-3-yl] methanol (185 mmol) in 750 mL of dichloromethane are successively added 91.71 g of chloride. tosyl (481 mmol), then, dropwise, 122.3 mL of ΛζΛζ / V-triethylamine (740 mmol). The reaction medium is then stirred at room temperature for 20 h. It is then diluted with dichloromethane, washed successively with IM HCl solution, saturated NaHCO ₃ solution, then saturated NaCl solution until neutral. The organic phase is then dried over MgSCL, filtered and 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; 300K): 7.75 (d, 2H, aromatic Hs, ortho O-tosyl); 7.6 (d, 2H, aromatic Hs, ortho N-tosyl); 7.5 (aromatic d, 2H, H, mixed 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, CH1-O-tosyl); 2.7 (2dd, 2H, aliphatic Hs, tetrahydroisoquinoline); 2.45 (s, 3H, O-SO1-Ph-CH3); 2.35 (s, 3H, N-SO ₂ -Ph- CH ₃ )

IR: v: -SO2: 1339-1165 cm ' ¹

DUPLICATE

-27 Stage B: (3R) -3-Methyl-2 - [(4-methylphenyl) sulfonyl] -l, 2,3,4-tetrahydroisoquinoline

To a suspension of 8.15 g (214.8 mmol) of L1AIH4 in 800 mL of methyl fo / 7-butyl ether (MTBE), 101.2 g of the ditosylated derivative obtained in Stage A (214.8 mmol) are added. in solution 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 12 mL of 5N NaOH solution are added dropwise. 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. The title product is then obtained in the form of a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 7.70 (d, 2H, aromatic Hs, ortho N-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, M-SO2-PI1-CH3); 0.90 (d, 3H, tetrahydroisoquinoline-CHj) IR: v: -SO2: 1332-1154 cm ' ¹

Stage C: (3R) -3-Methyl-1,2,3,4 ~ tetrahydroisoquinoline

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 chromatographic column on silica gel (dichloromethane / EtOH / NH4OH), the title product is obtained in the form of an oil.

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

HN (tetrahydroisoquinoline))

IR: v: -NH: 3248 cm ' ¹

DUPLICATE

-28 Stage D: (3R) -3-methyl-1,2,3,4-tetrahydroisoqiùnoline 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 an IM hydrochloric ether solution. 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; 300K): 9.57 (m, broad, 2H, NH ₂ ⁺ (tetrahydro isoquinoline) .7.22 (m, 4H, aromatic H, 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-CHb)

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

Preparation 2 ': (30) -3- [2- (morpholin-4-yl) ethyl] -l, 2,3,4tetrahydroisoquinoline hydrochloride

Stage A: tert-butyl (3S) -3- (2-Morpholino-2-oxo-ethyl) -3,4-dihydro-1H-isoquinoIine-2-carboxylate

To a solution of 3 g (10.30 mmol) of [(3S) -2- (terAbutoxycarbony 1) -1,2,3,4tetrahydroisoquinolin-3-yl] acetic acid in 100 mL of dichloromethane is added dropwise. 1.10 mL (11.32 mmol) of morpholine, always dropwise 4.3 mL (30.9 mmol) of triethylamine, 2.20 g (12.40 mmol) of 1,2-dichloromethane and 1.70 g (1.68 mmol) of hydroxybenzotriazole. The whole is stirred at room temperature for 15 h. The reaction medium is then diluted with dichloromethane, washed successively with 1M HCl solution, saturated NaHCCh solution, then saturated NaCl solution until neutral. The organic phase is then dried over MgSOj, filtered and concentrated to dryness. After purification by chromatographic column on silica gel (dichloromethane / MeOH), the title product is obtained in the form of an oil.

H NMR: δ (400 MHz; dmso-d6; 300K): 7.20-7.10 (m. 4H, aromatic PI, tetrahydroisoquinoline); 4.70 (m, 1H, aliphatic H, CH tetrahydroisoquinoline); 4.75DUPLICATA

-294.20 (2m, 2H, aliphatic H, CH ₂ in alpha of N tetrahydroisoquinoline); 3.60 (m, 8H, aliphatic Hs, morpholine); 3.00 and 2.70 (2dd, 2H, aliphatic H, tetrahydroisoquinoline); 2.50-2.20 (2d, 2H, aliphatic Hs, CH ₂ CO); 1.40 (s, 9H, ^l Bu)

IR: v: C = O: 1687; 1625 cm ' ¹

Stage B: 1- (morpholin-4-yl) -2 - [(3S) -l, 2,3,4-tetrahydroisoquinolin-3yljethanone hydrochloride

To a solution of 2.88 g (7.18 mmol) of the compound obtained in Stage A in 16 mL of dichloromethane is added dropwise 80 mL (80 mmol) of a 1M hydrochloric ether solution. The whole is stirred at room temperature for 15 h, then the suspension is filtered and the precipitate washed with ether. After drying, the title product is obtained as a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 9.80-9.50 (m, 2H, NH ₂ ⁺ ); 7.30-7.10 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.30 (m, 2H, aliphatic H, CH 2 alpha to N tetrahydroisoquinoline); 3.80 (m, 1H, aliphatic Hs, CH tetrahydroisoquinoline); 3,703.40 (2m, 8H, aliphatic Hs, morpholine); 3.15 and 2.8 (m, 4H, aliphatic H, CH ₂ tetrahydroisoquinoline and CH ₂ CO)

IR: v: -NH? ⁺ : 2800-1900 cnf *; v: C = O: 1620 cm ' ¹

Stage C: (3S) -3- [2- (morpholin-4-yl) ethyl] -l, 2,3,4tetrahydroisoquinoline hydrochloride

A solution of 2.2 g (7.44 mmol) of the compound obtained in Stage B in 22 mL of MTBE and 5 mL of dichloromethane is prepared. After cooling in an ice bath at 0 ° C., 15 ml (15 mmol) of a solution of 1 M L1AIH4 in tetrahydrofuran are added dropwise thereto. The whole is then stirred at room temperature for 6 h. It is placed at 0 ° C, then 1 mL of 5N NaOH solution is added dropwise. The whole is stirred at room temperature for 45 minutes. The solid is then filtered off and washed with MTBE, then with dichloromethane and the filtrate is concentrated to dryness. The oil thus obtained is diluted with dichloromethane and 6.3 mL of 1M hydrochloric ether solution is added dropwise. The whole is stirred at room temperature for 1 hour, then

DUPLICATE

-30filtered. The crystals thus obtained are washed with ethyl ether. After drying, the title product is obtained as a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 11.35 + 9.80 (2m, 2H, NH ₂ ⁺ ); 10.00 (m. H, NH ⁺ ); 7.20 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.30 (s, 2H, aliphatic H, CH 2 alpha to N tetrahydroisoquinoline); 4.00 + 3.85 (2m, 4H, aliphatic Hs, CH 2 alpha to N morpholine); 3.70 (m, 1H, aliphatic Hs, CH tetrahydroisoquinoline); 3,553.30 (m, 4H, aliphatic Hs, CH alpha to O morpholine and CH ₂ -Morpholine); 3.15 (dd, 1H, aliphatic H, CH ₂ tetrahydroisoquinoline); 3.10 (m, 2H, aliphatic H, CH in alpha of O morpholine); 2.90 (dd, 1H, aliphatic H, CH ₂ tetrahydroisoquinoline); 2.30 + 2.15 (2m, 2H, aliphatic H, CH ₂ -tetrahydroisoquinoline)

IR: v: NH ⁺ / -NH ₂ ⁺ : between 3500 and 2250 cm- ¹ ; v: C = C: low 1593 cm- ¹ ; v: aromatic CH: 765 cm ' ¹

Preparation 3 ': {2 - [(3> Sj-1,2,3,4-tetrahydroisoquinolin-3-yI] ethyl} tertbutyl carbamate

Stage A: (3S) -3- (2-Hydroxyethyl) -3,4-dihydroisoc [uinolin-2 (1H) -benzylcarboxylate The title compound is obtained from (35) -2- [acid (benzyloxy) cai'bonyl] -1, 2,3,4 tetrahydroisoquinoline-3-carboxylic based on a protocol in the literature (Jinlong Jiang et al Bioorganic & Medicinal Chemistry Lelters, 14, 1795, 2004).

Stage B: (3S) -3- {2 ~ [(Methylsulfonyl) oxy] ethyl} -3,4-dihydroisoquinoline-2 (1H) ~ benzyl carboxylate

Has a solution of 10.6 g of the compound of Stage A (35.6 mmol) in 350 mL of CH? C1? Anhydrous at 0 ° C., triethylamine 10.1 mL (71.2 mmol) is added successively and then, dropwise, methanesulfonyl chloride 3.1 mL (39 mmol). The reaction medium is then stirred at room temperature for 2 h. Then hydrolyzed by slowly adding water. The product is extracted several times with CI-LC1 ™. The organic phases are then combined and washed successively with IN HCl solution, saturated NaCl solution, saturated NaHCO 3 solution and saturated NaCl solution until neutral. They are then dried over MgSO ₄ and concentrated to dryness. After

DUPLICATE purification by chromatography on silica gel (petroleum ether / AcOEt gradient), the expected product is obtained in the form of a foam.

LC / MS: m / z = (M + H) ⁺ = 375

Stage C: (3S) -3- (Cyanomethyl) ~ 3,4-dihydroisoquinoline-2 (1H) -benzylcarboxylate

To a solution of 15.4 g of the derivative obtained in Stage B (41.02 mmol) in 250 mL of anhydrous DMSO, 22 g (449 mmol) of sodium cyanide are added. The whole is then heated at 60 ° C. for 12 h. Allowed to cool, then the reaction medium is diluted by adding ethyl acetate. Then hydrolyzed with a saturated NaHCO 3 solution. After 2 new extractions with ethyl acetate, the organic phases are combined, washed with H ₂ O, dried over MgSOd and concentrated to dryness. After purification by chromatography on silica gel (hexane / AcOEt 7/3), the expected product is obtained in the form of an oil.

LC / MS: m / z = [M + H] ⁺ = 307.1

Stage D: (3S) -3- (2-Aminoethyl) -3,4-dihydroisoquinoHne-2 (1H) -benzylcarboxylate

To a solution of 15.4 g of the derivative obtained in Stage C (50.3 mmol) in 300 mL of anhydrous THF placed at 0 ° C., a solution of BH3-THF IN is added dropwise. The reaction medium is allowed to return gradually to room temperature, then the whole is stirred for 14 h. The reaction medium is then hydrolyzed by the slow addition of a saturated NH4Cl solution. After 2 extractions with ethyl acetate, the organic phases are combined and dried over MgSO4. After concentration to dryness, the expected product is obtained in the form of a foam which is used directly without purification for the following protection step.

Stage E: (3S) -3- {2 - [(tert-Butoxycarbonyl) amino] ethyl} -3,4-diliydroisoquinoline-2 (1H) benzyl carboxylate

To a solution of 15.6 g of the derivative obtained in Stage D (50.3 mmol) in 670 mL of CH2Cl2, 13.2 g (60.36 mmol) of Boc ₂ O are successively added by shovelfuls, triethylamine 14 mL (100 , 6 / mmol) and DMAP in a catalytic amount. The set is

DUPLICATE

-32 stirred at room temperature for 5 hours. The reaction medium is then hydrolysed with water and extracted twice with CH2Cl2. The organic phases are combined, washed with water, and dried over MgSCU. After concentration to dryness and purification by chromatography on silica gel (heptane / AcOEt gradient), the expected product is obtained in the form of an oil.

LC / MS: m / z = (M + H) ⁺ = 411

Stage F: {2 - [(3S) -l, 2,3,4-TetrahvdroisoquinoHn-3-vl] ethyl} tert-butyl carbamate

To a solution of 10.4 g of the derivative obtained in Stage E (25.5 mmol) in 210 mL of anhydrous MeOH, 2.71 g (2.55 mmol) of 10% Pd / C are added. The whole is degassed for 30 minutes then stirred under a hydrogen atmosphere for 16 h. The reaction medium is then filtered and concentrated to dryness. The expected product is obtained in the form of a solid which is taken up in a pentane / Et ₂ O (90/10) mixture, triturated and filtered. After drying, 011 obtains the product as a solid.

‘11 NMR: δ (400 MHz; dmso-d6; 300K): 7.1-6.98 (m, 4H. H aromatics, tetrahydroisoquinoline); 6.83 (m, 1H, CH2NHB0C); 3.85 (s, 2H, aliphatic Hs, tetrahydroisoquinoline); 3.09 (q, 2H, CH2NHB0C); 2.73 (m, 1H, aliphatic Hs, tetrahydroisoquinoline); 2.70 and 2.39 (2m, 2H, aliphatic Hs, tetrahydroisoquinoline); 1.63 (m, 2H, aliphatic H); 1.38 (s, 9H, NHCOOtBu)

IR: v:> NH: 3378, -3201 cm- ¹ (amine, amide); v:> C = O: 1683 cnf ¹ (amide); v:> NH: 1524 cnf ¹ (amide); v:> C = O: 1168 cm ' ¹

LC / MS: m / z = [M + H] ⁺ = 277

Preparation 4 ': (3R) -3- [3- (Morpholin-4-yl) propyl] -l, 2,3,4-tetrahydroisoquinoline

Stage A: {(3S) -2 - [(4-Methylphenyl) sulfonylJ ~ 1,2,3,4-tetrahydroisoquinoliii-3-yl} inethyl

4-methylbenzenesulfonate

The process is identical to that of Stage A of Preparation 1 '.

DUPLICATE

-33 Stage B: 2 - ({(3R) -2 ~ [(4-Methylphenyl) sulfonylJ-l, 2,3,4-tetraliydroisoquinolin-3yl} methyl) -3- (morpholin-4-yl) -3-oxopropanoate tert-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 tert-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 saturated ammonium chloride is added. This solution is extracted with dichloromethane. The organic phase is then dried over MgSCfi, filtered and concentrated to dryness. After purification by chromatography column on silica gel (dichloromethane / MeOH), the expected product is obtained in the form of an oil.

1 H NMR (500 MHz, dmso-d6) δ ppm: 7.63 / 7.59 (2d, 2 H), 7.3 / 7.26 (2d, 2 H), 7.13 (m, 2 H), 7.09 / 6.97 (2t, 2 H ), 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: Acid 2 - ({(3R) ~ 2 - [(4-methylphenyl) sulfonyl] -l, 2,3,4-tetrahydroisoquinolin-3yl} methyl) -3 ~ (morpholin-4-yl) -3- oxopropanoiqite

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, 1 H), 7.6 (2 * d, 2 H), 7.3 (2 * d, 2 H), 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

DUPLICATE

-34 Stage D: 3 - {(3R) -2 - [(4-Methylphenyl) sidfonyl] -l, 2,3,4 ~ tetrahydroisoquinolin-3-yl} -l (morphoIin-4-yl) propan-l ~ one

To a solution of 7.80 g (I6.5l mmol) of the compound obtained in Stage C in 100rnL 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%. The reaction medium is then diluted with dichloromethane, washed successively with a saturated solution of lithium chloride, then a saturated solution of NaCl. The organic phase is then dried over MgSO ₄ . filtered, concentrated to dryness. After purification by chromatographic column on silica gel (cyclohexane / ethyl acetate), the expected product is obtained in the form of an oil.

1 H NMR (400 MHz, dmso-d6) 5 ppm: 7.65 (d, 2 H), 7.3 (d, 2 H), 7.15 / 7 (2 m, 4 H), 4.6 (d, 1 H), 4.25 (d, 1 H), 4.2 (m, 1 H), 3.5 (m, 4 H), 3.4 (2 m, 4 H), 2.6 (2 dd, 2 H), 2.35 (s, 3 H), 2.3 (m, 2 H), 1.5 (quad., 2 H)

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

Stage E: (3R) -2 - [(4-Methylphenyl) sulfonylJ ~ 3- [3- (morpholin-4-yl) propylJ-l, 2,3,4tetrahydro isoq uinoline

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 MgSO ₄ , filtered, and concentrated to dryness. After purification by chromatographic column on silica gel (dichloromethane / EtOLI / NH ₄ OH), the expected product is obtained in the form of an oil.

NMR 'H (400 MHz, dmso-d6) δ ppm: 7.68 (d, 2 H), 7.32 (d, 2 H), 7.1 (solid, 4 H), 4.65 / 4.23 (AB, 2 H), 4.2 ( m, 1 H), 3.55 (t, 4 H), 2.7 / 2.6 (ABx, 2 H), 2.35 (s, 3 H), 2.25 (t. 4 H), 2.2 (t, 2 H), 1.4 / 1.3 (2m, 4H).

DUPLICATE

-35 IR (ATR) cnf ¹ : v: -SO2: 1333-1158

Stage F: (3R) ~ 3- [3- (Morpholin-4-yl) propyl] -l, 2,3,4-tetrahydroisoc [uinoline

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 chromatographic column on silica gel (dichloromethane / EtOH / NH4OH), the expected product is obtained in the form of an oil.

NMR 'H (400 MHz, dmso-d6) δ ppm: 7.3 (d, 2 H), 7.1 (t, 2 H), 7.1 (d + t, 3 H), 7 (d, 2 H),

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) cnf ¹ : v:> NH2 + / NH +: 3500-2300; v:> COC <: 1115

High resolution ground (ESI + -l ¥ iAll: Ift):

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

Preparation 5 ': (30) -3- (2- (3,3-difluoropiperidin-1-yl) ethyl] -l, 2,3,4tetrahydroisoquinoline hydrochloride

The procedure is carried out according to the method of Preparation 2 ’, replacing the morpholine used in Stage A by 3,3-difluoro-1-piperidine.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 11.3 (m, 1H, NH ⁺ ); 10.2-9.8 (m, 2H, NH /);

7.25 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.3 (broad s, 2FI, aliphatic H, CH tetrahydroisoquinoline); 4.0-3.3 (m, 7H, aliphatic H); 3.15-2.95 (dd, 2FI, aliphatic FI, CH tetrahydroisoquinoline); 2.4-1.9 (m, 6H, aliphatic H. H 3,3-difluoro-lpiperidine)

IR: v: NH ⁺ / NH ₂ ⁺ : between 300 and 2500 cnf ¹ ; v: CF: 1204 cnf ¹

DUPLICATE

-36 Preparation 6 ': (3S) -3- [2- (3-methoxyazetidin-1-yl) ethyl] -l, 2,3,4tetrahydroisoquinoline hydrochloride

The procedure is carried out according to the method of Preparation 2 ’, replacing the morpholine used in Stage A by 3-methoxyazetidine.

NMR ^! H: δ (400 MHz; dmso-d6; 300K): 11.3 (m, 1H, NI-I ⁺ ); 10.00 (m, 2H, NH ₂ ⁺ ); 7.20 (m, 4H, aromatic Hs, tetrahydroisoquinoline); 4.4 (m, 1H, aliphatic H, 3-Methoxy azetidine); 4.30 (s, 2H, aliphatic Hs, tetrahydroisoquinoline); 4.2 -3.45 (m, 4H. 3Methoxyazetidine); 4.2 -3.6 (m, 3H, aliphatic H); 3.1 and 2.95 (dd, 2H, aliphatic H);

3.25 (s, 3H, OCH ₃ )

Preparation 7 ': (35) -3-methyl-1,2,3,4-tetrahydroisoquinoIine hydrochloride

The procedure of Preparation Γ is carried out by replacing the [(3.9) -1,2.3,4tetrahydroisoquinolin-3-yl] methanol used in Stage A by [(3 /?) - 1,2.3.4tétrahydroisoquinoIin-3-yl ] methanol.

Preparation 1 ”: / V- (4 - {[f6 / 7-Butyl (dimethyl) silyl] oxy} phenyl) -l-methylI-1 // pyrazol-4-amine

Stage A; 4 - {[tert-Butyl (dimethyl) silyl] oxy} aniline

The title compound is obtained from 4-aminophenoI in THF in the presence of imidazole and A? Rt-butyl (dimethyl) silyl chloride according to the protocol described in the literature (S. Knaggs et cil, Organic & Biomolecular 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 (CFI ₃ ) ₂ ) IR: v: -NH ₂ ⁺ : 3300-3400 cm ' ¹

Stade_Bj_N- [4- [tert-Butyl (dimethyl) silyl] oxyphenyl] -l-methyl-pyrazol-4-amine

DUPLICATE

-37 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 te / 7-butoxide (0.310 mol), 4.55 g of Pd2 are successively added (dba) 3 (also called tris (dibenzylideneacetone) dlpalladium (0)) (4.96 mmol), 4.81 g of 2-di-fërz'-butylphosphino-2 ', 4', 6'-tri-isopropyl- 1,1'-Biphenyl (9.91 mmol) and 12.8 mL of 4bromo-1-methyl-1H-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 (gradient CI ~ I ₂ Cl ₂ / AcOEt) 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, NFI ₂ -Ph); 6.64 (m, 4H, aromatic Hs); 3.77 (s, 3H, CH ₃ -pyrazole); 0.90 (s, 9H, Si (CH ₂ ) ₂ CH (CH ₃ ) ₂ ); 0.12 (s. 6H, Si (CH ₂ ) ₂ CH (CPI ₃ ) ₂ )

IR: v -NH ⁺ : 3275 cm- ¹ ; v Ar and C = N: 1577 and 1502 cm- ¹ ; v -Si-C-: 1236 cm- ¹ ; v -Si-O-: 898 cm- ¹ ; v -Si-C-: 828, 774 cm ' ¹

Preparation 2 ”:? Z- (4 - {[ti? / 7-Butyl (dimethyl) siIyl] oxy} phenyl) -l-methylI-ljH ^r -indoI-5amine

The procedure is carried out according to the method of Preparation Γ ’, replacing the 4-bromo-1-methyl-1Hpyrazole used in Stage B by 5-bromo-1-methyl-1H-indole.

Preparation 3 ”: / V- (4 - {[tert-Butyl (dimethyl) siIyI] oxy} phenyI) -l- [2- (morpholin-4yI) ethyI] -l / Z-indoI-5-amine

Stage A: 5-Bromo-l- [2- (morpholin-4-yl) ethylJ-1H-indole

To a suspension of NaH (4.5 g; 112 mmol) in anhydrous THF (300 mL) placed at 0 ° C., 5-bromo-1H-indole (10.4 g; 51 mmol) is added in portions. After 20 minutes of stirring at 0 ° C, 4- (2-chloroethyl) morpholine hydrochloride (10.4 g; 56 mmol) is added in portions over 1 hour. After stirring overnight at room temperature, the reaction medium is placed for 5 h at 80 ° C. It is then poured over a mixture of baking soda

DUPLICATE

-38de aqueous sodium and dicholoromethane. The aqueous phase is extracted with dichloromethane. The organic phase is dried over MgSO4, concentrated to dryness and the residue is purified by chromatography on silica gel (CPhCE / MeOH gradient) to provide the expected product in the form of an oil.

NMR ‘H: δ (400 MHz; CDCl3; 300K): 7.75 (d, 1H); 7.30 (dd, 1H): 7.20 (d, 1H); 7.15 (d, 1H); 6.40 (d, 1H); 4.20 (t, 2H); 3.70 (m, 4H); 2.75 (t, 2H); 2.45 (m, 4H)

Stage B: 5-Bromo-l- [2- (morpholin-4-yl) ethyl] -lH-indole

The procedure of Preparation 1 ”is carried out, replacing the 4-bromo-1-methyl-l / 7pyrazole used in Stage B by the compound obtained in Stage A.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 7.35 (d, 1H); 7.15 (s, 1H); 6.85 (d, 3H); 6.70 (d, 2H); 7.30 (d, 1H); 6.25 (d, 1H), 4.20 (t, 2H); 3.55 (m, 4H); 2.65 (t. 2H); 2.45 (m, 4H); 1.45 (s, 9H), 0.15 (s, 6H)

Preparation 4 ”: 7V- (4 - {[ter / -Butyl (dimethyl) silyl] oxy} phenyI) -l- [2- (niorpholin-4yl) ethyl] -2,3-dihydro-1 // - indol- 5-amine

The procedure of Preparation 2 ”is carried out by replacing the 5-bromobindole used in Stage A by 5-bromo-2,3-dihydro-1/7-indole.

Preparation 5 ”: 2V- (4- {| 7th / 7-Butyl (dimethyl) silyl] oxy} phenyl) -4-fluoroaniline

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

Preparation 6 ”: 7V- (4- {| 7 <? RAButyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4methylaniline

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-1Wpyrazole used in Stage B by 4-bromo-2-fluoro-1-methylbenzene.

Preparation 7 ”: A ^/ - (4 - {[/ erA-Butyl (dimethyl) silyi] oxy} phenyI) -l-methyI-1 // indazol-5-amine

DUPLICATE

The procedure is carried out according to the method of Preparation 1 ”, replacing the 4-bromo-1-methyl-1 / 7pyrazole used in Stage B by 5-bromo-1-methyl-1H-indazole.

Preparation 8 ”: 4 - {[te / 7-Butyl (diniethyl) silyl] oxy} - / V-phenyIaniIine

To a solution of 12 g of 4-anilinophenol (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 zertbutyl (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.

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

IR: v:> NH: 3403 cm- ¹ ; > Ar: 1597 cm ' ¹

Preparation 9 ”: 4-Benzyloxy-7V-pIienyl-aniIine

To a solution of 4-hydroxy-jV-phenyl-aniline (30 g; 162 mmol) in acetonitrile (400 mL) was added 58 g of Cs2CO3 (178 mmol) and stirred for 15 minutes at room temperature. Benzyl bromide (22.5 mL; 178 mmol) is then added dropwise and the reaction medium is then heated under reflux for 4 h. After filtration and rinsing with acetonitrile, the filtrate is concentrated and chromatographed on silica gel (petroleum ether / AcOEt gradient). The title product is then obtained in the form of a colorless solid.

Preparation 10 ”: N- (4 - {[te / 7-Butyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4- [2 (morpholin-4-yl) ethoxy] aniline

The procedure is carried out according to the method of Preparation 3, replacing 5-bromo-1A-indole

DUPLICATE

-40 used in Stage A by 4-bromo-2-fluorophenol.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 7.75 (d, 1H); 7 (dd, 1H); 6.9 (d, 2H); 6.75 (m, 3H); 6.7 (ddd, 1H); 4.05 (t, 2H); 3.6 (t, 4H); 2.65 (t2H); 2.45 (t, 4H); 0.95 (s, 9H); 0.2 (s, 6H)

Preparation 11 ”: 7V- (4 - {[ter / -Butyl (dimethyl) silyl] oxy} phenyl) pyridin-4-ainine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-1 / - / pyrazole 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 12 ”: 3 - [(4 - {[Zert-Butyl (dimethyl) silyl] oxy} phenyl) amino] benzonitrile

The procedure is carried out according to the process of Preparation 1 ”, replacing the 4-bromo-1-methyl-1Hpyrazole used in Stage B by 3-bromobenzonitrile.

Preparation 13 ”: 7V- (4 - {[i <? / 7-Butyl (dimethyl) silyl] oxy} phenyl) -3-fluoroaniline

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-1 // pyrazole used in Stage B by 1-bromo-3-fluorobenzene.

Preparation 14 ”: 7V- (4 - {[/ erZ-ButyI (dimethyl) siIyI] oxy} phenyl) -3,4-difluoroaniline

The procedure is carried out according to the method of Preparation 1 ”, replacing the 4-bromo-1-methyl-1 / 7pyrazole used in Stage B by 4-bromo-l, 2-difluorobenzene.

Preparation 15 ”: 4 - {[/ ^ rZ-Butyl (dimethyl) silyl] oxy} -7V- {4 - [(3,3-difluoropiperidin-lyl) methyl] phenyl} aniline

Stage A: 1- (4-Bromobenzvl) -3,3-difhioropiperidine

DUPLICATE

-4l To a solution of 4-bromobenzaldehyde (500 mg; 2.7 mmol) in 12 mL of dichloromethane are added, in this order, 3,3-difluoropiperidine hydrochloride (470 mg; 3 mmol), sodium triacetoxyborohydride (860 mg; 4 mmol) and acetic acid (0.17 mL; 3 mmol). After stirring for 1 h at room temperature, the reaction medium is poured into a mixture of aqueous sodium bicarbonate and dicholoromethane. The aqueous phase is extracted with dichloromethane. The organic phase is dried over MgSO4, concentrated to dryness and the residue is purified by chromatography on silica gel (CI-LCL / MeOH gradient) to provide the expected product in the form of an oil.

H NMR: δ (400 MHz; dmso-d6; 300K): 7.55 (dd, 2H); 7.25 (dd, 2H); 3.55 (s, 2H); 2.7 (t, 2H); 2.35 (t, 2H); 1.85 (m, 2H); 1.65 (m, 2H)

Stage_______B: 4 - {[tert-Butyl (dùnethyl) sUyl] oxy} -N- {4 - [(3,3-difluoropiperidin-lyl) methyl] phenyl} aniline

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-1Hpyrazole used in Stage B by 1 - [(4-bromophenyl) methyl] -3,3-difluoiO-piperidine.

Preparation 16 ”: / V- (4 - {[terLButyl (diinethyl) siIyI] oxy} phenyl) quinolin-6-amine

The procedure is carried out according to the method of Preparation 1 ”, replacing the 4-bromo-1-methyl-127pyrazole used in Stage B by 6-bromo-quinoline.

IR: v -NH-: 3300 cnï ¹

Preparation 17 ”: / V- (4 - {[/ i '/ 7-Butyi (dimethyl) silyl] oxy} phenyl) -2-methylpyridin-4amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-I-methyl-1 / 7pyrazole used in Stage B by 4-bromo-2-methyl-pyridine.

IR: v-NH-: 3200 and 3100 cm ' ¹

DUPLICATE

-42 Preparation 18 ”: A ^z - (4 - {[te / 7-Butyl (dimethyl) silyl] oxy} phenyI) -l-methyl-1 / Zpyrrolo [2,3-6] pyriclin-5-amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1 -methyl-1 TYpyrazole used in Stage B by 5-bromo-1-methyl-127-pyrrolo [2,3-6] pyridine (obtained according to a protocol from the literature: Heterocycles, 60 (4), 865, 2003).

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

Preparation 19 ”: / V- (4 - {[te / 7-Butyl (dimethyl) silyl] oxy} phenyl) pyridin-3-ainine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-1 // pyrazole used in Stage B by 3-bromo-pyridine.

Preparation 20 ”: 4 - {[te / 7-Butyl (dnnethyl) silyl] oxy} - / V- {4 - [(3,3-difluoropiperidin-ly 1) ethy I] pheny 1} aniline

Stage A: 2- (4-Bromophenyl) -l- (3,3-difluoropiperidin-l-yl) ethanone

To a solution of 4-bromophenylacetic acid (4 g; 18.6 mmol) and of 3,3difluoropiperidine hydrochloride (2.5 g; 20.4 mmol) in chlorine methane (190 mL) are added EDC (3.8 g; 22.3 mmol), PIOBt (3 g; 22.3 mmol) and triethylamine (1.3 mL; 593 mmol). The reaction medium is left under stirring for 17 hours at room temperature and then poured into a mixture of aqueous sodium bicarbonate and ethyl acetate. The aqueous phase is extracted with ethyl acetate. The organic phase is washed with 0.1 N hydrochloric acid, water, and brine before being dried over MgSCL. concentrated to dryness. The residue is purified by chromatography on silica gel (petroleum ether / ethyl acetate gradient) to provide the expected product in the form of a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 7.5 (d, 2H); 7.2 (d, 2H); 3.8 (t, 2H); 3.7 (s, 3H); 3.5 (t, 2H); 2 (m, 2H); 1.6 (m, 2H)

Stage B: 1- [2- (4-Bromophénvl) ethyl] -3,3-difluoropiperidine

To a solution of the compound of Stage A (4.6 g; 14.5 mmol) in anhydrous THF (145 mL) is added a 1M solution of dimethyl boranesulfide in TFIF (14.5 mL;

DUPLICATE

14.5 mmol). The reaction medium is heated at 80 ° C. for 3 h, then the solvent is evaporated off under reduced pressure. The residue is treated with methanol (50 mL) followed by 5N HCl (5.8 mL). After stirring overnight at room temperature and 3 h at reflux, the pH of the reaction medium is adjusted to 8 with a saturated solution of aqueous sodium bicarbonate, then the aqueous phase is extracted with dichloromethane. The organic phase is dried over MgSO4, concentrated to dryness and the residue is purified by chromatography on silica gel (CHzCh / MeOH gradient) to provide the expected product in the form of an oil.

NMR ‘H: δ (400 MHz; dmso-d6; 300K): 7.45 (d, 2H); 7.20 (d, 2H); 2.71 (m, 2H); 2.69 (t, 2H); 2.58 (dd, 2H); 2.45 (dd, 2H); 1.86 (m, 2H); 1.63 (m, 2H)

Stage________C: 4 - {[tert ~ Butyl (dimethyl) silyl] oxy} -N- {4 ~ [(3,3-difluoropiperidin-l ~ yl) ethyljph enyl} an iline

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

NMR H: δ (400 MHz; dmso-d6; 300K): 7.7 (s, 1H); 7.45 (d, 2H); 7.39 (t, 2H); 7.31 (t, 1H); 7.0 (m, 4H); 6.9 (d, 2H); 6.81 (d, 2H); 5.05 (s, 2H); 2.7 (t, 2H); 2.6 (t, 2H); 2.5 (t, 2H); 2.45 (ΐ, 2H); 1.89 (m, 2H); 1.68 (m, 2H)

Preparation 21 ”: 4 - {[te / 7-Butyl (dimethyl) silyl] oxy} -TV- {4- [2- (3,3-difluoropyrrolidin-ly I) ethy I] pheny 1} aniline

The procedure is carried out according to the method of Preparation 19 ”, replacing in Stage A the hydrochloride of 3,3-difluoropiperidine by the hydrochloride of 3,3-difluoropyiTolidine.

NMR ‘H: δ (400 MHz; dmso-d6; 300K): 7.7 (s, 1H); 7.45 (d, 2H); 7.35 (t, 2H); 7.34 (t, 1H); 7.05-6.85 (m, 8H); 5.05 (s, 2H); 2.9 (t, 2H); 2.75-2.25 (m, 8H)

Preparation 22 ”: A ^z - (4 - {[ie / V-Butyl (dimethyl) silyl] oxy} phenyl) -2,6-diinethylpyridin-4amine

The procedure of Preparation 1 ”is carried out, replacing the 4-bromo-1-methyl-1Hpyrazole used in Stage B by 4-bromo-2,6-dimethylpyridine.

DUPLICATE

-44IR: v: -NH-: 3300 and 2700 cm- ¹ ; v: -Si-O-: 900 cm- ¹ ; v: -If-C-: 823 cm ' ¹

Preparation 23 ”: A- (4 - {[ter / -Butyl (dimethyl) silyl] oxy} phenyl) -l- [2- (morpholin-4yl) ethyl] -lH-pyrazol-4-anim

The procedure of Preparation 2 ”is carried out by replacing the 5-bromobindole used in Stage A by 4-bromo-1H-pyrazole.

NMR ‘H: δ (400 MHz; dmso-d6; 300K): 7.61 (s, 1H); 7.25 (s, 1H); 7.18 (s, 1H); 6.65 (m, 4H); 4.15 (t, 2H); 3.55 (t, 4H); 2.7 (t, 2H); 2.4 (t, 4H); 0.95 (s, 9H); 0.15 (s. 6h)

Preparation 24 ”: A- (4 - {[te / V-Butyl (dimethyl) silyl] oxy} phenyl) -3-fiuoropyridin-4amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-1Hpyrazole used in Stage B by 4-bromo-3-fluoro-pyridine.

IR: v -NH-: 3200 and 3000 cm- ¹ ; v -Si-O-: 900 cm- ¹ ; v -Si-C-: 820 cm ' ¹

Preparation 25 ”: N- (4 - {[ter AButyl (dimethyl) sily 1] oxy} phenyl) imidazo [1,2-a] pyridin-7-amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-l / 7pyrazole used in Stage B by 7-bromoimidazo [l, 2 -“] pyridine (prepared from 4bromopyridin-2 -amine according to a protocol from the literature: WO 2008124323 A1).

IR: v-NH-: 3300-3000 cm- ¹ ; vC = N-: 1652 cm- ¹ ; vC = C-: 1610 cm- ¹ ; v-Si-C-: 1236 cm- ¹ ; v -Si-O-: 898 cm- ¹ ; v -Si-C-: 828, 774 cm ' ¹

Preparation 26 ”: A- (4 - {[ter / -Butyl (dimethyl) siIyI] oxy} phenyl) -2-methyl imidazo [1,2-a] pyridin-7-amine

DUPLICATE

-45 -

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-1 / 7pyrazole used in Stage B by 7-bromo-2-methyl-imidazo [1,2-n] pyridine (prepared in starting from 4-bromopyridin-2-amine according to a protocol in the literature: AJ Helliot and J. Heterocyclic Chemistry 19, 1437, 1982).

IR: v -NH-: 3300-3000 cm- ¹ ; v -C = N-: 1652 cm- ¹ ; v -C = C-: 1610 cm- ¹ ; v -Si-C-: 1236 cm- ¹ ; v -Si-O-: 898 cm- ¹ ; v -Si-C-: 828, 774 cm ' ¹

Preparation 27 ”: jV- (4 - {[tert-Butyi (dimethyl) siIyl] oxy} phenyI) -6-methylpyridin-3-

amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-1 / 7pyrazole used in Stage B by 3-bromo-6-methyl-pyridine.

IR: v -NH-: 3251 cm- ¹ ; v -C = C- aromatics: 1605 cm ' ¹

Preparation 28 ”: N- (4 - {[ter / -ButyI (dimethyl) silyI] oxy} phenyl) -5-fluoropyridin-3-

amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1 -methyl-1Hpyrazole used in Stage B by 3-bromo-5-fluoro-pyridine.

IR: v -NH-: 3400-3000 cm- ¹ ; v -CF-: 1245 cm ' ¹

Preparation 29 ”: N- (4 - {[ft77-Butyl (dimethyl) silyl] oxy} phenyl) -2-methoxypyridin-

4-amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1 -methyl- \ Hpyrazole used in Stage B by 4-bromo-2-methoxy-pyridine.

IR: v -NH-: 3200 and 3000 cm- ¹ ; v -C = C aromatics-: 1618, 1601 cm ' ¹

Preparation 30 ”: 7V- (4 - {[tenf-ButyI (dimethyl) silyl] oxy} phenyl) -2- (propan-2- yl) pyridin-4-amine DUPLICATE

-46-

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl-177pyrazole used in Stage B by 4-bromo-2- (propan-2-yl) pyridine.

IR: v-NH-: 3300 and 3100 cm ' ¹

Preparation 31 ”: ? V- (4 - {[te / Ÿ-Butyl (dimethyl) silyl] oxy} phenyl) pyrazolo | 1,5-

n] pyrimidin-6-amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1 -methyl-1 Hpyrazole used in Stage B by 6-bromopyrazolo [1,5 - ″] pyrimidine.

IR: v -NH-: 3272 cm- ¹ ; v -C = N-: 1634 cm ¹ ; v -C = C-: 1616 cm ' ¹

32 ”preparation: 7V- (4 - {[/ erAButyl (diniethyl) silyl] oxy} phenyl) -3,3a-

dihydro [1,2,4] triazolo [1,5 - "] pyrimidin-6-amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1 -methyl-1 Hpyrazole used in Stage B by 6-bromo-3,3a-dihydro [1,2,4] triazolo [1,5 -a] pyrimidine prepared according to the literature (WO 2011015343) from 477-1,2,4-triazol-3-amine and 2bromopropanedial.

IR: v -NH-: 3244 cm ' ¹

Preparation 33 ”: A / - (4 - {[terAButjd (dimethyl) siIyI] oxy} phenyl) pyridin-4-amine 1-

oxide

The procedure is carried out according to the method of Preparation 1 ”by replacing the 4-bromo-1 -methyl-1 Hpyrazole used in Stage B by 4-bromopyridine 1-oxide prepared according to the literature (WO 2009117269) from 4-bromopyridine .

IR: v -NH-: 3246 cm- ¹ ; v -C = C- aromatics: 1618 cm ' ¹

Mass Spectrum:

Molecular formula: C17H24N2O2S1 [M] ⁺ . measured m / z: 316

DUPLICATE

-47 [MO] ⁺ . measured m / z: 300 [M-C4Hc)] ⁺ . measured m / z: 259

Preparation 34 ”: 7V- [4 - [/ er / -butyl (dimethyl) silyl] oxyphenyl] -l-methylpyridin-1-ium-4-amine chloride

The procedure of Preparation 1 ”is carried out by replacing the 4-Bromo-1-methyl-1Hpyrazole used in Stage B by 4-bromo-1-methyl-pyridin-1-ium chloride prepared according to the literature from 4-bromopyridine.

Preparation 35 ": 7′V- [4 - [/ é? / 7-butyl (dimethyl) silyI] oxyphenyl] -l-methylpy razolo [3,4-û] pyridin-5-amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1-methyl- \ Hpyrazole used in Stage B with 5-bromo-1-methyl-pyrazolo [3,4-è] pyridine prepared according to the literature. (WO 2006052568).

1 H NMR (400 MHz, dmso-d6) δ ppm: 8.33 (d, 1 H), 7.94 (si, 1 H), 7.92 (s, 1 H), 7.71 (d, 1 H), 6.95 (d, 2H), 6.76 (d, 2H), 4.01 (s, 3H), 0.95 (s, 9H), 0.17 (s, 6H)

IR (ATR) cm ': 3290 v>OH; 1503 v Ar; 1249 γ -Si-CH ₃

Preparation 36 ”: 7V- [4- [to7-butyl (dimethyl) silyl] oxyphenyl] -3-methyl-pyrazolo [1,5“] pyrimidin-6-amine

The procedure of Preparation 1 ”is carried out by replacing the 4-bromo-1 -methyl- \ Hpyrazole used in Stage B by 6-bromo-3-methyl-pyrazolo [1,5-i?] Pyrimidine prepared according to literature (WO 2011015343 and WO2011049917).

NMR ′ H (400 MHz, dmso-d6) δ ppm: 8.49 (d, 1H), 8.4 (d, 1H), 7.98 (m, 1H). 7.87 (s. 1H), 7 (d, 2H), 6.81 (d, 2H), 2.29 (s, 3H), 0.98 (s, 9H), 0.2 (s, 6H)

IR (ATR) cm ¹ : 3257 v> NH

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

DUPLICATE

-48literature (Surry D.S. et cil., Chemical Science, 20Π, 2, 27-50, Charles M.D. et al., Organic Letters, 2005, 7, 3965-3968). The reaction for protecting the hydroxy function of 4-anilinophenol described in Preparation 8 ”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, tertbutyl (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- (4chloroanilino) phenol, 4- (3-fluoro- 4-methylanilino) phenol, 4- [4 (trifluoromethoxy) anilino] phenol. 4- [4-hydroxyanilino] phenol, {4 - [(1-methyl-1 / 7indol-6-yl) amino] phenyl} methanol, 4- (2,3-dihydro-1Æ-indol-6- ylamino) phenol, 4 [(1 -methyl-2,3-dihydro-1 / f-indol-6-yl) amino] phenol, 4 - [(1 -methyl-1 // - indol-6yl) amino] phenol, 4 - [(1-methyl-1 / f-indol-6-yl) amino] cyclohexanol, 4 - [(l-methyl-1, 2,3,4-tetrahydro-6-quinolinyl) amino] phenol, 4 - [(4-methyl-3,4-dihydro-2 # -l, 4benzoxazin-7-yl) amino] phenol, 4- [4- (diethylamino) anilino] phenol, 4- (2 , 3-dihydro177-inden-5-ylamino) phenol, 4 - [(1-methyl-1 / Z-indazol-5-yl) amino] phenol, 4 - [(Γmethyl-r, 2'-dihydrospiro [ cyclopiOpane-1,3'-indol] -5'-yl) amino] phenol. 4 - [(1,3,3trimethyl-2,3-dihydro-17i-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-indol-5-yl) amino] phenol, 4 - [(l -ethyl-1 # -indol-5-yl) amino] phenol, 4 - [(1-ethyl-2,3-dihydro-1 // - indol-5yl) amino] phenol, 4 - [(l- isopropyl-2,3-dihydro-l # -indol-5-yl) amino] phenol, 4 (butylamino) phenol, 3 - [(l-methyl-l # -indol-5-yl) amino] -l -propanol, 4 - [(1-methyll # -indol-5-yl) amino] -l-butanol, 4 - [(3-fluoro-4-methylphenyl) amino] phenol, 4 - [(3chloro- 4-methylphenyl) amino] phenol, 4 - [(4-fluorophenyl) amino] phenol, 4 - ((1methyl-l # -pyrrolo [2,3-b] pyridin-5-yl) amino] phenol, 4 - [(4-fluorophenyl) amino] phenoL 4 - [(2-fhiorophenyl) amino] phenol, 4 - [(3-fluorophenyl) amino] phenol, 4 - ((2.4difluorophenyl) amino] phenol, 4 - [(3,4-difluorophenyl) amino] phenol, 3 - ((4hydroxyphenyl) amino] benzonitrile, 4 - [(3-methoxyphenyl) amino] phenol, 4 - ((3,5DUPL1CATA

-49difluorophenyl) amino] phenol, 4 - [(3-methylphenyl) amino] phenol, 4 - [(4-hydroxy phenyl) amino] benzonitrile, 4 - [(3-chlorophenyl) amino] phenol, 4- (pyrimidin-2ylamino) phenol, 4 - [(cyclobutylmethyl) amino] phenol, 2 - ((4hydroxyphenyl) amino] benzonitrile, 4- {[(l -methyl l-1 Æ-pyrazol-4-yl) methyl ] amino} phenol, 4 - ((cyclopropylmethyl) amino] phenol, 4 - {[(1-methyl-lET-pyrazol-3yl) methyl] amino} phenol, 4- (but-2-yn-l- ylamino) phenol, 4- (pyrazin-2-ylamino) phenol, 4- (pyridin-2-ylamino) phenol, 4- (pyridazin-3-ylamino) phenol, 4- (pyrimidin-

5-ylamino) phenol, 4- (pyridin-3-ylamino) phenol, 4 - ((3,5-difluoro-4-methoxyphenyl) amino] phenol, 4- (pyridin-4-ylamino) phenol. 4 - [(3-fluoro-4-methoxy phenyl) amino] phenol, 2- (phenylamino) pyrimidin-5-oI, 5 - ((4-hydroxyphenyl) aminoJ2-methoxybenzonitrile, 4 - {[3- ( trifluoromethyl) phenyl] amino} phenol, 4 (methylamino) phenol, 4- (ethylamino) phenol and 4- (propan-2-ylamino) 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.

Example 1. 7V- (4-Hydroxyphenyl) -3- (6 - {[(3J?) - 3-methyl-3,4-dihydroisoquinolin2 (l / f) -yl] carbonyl} -l, 3-benzodioxol-5 -yI) -7V- (1-methyl-177-indol-5-yl) -5,6,7,8tetrahydroindolizine-1-carboxamide

Stage A: 3- (6 - {[(3R) ~ 3-Methyl-3,4-dihydroisoquinolin-2 (lH) ~ yl] carbonyl} -l, 3benzodioxol-5-yl) -5,6,7,8 -tetrahydroindolizine-1-methyl carboxylate

To a solution of 2 g of the compound of Preparation 1 in 20 mL of dichloromethane is added at room temperature 5.5 mL of N, NyV-triethylamine (6.96 mmol), the compound of Preparation Γ (6.96 mmol), then 0.94 g of hydroxybenzotriazole (HOBT) and 1.34 g of Iethyl-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 an ammonium chloride solution 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 (heptane / AcOEt gradient) to yield the expected product.

DUPLICATE

-50RMN'H: δ (400 MHz; dmso-d6; 300K): 7.2-6.8 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 7.10 (s, 1H, aromatic H, benzodioxole); 6.92 (s, 1H, aromatic H, benzodioxole); 6.25 (m, 1H, H tetrahydroindolizine); 6.10 (s, 2H, aliphatic H, OCH2O); 4.80 (m, 1H, aliphatic H, H tetrahydroisoquinoline); 4.20 (m, 1H, aliphatic H, H tetrahydroisoquinoline); 4.1-3.5 (m, 3H); 3.60 (s, 3H, COOCH3); 2.90 (m, 2H, aliphatic H, H tetrahydroindolizine); 2.45 (m, 2H, aliphatic H, H tetrahydroisoquinoline); 1.70 (m, 4H, aliphatic H, H tetrahydroindolizine); 0.80 (m, 3H, aliphatic H, CH ₃ -THIQ).

IR: v:> C = O 1694 cm- ¹ (conjugated ester); v:> C = O 1624 cm- ¹ (amide); v:> C-Ar 772-742 cm ' ¹

Stage_____B: 3- (6 - {[(3R) -3-Methyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3benzodioxol-5 ~ yl) -5,6,7,8- lithium tetrahydroindolizine-1-carboxylate

To a solution containing 8.26 mmol of the compound of Stage A in 24 mL of dioxane is added a solution of lithium hydroxide (675 rng, 16.1 mmol). The assembly is placed in a microwave oven at 140 W, 100 ° C for a period of 2h30. The reaction medium is then filtered and evaporated. The solid thus obtained is dried at 40 ° C. in an oven in the presence of P2O5.

Stage C: N- (4 - {[tert-Butyl (dimethyl) silyl] oxy} phenyl) -3 ~ (6 - {[(3R) -3-methyl-3,4dihydroisoquinolin-2 (1H) -yl] carbonyl } -l, 3-benzodioxol-5-yl) -N- (1-methyl-1H-indol-5yl) -5,6,7,8-tetrahydro in dol izin e-1 -carboxamide

To a solution containing 4.73 mmol of the compound of Stage B in 47 mL of dichloromethane are added, dropwise, 1.2 mL of oxalyl chloride at 0 ° C. 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 containing 7.1 mmol of the compound obtained in Preparation 2 ”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) to yield the expected product.

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-51 Stage D: N- (4-Hydroxyphenyl) -3- (6 - {[(3R) -3-inethyl-3,4-dihydroisoquinolin-2 (1H) yl] carbonyl} -l, 3-benzodioxol-5 -yl) -N- (1-methyl-1H-indol-5-yl) -5,6,7,8tetrahydroindolizine-1-carboxamide

0.646 g (11.5 mmol) of potassium hydroxide dissolved in 8 mL of methanol is added to a solution containing 2.3 mmol of the compound obtained in Stage C in 4 mL of methanol. The whole is stirred at room temperature for 30 min. The reaction medium is then diluted in dichloromethane and washed successively with 1N HCl solution, saturated NaHCCL solution, then saturated NaCl solution 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 on silica gel (dichloromethane / methanol gradient), then lyophilized to provide the expected product.

High resolution mass (ESI +):

Molecular Formula: C42H38CN4O5 [M + H] ⁺ Calculated: 679.2920 [M + H] ⁺ Measured: 679.2908

Example 2. A '- (4-Hydroxyphenyl) -3- (6- {| (37?) - 3-niethyl-3,4dihydroisoquinolin-2 (1 //) - yl] carbonyl} -l, 3- hydrochloride benzodioxol-S-yl) -W- {l- [2- (morphoIin-4yl) ethyl] -lH-indol-5-yl} -5,6,7,8-tetrahydroindoIizine-1-carboxamide

The procedure is carried out according to the methods described in Steps A-D of Example 1 using the appropriate reagents. After the purification step on silica gel (cf. Stage D), the solid is then dissolved in dichloromethane and 2 mL of IN hydrochloric ether are 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 = 69.32: 68.93; % H = 5.94: 5.74; % N = 8.6: 8.51; % Cl- = 4.35: 4.6

Unless otherwise indicated, the compounds of the following Examples are synthesized according to the method of Example 1 using in Stage A: (i) the appropriate acid obtained according to

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-52one of Preparations 1 to 18 and (ii) the appropriate tetrahydroisoquinoline derivative obtained according to one of Preparations 1 'to 7', as well as in Stage C: (iii) the adequate NHR3R4 amine (a list not is provided in Preparations 1 ”to 36”).

Example 3. 6- (5-Chloro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin2 (lZ /) - yl] carbonyl} phenyl) -7V- (4-hydroxyphenyl) -A hydrochloride - (1-methyl-1F / -indol-5-yI) -l, 2,3,4tetrahydropyrrolo [1,2 - “] pyrazine-8-carboxamide

The process of Example 1 is carried out by replacing, on the one hand, the compound of Preparation 1 used in Stage A by the compound of Preparation 2, and on the other hand the compound of Preparation 1 ”used in Stage C with N- (4 - {[/ cv7butyl (dimethyl) silyl] oxy} phenyl) -l-methyl-177-indol-5-amine, it being understood that the product thus obtained is not subjected to a salification step in the presence of hydrochloric ether as described in Stage D of Example 1. The compound thus obtained is deprotected in the presence of 10 equivalents of trifluoroacetic acid in dichloromethane (10 mL / mmol) at room temperature overnight. Then, the product is then isolated by concentrating the reaction medium to dryness. It is finally subjected to a salification step in the presence of hydrochloric ether.

Elemental microanalysis: (% theoretical: measured)% C = 67: 99: 65.52; % H == 5.28: 4.49; % N = 9.91: 9.24; % C1 = 10.O3: 9.95; % Cl- = 5.02: 5.45

High resolution mass (ESI +):

Molecular Formula: C40FI36CIN5O3 [M + H] ⁺ Calculated: 670.2585 [M + H] ⁺ Measured: 670.2587

Example 4. 3- [5-Chloro-2- (3,4-dihydroisoquinolin-2 (17Z) -ylcarbonyl) phenyl] - / V- (4hydroxyphenyl) -7V- {1- [2- (inorpholin-4-yl ) ethyl] -l // - indol-5-yl} -5,6,7,8tetrahydroindolizin-1-carboxamide

Elemental microanalysis:% measured (theoretical)% C = 70.85 (71.65);% H = 5.39 (5.88);% N = 9.11 (9.28);% Cl = 4.48 (4.7)

DUPLICATE

- 53 Example 5. 3- [5-Chloro-2- (3,4-dihydroisoquinoIin-2 (1H) -yIcarbonyI) phenyI] - / V- (4hydroxyphenyI) -A- {1- [2- (morpholin-4 -yl) ethyl] -2,3-dihydro-1 / f-indol-5-yl} -5,6,7,8tetrahydroindolizine-1-carboxamide

Stage________A_: N- (4 - {[tert-Butyl (dimethyl) silyl] oxy} phenyl) -3- [5-chloro-2- (3,4dUiydroisoquinolin-2 (1H) -ylcarbonyl) phenyl] -N- {l - [2- (morpholin-4-yl) ethyl] -2,3dihydro-1H-indol-5-yl} -5,6,7,8-tetrahydroindolizin-1-carboxamide

One proceeds according to the protocols described in Stages A-C of Example 1 using the compound of Preparation 3 and 1,2,3,4-tetrahydroisoquinoline in Stage A, as well as the compound of Preparation 4 ”in Stage C.

Stage B: 3- [5-Chloro-2- (3,4-dihydroisoquinolin-2 (1H) -ylcarbonyl) phenyl] -N- (4hydroxyphenyl) -N- {l- [2- (morpholin-4-yl) ethyl] -2,3-dihydro-1H-indol-5-yl} -5,6,7,8tetrahydroindolizine-1-carboxamide

To a solution of 1.3 g (1.45 mmol) of the compound of Stage A in 13 mL of acetic acid is added at room temperature sodium cyanoborohydride (900 mg; 15 mmol). After stirring for 2 hours, the reaction medium is concentrated to dryness, then diluted with methanol (8 mL) and treated with a molar solution of potassium hydroxide in methanol (6.3 mL; 6.3 mmol). After 1 hour at room temperature, the reaction medium is concentrated to dryness. then chromatographed on silica gel (dichloromethane / methanol gradient). then lyophilized to provide the expected product in the form of a powder.

Elemental microanalysis:% measured (theoretical)% C = 70.74 (71.46);% H = 5.74 (6.13);% N = 9 (9.26);% C1 = 4.46 (4.69)

Example 6. / V- (4-Hydroxyphenyl) -2-methyl-6- (7 - {[(37?) - 3-methyl- hydrochloride

3,4-dihydroisoquinoIin-2 (ljfi?) - yl] carbonyl} -2,3-dihydro-l, 4-benzodioxin-6-yl) - / V- (lmethyl-l / Z-indol-5-yl) -l, 2,3,4-tetrahydropyrrolo [1,2-rt] pyrazine-8-carboxamide

The process is analogous to that described for Example 7 by substituting in Stage A the compound of Preparation 2 by the compound of Preparation 4.

Elemental microanalysis: (% theoretical: measured)

DUPLICATE

-54% C = 69.39: 69.13; % H = 5.69: 4.98; % N = 9.41: 9.37; % Cl- = 4.76: 4.65

Example 7 6- (5-ChIoro-2 - {[(31?) - 3-methyl-3,4-dihydroisoquinolin-2 (1 //) yl] carbonyl} phenyl) -7V- (4_hydroxyphenyl) -2- methyl- / V- (1-methyl-1H-indol-5-yI) - 1,2,3,4-tetrahydropyrrolo [1,2 - “] pyrazine-8-carboxamide

Stage______A__: 8 - [(4 - {[tert-Butyl (dimethyl) silyl] oxy} phenyl) (1 ~ methyl-1H-indoI-5yl) carbamoyl] -6- (5-chloro-2 - {[(3R) -3-methyl [-3,4-dihydroisoquinolui-2 (1H) -yl] carbonyl} phenyl) -3,4-diliydropyrrolo [1,2-a] pyrazine-2 (1H) -tert-butylcarboxylate

The procedure is carried out according to the protocols described in Stages A-C of Example 1 using the compounds of Preparations 2 and Γ in Stage A, as well as the compound of Preparation 2 ”in Stage C.

Stage________B: 6- (5-Chloro-2 - {[(3R) -3-methyl-3,4 ~ dihydroisoqiiinoHn-2 (1H) ~ yl] carbonyl} phenyl) -8 - [(4-hydroxyphenyl) (l- methyl-1H-indol-5-yl) carbamoyl] -3,4dihydropyrrolo [1,2-a] pyrazine-2 (1H) -ter-butylcarboxylate

To a solution of the compound of Stage A (1.1 g; 1.25 mmol) in methanol (6 mL) is added an IM solution of potassium hydroxide in methanol (6.2 mL; 6.2 mmol). After 2 h at room temperature, the methanol is evaporated off in vacuo and the residue is taken up in a mixture consisting of dichloromethane and a saturated solution of sodium bicarbonate. The combined organic phases are dried over MgSCX and concentrated to dryness. The residue obtained is purified by chromatography on silica gel (CfLCf / MeOH gradient) to provide the expected product in the form of a solid.

IR: v: NH: 3450 cm- ¹ ; v: CO: 1745-1620 cm ¹

Stage _________ Ç_: 6- (5-Cliloro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (1H) yI] carbolyl} phenyl) -8 - [{4 - [(2,2- dimethylpropanoyl) oxy] phenyl} (1-methyl-1H-indol-5yl) carbamoylJ-3,4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -tert-butylcarboxylate

To a solution of the compound of Stage B (0.7 g; 0.93 mmol) in dichloromethane (7 mL) are added, at room temperature, triethylamine (0.2 mL; 1.39 mmol) then chloride pivaloyl (0.11 mL; 0.93 mmol). After 2 hours of stirring at temperature

DUPLICATE

- 55 ambient, the reaction medium is washed with water, with brine, dried over MgSO.i and concentrated to dryness. The residue obtained is used as it is for the next step without analysis.

Stage______D: 4 - [{[6- (5-Chloro-2 - {[(3R) -3-niethyl-3,4-dihydroisoqiiiiwlin-2 (1H) yl] carbonyl} phenyl) -l, 2,3,4 2,2-dimethyl -tetrahydropyrrolo [1,2-a] pyrazin-8-yl] carbonyl} (1-methyllH-indol-5-yl) amino] phenylpropanoate

To a solution of the compound of the preceding stage (0.82 g; 0.93 mmol) in dichloromethane (9 mL) is added at 0 ° C of trifluoroacetic acid (0.7 mL; 13.9 mmol) dropwise by drop. After stirring for 15 hours at room temperature, a saturated solution of sodium bicarbonate is slowly added to the reaction medium, then the phases are separated. The aqueous phase is extracted with dichloromethane. The combined organic phases are dried over MgSCfl and concentrated to dryness. The residue obtained is purified by chromatography on silica gel (CFhCh / MeOH gradient) to provide the expected product in the form of a solid.

LC / MS: m / z = [M + H] ⁺ = 754.30

Stage_______E_: 4 - [{[6- (5-βΜοΐΌ-2 - {[(3Κ) -3-ηιέί1ιγΙ-3,4-άΐ1 ^ άΓθΪ5θ (μιΐηοΙίη-2 (1Ι-Ι) yl] carbonyl} phenyl) -2 -methyl-1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazin-8 ~ yl] carbonyl} (l ~ methyI-1H-indol-5-yl) amino] phenylpropanoate, 2,2-dimethyl

Formaldehyde (48 pL; 1.74 mmol) is added at room temperature to a solution of the compound of the preceding stage (0.41 g; 0.54 mmol) in dichloromethane (2 mL), then sodium triacetoxyborohydride (16 l mg; 0.76 mmol). After stirring for 2 hours at room temperature, the reaction medium is diluted in dichloromethane, then washed with saturated sodium bicarbonate solution. The organic phase is dried with MgSCU and concentrated to dryness. The residue obtained is purified by chromatography on silica gel (CI-RCh / MeOH gradient). The expected product is obtained in the form of a solid.

LC / MS: m / z = [M + H] ⁺ = 768.32

Stage________F_: 6- (5-Chloro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (IH) yl] carbonyl} phenyl) -N- (4-hydroxyphenyl) -2-methyl- N- (1-methyl-1H-indol-5-yl) -l, 2,3,4tetrahydropyrrolo [1,2-a] pyrazine-8-carboxamide

DUPLICATE

-56A a solution of the compound of the previous stage (0.25 g; 0.32 mmol) in dioxane (l mL) is added a solution of lithium hydroxide (27 mg; 0.65 mmol) in water ( l mL). After 5 hours of stirring at room temperature, the reaction medium is concentrated and diluted with a saturated solution of sodium bicarbonate. The aqueous phase is extracted with CH2Cl2. The organic phase is dried over MgSCL and concentrated to dryness. The residue obtained is purified by chromatography on silica gel (CH ₂ Cl ₂ / MeOH gradient). The expected product is then obtained in the form of a solid.

Elemental microanalysis: (% theoretical: measured)% C = 71.97: 71.51; % H = 5.6: 5.25; % N = 10.24: 10.12

Example 8. 3- (5-Chloro-2 - {[(37?) - 3-methyl-3,4-dihydroisoquinolin2 (1 //) - yl] carbonyl} phenyl) -A ^r - (4-hydroxyphenyl) hydrochloride ) -A ^f - {l- [2- (morpholin-4-yl) ethyl] -l // indol-5-yl} indolizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69: 69.16; % H = 5.41: 4.82; % N = 8.75: 8.69; % CI- = 4.43: 4.13

Example 9. 6- (5-Fluoro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin2 (Ui) -yl] carbonyl} phenyl) -A ^/ - (4-fluorophenyl) - hydrochloride? / - (4-hydroxyphenyl) -l, 2,3,4tetrahydropyrroIo [l, 2-iz] pyrazine-8-carboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 6. and on the other hand the compound of Preparation 1 ”used in Stage C by the compound of Preparation 5, it being understood that the product thus obtained is not subjected to a salification step in the presence of hydrochloric ether as described in Stage D of Example 1. The compound thus obtained is deprotected in the presence of 10 equivalents of trifluoroacetic acid in dichloromethane (10 mL / mmol) at room temperature overnight. Then, the product is then isolated by concentrating the reaction medium to dryness. It is finally subjected to a salification step in the presence of hydrochloric ether.

DUPLICATE

-57 Elemental microanalysis: (%> theoretical: measured)% C = 67.83: 67.4l; % H = 5.08: 4.6l; % N = 8.55: 8.39:% Cl- = 5.4l: 5.28

Example 10. 6- (5-Fluoro-2 - {[(32?) - 3-methyl-3,4-dihydroisoquinolin2 (lZZ) -yl] carbonyl} phenyl) -7V- (3-fluoro-4- hydrochloride) methylphenyl) -7V- (4-hydroxyphenyl) -l, 2,3,4tetrahydropyrrolo [1,2 - “] pyrazine-8-carboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 6, and on the other hand the compound of Preparation 1 ”used in Stage C by the compound of Preparation 6, it being understood that the product thus obtained is not subjected to a salification step in the presence of hydrochloric ether as described in Stage D of Example 1. The compound thus obtained is deprotected in the presence of 10 equivalents of trifluoroacetic acid in dichloromethane (10 mL / mmol) at room temperature overnight. Then, the product is then isolated by concentrating the reaction medium to dryness. It is finally subjected to a salification step in the presence of hydrochloric ether.

Elemental microanalysis: (% theoretical: measured)% C = 68.21: 68.29; % H = 5.27: 4.91; % N = 8.37: 8.34; % Cl- = 5.3: 5.17

Example 11. A ^L (4-Hydroxyphenyl) -6- (6 - {[(3À) -3-methyl-3,4dihydroisoquinolin-2 (1/7) -yl] carbonyl} -l, 3-benzodioxol- hydrochloride 5-yl) -A ^/ '- (1-methyl-177indazol-5-yI) -l, 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8-carboxamide

The procedure of Example 1 is carried out by 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 with N- (4 - {[tertbutyl (dimethyl) silyl] oxy} phenyl) -l-methyl-lÆ-indazol-5-amine, it being understood that the product thus obtained is not subjected to a salification step in presence of hydrochloric ether as described in Stage D of Example 1. The compound thus obtained is deprotected in the presence of 10 equivalents of trifluoroacetic acid in dichloromethane (10 mL / mmol) at room temperature overnight. Then, the product is then isolated by concentrating the reaction medium to dryness. It is finally subjected to a salification step in the presence of hydrochloric ether.

DUPLICATE

-58 Elemental microanalysis: (%> theoretical: measured)% I-> 5.2: 4.83; % N = 11.72: 11.64; % Cl- = 4.94: 5.34; % C = 66.99: 66.19

Example 12. 6- (5-Chloro-2 - [[(3R) -3-methyl-3,4-dihydroisoquinoIin2 (17Z) -yl] carbonyl} phenyl) -7V- (4-hydroxyphenyl) -2V- hydrochloride (1 ~ methyl-1H-indazol-5-yl) - 1,2,3,4-tetrahydropyrroIo [1,2 - “] pyrazine-8-carboxamide

The process of Example 1 is carried out by replacing, on the one hand, the compound of Preparation 1 used in Stage A by the compound of Preparation 2, and on the other hand the compound of Preparation 1 ”used in Stage C by 77- (4 - {[/ ertbutyl (diniethyl) silyl] oxy} phenyl) -l-methyI-l / 7-indazol-5-amine, it being understood that the product thus obtained is not subjected to a step salification in the presence of hydrochloric ether as described in Stage D of Example 1. The compound thus obtained is deprotected in the presence of 10 equivalents of trifluoroacetic acid in dichloromethane (10 mL / mmol) at room temperature for a period of night. Then, the product is then isolated by concentrating the reaction medium to dryness. It is finally subjected to a salification step in the presence of hydrochloric ether.

Elemental microanalysis: (% theoretical: measured)% C = 66.19: 65.83; % H = 5.13: 4.99; % N = 11.88: 11.85; % C1- = 5.01: 5.36

Example 13. 7V- (4-Hydroxyphenyl) -3- (6 - {[(3 _l S) -3- [2- (morpholin-4yl) ethyl] -3,4-dihydroisoquinolin-2 (l / 7) hydrochloride ) -yl] carbonyl} -l, 3-benzodioxol-5-yl) - / V-phenyl-

5,6,7,8-tetrahydroindolizine-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.42: 69.47; % H = 5.96: 5.58; % N = 7.36: 7.36; % Cl- = 4.66: 4.42

Example 14. A '- (4-Hydroxyphenyl) -A ^/ - (1-methyl-1 / Z-indazol-5-yl) -3 (6 - {[(35) -3- [2- (morpholin) hydrochloride -4-yl) ethyl] -3,4-dihydroisoquinoIin-2 (l / 7) -yl] ^cai 'bonyl} -l, 3benzodioxol-5-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide

DUPLICATE

-59 Elemental microanalysis: (% theoretical: measured)% C = 67.76: 67.81; % H = 5.81: 5.63; % N = 10.31: 10.13; % Cl- = 4.35: 4.22

Example 15, 7-Amino-, 'V- (4-hydroxyphenyl) -3- (6 - {[(3Æ) -3-methyl- hydrochloride

3,4-dihydroisoquinolin-2 (lZ /) - yr] carbolyl} -l, 3 “benzodioxol-5-yl) -A ^r -phenyl-5,6,7,8tetrahydroindolizine-l-carboxamide

Stage A: 3 '- (6 - {[(3R) -3-Methyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3benzodioxol-5-yl) -5', 6'- dihydro-8 'H-spiro [1,3-dioxolane-2,7'-indolizine] -l' -carboxylate

The procedure is carried out according to the protocol of Stage A of Example 1, replacing the compound of Preparation 1 with the compound of Preparation 8.

Stage B: 3- (6 - {[(3R) -3 ~ Methyl-3,4-dihydroisoquinolin-2 (lH) -yl] carbonyl} ~ 1,3benzodioxol-5-yl) -7-oxo-5,6 , Methyl 7,8-tetrahydroindolizine-1-carboxylate

4.47 mmol of the compound of Stage A dissolved in 75 mL of THF are stirred in the presence of 37 mL of 1 M HCl at reflux for 15 h. 100 mL of water and 100 mL of ethyl acetate are added to the reaction medium. Then 4 g of powdered NaHCO ₃ (4.7 mmol) are added until a basic pH is reached. The compound is extracted with ethyl acetate, the organic phase is dried over MgSO4, filtered and concentrated to dryness.

Stage C: 7-Hydroxy-3- (6 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} - l, 3-benzodioxol-5-yl) -5 , Methyl 6,7,8-tetrahydroindolizine-1-carboxylate

To a solution of 4.47 mmol of the compound obtained in Stage B in 30 ml of methanol are added per portion 558 mg (14.75 mmol) of sodium borohydride. The reaction medium is stirred for 1 h at room temperature. 50 mL of IM HCl are then added and the methanol is evaporated off. The aqueous phase is then neutralized with NaHCO ₃ , then extracted with dichloromethane. The organic phase is successively washed with I-I2O. dried over MgSCU, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (dichloromethane / ethanol-ammonia gradient) to yield the expected product.

DUPLICATE

-60 Stage D: 3- (6 - {[(3R) -3 ~ Methyl-3,4-dihydroisoquinolin-2 (lH) -yl] carbonyl} -l, 3benzodioxol-5-yl) -7- (prop-2 methyl -en-1-yloxy) -5,6,7,8-tetrahydroindolizin-1-carboxylate

To a suspension of 331 mg (8.26 mmol) of sodium hydride in 15 mL of anhydrous THF cooled to 0 ° C., 4.13 mmol of the compound obtained in Stage C. is added. This suspension is stirred for 15 min at 0 ° C., then a solution of 790 μL (9.1 mmol) of allyl bromide in 10 mL of THF is added slowly (over 15 min). The reaction medium is stirred for 1 h at 0 ° C., then 15 h at room temperature. This solution is hydrolyzed with an aqueous solution saturated with NH4Cl. The compound is extracted with ethyl acetate; the organic phase is dried over MgSO4, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (cyclohexane / ethyl acetate gradient) to yield the expected product.

Stage E: N- (4 - {[tert ~ Butyl (dimethyl) silyl] oxy} phenyl) -3- (6 - {[(3R) -3-methyl-3,4dihydroisoqiünolin-2 (1H) -yl] carbonyl } -l, 3-Benzodioxol-5-yl) -N-phenyl-7- (prop-2-en-lyloxy) -5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure is carried out according to the methods described in Steps B and C of Example 1 using the appropriate reagents.

Stage F: N- (4 - {[tert-Butyl (dimethyl) silyl] oxy} phenyl) -7-hydroxy-3- (6 - {[(3R) -3-methyl-

3,4-dihydroisoquinoliii-2 (1H) -yl] carbonyl} -l, 3-benzodioxol-5-yl) -N-phenyl-5,6,7,8tetrahydroindolizine-l-carboxamide

A deprotection reaction of the allyl group is then carried out in the presence of 1,3dimethylpyrimidine-2,4,6 (177.3I7.5 / V) -trione (also called dimethylbarbiturate) and tetrakis (triphenylphosphine) palladium in a mixture of methanol and dichloromethane.

Stage G: 7-Azido-N- (4 - {[tei't-butyl (dimethyl) silyl] oxy} phenyl) -3- (6 - {[(3R) -3-methyl-3,4dihydroîsoquinolin-2 ( 1H) -yl] carbonyl} -l, 3-benzodioxol-5-yl) -N-phenyl-5,6,7,8tetrahydroindolizine-1-carboxamide

DUPLICATE

-6I To a solution of the compound of Stage F (550 mg; 0.72 mmol) in methylene chloride (6 mL), are added at room temperature triethylamine (300 pL; L8 mmol) and mesyl chloride (0 , 14 mL; 1.8 mmol). After 20 minutes of stirring, the reaction medium is concentrated to dryness, then diluted in 10 mL of DMSO. 470 mg of powdered NaN3 (7.2 mmol) are added thereto. The reaction medium is left for 20 h at room temperature, then 20 h at 50 ° C. It is then poured onto a mixture of dichloromethane and water. The organic phase is washed 3 times with water, then with brine, dried over MgSO4 and then concentrated to dryness to give the expected product which is used as it is in the following step.

Stage H: 7-Amino-N- (4-hydroxyphenyl) -3- (6 - {[(3R) -3-methyl-3,4dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3- hydrochloride benzodioxol-5-yl) -N-phenyl-5,6,7,8tetrahydroindolizine-l-carboxamide

To a solution of 550 mg of the compound of Stage G (0.7 mmol) in ethanol (10 mL) is added at room temperature 20 mg of 10% Pd / C. After 15 h of stirring under 1 bar of hydrogen, the reaction medium is filtered through Whatman and concentrated to dryness. After purification by chromatographic column on silica gel (dichloromethane / methanol gradient), the solid is then dissolved in dichloromethane and 2 mL of IN hydrochloric ether are 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 to yield the expected compound in the form of a powder.

Elemental microanalysis: (% theoretical: measured)% C = 69.17: 68.68; % H = 5.51: 5.09; % N = 8.27: 8.41; % Cl- = 5.24: 5.28

Example 16. 3- (6 - {[(35) -3- (Hydroxymethyl) -3,4-dihydroisoquinolin-2 (ljyjyl] carbonyl} -l, 3-benzodioxol-5-yI) -A ^r - (4- hydroxyphenyl) - / V-phenyl-5,6,7,8tetrahydroindolizine-l-carboxamide

Stage A: 3- (6 - {[(3S) -3- (Hydroxymethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3benzodioxol-5-yl) -5,6,7 , Methyl 8-tetrahydroindolizine-1-carboxylate

DUPLICATE

The procedure is carried out according to the process in Stage A of Example 1 using (35) -1,2,3,4tetrahydroisoquinolin-3 -ylmethanol.

Stage B: 3- (6 ~ {[(3S) -3 - [(Prop-2-en-1-yloxy) methyl] -3,4-dihydroisoqumolin-2 (IH) yl] carbonyl} ~ l, 3- methyl benzodioxol-5-yl) -5,6,7,8-tetrahydroindolizine-1-carboxylate To a suspension of NaH (703 mg; 17.6 mmol) in THF (20 mL) is added a solution 7,8 g of the compound of Stage A (16 mmol) dissolved in a mixture of THF (50 mL) and DMF (30 mL). After 1 hour of stirring, allyl bromide (1.7 mL; 19 mmol) is added. The reaction medium is left under stirring for 48 h at room temperature, then it is poured into a mixture of ethyl acetate and water. The organic phase is washed 3 times with water, with saturated LiOH solution, dried over MgSO4, concentrated to dryness. After purification by chromatography on silica gel (dichloromethane / methanol gradient), the expected product is obtained in the form of a solid.

¹ H NMR: δ: (500MHz; dmso-d6; 300K): 7.2-6.9 (m, 4H); 7.05 (m, 1H); 6.9 (m, 1H): 6.45-6.1 (m, 1H); 6.15 (m, 2H); 5.9-5.65 (m, 1H); 5.2-5.0 (m, 2H); 5.05-3.8 (m, 1H); 4.85-

4.25 (m, 2FI); 4.3-3.45 (m, 7H); 3.4-2.4 (m, 6H); 1.95-1.45 (m, 4H)

Stage C: N- [4- (Benzyloxy) phenyl] -N-phenyl-3- (6 - {[(3S) -3 - [(prop-2-n-1-yloxy) methyl] -

3,4-dihydroisoquinolin-2 (lH) -yl] carbonyl} -l, 3-benzodioxol-5 ~ yl) -5,6,7,8tetrahydroindolizine-l ~ carboxamide

The procedure is carried out according to the methods of Stages B and C of Example 1 using 4 (benzyloxy) -iV-phenylaniline (cf. Preparation 9 ”).

Stage D: 3- (6 - {[(3S) -3- (Hydroxymethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3benzodioxol-5-yl) -N- (4- hydroxyphenyl) -N-phenyl-5,6,7,8-tetrahydroiiidolizine-lcarboxamide

To a suspension of 5.1 g (6.65 mmol) of the compound of Stage C in a mixture of dichloromethane (7 mL) and methanol (2 mL), there is added dimethylbarbituric acid (2.1 g; 13, 3 mmol) and tetrakis (triphenylphosphine) palladium (0) (300 mg; 0.3 mmol). After 15 hours of stirring at 45 ° C, the reaction medium is poured into a mixture of ethyl acetate and water. The organic phase is washed twice with water, dried over MgSO4,

DUPLICATE

-63 concentrated to dryness and diluted in methanol (5 mL). The whole is then stirred for 24 h under a hydrogen atmosphere in the presence of Pd / C (100 mg). The reaction medium is then filtered through Whatman, concentrated to dryness, then chromatographed on silica gel (dichloromethane / methanol gradient) and finally lyophilized to yield the expected product in the form of a powder.

Elemental microanalysis:% measured (theoretical)% C = 72.38 (73);% H = 5.22 (5.5);% N = 6.59 (6.55)

Example 17. 7V- {3-Iluoro-4- [2- (morpholin-4-yl) ethoxy] phenyl} -7V- (4hydroxyphenyl) -3- (6 - {[(37?) - 3-methyl hydrochloride -3,4-dihydroisoquinolin-2 (1H) -yI] carbonyI} -l, 3benzodioxoI-5-yl) indolizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 67.12: 66.79; % H = 5.26: 4.98; % N = 6.96: 7.17; % Cl- = 4.4: 4.77

Example 18. 3- [6- (3,4-DihydroisoquinoIin-2 (lZ7) -ylcarbonyl) -l, 3benzodioxol-5-yl] -2V- {3-fluoro-4- [2- (morphoIin-4) hydrochloride -yI) ethoxy] phenyl} -? V- (4hydroxyphenyl) mdolizine-1-carboxamide

Elemental microanalysis:% measured (theoretical)% C = 66.99 (66.79);% H = 4.93 (5.1);% N = 7.11 (7.08);% Cl- = 4.46 (4.48)

Example 19. N- (4-Hydroxyphenyl) -3- (5-methyl-2 - {[(35) -3- [2 (morpholin-4-yl) ethyl] -3,4-dihydroisoquinolin-2 ( 1/7) -yl] carbonyl} phenyI) -7V-phenyl-

5,6,7,8-tetrahydroindoIizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 72.26: 72.51; % H = 6.48: 6.13; % N = 7.66: 7.71; % C1 = 4.85: 4.95; % Cl- = 4.85: 4.64

Example 20. 7V- (4-Hydroxyphenyl) -3- (2 - {[(3S) -3- [2- (morpholin-4yl) ethyI] -3,4-dihydroisoquinolin-2 (lZ /) - yl hydrochloride ] carbonyl} phenyl) -yV-phenyI-5,6,7,8tetrahydroindolizine-1-carboxamide

DUPLICATE

-64 Elemental microanalysis: (% theoretical: measured)% C = 72: 7l.ll; % H = 6.32: 5.94; % N = 7.81: 7.65; % CI- = 4.94: 5.08

Example 21. γV- (4-Hydroxyphenyl) -3- (6 - {[(37?) - 3-methyl-3,4dihydroisoquinoIin-2 (lZZ) -yl] carbonyl} -l, 3-benzodioxol-5 hydrochloride -yl) -7V- (pyridin-4yl) indolizine-1-carboxamide

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

Example 22. N- (4-Hydroxyphenyl) -6- (6 - {[(35) -3- [2- (morpholin-4yl) ethylj-3,4-dihydroisoquinolin-2 (17 /) - yl] hydrochloride) carbonyI} -1.3 - benz () dioxoI-5-yl) - / Vphenylpyrrolo [1,2 - «] pyrimidine-8-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 68.11: 66.66; % H = 5.32: 4.93; % N = 9.24: 8.84; % Cl- = 4.68: 5.78

High resolution mass (ESI +):

Molecular Formula: C43H39N5O6 [M + H] ⁺ Calculated: 655.2915 [M + H] ⁺ Measured: 655.2915

Example 23. M (3-Cyanophenyl) - / V- (4-hydroxyphenyl) -3- (6 - {[(35) -3 [2- (morphoIin-4-yl) ethyI] -3,4- hydrochloride dihydroisoquinolin-2 (177) -yl] carbonyI] -l, 3-benzodioxol5-yl) -5,6,7,8-tetrahydroindolizine-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 68.74: 68.59; % H = 5.64: 5.5; % N = 8.91: 8.98; % Cl- = 4.51: 4.48

Example 24. N- (3-Fluorophenyl) -lV- (4-hydroxyphenyl) -3- (6 - {[(35) -3 [2- (morpholin-4-yI) ethyl] -3,4- hydrochloride. dihydroisoquinolin-2 (lF7) -yI] carbonyl} -l, 3-benzodioxoIDUPLICATA

- 65 5-yl) -5,6,7,8-tetrahydroindolizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 67.81: 67.45; % H = 5.69: 5.61; % N = 7.19: 7.42; % Cl- = 4.55: 4.84

Example 25. 7V- (3,4-Difluorophenyl) ~ 7V- (4-hydroxyphenyl) -3- (6 {[(35) -3- [2- (morphoIm-4-yl) ethyl] -3 hydrochloride, 4-dihydroisoquinolin-2 (17 /) - yl] carbonyl} -l, 3benzodioxoI-5-yl) -5,6,7,8-tetrahydroindolizine-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 66.28: 66.56; % H = 5.44: 5.25; % N = 7.03: 7.21; % Cl- = 4.45: 4.32

Example 26. 7V- (3-Fluorophenyl) -3- (6 - {[(35) -3- [2- (morpholin-4yl) ethyI] -3,4-dihydroisoquinoIin-2 (17 /) - yl hydrochloride ] ^ca rbonyl} -l, 3-benzodioxol-5-yl) -. / V-phenyl · -

5,6,7,8-tetrahydroindolizine-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.24: 70.16; % H = 5.81: 5.79; % N = 7.34: 7.47; % Cl- = 4.64: 4.58

Example 27. 3- (5-Chloro-2 - {[(35) -3- [2- (morpholin-4-yl) ethyl] -3,4dihydroisoquinolin-2 (lZij-yl] ^car bonyl} phenyl) hydrochloride -7V- (3-fluorophenyl) -A ^, - (4hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 67.1: 67.68; % H = 5.63: 5.4; % N = 7.28: 7.34; % C1- = 4.61: 4.59

Example 28. 7V- (4-Hydroxyphenyl) -3- (5-methoxy-2 - {[(3Y) -3- [2 (morpholin-4-yl) ethyl] -3,4-dihydroisoquinolin-2 ( U7) -yl] carbonyl} phenyI) -7V-phenyl-

5,6,7,8-tetrahydroindolizine-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 7Q.T2: 7Q.Q5; % H = 6.34: 5.95; % N = 7.5: 7.33; % Cl- = 4.74: 4.74

DUPLICATE

-66 Example 29.? 7- (4-Hydroxyphenyl) -3- (4-methoxy-2 - {[(35) -3- [2 (morphoIin-4-yl) ethyl] -3,4-dihydroisoquinolin- hydrochloride- 2 (lJT) yl] carb ^o nyl} phenyl) - / V-phenyl-

5,6,7,8-tetrahydroindolizine-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 70.72: 68.96; % H = 6.34: 5.78; % N = 7.5: 7.24; % Cl- = 4.74: 4.62

High resolution ground (ESI +);

Molecular Formula: C44 H46 N4 O5 [M + H] ⁺ Calculated: 711.3546 [M + H] ⁺ Measured: 711.3540

Example 30. 7V- {4 - [(3,3-difluoropiperidin-1-yl) methyl] phenyl} -7V- (4hydroxyphenyl) -3- (6 - {[(3J?) - 3-methyl-3 hydrochloride , 4-dihydroisoquinolin-2 (ljH) -yl] carbonyl} -l, 3benzodioxol-5-yI) indoIizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 68.31: 69.12; % H = 5.22: 4.93; % N, 7.08: 6.96; % Cl- = 4.48: 4.07

Example 31. TV- (4-Hydroxyphenyl) -3- (6 - {[(37f) -3-methyl-3,4dihydroisoquinolin-2 (1 / Z) -yl] carbonyl} -l, 3-benzodioxol- hydrochloride 5-yl) -N- (quinolin-6yl) indolizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 71.13: 71.29; % H = 4.69: 4.39; % N = 7.9: 8.14; % Cl- = 5: 4.5

Example 32. W- (4-Hydroxyphenyl) -3- (6 - {[(3J?) - 3-methyl-3,4dihydroisoquinolin-2 (l / f) -yl] carbonyI} -l, 3-benzodioxoI hydrochloride -5-yl) -7V- (2-methylpyridin-4yl) indolizin-1-carboxamide

Elemental microanalysis: (%> theoretical: measured)% C = 69.59: 69.81; % H = 4.94: 4.53; % N = 8.32: 8.59; % C1- = 5.27: 5.O1

DUPLICATE

Example 33. 7V- (4-Hydroxyphenyl) -3- (6 - {[(3I?) - 3-methyl-3,4dihydroisoquinolin-2 (1H) -yl] carbonyI} -l, 3-benzodioxol- hydrochloride 5-yl) -A ^z - (1-methyl-lZZpyrrolo [2,3-ô] pyridin-5-yl) indolizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.14: 70.09; % H = 4.81: 4.55; % N = 9.83: 10.09; % Cl- = 4.'98: 3.26

Example 34. 7V- (4-Hydroxyphenyl) -3- (6 - {[(3 /?) - 3-methyl-3,4dihydroisoquinolin-2 (Lif) -yl] carbonyl} -1, 3-benzodioxoI- hydrochloride 5-yl) - / V- (pyridin-3yl) indolizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.24: 70.21; % H = 4.74: 4.42; % N = 8.5: 8.5l; % Cl- = 5.38: 3.33

Example 35. W- {4- [2- (3,3-difluoropiperidin-1-yI) ethyl] phenyi} - / V- (4hydroxyphenyl) -3- (6 - {[(37?) - 3- hydrochloride methyl-3,4-dihydroisoquinolin-2 (lZ /) - yl] carbonyl} -l, 3benzodioxol-5-yl) indolizin-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 68.61: 67.96; % H = 5.38: 5.14; % N = 6.96: 6.76; % Cl- = 4.4: 4.36

Example 36. 7V- {4- [2- (3,3-difluoropyrrolidin-1-yl) ethyl] phenyl} -JV (4-hydroxyphenyl) -3- (6 - {[(3R) -3-methyl hydrochloride -3,4-dihydroisoquinolin-2 (l / Z) -yl] carbonyl} - l, 3-benzodioxol-5-yl) indolizin-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 68.31: 68.51; % H = 5.22: 4.85; % N = 7.08: 6.83; % Cl- = 4.48: 4.48

Example 37. 3- (6 - {[(35) -3- (2-aminoethyl) -3,4-dihydroisoquinolin2 (lf /) - yI] carbonyl} -l, 3-benzodioxol-5-yl) - hydrochloride / V- (4-hydroxyphenyl) -A ^/ '-phenyl-5,6,7,8tetrahydroindolizine-1-carboxamide

Stage A: 3- (6 - {[(3S) -3- {2 - [(tert-Butoxycarbonyl) amino] ethyl} -3,4dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3-benzodioxol- 5-yl) -5,6,7,8DUPL1CATA

-68tetrahydroindolizine-1-methyl carboxylate

Has a solution of 2 g of the compound of Preparation 1 in 20 mL of dichloromethane. 5.5 mL of A / A / TV-triethylamine (6.96 mmol), the compound of Preparation 3 '(6.96 mmol), then 0.94 g of hydroxybenzotriazole (HOBT) are added at room temperature and 1.34 g of Iethyl-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 an ammonium chloride solution 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 (heptane / AcOEt gradient) to yield the expected product.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 7.2-6.8 (m, 4H, aromatic Hs, H tetrahydroisoquinoline); 7.15-6.90 (m, 4H, aromatic H, tetrahydroisoquinoline); 7,006.80 (m, 2H, aromatic H, benzodioxole); 6.68 + 6.55 + 6.25 (m, 1H, NH); 6.50-6.05 (m, 1H, aromatic H, tetrahydroindolizine); 6.12 (m, 2H, aliphatic H, OCH ₂ O); 4.95 + 4.20 + 4.10 (m, 2H, aliphatic H, CH ₂ N tetrahydroisoquinoline); 4.85 + 4.78 + 3.80 (m, 1H, aliphatic H, CH tetrahydroisoquinoline); 4.00-3.40 (m, 2H, aliphatic H, CH ₂ N tetrahydroindolizine); 3.70-3.50 (m, 3H, COOCH3); 2.95-2.45 (m, 2H, aliphatic Hs, CH ₂ NHBoc); 2.98-2.30 (m, 2H, aliphatic Hs, CH ₂ C tetrahydroindolizine); 3.00 + 2.60 + 2.42 (m, 2H, aliphatic H, CH ₂ CEI tetrahydroindolizine); 1.95-1.40 (m. 4H, aliphatic H, CH ₂ CH ₂ tetrahydroindolizine); 1.35-1.25 (m, 9H, aliphatic Hs. TBu); 1.50-1.15 (m, 2H, aliphatic H, CH ₂ CH ₂ NHBoc)

Stage B: 3- (6 - {[(3S) -3- {2 - [(tert-Butoxycarbonyl) amino] ethyl} -3,4-dihydroisoquinolin2 (1H) -yl] carbonyl} -l, 3-benzodioxol- Lithium 5 ~ yl) ~ 5,6,7,8-tetrahydroindolizine-l-carboxylate

To a solution containing 8.26 mmol of the compound of Stage A in 24 mL of dioxane is added a solution of lithium hydroxide (675 mg, 16.1 mmol). The whole is placed in a microwave oven at 140 W, 100 ° C for a period of 2:30. The reaction medium is then filtered and evaporated. The solid thus obtained is dried at 40 ° C. in an oven in the presence of P ₂ O5.

DUPLICATE

-69 Stage C: (2 - {(3S) -2 - [(6- {l - [(4 - {[tert-Butyl (dîmethyl) silyl] oxy} phenyl) (phenyl) carbamoyl] -5,6,7 , 8-tetrahydroindolizin-3-yl} -l, 3-benzodioxol-5-yl) carbonyl] -l, 2,3,4tetrahydroisoquinolin-3-yl} ethyl) tert-butyl carbamate

To a solution containing 4.73 mmol of the compound of Stage B in 47 mL of dichloromethane are added, dropwise, 1.2 mL of oxalyl chloride at 0 ° C. 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 containing 7.1 mmol of the compound obtained in Preparation 8 ”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) to yield the expected product.

1 H NMR: δ (400 MHz; dmso-d6; 300K): 7.0 (m, 11H, aromatic H, Ph + 4H, tetrahydroisoquinoline + 2H, PhO); 6.80-6.65 (m, 2H, aromatic Hs, PhO); 6.95-6.85 (m, 2H, aromatic H, benzodioxole); 6.70 + 6.40 (3tl, 1H, NH); 6.10 (m, 2H, aliphatic H, OCH2O); 5.25-4.85 (m, 1H, aromatic H, tetrahydroindolizine); 5.00 + 4.00 (m, 2H, aliphatic H, CH2N tetrahydroisoquinoline); 4.90-3.60 (m, 1H, aliphatic PI, CH tetrahydroisoquinoline); 4.10-3.40 (m, 2H, aliphatic H, CH ₂ N tetrahydroindolizine); 3.00-2.50 (m, 2H, aliphatic Hs, CH2C tetrahydroindolizine); 3.00 + 2.40 (m, 2H, aliphatic Hs, CH2CH tetrahydroindolizine); 3.00-2.50 (m, 2H, aliphatic Hs, CH2NHB0C); 1.80-1.50 (m, 4H, aliphatic Hs, CH2Cl-Ltetrahydroindolizine); 1.50-1.30 (m, 2H, aliphatic Hs, CH2CH2NHB0C); 1.35 (2s. 9I-I, aliphatic Hs, tBu); 0.90 (s, 9H, aliphatic H, tBu-Si); 0.10 (m, 6H, aliphatic H, MeSi)

Stage D: 3- (6 - {[(3S) -3- (2-amuwethyl) -3,4-dihydroisoquinolin-2 (1H) yl] carbonyl} -l, 3-benzodioxol-5-yl) - hydrochloride N- (4-hydroxyphenyl) -N-phenyl-5,6,7,8tetrahydroindolizine-1-carboxamide

To a solution of 800 mg (0.92 mmol) of the compound of Stage C in 10 mL of methanol. 258 mg (4.60 mmol) of KOH are added. After 3 hours of stirring at room temperature, the reaction medium is treated with a solution of 4M HCl in 6 mL of dioxane. After 2h

DUPLICATE

Stirring at room temperature, the reaction medium is concentrated and treated with a saturated aqueous solution of NaHCCL and extracted with methylene chloride. 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 compound is then dissolved in 5 ntL of dichloromethane and 2.5 mL of 1M hydrochloric ether is added. The compound is filtered and dried under vacuum. The expected product is obtained in the form of a foam.

Elemental microanalysis: (% theoretical: measured)% C = 69.51: 69.53; % H = 5.69: 5.27; % N = 8.11: 8.04; % Cl- = 5.13: 5.2

High resolution mass (ESI +):

Molecular Formula: C40H38N4O5 [M + H] ⁺ Calculated: 655.2915 [M + H] ⁺ Measured: 655.2915

1 H NMR: δ (400 MHz; dmso-d6; 300K): 9.55 + 9.45 (2s, 1H, OH); 7.80 + 7.75 (2s, 3H, NH3 ⁺ ); 7.46-6.55 (m, 11H, aromatic Hs, Ph + 4H, tetrahydroisoquinoline + 2H. PhO): 6.90-6.55 (m, 2H, aromatic Hs, PhO); 7.00-6.70 (several s. 2H, aromatic H, benzodioxole); 5.35-5.00 (several s, 1H, aromatic H, tetrahydroindolizine); 6.10 (several s, 2H, aliphatic Hs, OCH2O); 5.00-3.35 (several m, 4H, aliphatic H, CH2N tetrahydroisoquinoline + CILN tetrahydroindolizine); 4.85 + 4.75 + 3.60 (several m, 1H, aliphatic H, CH tetrahydroisoquinoline); 2.85-2.45 (several m, 2H. Aliphatic Hs, CH ₂ NH ₂ ); 3.00-2.45 (several m, 2H, aliphatic Hs, CH tetrahydroindolizine); 3.05 + 2.30 (several m, 2H, aliphatic Hs, CH ₂ CH tetrahydroisoquinoline); 1.85-1.40 (several m, 2H, aliphatic Hs, CIL tetrahydroisoquinoline); 1.95-1.35 (several m, 2H, aliphatic Hs, CH2 tetrahydroisoquinoline); 1.75-1.40 (several m, 2H, aliphatic H, CH2CH2NH2)

IR: v: -OH: 3375 cm- ¹ (phenol); v: -NH3 ⁺ : 3500-2300 cm- ¹ (primary amine salt); v:> C = O 1612 cm ' ¹ + shoulder (amide)

DUPLICATE

Example 38. A ⁱ '- (4-hydroxyphenyl) -3- (6 - {[(31?) - 3- [3- (morpholin-4yl) propyl] -3,4-dihydroisoquinolin-2 ( 1/7) ^_ yl] ^car bonyl} -l, 3-benzodioxol-5-yl) -? / phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.71: 69.62; % H = 6.11: 5.67; % N = 7.23: 7.12; % C1- = 4.57: 4.81

Example 39. N- (2,6-Dimethylpyridin-4-yl) -7V- (4-hydroxyphériyl) -3 (6 - {[(3j?) - 3-methyl-3,4-dihydroisoquinoIin-2 ( lJ7) -yl] carbonyl} -l, 3-benzodioxol-5yl) indolizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.91: 69.68; % H = 5.13: 4.78; % N = 8.15: 8.03; % C1- = 5.16: 5.16

Example 40. 2V- (4-Hydroxyphenyl) -3- (6 - {[(31?) - 3-methyl-3,4-dihydroisoquinolin2 (1 / Z) -yl] carbonyl} -l, 3-benzodioxol-5 -yl) -? / - phenyl-5,6,7,8-tetrahydroindolizine-lcarboxamide

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

Example 41. 3- (6 - {[(35) -3- [2- (3,3-difluoropiperidin-1-yl) ethyl] -3,4dihydroisoquinolin-2 (lÆ) -yl] carbo ⁿ yl} hydrochloride -l, 3-Benzodioxol-5-yl) - / V- (4-hydroxyphenyl) -A / phenyI-5,6,7,8-tetrahydroindolizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 67.96: 68.34; % H = 5.7, 5.4; % N = 7.04: 6.97; % Cl- = 4.46: 4.27

Example 42. 7V- (4-Hydroxyphenyl) -3- (6 - {[(37 <') - 3-inethyl-3,4dihydroisoquinolin-2 (17i) -yl] carbonyl} -1, 3-benzodioxoI- hydrochloride 5-yl) -N- (pyridin-4-yl) -5,6,7,8tetrahydroindolizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 68.82: 69.46; % H = 5.32: 4.95; % N = 8.45: 8.48; % Ci- = 5.35: 4.6

DUPLICATE

-72Example 43. 3- (6 - {[(35) -3- {2 - [(2,2-Difluoroethyl) amino] ethyl} -3,4dihydroisoquinolin-2 (lZZ) -yl] carbonyl} -l, 3 -benzodioxoI-5-yl) -7V- (4-hydroxyphenyl) -7Vphenyl-5,6,7,8-tetrahydroindolizine-l-carboxannde

Stage A: 3- (6 - {[(3S) -3- {2 - [(tert-Butoxycarbonyl) amino] ethyl} -3,4dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3-benzodioxol- Ethyl 5-yl) -5,6,7,8tetrahydroindolizin-1-carboxylate

The process is analogous to that described in Stage A of Example 37.

Stage B: 3- (6 - {[(3S) -3- {2 - [(tert-Butoxycarbonyl) (2,2-difluoroethyl) amino] ethyl} -

Ethyl 3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} -l, 3-benzodioxol-5-yl) -5,6,7,8tetrahydroindolizine-1-carboxylate

To a suspension of 337 mg of NaH (60%) (8.41 mmol) in 13 mL of dimethylformamide, a solution of 1.01 g (1. 68 mmol) of the compound of Stage A in 13 mL of dimethylformamide. This suspension is stirred at room temperature for 15 min, then 1.08 g (5.04 mmol) of 2,2difluoroethyl trifhioromethanesulfonate in 13 mL of dimethylformamide is added. The whole is stirred at room temperature for 2 hours. A solution of 20 mL of saturated ammonium chloride is added. The solution is extracted with ethyl acetate. The organic phase is then dried over MgSCh, filtered and concentrated to dryness. After purification by chromatography column on silica gel (cyclohexane / ethyl acetate), the expected product is obtained in the form of an oil.

High resolution mass (ESI +):

Molecular formula: C37H43CN3O7 [M + H] ⁺ calculated: 680.3142 [M + Hf measured: 680.3145

NMR: δ (400 MHz; dmso-d6; 300K): 7.25-6.90 (m, 4FI, aromatic Hs, tetrahydroisoquinoline); 7.10-6.75 (m, 2FI, aromatic H, benzodioxole); 6.40-6.05 (m, 1H, aromatic H, tetrahydroindolizine); 6.10 (m, 2H, aliphatic H, OCH2O); 6.25-5.90

DUPLICATE

-73 (m, 1Η, aliphatic H, CHF ₂ ); 4.95-4.10 (m, 2H, aliphatic H, CII ₂ N tetrahydroisoquinoline); 4.80 + 3.80 (2m, 1H, aliphatic H, CH tetrahydroisoquinoline); 4.10-4.00 (m, 2H, CH ₂ Et); 4.05-3.40 (m, 2H, aliphatic H, CH ₂ N tetrahydroindolizine);

3.60-2.60 (m, 4H, aliphatic H, CH ₂ CHF ₂ + CH ₂ NBoc); 3.00-2.35 (m, 2H. Aliphatic H, CH ₂ C tetrahydroindolizine); 3.00 + 2.45 (m, 2H, aliphatic FI, CH ₂ CH tetrahydroisoquinoline); 1.95 + 1.40 (m, 4H, aliphatic H, CH ₂ CH ₂ tetrahydroindolizine); 1.40 (m, 9H, aliphatic H, * Bu); 1.65-1.20 (m, 2H, aliphatic Hs, CH ₂ CH ₂ NBoc); 1.18 + 1.10 (2t, 3H, H aliphatic CI-I ₃ Et)

Stage______C: (2 - {(3S) -2 - [(6- {l - [(4 - {[tert-Butyl (dimethyl) silyl] oxy} phenyl) (plienyl) carbamoylJ-5,6,7,8- tetrahydroindolizin-3-yl} -l, 3-benzodioxol-5-yl) carbonyl] -l, 2,3,4tetrahydroisoquinolin-3-yl} ethyl) (2,2-difluoroethyl) tert-butyl carbamate

The process is analogous to that described in Steps B and C of Example 37.

¹ FI NMR: δ (400 MHz; dmso-d6; 300K): 7.30-6.60 (m, 9H, aromatic H, 4H tetrahydroisoquinoline + Ph); 6.90-6.70 (m, 2H, aromatic H, benzodioxole); 6.80-6.60 (m, 4H, PhO); 6.10 (m, 2H, aliphatic H, OCH ₂ O); 6.20-5.90 (m, 1H, aliphatic Hs, CHF ₂ ); 5.50-4.80 (4s, 1H, aromatic H, tetrahydroindolizine); 5.20-4.00 (m, 2H, aliphatic H, CH ₂ N tetrahydroisoquinoline); 4.80 + 4.70 + 3.50 (3m, 1H, aliphatic H. CH tetrahydroisoquinoline); 4.20-3.40 (m, 2H, aliphatic H, CH ₂ N tetrahydroindolizine);

3.60-3.10 (m, 4H, aliphatic H, CH ₂ CHF ₂ + CH ₂ NBoc); 3.00 + 2.60 (m, 2H, aliphatic H, CH ₂ CH tetrahydroisoquinoline); 3.00-2.50 (m, 2H, aliphatic H, CI-1 ₂ C tetrahydroindolizine); 1.80 + 1.50 (m, 4H, aliphatic Hs, CH ₂ CH ₂ tetrahydroindolizine);

1.60-1.30 (m, 2H, aliphatic Hs, CH ₂ CH ₂ NBoc); 1.40-1.30 (m, 9H, aliphatic FI, tBu); 0.90 (4s, 9H, aliphatic H, tBu-Si); 0.10 (4s, 6H, aliphatic H, Me-Si)

Stage D: 3- (6 ~ {[(3S) -3- {2 - [(2,2-Difluoroethyl) amino] ethyl} -3,4-dihydroisoquinolin2 (1H) -yl] carbonyl} -l, 3- benzodioxol-5-yl) -N- (4-hydroxyphenyl) -N-phenyl-5,6,7,8tetrahydroindolizine-l-carboxamide

To a solution of 933 mg (1.00 mmol) of the compound of Stage C in 10 mL of methanol. 280 mg (5.00 mmol) of KOH are added. After 3 hours of stirring at room temperature, the reaction medium is treated with a solution of 4M HCl in 6 mL of dioxane. After 2h

DUPLICATE

Stirring at room temperature, the reaction medium is concentrated and treated with a saturated aqueous solution of NaHCO ₃ , then extracted with methylene chloride. 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) to give the expected product in the form of a foam.

Elemental microanalysis: (% theoretical: measured)% C = 70.18: 69.79; % H = 5.6l: 5.67; % N = 7.'79: 7.7

High resolution mass (ESI +):

Molecular Formula: C42H40F2N4O5 [M + H] ⁺ Calculated: 655.2915 [M + H] ⁺ Measured: 655.2915

Example 44. N- (4-Hydroxyphenyl) -3- (6 - {[(35j-3- [2- (3-methoxyazetidin-1-yl) ethyl] -

3,4-dihydroisoquinolin-2 (177) -yl] carbonyl} -l, 3-benzodioxoI-5-yl) - / V-phenyl-5,6,7,8tetrahydroindolizine-l-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 72.9 \: 72.73; % H = 6.12: 5.67; % N = 7.73: 7.74

Example 45. 2V- (4-Hydroxyphenyl) -3- (6- {1 (37?) - 3-methyl-3,4dihydroisoquinolin-2 (I //) - yl] carbonyl} -l, 3-benzodioxol hydrochloride -5-yl) - / V- (l- [2- (morpholin-4yl) ethYl] -l / 7-pyrazoI-4-yl} indoIizin-1-ciirboxainide

Elemental microanalysis: (% theoretical: measured)% C = 66.27: 66.05; % H = 5.43: 5.27; % N = 11.04: 11.07; % C1- = 4.66: 4.61

Example 46, 7V- (3-Fluoropyridin-4-yl) -? / - (4-hydroxyphenyl) -3- (6 {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (l / Z) -yll ^car b ^o nyI} -l, 3-benzodioxol-5yl) indolizine-l-carboxamide

High resolution mass (ESI +):

Molecular formula: CssFhçF ^ Oj

DUPLICATE i

-75 [M + H] ⁺ calculated: 641.2195 [M + H] ⁺ measured: 641.2195

Example 47. 3- (5-Chloro-2 - {[(32?) - 3-methyl-3,4-dihydroisoquinolin-2 (1 / jT) yl] carbonyl} phenyl) -A ^r - (4-hydroxyphenyl) -IV- (1-methyl-1 / f-pyrazol-4-yl) -5,6,7,85 tetrahydroindolizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.72: 69.53; % H = 5.53: 5.6; % N = 11.29: 10.85

Example 48. A ^r - (4-Hydroxyphenyl) -3- (7 - {[(37?) - 3-methyI-3,4-dihydroisoquinolin2 (1H) -yI] carbonyI} -2,3-dihydro-l, 4-benzodioxiii-6-yI) -7V- (1-methyl-lFI-pyrazol-4-yl) 10 5,6,7,8-tetrahydroindolizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 70.9: 70.89; % H = 5.79: 5.56; % N = 10.88: 10.8

Example 49. 3- (5-Chloro-2 - {[(3J?) - 3-methyl-3,4-dihydroisoquinolin2 (1 / Z) -yl] carbonyl) phenyl) -2V- (4-hydroxyphenyl) hydrochloride -7V- (pyridin-4-yl) indolizin-l15 carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 68.42: 68.17; % H = 4.65: 4.48; % N = 8.63: 8.48; % CI- = 5.46: 5.13

Example 50. 3- (5-Chloro-2 - {[(32?) - 3-methyl-3,4-dihydroisoquinoIin-2 (1 //) yl] carbonyl} phenyl) -2V- (4-hydroxyphenyl) - A ^z - (l-methylI-lFI-pyrrolo [2,3 - />] pyridin-520 yl) indolizine-1-carboxamide

Elemental microanalysis: (%> theoretical: measured)% C = 72.12: 71.58; % H = 4.84: 4.84; % N = 10.51: 10.48

Example 51. 7V- (4-Hydroxyphenyl) -7V- (imidazo [1,2-fl] pyridin-7-yl) - hydrochloride

3- (6 - {[(37f) -3-methyl-3,4-dihydroisoquinolin-2 (lJ ^! Î) “yl] ^car bonyl} -l, 3-benzodioxol-5-yl) indolizine-1-carboxamide

DUPLICATE

-76 Elemental microanalysis: (% theoretical: measured)% C = 68.81: 68.28; % H = 4.62: 4.59; % N = 10.03: 9.66; % C1- = 5.O8: 4.81

Example 52. AC (4-Hydroxyphenyl) -3- (2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin2 (I //) - yI | carbonyi} phenYl) -Atyl-niethyl41H-pyrrolo | 2 , 3- / tipyridin-5-yl) indoIizine - Icarboxamide

Elemental microanalysis: (% theoretical: measured)% C = G6.05: 75.88; % H = 5.26: 5.24; % N = 11.09: 11.09

Example 53. 7V- (4-Hydroxyphenyl) -3- (6 - {[(3 _J R) -3-methyl-3,4dihydroisoquinolin-2 (1 / Z) -yl] carbonyl} -l, 3- hydrochloride benzodioxol-5-yl) -JV- (2methylimidazo [1,2-a] pyridin-7-yI) indolizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.14: 69.65; % H = 4.81: 4.75; % N = 9.83: 9.79; % Cl- = 4.98: 4.7

Example 54. 7V- (4-Hydroxyphenyl) -3- (6 - {[(32?) - 3-methyl-3,4dihydroisoquinolin-2 (17i) -yl] carbonyl} -1, 3-benzodioxol-5 hydrochloride -yl) - / V- (6-methylpyridin-3yl) indolizine-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 69.59: 68.78; % H = 4.94: 5; % N = 8.32: 8.33; % Cl- = 5.27: 5.18

Example 55. 7V- (5-Fluoropyridin-3-yI) -? 7- (4-hydroxyphenyl) -3- (6 - {[(3R) -3-methyl-

3.4- dihydroisoquinoIin-2 (l //) - yl] carbonyl} -l, 3-benzodioxol-5-yl) indolizin-lcarboxamide

Elemental microanalysis: (% theoretical: measured)% C = 71.24: 70.77; % H = 4.56: 4.36; % N = 8.75: 8.82

Example 56. A- (4-Hydroxyphenyl) - / V- (2-methoxypyridin-4-yl) -3- (6 - {[(3R) -3-methyl-

3.4- dihydroisoquinolin-2 (l / Z) -yl] ^car bonyl} -l, 3-benzodioxol-5 “yl) indolizine-lDUPL1CATA carboxamide

High resolution mass (ESI +):

Molecular Formula: C39H32N4O6 [M + H] ⁺ Calculated: 653.2395 [M + H] ⁺ Measured: 653.2385

Example 57. 3- [6- (3,4-Dihydroisoquinolm-2 (1H) -ylcarbonyI) -1, 3-benzodioxoI-5-yI] N- (4-hydroxyphenyl) -N-phenyl-5,6,7 , 8-tetrahydroindolizine-1-carboxamide

Elemental microanalysis:% measured (theoretical)% C = 74.l7 (74.62);% H = 5.43 (5.44);% N = 6.87 (6.87)

Example 58. 7 / - (4-Hydroxyphenyl) -3- (6 - {[(31?) - 3-methyl-3,4dihydroisoquinolin-2 (1 //) - yl] carbonyl} -l, 3- hydrochloride benzodioxol-5-yl) - / V- [2- (propan-2yl) pyridin-4-yI] mdoIizin-1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 70.23: 69.95; % H = 5.32: 5.4; % N = 7.99: 7.99; % Cl- = 5.06: 4.92

Example 59. 2V- (4-Hydroxyphenyl) -3- (6 - {[(3 /?) - 3-methyl-3,4-dihydroisoquinolin2 (l #) - yl] carbonyl} -l, 3-benzodioxoI-5 -yl) - / V- (pyrazolo [l, 5-iz] pyrimidin-6-yl) indolizin1-carboxamide

Elemental microanalysis: (% theoretical: measured)% C = 70.68: 70.47; % H = 4.56: 4.61; % N = 12.68: 12.45

Example 60. 3- (5-Fluoro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolm-2 (12Z) yl] carbonyl} phenyl) -? / - (4-hydroxyphenyl) -7V- (l-methyl-lFZ-pyrazoI-4-yI) indolizine-lcarboxamide

Elemental microanalysis:% measured (theoretical)% C = 71.85 (72.11);% H = 4.78 (5.04);% N = 10.79 (11.68)

DUPLICATE

-78 Example 61. 3- (5-Fluoro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (1/7) yl] carbonyl} phenyl) - / V- (4-hydroxyphenyl) -A ^r - (1-methyl-1 // - pyrazol-4-yl) -5,6,7,8tetrahydroindolizine-1-carboxamide

Elemental microanalysis:% measured (theoretical)% C = 72.31 (71.62);% H = 5.6 (5.68);% N = T0.94 (11.6)

Example 62. 3- (5-Fluoro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (1H) yl] carb <myl} phenyl) -7V- (4-hydroxyphenyI) -7V - (pyridin-4-yl) indolizin-1-carboxamide

Elemental microanalysis:% measured (theoretical)% C = 74.08 (74.48);% H = 4.82 (4.9);% N = 8.59 (9.39)

Example 63. 3- (5-FIuoro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (1ZT) yl] carbonyl} phenyl) - / V- (4-hydroxyphenyl) -? / - (l-methyl-lZ / -pyrrolo [2,3 - /?] pyridin-5yl) indolizine-l-carboxamide

Elemental microanalysis:% measured (theoretical)% C = 73.14 (73.95);% H = 4.83 (4.96);% N = 10.29 (10.78)

Example 64. 3- (5-Fluoro-2 - {[(37?) - 3-methyl-3,4-dihydroisoquinolin-2 (l / f) yl] carbonyl} phenyl) -A ^/ - (4-hydroxyphenyl) -A ^z - (pyridin-4-yl) -5,6,7,8tetrahydroindolizin-1-carboxamide

Elemental microanalysis:% measured (theoretical)% C = 74.61 (73.98);% H = 5.26 (5.54);% N = 8.94 (9.33)

Example 65. 3- (5-FIuoro-2 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (lj7) yl] carbonyl} phenyl) - / V- (4-hydroxyplienyl) -7V- (1-methyl-1 / Z-pyrrolo [2,3-Z>] pyridin-5yl) -5,6,7,8-tetrahydroindoIizine-1-carboxamide

Elemental microanalysis; % measured (theoretical)% C = 73.59 (73.49);% H = 5.22 (5.55);% N = 9.93 (10.71)

DUPLICATE

-79 Example 66. 7V- (4-Hydroxyphenyl) -3- (6 - {[(3R) -3-methyl-3,4-dihydroisoquinoIin2 (1 #) - yI] carbonyl} -1, 3-benzodioxol-5- yl) -2V - ([1,2,4] triazolo [l, S-iz] pyrimidin-6yl) indolizin-1-carboxamide

Elemental microanalysis:% measured (theoretical)% C = 68.57 (68.77);% H = 3.92 (4.4);% N = l4.2l (l4.77)

High resolution mass (ESI +):

Molecular Formula: C38H29N7O5 [M + H] ⁺ Calculated: 664.2303 [M + H] ⁺ Measured: 664.2310

Example 67. A ^r - (4-Hydroxyphenyl) -3- (6 - {[(37?) - 3-methyl-3,4-dihydroisoquinolin2 (1H) -yl] carbonyl} -l, 3-benzodioxol-5- yl) - / V- (l-oxidopyridin-4-yl) mdolizme-lcarboxamide

Elemental microanalysis:% measured (theoretical)% C = 69.7 (71.46); %% H = 4.43 (4.73);% N = 8.54 (8.77)

High resolution mass (ESI +):

Molecular Formula: C38H30N4O6 [M + H] ⁺ Calculated: 639.2238 [M + H] ⁺ Measured: 639.2234

Example 68. 2V- (4-Hydroxyphenyl) -3- (2 - {[(37?) - 3-methyl 1-3,4dihydroisoquinoIin-2 (177) -yl] carbonyl} phenyl) - / V- ( pyridin-4-yl) indolizin-lcarboxamide

Elemental microanalysis:% measured (theoretical)% C = 71.97 (72.25);% H = 5.21 (5.08);% N = 8.99 (9.11);% Cl- = 5.32 (5.76)

High resolution mass (ESI +):

Empirical Formula: C37H30N4O3

DUPLICATE

-80 [M + H] ⁺ calculated: 579.2391 [M + H] ⁺ measured: 579.2403

Example 69. A ^z - (4-Hydroxyphenyl) -A ^/ - (1-methyl-1/7-pyrrolo [2,3 />] pyridin-5-yl) -3- (6 - {[(37) hydrochloride ?) - 3- [3- (morpholin-4-yl) propyI] -3,4-dihydroisoquinolin2 (17 /) - yl] carbonyl} -l, 3-benzodioxol-5-yl) -5,6,7, 8-tetrahydroindolizine-l-carboxamide

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 mass (ESI +):

Molecular formula: C ^ FLigNôOô [M + H] ⁺ calculated: 793.3708 [M + H] ⁺ measured: 793.3704

Example 70. A ^r - (4-Hydroxyphenyl) -3- (6 - {[(3 /?) - 3-methylI-3,4-dihydroisoquinolin2 (1F /) - yl] carbonyl} -l, 3-benzodioxol- 5-yl) -. / V- (1-methyl-1H ^r -pyrazoIo [3,4-6] pyridin-5yl) indolizin-1-carboxamide

Stage A: N- [4- [tert-Butyl (dimethyl) silyl] oxyphenyl] -3- [6 - [(3R) -3-methyl-3,4-dihydro-1Hisoquinoline-2-carbonyl] -l, 3 -benzodioxol-5-ylJ-N- (1 -mélhyl-1 H-pyrazolo [3,4-bJpyridi.n-5yl) indolizin-1-carboxamide

The title product is obtained according to the process of Stage A of Example 86 by replacing the compound of Preparation 36 "by that of Preparation 35".

LCMS: [M + H] ⁺ = 791.4 for 791.3 calculated

Stage B: N- (4-Hydroxyphenyl) -3- (6 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (1H) yl] carbonyl} -l, 3-benzodioxol-5-yl ) -N- (1 -methyl-1 H-pyrazolo [3,4-b] pyridin-5-yl) indolizin-1-carboxamide

The procedure is carried out according to a protocol similar to that described in Stage D of Example 1. The product thus obtained is subjected to a salification step in the presence of hydrochloric ether.

DUPLICATE

-8l IR (ATR) cm ¹ : 2500 to 3000 v-OH, 1614 v> C = O amides, 1236 v> COC <,

740 γ> CH-Ar

Elemental microanalysis:% measured (theoretical)% C = 71.07 (70.99);% H = 4.45 (4.77);% N = 12.37 (12.42)

High resolution mass (ESI +):

Molecular Formula: C40H32N6O5 [M + H] ⁺ Calculated: 677.2507 [M + H] ⁺ Measured: 677.2510

Example 71. 4 - [(4-hydroxyphenyl) {[3- (6 - {[(37?) - 3-methyl-3,4dihydroisoqumolin-2 (1H) -yI] carbonyl} -l, 3-benzodioxol chloride -5-yl) indolizin-1-yl] carbonyl} aminoj-1-methylpyridinium

Stage A: 4 - [(4-hydroxyphenyl) {[3- (6 - {[(3R) -3-methyl-3,4-diïiydroisoquinolin2 (1H) -yl] carbonyl} -l, 3-benzodioxol- iodide 5-yl) indolizin-1-yl] carbonyl} ciminoJ-1-methyl pyridinium

The compound of Example 21 (311 mg, 0.5 mmol) is dissolved in dichloromethane and washed with a saturated aqueous solution of sodium hydrogencarbonate. After drying the organic phase with magnesium sulfate and evaporating to dryness, the residue is dissolved in ethanol (30 mL). Methyl iodide (45 µL, 0.7 mmol) is then added and the reaction medium is heated to 40 ° C. The solution thus obtained is evaporated to dryness. The reaction crude is purified on a silica gel column using dichloromethane and methanol as solvents. The compound is obtained in the form of a white powder, which is used directly in the next step.

NMR * H (500 MHz, dmso-d6) δ ppm: 9.95 (si, 1 H), 8.6-8.45 (m, 2 H), 8.35-8.05 (several m, 1 H), 8.3-8 (several m, 1 H), 7.45-6.7 (several m, 8 H), 7.4-6.9 (several m, 4 H), 6.45-6.3 (several s, 1 H), 6.45-6.3 (m, 2 H), 6.15 (s , 2H). 5.05-3.55 (several d. 2 H), 4.75 / 3.8 (m + m, 1 H), 4.15 (2 * s, 3 H), 2.95-2.1 (several sts, 2 H), 1-0.15 (several sts , 3H)

DUPLICATE

-82 Stage B: 4 - [(4-hydroxyphenyl) {[3- (6 - {[(3R) -3-methyl-3,4dihydroisoquinolin-2 (1 H) -yl] carbonyl} -l, 3- benzodioxol-5-yl) indolizin-l ylJcarbonyl} amino] -l-methyl pyridinium

The compound of the previous stage (320 mg, 0.42 mmol) is dissolved in methanol (20 mL), then silver carbonate (173 mg, 0.628 mmol) is added in portions over 10 minutes. This suspension is stirred for 1 hour at room temperature; the precipitate is filtered off and washed with methanol. The filtrate is concentrated to dryness, then treated with 50 mL of a 2N hydrochloric acid solution, heated at 60 ° C. for 30 minutes then evaporated to dryness. The final product is obtained after purification on a C18 silica column using a 0.1% hydrochloric acid solution and acetonitrile as solvents. The title compound is obtained in the form of a white powder which is lyophilized in a water / acetonitrile mixture.

IR (ATR) cm ¹ : 3388 v -OH phenol, 1650 + 1627 v> C = O amides

High resolution mass (ESI +):

Molecular formula: C39FI33N4O5 [M] ⁺ calculated = 637.2445.

[M] ⁺ measured = 637.2431

The compounds of Examples 72, 73, 77, 78-80, 84 and 85 are synthesized according to the method of Example 3 using the acid of Preparation 7, 1,2,3,4tetrahydroisoquinoline or the appropriate derivative obtained. according to one of Preparations Γ to 7 ', as well as adequate Famine NHR3R4.

Example 72. 7V- (4-Hydroxyphenyl) -N-methylI-6- (6 - {[(3R) -3-methyl-3,4dihydroisoquinolin-2 (1 //) - yI] carbonyl} -l, 3- benzodioxol-5-yl) -l, 2,3,4tetrahydropyrrolo [1,2-a] pyrazine-8-carboxamide

LC / MS (C33H32N4O5) 565 [M + H] ⁺ ; RT 1.47 (Method B) with the understanding that RT indicates the retention time

Example 73. / V-Ethyl-jV- (4-hydroxyphenyl) -6- (6 - {[(3R) -3-methyl-3,4DUPLICATA

-83dihyd rois oquinolin-2 (l //) - yl] carbonyl} - !, 3-benzodioxol-5-yl) -l, 2,3,4tetrahydropyrrolo [l, 2 - «] pyrazine-8-carboxamide

LC / MS (C34H34N4O5) 579 [M + H] ⁺ ; RT 1.55 (Method B)

Example 74. 3- [6- (3,4-Dihydroisoqumolin-2 (I //) - ylcarbonyl) -1, 3-benzodioxoI-5-yl] A '- (4-hydroxyphenyl) -A' '- methyl- 5,6,7,8-tetrahydroindolizine-l-carboxamide

LC / MS (C33H31N3O5) 550 [M + H] ⁺ ; RT 1.24 (Method B)

Example 75. 3- [6- (3,4-Dihydroisoquinolin-2 (I //) - ylcarbonyl) -1, 3-benzodioxol-5-ylj? / - ethyl- / V- (4-hydroxyphenyl) -5, 6,7,8-tetrahydroindolizine-l-carboxamide

LC / MS (C34H33N3O5) 564 [M + H] ⁺ ; RT 1.30 (Method B)

Example 76. A'-ButyI-3- [6- (3,4-dihydroisoquinoIin-2 (I //) - ylcarbonyl) -l, 3benzodioxol-5-yl] -A ^z - (4-hydroxyphenyl) -5, 6,7,8-tetrahydroindolizine-l-carboxamide

LC / MS (C36H37N3O5) 592 [M + H] ⁺ ; RT 1.39 (Method B)

Example 77. A ^r -Ethyl-A ^z - (4-hydroxyphenyl) -6- (6 - {[(30 ') - 3-methyl-3,4dihydroisoqumolin-2 (l / Z) ^- yl] carbonyl} -l , 3-benzodioxol-5-yl) -l, 2,3,4tetrahydropyrrolo [1,2 - “] pyrazine-8-carboxamide

LC / MS (C ₃₄ H34N ₄ O ₅ ) 579 [M + H] ⁺ ; RT 1.50 (Method B)

Example 78. A /, / V-Dibutyl-6- (6 - {[(3R) -3-methyl-3,4-dihydroisoquinolin-2 (1 / T) yl] carbonyl} -l, 3-benzodioxol-5 -yl) -1, 2,3,4-tetrahydropyrrolo [1,2-iz] pyrazine-8carboxamide

LC / MS (C34H42N4O4) 571 [M + H] ⁺ ; RT 1.79 (Method B)

Example 79, A ^L Butyl-A ^r - (4-hydroxyphenyl) -6- (6 - {[(37?) - 3-methyl-3,4dihvdroisoquinolin-2 (1/7) -yl] carbonyl} -l, 3-benzodioxol-5-yl) -l, 2,3,4tetrahydropyrrolo [1,2 - “] pyrazine-8-carboxamide

LC / MS (C ₃₆ H3 ₈ N ₄ O ₅ ) 607 [M + H] ⁺ ; RT 1.65 (Method B)

DUPLICATE

-84 Example 80, W- (4-Hydroxyphenyl) -6- (6 - {[(3R) -3-methyI-3,4-dihydroisoquinolin2 (lZZ) -yl] carbonyl} -l, 3-benzodioxol-5-yl ) - / V- (propan-2-yl) -l, 2,3,4tetrahydropyrroIo [1,2-a] pyrazine-8-carboxamide

LC / MS (C35H36N4O5) 593 [M + H] ⁺ ; RT 1.58 (Method B)

Example 81. 7V- (4-Hydroxyphenyl) -A-methyl-3- (6 - {[(3R) -3-methyl-3,4dihydroisoquinolin-2 (12 /) - yl] carbonyl} -l, 3-benzodioxol -5-yl) -5,6,7,8tetrahydroindolizin-1-carboxamide

LC / MS (C34H33N3O5) 564 [M + H] ⁺ ; RT 2.48 (Method A)

Example 82.! V- (4-Hydroxyphenyl) -W-methyI-3- (6 - {[(3S) -3-methyl-3,4dihydroisoquinolin-2 (12 /) - yl] carbonyl} -l, 3- benzodioxol-5-yl) -5,6,7,8tetrahydroindolizine-1-carboxamide

LC / MS (C34H33N3O5) 564 [M + H] ⁺ ; RT 2.55 (Method A)

Example 83. 3- (6- (3,4-Dihydroisoquinolin-2 (1H) -yIcarbonyl) -1, 3-benzodioxol-5-yI] A '- (4-hydroxyphenyl) -,' V-inethylindoliziiie-l- carboxamide

LC / MS (C33H27N3O5) 546 [M + H] ⁺ ; RT 2.40 (Method A)

Example 84. 6- [6- (3,4-Dihydroisoquinolin-2 (l / i) -yl ^car bonyl) -l, 3-benzodioxol-5-yl] A- (4-hydroxyphenyl) -W-methyl-1 , 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine-8carboxamide

LC / MS (C32H30N4O5) 551 [M + H] ⁺ ; RT 1.45 (Method B)

Example 85. 6- (6- (3,4-DihydroisoquinoIin-2 (l / Z) -yIcarbonyI) -1, 3-benzodioxol-5-yl] 7V-ethyl- / V- (4-hydroxyphenyl) -l, 2,3,4-tetrahydropyrroIo (1,2 - "] pyrazine-8carboxamide

LC / MS (C33H32N4O5) 565 [M + H] ⁺ ; RT 1.49 (Method B)

Example 86. A ^r - (4-Hydroxyphenyl) -3- [6 - [(3R) -3-methyl-3,4-dihydroDUPLICATA hydrochloride

- 85 l / 7-isoquinoline-2-carbonyl] -l, 3-benzodioxoI-5-yl] -A- (3-methylpyrazoIo [l, 5-iz] pyrimidin-6-yI) indolizine-1-carboxamide

Stage A: N- [4- [tert-butyl (dimethyl) silyl] oxyphenyl] -3- [6 - [(3R) -3-methyl-3 _; 4-dihydro-lHisoquinoline-2-carbonyl] -l, 3-benzodioxol-5-yl] -N- (3-methylpyrazolo [1,5-a] pyrimidin-6yl) indolizine-1-carboxam ide

Has a solution of 0.6 g of 3- (6 - {[(3À) -3-methyl-3,4-dihydroisoquinolin-2 (l / 7) yl] carbonyl} -l, 3-benzodioxol-5 acid -yl) indoIizine-1-carboxylic acid (l, 3 mmol) in 6 mL of dichloroethane is added 0.18 mL of l-chloro- / V, / V, 2-trimethyl-piOp-l-en-l-amine ( 2 mmol). The reaction medium is stirred at room temperature for 2 hours, then 0.8 g of the compound of Preparation 36 ”(2.2 mmol) is added. The whole is heated at reflux for 20 hours, then cooled and diluted in a mixture of dichloromethane and a saturated solution of NaHCCh. After decantation, the organic phase is dried over MgSO.i and concentrated to dryness. The crude product thus obtained is purified by chromatography on silica gel (dichloromethane / methanol gradient).

LC / MS: [M + H] ⁺ = 791.4 for 791.3 calculated

Stage B: N- (4hydroxyphenyl) -3- [6 - [(3R) -3-methyl-3,4-dihydro-1Hisoquinoline-2-carbonyl] -l, 3-benzodioxol-5-yl] hydrochloride -N- (3-methylpyrazolo [1,5-a] pyrimidin-6yl) indolizine-1-carboxamide

The procedure is carried out according to a protocol similar to that described in Stage D of Example 1. The product thus obtained is subjected to a salification step in the presence of hydrochloric ether.

IR (ATR) cm ¹ : 2500 to 3000 v -OH, 1614 v> C = O amides, 1236 v> COC <,

740 γ> CH-Ar

High resolution mass (ESI +):

Molecular Formula: C40H32N6O5 [M + H] ⁺ Calculated: 677.2507 [M + H] ⁺ Measured: 677.2506

DUPLICATE

-86 PHARMACOLOGICAL STUDY

EXAMPLE A: Inhibition of BcI-2 by the fluorescence polarization technique

The fluorescence polarization tests were carried out in microplates (384 wells). The labeled Bcl-2 protein (histag-Bcl-2 such as Bcl-2 corresponds to the primary UniProtKB® order number: P10415), at the final concentration of 2.50.10 ' ^s M, is mixed with a fluorescent peptide (Fluorescein-REIGAQLRRMADDLNAQY), at the final concentration of 1.00. 10 ' ^S M in a buffer solution (10 mM Hepes, 150 mM NaCl, 0.05% Tween20, pH 7.4), in the presence or absence of increasing concentrations of compounds to be tested. After incubation for 2 hours, the fluorescence polarization is measured.

The results are expressed as IC50 (concentration of compound which inhibits fluorescence polarization by 50%) and are presented in Table 1 below.

The results show that the compounds of the invention inhibit the interaction between the Bcl-2 protein and the fluorescent peptide described above.

EXAMPLE B: In vitro cytotoxicity.

Cytotoxicity studies were performed on the leukemia tumor line RS4; 11.

The cells are distributed in microplates and exposed to the test compounds for 48 hours. Cell viability is then quantified by a colorimetric assay. the Tetrazolium Assay Microculture (Cancer Res., 1987, 47, 939-942).

The results are expressed as IC50 (concentration of compound which inhibits cell viability by 50%) and are presented in Table 1 below.

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

DUPLICATE

-87 Table 1: ICgo of Bcl-2 inhibition (fluorescence polarization test) and cytotoxicity for RS4 cells; 11

IC _51I (nM) Bcl-2 FP IC ₅₁ > (nM) MTT RS4; 11 IC _5U (nM) Bcl-2 FP IC ₅₁₁ (11M) MTT RS4JI Example 1 17.9 11.3 Example 29 19.0 163 Example 2 17.0 36 Example 30 10.4 52.3 Example 3 33.6 66.5 Example 31 5.4 13.7 Example 4 56.4 251 Example 32 5.0 32.7 Example 5 55.9 416 Example 33 4.6 6.33 Example 6 60.3 161 Example 34 5.6 27.3 Example 7 46.4 108 Example 35 15.1 62.2 Example 8 24.5 20.5 Example 36 12.6 49.7 Example 9 40.6 780 Example 37 2.9 24.7 Example 10 24.7 439 Example 38 4.6 9.52 Example 11 10.9 83.7 Example 39 4.6 26.3 Example 12 10.4 116 Example 40 6.0 49 Example 13 5.8 33.65 Example 41 41.5 294 Example 14 3.7 7.6 Example 42 5.1 57.6 Example 15 5.7 166 Example 43 4.8 26 Example 16 7.5 252 Example 44 2.9 8.56 Example 17 3.4 11.8 Example 45 3.8 63.8 Example 18 7.5 47.7 Example 46 4.1 27.9 Example 19 8.0 235 Example 47 4.3 90.1 Example 20 11.1 205 Example 48 3.6 24.7 Example 21 4.6 25.3 Example 49 3.7 84.7 Example 22 12.9 263 Example 50 2.2 28.2 Example 23 3.8 9.99 Example 51 4.8 68.8 Example 24 6.2 28.4 Example 52 7.9 20.9 Example 25 7.9 30 Example 53 5.4 70.9 Example 26 16.6 300 Example 54 6.6 45 Example 27 7.7 44.1 Example 55 5.5 22.8 Example 28 8.8 112 Example 56 4.7 36.7

DUPLICATE

IC _{5 (} > (nM) Bcl-2 FP 1C _S > (nM) MTT RS4; 11 IC _S) (nM) Bcl-2 FP IC _5I > (nM) MTT RS4; 11 Example 57 21.2 282 Example 72 90.2 1520 Example 58 6.4 68.5 Example 73 83.6 1320 Example 59 4.0 21.2 Example 74 68.7 1340 Example 60 5.4 60.3 Example 75 67.7 1360 Example 61 7.0 61.3 Example 76 77.6 1630 Example 62 5.6 96.6 Example 77 25.1% @ 10 μΜ 1880 Example 63 6.2 25.4 Example 78 823.3 1880 Example 64 7.8 282 Example 79 99.1 1010 Example 65 5.3 62.8 Example 80 299.3 1880 Example 66 4.7 42 Example 81 12.1 778 Example 67 ND ND Example 82 42% @ 10 μΜ 1880 Example 68 8.3 82.4 Example 83 35.8 1500 Example 69 4.6 1.38 Example 84 524.9 ND Example 70 5.2 6.17 Example 85 242.7 ND Example 71 49 ND Example 86 5 20.1

ND: not determined

For partial inhibitors, the percentage inhibition of fluorescence polarization for a given concentration of the test compound is indicated. Thus, 25.1% @ 10 μΜ 5 means that there is 25.1% inhibition of fluorescence polarization for a concentration of test compound equal to 10 μΜ.

EXAMPLE C: Induction of caspase activity in vivo.

The ability of the compounds of the invention to activate caspase 3 is evaluated in an RS4 leukemia cell xenograft model; 11.

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

DUPLICATE

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 results obtained show that the compounds of the invention are capable of inducing apoptosis in RS4; 11 tumor cells in vivo.

EXAMPLE D Quantification of the cleaved form of caspase 3 in vivo.

The ability of the compounds of the invention to activate caspase 3 is evaluated in an RS4 leukemia cell xenograft model; 11.

1.10 RS4 cells; 11 are grafted subcutaneously in immunocompromised mice (SCID strain). 25 to 30 days after the transplant, the animals are treated orally with the different compounds. After the treatment, the tumor masses are collected (after a time T), 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 the invention are able to induce apoptosis in RS4; 11 tumor cells in vivo.

DUPLICATE

-90 Table 2: Caspase activation factors (caspase 3 cleaved MSD test in tumors of treated mice versus control mice) in vivo, after oral treatment (doses specified in brackets)

Compound tested Time after which the tumor is removed (T) Activation factor ± SEM (versus control) Example 2 611 14.6 (50 mg / kg) Example 13 2 hrs 23.1 (50 mg / kg) Example 17 2 hrs 15.3 (50 mg / kg) Example 21 2h 24.8 ± 1.4 (50 mg / kg) Example 32 2 hrs 54.4 ± 2.8 (25 mg / kg) Example 33 2 hrs 31.1 ± 10.8 (25 mg / kg) Example 38 2 hrs 27.5 ± 2.6 (25 mg / kg) Example 39 2h 34.1 ± 2.4 (25 mg / kg) Example 42 2 hrs 77.5 ± 4.8 (25 mg / kg) Example 50 2h 45.2 ± 3.9 (25 mg / kg) Example 56 2 hrs 10.3 ± 4.2 (25 mg / kg)

EXAMPLE E: 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 RS4 cells; 11 are grafted subcutaneously in immunocompromised mice (SCID strain). 25 to 30 days after the transplant, when the tumor mass 10 has reached approximately 150 mm ^J , 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 per week for two weeks). The tumor mass is measured twice a week from the start of treatment.

The results obtained therefore show that the compounds of the invention are capable of inducing significant tumor regression during the treatment period.

DUPLICATE

-91 EXAMPLE F: Pharmaceutical composition: Tablets

1000 tablets containing 5 mg of a compound chosen from Examples 1 to 86 ............ 5g

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

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

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

Magnesium stearate ............................................... .............................................

Silica................................................. .................................................. .....................

Hydroxypropylcellulose ................................................. .........................................

DUPLICATE

Claims (24)

1. Compound of formula (I): r ₃ 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, the Het part of the group represents an optionally substituted ring, aromatic or not , consisting of 5, 6 or 7 links, and may contain. in addition to the nitrogen represented by X or by Y, one to 3 heteroatoms independently selected 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 a linear or branched (Ci-C6) alkyl group. ♦ T represents a hydrogen atom, a linear or branched (Ci-C6) alkyl optionally substituted with one to three halogen atoms, an alkyl group (C2-C4) -NRiR.2, or an alkyl group (C | -C4) -OR ₆ , ♦ Ri and R ₂ represent, independently of one another, a hydrogen atom or a linear or branched (C | -C6) alkyl group, DUPLICATE -93 or R, and R? together with the atom which bears them cl'azote heterocycloalkyl, ♦ R ₃ represents an alkyl (Ci-alkyl) linear or branched, alkenyl (C ₂ -CO) -straight or branched alkynyl (C ₂ -CO) -straight or branched, cycloalkyl, cycloalkyl (C ₃ -Cio) linear or branched (Cj-C6) 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), ♦ R4 represents an aryl, heteroaryl, cycloalkyl or (Cj-C6) linear or branched group, it being understood that one or more carbon atoms of the preceding groups, or of their optional substituents, can ( vent) be deuterated, ♦ R5 represents a hydrogen or halogen atom, a linear or branched (Cj-C'6) alkyl group, or a linear or branched (Cj-C6) alkoxy group, Φ R _ô represents a hydrogen atom or a linear or branched (Cj-C6) alkyl group, ♦ R _a . Rb, R _c and R _d represent independently of each other R ₇ , a halogen atom, a linear or branched (Cj-C6) alkoxy group, a hydroxy group, a linear or branched polyhaloalkyl (Cj-C6) group, a trifluoromethoxy group, -NR7R7 ', nitro, R ₇ -CO-alkyl (Co-C6) -, R ₇ -CO-NH-alkyl (Co-C6) -, NR ₇ R7'-CO-alkyl (Co-C ₆ ) -, NR ₇ R7'-CO-alkyl (Co-C6) -0-, R ₇ -S0 ₂ -NH-alkyl (Co-C ₆ ) -, R ₇ -NH-CO-NH-alkyl (Co -C ₆ ) -, R ₇ -O-CO-NH-alkyl (C ₀ -C ₆ ) -. a heterocycloalkyl group, or else the substituents of one of the pairs (R _a , Rb), (Rb, R _c ) or (R _c , R _d ) together with the carbon atoms which carry them form a ring consisting of 5 7-membered, 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 can be deuterated or substituted by one to 3 groups chosen from halogen or linear or branched (Cj-C6) alkyl, ♦ R7 and R ₇ 'represent, independently of one another, hydrogen, linear or branched (CjC6) alkyl, linear or branched (C ₂ -C6) alkenyl , a linear or branched (C ₂ -C6) alkynyl, an aryl or a heteroaryl, or else R7 and R ₇ 'form together with the nitrogen atom which carries them a heterocycle consisting of 5 to 7 members. Being heard that : DUPLICATE - 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 means 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 1 with 3 heteroatoms chosen from oxygen, sulfur, SO, SO? or nitrogen, the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups which may be substituted with 1 to 3 groups chosen from linear or branched alkyl (Cj-C6) optionally substituted, spiro (C) ₃ -C ₆ ), optionally substituted linear or branched (Cj-C6) alkoxy, (Ci-C6) alkyl-S-. hydroxy, oxo (or TV-oxide where appropriate), nitro, cyano, -COOR ', -OCOR', NR'R ”, linear or branched polyhaloalkyl (Ci-C6), trifluoromethoxy, (C | 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 of one another, a hydrogen atom or an alkyl group (Ci-C6) linear or branched optionally substituted, the Het part of the group defined in formula (I) possibly being substituted by one to three groups chosen from linear or branched (Cj-C6) alkyl, hydroxy, linear or branched (Ci-C6) alkoxy, NR / Rj ”, or halogen, it being understood that Rf 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 an acid or with a pharmaceutically base acceptable. 2. A compound of formula (I) according to claim 1 wherein the group DUPLICATA represents one of the following groups: 5,6,7,8-tetrahydroindolizine optionally substituted with an amino group; indolizine; 1,2,3,4-tetrahydropyrrolo (1,2-a] pyrazine optionally substituted with methyl; pyrrolo [1,2-iz] pyrimidine. 3. Compound of formula (I) according to claim 1 or 2 wherein T represents a hydrogen atom, a methyl group, a 2- (morpholin-4-yl) ethyl, 3 (morpholin-4-yl) propyl group. , -CH2-OH, 2-aminoethyl, 2- (3,3-difluoropiperidin-1-yl) ethyl, 2 - ((2,2-difluoroethyl) amino] ethyl or 2- (3-methoxy azetidin-1 -yl )ethyl. 4. Compound of formula (I) according to one of claims 1 to 3 wherein R _a and R _c each represent a hydrogen atom and (Rb, R _c ) together with the carbon atoms which carry them form a 1,3-dioxolane group or 1,4-dioxane group, or else R _a , R _c and Ra each represent a hydrogen atom and Rb represents a hydrogen, a halogen, a methyl or a methoxy, or else R _a , Rb and Rd each represent a hydrogen atom and R _c represents a hydroxy or methoxy group. 5. Compound of formula (I) according to one of claims 1 to 4 wherein R4 represents a 4-hydroxyphenyl group. 6. Compound of formula (I) according to one of claims 1 to 5 in which R ₃ represents a linear (Ci-C6) alkyl, aryl or heteroaryl group, the latter two groups possibly being substituted with one to three groups chosen from halogen, linear or branched (Cj-C6) alkyl, linear or branched (Cj-C6) alkoxy and cyano. 7. Compound of formula (I) according to one of claims 1 to 6 wherein R3 represents a heteroaryl group chosen from the following group: 1 / f-indole, 2,3dihydro-l / f-indole, l / Z- indazole, pyridine, l / Z-pyiTolo (2,3-b] pyridine, 1 // - pyrazole, imidazo (l, 2-a] pyridine, pyrazolo [l, 5-i /] pyrimidine, [l, 2, 4] triazolo [1,5-iz] pyrimidine, \ Hpyrazolo [3,4-b] pyridine, all of which may be substituted with a linear or branched alkyl group (Cj-Co). DUPLICATE 8. Compounds of formula (I) according to claim l chosen from the following group: - N- (4-hydroxyphenyl) -3- (6- {[(37?) - 3-methyl-3,4-dihydroisoquinolin-2 (1 H) yl] carbonyl} -l, 3-benzodioxol-5-yl ) -N- {1- [2- (morpholin-4-yl) ethyl] -lZ7-indol-5yl} -5,6,7,8-tetrahydroindolizine-1-carboxamide, - At ⁱ - (4-hydroxyphenyl) -3- (6 - {[(3 _< S) -3- [2- (rnorpholin-4-yl) ethyl] -3,4dihydroisoquinolin-2 (lZiZ) -yl] carbonyl } -l, 3-benzodioxol-5-yl) -ZV-phenyl-5,6,7,8tétraliydroindolizine-1 -carboxamide, - {3-fluoro-4- [2- (morpholin-4-yl) ethoxy] phenyl} -7V- (4-hydroxyphenyl) -3- (6- {[(37?) - 3-methyl-3,4 -dihydroisoquinolin-2 (127) -yl] carbonyl} -1,3-benzodioxol-5yl) indolizine-l -carboxamide, - À ^L (4-hydroxyphenyl) -3- (6 - [[(3Z?) - 3-methyl-3,4-dihydiOisoquinolin-2 (lZZ) - yl] carbonyl} -1,3-benzodioxol-5-yl ) -7V- (pyridin-4-yl) indolizin-1-carboxamide, - À '- (4_hydroxyphenyl) -3- (6 - {[(37?) - 3-methyl-3,4-dihydiOisoquinolin-2 (17 /) yl] carbonyl} -l, 3-benzodioxol-5-yl) -7V- (2-methylpyridin-4-yl) indolizin-lcarboxamide, - / V- (4-hydiOxyphenyl) -3- (6 - {[(3Z?) - 3-methyl-3,4-dihydroisoquinolin-2 (lZZ) yl] carbonyl} -l, 3-benzodioxol-5-yl ) - / V- (1-methyl-1H-pyrrolo [2,3-6] pyridin-5yl) indolizine-1 -carboxamide, - / V- (4-hydroxyphenyl) -3- (6 - {[(3R) -3- [3- (morpholin-4-yl) propyl] -3,4dihydroisoquinolin-2 (lZZ) -yl] carbonyl} - 1,3-benzodioxol-5-yl) - / V-phenyl-5,6,7,8tetrahydroindolizine-1 -carboxamide, - / 7- (2,6-dimethylpyridin-4-yl) - / Y- (4-hydroxyphenyl) -3- (6 - {[(37?) - 3-methyl-3,4dihydroisoquinolin-2 (l / Z ) -yl] carbonyl} -l, 3-benzodioxol-5-yl) indolizine-lcarboxamide, - ZV- (4-hydiOxyphenyl) -3- (6 - {[(3Z?) - 3-methyl-3,4-dihydroisoquinolin-2 (lZ /) yl] cai-bonyl} -l, 3-benzodioxol-5 -yl) -N- (pyridin-4-yl) -5,6,7,8-tetrahydroindolizine- 1-carboxamide, - 3- (5-Chloro-2 - {[(3Z?) - 3-methyl-3,4-dihydroisoquinolin-2 (l / Z) -yl] carbonyl} phenyl) / V- (4-hydroxyphenyl) -7 / - (1-methyl-17Y-pyriOlo [2,3-6] pyridin-5-yl) indolizin-lcarboxamide, - / V- (4-Hydroxyphenyl) - / V- (2-methoxypyridin-4-yl) -3- (6 - {[(37?) - 3-methyl-3,4dihydroisoquinolin-2 (lZ /) - yl ] carbonyl} -l, 3-benzodioxol-5-yl) indolizin-1carboxamide, their enantiomers and diastereomers, as well as their addition salts with an acid or with a DUPLICATE Pharmaceutically acceptable base. 9. Process for preparing the compounds of formula (I) according to claim 1, characterized in that the starting product is the compound of formula (II): 5 in which R _a . Rb, R _c and R _d are as defined in formula (I), a compound of formula (II) which is subjected to a Heck reaction, in aqueous or organic medium, in the presence of a palladium catalyst, of a base, a phosphine and the compound of formula (III): in which the groups X, Y and Het are as defined in formula (I), to obtain the compound of formula (IV): DUPLICATE -98Ο ^R c in which R _a . Rb, R _c , Rd, X, Y and Het are as defined in formula (I), a compound of formula (IV) whose aldehyde function is oxidized to carboxylic acid to form the compound of formula (V): in which R _a , Rb> Rc, Rd, X, Y and Het are as defined in formula (I), compound of formula (V) which then undergoes peptide coupling with a compound of formula (VI): (VI) Wherein T and R5 are as defined in formula (I). DUPLICATE -99 to lead to the compound of formula (VII): in which R _a , Rb, R _c , Rd, T, Rs, X, Y and I-Iet are as defined in formula (1), compound of formula (VII) in which the ester function is hydrolyzed to lead to l 'carboxylic acid or the corresponding carboxylate, which can be converted to an acid derivative such as acyl chloride or the corresponding anhydride, before being coupled with an amine NHR3R4, in which R3 and R4 have the same meaning than in formula (I), to lead to the compound of formula (I), compound of formula (I) which can be purified according to a conventional separation technique, which is converted, if desired, into its salts d addition to an acid or to a pharmaceutically acceptable base and from which the isomers are optionally separated 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. ) synthetic reagents or intermediates can be protected and then deprotected for the purposes of synthesis. 10. Preparation process according to claim 9 of a compound of formula (I) in which one of the groups R3 or R4 is substituted by a hydroxyl function, characterized in that the amine NHR3R4 is previously subjected to a protection reaction. of the hydroxy function before any coupling with the carboxylic acid of the compound of formula (VII), or with one of the corresponding acid derivatives, the protected compound of formula (I) DUPLICATE - The resulting 100 then undergoes a deprotection reaction and is optionally converted into one of its addition salts with a pharmaceutically acceptable acid or base. 11. Pharmaceutical composition containing a compound of formula (I) according to any one of claims 1 to 8 or one of its addition salts with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients. 12. A pharmaceutical composition according to claim 11 for its use as a pro-apoptotic agent. 13. Pharmaceutical composition according to claim 11 for its use in the treatment of cancers, autoimmune diseases and the immune system. 14. Pharmaceutical composition according to claim 11 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's lymphoma, melanoma, hematologic malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. 15. Use of a pharmaceutical composition according to claim 11 for the manufacture of a medicament useful as a pro-apoptotic agent. 16. Use of a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment of cancers, autoimmune diseases and the immune system. 17. Use of a pharmaceutical composition according to claim 11 for the manufacture of a medicament intended for 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. esophagus, liver, lymphoblastic leukemia, non-Hodgkin's lymphoma. DUPLICATE - ΙΟΙ melanoma, hematologic malignancies, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. 18. Compound of formula (I) according to one of claims 1 to 8, or one of its addition salts with an acid or a pharmaceutically acceptable 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 the ovary, non-small cell lung cancer, prostate cancer and small cell lung cancer. 19. Use of a compound of formula (I) according to one of claims 1 to 8, or one of its addition salts with an acid or a pharmaceutically acceptable 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, hematologic malignancies , myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. 20. Association of a compound of formula (I) according to any one of claims 1 to 8 with an anti-cancer agent chosen from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors. or antibodies. 21. A pharmaceutical composition containing a combination according to claim 20 in combination with one or more pharmaceutically acceptable excipients. 22. Combination according to claim 20 for its use in the treatment of cancer. DUPLICATE - 102- 23. Use of a combination according to claim 20 for the manufacture of a medicament useful in the treatment of cancer. 24. A compound of formula (I) according to any one of claims 1 to 8 for its use in combination with radiotherapy in the treatment of cancer.