OA16963A - New indolizine derivatives, their preparation process and pharmaceutical compositions containing them. - Google Patents

Abstract

Compounds of formula (I): in which Ra, Rb, Rc, Rd, R1, R2, R3, R4, R5, X, Y and H and are as defined in the description. Medicines.

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 which will degrade key structural components of the cell. to 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 BcI-2 family are associated with numerous pathologies. The involvement of proteins of the Bcl-2 family is described in many types of cancer, such as colorectal cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, cancer. bladder, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, follicular lymphoma, myeloma, prostate cancer ... Overexpression of antiapoptotic proteins of the Bc! -2 family is involved in tumorogenesis, resistance to chemotherapy and the clinical prognosis of cancer patients. So there is

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

The compounds of the present invention, in addition to their novelty, exhibit proapoptotic properties making it possible to use them in pathologies involving a defect in apoptosis, such as, for example, in the treatment of cancer, immune and autoimmune diseases.

The present invention relates more particularly to the compounds of formula (I):

(1)

in which :

♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they cannot simultaneously represent two carbon atoms or two nitrogen atoms, Z \ ♦ the Het part of the group represents an optionally substituted ring, aromatic or not, consisting of 5, 6 or 7 members, and may contain, in addition to the nitrogen represented by X or by Y, one to 3 heteroatoms chosen independently from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question can be substituted by a group representing a hydrogen atom,

DUPLICATE a linear or branched alkyl (Cj-Ce) group or a -C (O) -O-Alk group in which Alk is a linear or branched alkyl (Cj-Ce) group, ♦ Ri and R ₂ independently represent one on the other hand, a hydrogen atom or a linear or branched alkyl group (CpCe), or else R 1 and R _2, together with the nitrogen atom which carries them, form a heterocycloalkyl consisting of 4 to 7 members and which may contain, in addition to the nitrogen atom, another heteroatom chosen from oxygen, sulfur, SO ₂ and NR in which R represents a hydrogen atom, a linear or branched alkyl group (C | -Ce), a group (C | -Ce) alkylsulfonyl, a linear or branched polyhaloalkyl (Ci-Ce) group, or a -C (O) -O-Alk group in which Alk is a linear or branched (Cj-Cê) alkyl group, ♦ R ₃ represents alkyl (Cj-Ce) -straight or branched, alkenyl (C ₂ -This), alkynyl (C ₂ -This), cycloalkyl, cycloalkyl (C4-Cjo) alkyl (Ci-Ce) linear or branched, aryl or heteroaryl, ♦ R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched (Ci-Cè) alkyl group, ♦ R5 represents a hydrogen or halogen atom, ♦ R ,. Rt, R "and R <j represent, independently of each other, a hydrogen atom, a halogen atom, a linear or branched alkyl (CpCe) group, a linear or branched (Cj-C6) alkoxy group, a group hydroxy, a linear or branched polyhaloalkyl (C 1 -Cé) group, or a trifluoromethoxy group, or else the substituents of one of the pairs (R ₈ , Rb), (Rb, R “) or (Rc, Rd) form together with the carbon atoms which carry them, a ring consisting of 5 to 7 members, which may contain from one to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing an atom of hydrogen, a linear or branched alkyl (C | C $) group or a -C (O) -O-Aïk group in which Alk is a linear or branched (Cj-Ce) alkyl group, it being also understood that a or several carbon atoms of the previously defined cycle can be deuterated, it being understood that:

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-4 by aryl means a phenyl, naphthyl, biphenyl or indenyl group, by heteroaryl ”means any mono or bî-cyclic group consisting of 5 to 10 members, having at least one aromatic part, and containing from 1 to 3 heteroatoms chosen from oxygen, sulfur or nitrogen, "cycloalkyl" means any non-aromatic carbocyclic group, mono or bi-cyclic, containing 4 to 10 members, the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined which can be substituted by 1 to 3 groups chosen from optionally substituted linear or branched (Ci-C6) alkyl, spiro (Cî-Ce), linear or branched (C | -C ₆ ) alkoxy, (C | 10 C ₆ ) alkyl-S-, hydroxy, oxo (or A-oxide where appropriate), nitro, cyano, -COOR ', NR'R ”, linear or branched polyhaloalkyl (Ci-C6), trifluoromethoxy, (Ci-C6) alkylsulfonyl or halogen, it being understood that R' and R ”represent, independently of one another, a hydrogen atom or a linear (C | -Ce) alkyl group re or branched, the Het part of the group defined above possibly being substituted by a group chosen from linear or branched (Cj-Cé) alkyl, hydroxy, NR / R 1 ”, or halogen, it being understood that Rf and Rf 'have the same definitions as the groups R ′ and R ″ mentioned above, their enantiomers and diastereomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartric, maleic, citric, ascorbic, oxalic, methane acids 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: s—

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-5 represents one of the following groups: 5,6,7,8-tetrahydroindolizine optionally substituted by a hydroxy, indolizine, l, 2,3,4-tetrahydropyrrolo [l, 2-a] pyrazine, 3,4dihydropyrrolo [l, 2-a] pyrazine-2 (lZ /) - / ert-butyl carboxylate, 3,4-dihydro-lHpyrrolo [2, lc] [l, 4] oxazine, 2,3-dihydro-l // - pyrrolizine optionally substituted with a hydroxy, 6,7,8,9-tetrahydro-5H-pyrrolo [1,2-a] azepine or pyrrolo [1,2-a] pyrazine.

In the preferred compounds of the invention, Rj and R ₂ each represent an alkyl group optionally substituted with a methoxy, or else R | and R ₂ form, with the nitrogen atom which carries them, a heterocycloalkyl chosen from the following groups: morpholine optionally substituted by one or more linear or branched (C | -Cb) alkyl (s), oxidomorpholine , thiomorpholine 1,1-dioxide, 1,4-oxazepane, 3-methoxypyrrolidine, 3,3difluoropyrrolidine, 3-methoxyazetidine, 3-fluoroazetidine, oxopiperazine or piperazine, the last two groups being substituted by a linear alkyl group (Cj-Cb) or branched, linear or branched polyhaloalkyl (Cj-Cè) or methylsulfonyl.

Preferably, R _a and each represent a hydrogen atom and (Rt>, Rc) together with the carbon atoms which bear them form a 1,3-dioxolane group in which one of the carbon atoms is optionally deuterated, a 1,4-dioxane group, 1,4-oxepane group, or alternatively R _a , R "and Rj each represent a hydrogen atom and Rb represents a halogen, a methyl, a methoxy, an ethoxy, a trifluoromethyl or a trifluoromethoxy.

The preferred R4 group is 4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl or 5hydroxypyrimidine.

In preferred compounds, R3 represents a group selected from phenyl, indole, indoline, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, indane, Hindazole, 1H-pyrrolo [ 2,3-Z>] pyridine, pyrimidine, cyclobutylmethyl, cyclopropylmethyl,

H-pyrazole, pyridine, pyridazine, these groups optionally comprising one or more substituents chosen from halogen, linear or branched (C 1 -Cb) alkyl, cyano or

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-6alkoxy (CpCe) linear or branched.

Preferred compounds of the invention are listed below:

- 7V- (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholÎnylmethyl) -3,4-dihydro-2 (1 //) isoquinolinyl) carbonyl] -l, 3-benzodioxol -5-yl} -7V-phenyl-5,6,7,8-tetrahydro-lindolizine carboxamide,

- 3- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (lZ /) - isoquinolinyl) carbonyl] phenyl) -7V- (4-hydroxyphenyl) -2V- (1-methyl-1 // - indol-5-yl) -5,6,7,8tetrahydro-1 -indolizine carboxamide,

- y- (4-hydroxyphenyl) -M (1-methyl-1 H-indazol-5-yl) -3- {2,2-dideuterio-6 - [((3S) -3 (4-morpholinylmethyl) -3 , 4-dihydro-2 (lZ /) - isoquinolinyl) carbonyl] -l, 3benzodioxol-5-yl} -5,6,7,8-tetrahydro-1 -indol izine carboxamide,

- M- (4-hydroxyphenyl) -y- (1-methyl-1H-indazol-5-yl) -3- (6 - {[(3S ') - 3- (morpholin-4ylmethyl) -3,4-dihydroisoquinolin -2 (1 //) - yl] carbonyl} -1, 3-benzodioxol-5-yl) 5,6,7,8-tetrahydroindolizine-1-carboxamide,

- V- (4-hydroxyphenyl) -3- {7 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (l /) isoquinolinyl) carbonyl] -2,3-dihydro- 1,4-benzodioxin-6-yl} -jV-phenyl-5,6,7,8tetrahydro-1-indolizine carboxamide,

- M- (4-hydroxyphenyl) -W- (1 -methyl-1 H-indol-5-yl) -3- {6 - [((3S) -3 - [(4-methyl-1 piperazinyl) methyl] -3,4-dihydro-2 (1W) -isoquinolinyl) carbonyl] -l, 3-benzodioxol-5yl} -l-indolizine carboxamide,

- N- [4- (hydroxy) phenyl] -N- (1-methyl-1H-indol-5-yl) -3- {6 - [((3S ') - 3- (4-morpholinyl methyl) - 3,4-dihydro-2 (lZ /) - Îsoquinolinyl) carbonyl] -l, 3-benzodioxol-5-yl} -5,6,7,8tétrahydro-1-indolizine carboxamide,

- y- (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (lZ /) isoquinolinyl) carbonyl] -l, 3-benzodioxol- 5-yl} -? / - phenyl-1-indolizine carboxamide,

- 3 - {5-chloro-2 - [((3S) -3 - (4-morphol inylmethyl) -3,4-dihydro-2 (1H) isoquinolinyl) carbonyl] phenyl) -y- (4-hydroxyphenyl) - / V- (1 -methyl-1/7-indol-5-yl) 1-indolizine carboxamide,

- 6- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (l / 7) -isoquinolinyl) carbonyl] phenyl} -2V- (3-fluoro -4-methylphenyl) -N- (4-hydroxyphenyl) -3,4-dihydro-

H-pyrrolo [2,1 -c] [1,4] oxazine-8-carboxamide,

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-7- 3 - (5 -chl oro-2- {[(3S) -3 - (morpholi n-4-y lméthy 1) -3,4-dihy droisoqui nol i n-2 (1H) yljcarbony l} phenyl ) -jV- (4-hydroxyphenyl) -jV- (1 -methyl-1 H-pyrazol-4-yl) -5,6,7,8tetrahydroindolizine-1-carboxamide,

- A ^r - (3-fluoro-4-methylphenyl) -A ^r - (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4- morpholinylmethyl) -3,4-dihydro-2 ( l H) -isoquinolinyl) carbonyl] -l, 3-benzodioxol-5yl} -5,6,7,8-tetrahydro-l-indolizine carboxamide,

- jV- [4- (hydroxy) phenyl] -M (1-methyl-2,3-dihydro-1W-Indol-5-yl) -3- {6 - [((3S) -3- (4morpholinylmethyl) - 3,4-dihydro-2 (1 H) -isoquinolinyl) carbonyl] -l, 3-benzodioxol-5yl} -5,6,7,8-tetrahydro-l-indolizine carboxamide,

- 3- {5-chIoro-2 - [((3S) -3 - (4-morpholinylmethyl) -3,4-dihydro-2 (1 H) isoquinolinyl) carbonyl] phenyl} -A ^r - (4-hydroxyphenyI) -A ^r - (l-methyI-2,3-dihydrolH-indol-5-yl) -5,6,7,8-tetrahydro-l-indolizine carboxamide,

- A ^r - (4-hydroxyphenyl) -A ^r - (1-methylI-1H-indol-5-yI) -3- (6 - [((3S) -3- (4morpholinylmethyl) -3,4-dihydro- 2 (1H) -isoquinolinyl) carbonyl] -1, 3-benzodioxol-5-yl} -l-indolizine carboxamide,

- 3- {5-chloro-2 - [((3S) -3- (4-morpholÎnylmethyl) -3,4-dihydro-2 (1H) -isoquinormyl) carbonyl] phenyl} -jV '(4-hydroxyphenyl) - jV- (1-methyl-2,3-dihydro-lW-indo! -5-yl) -lindolizine carboxamide,

- 6- {5-chIoro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (IH) -isoquinolÎnyl) carbonyljphenyl} -jV- (4-hydroxyphenyl) - / V -pheny! -3,4-dihydro-1 H-pyrrolo [2, l -

c] [1,4] oxazi ne-8-carboxami de,

- A ^r - (3-fluorophenyl) -A ^r - (4-hydroxyphenyl) -3- (6 - {[(3S) -3- (morphoIin-4-ylmethyl) -

3,4-dihydroïsoqui nolin-2 (1 H) -y ljcarbonyl} -1,3-benzodioxol-5-yl) -5,6,7,8tetrahydroindolizine-1 -carboxamide, their enantiomers and diastereomers, as well as their salts of addition to a pharmaceutically acceptable acid or 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:

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Rc in which R., Rb, Rc and Rd 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 catalyst with palladium, 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):

\

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

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(V) in which Rg, Rt, Rc, R <t, X, Y and Het are as defined in formula (I), compound of formula (V) which then undergoes peptide coupling with a compound of formula (Vl ):

where Rt, R ₂ , and R; are as defined in formula (I), to lead to the compound of formula (VII):

(VH)

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-ίο in which R ,, Rb, Rc, R <j, Ri, R ₂ , Rj.X, Y and Het are as defined in formula (I), compound of formula (Vil) whose ester function is hydrolyzed for lead to the carboxylic acid or the corresponding carboxylate, which can be converted into an acid derivative such as acyl chloride or the corresponding anhydride, before being coupled with an amine NHR3R4, in which 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 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 ...) reagents or synthesis intermediates can be protected and then depro tegés for the needs of the synthesis.

More particularly, when one of the groups R3 or R ”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 with an acid. pharmaceutically acceptable base.

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

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

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-π More particularly, the compounds according to the invention will be useful in the treatment of chemo or radioresistant cancers, as well as in hematologic malignancies and small cell lung cancer.

Among the cancer treatments contemplated there may be mentioned, but not limited to, cancers of the bladder, brain, breast, uterus, chronic lymphoid leukemias, colorectal cancer, cancers of the esophagus, liver, lymphoblastic leukemias, follicular lymphomas, melanomas, hematologic malignancies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer .

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

Among the pharmaceutical compositions according to the invention, there may be mentioned, more particularly those which are suitable for oral, parenteral, nasal, per 15 or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or sugar-coated tablets, tablets. sublinguals, sachets, packets, capsules, glossettes, tablets, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.

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

Furthermore, the present invention also relates to the association of a compound of formula (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 a

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-12radiotherapy in the treatment of cancer.

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

Preparation 1 ô-fl-IIIiiiiethoxycarbonyl-S6 / β-tetrahydro-S-indolizinyl] 13-benzodioxole-5-carboxylic acid

Stage A: 1-Formyl-2-plperldine carboxylic acid

To a solution of 40 g of a racemic mixture of 2-piperidine carboxylic acid (0.310 mmol) in 300 ml of formic acid placed at 0 ° C, is added dropwise 200 ml (2.15 mmol) of acetic anhydride. The whole is then stirred at room temperature overnight. Then, the reaction medium is cooled to 0 ° C, hydrolyzed by the addition of 250 mL of water, and stirred for half an hour at 0 ° C before being concentrated to dryness. The oil thus obtained is taken up in 200 mL of methanol and then concentrated to dryness. The title product is obtained in the form of an oil with a yield of 98%. It is used directly, without further purification, for the next step.

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

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

Stage B15,6,7,8-Tetrahydro-1-! Ndolizine methyl carboxylate

To a solution of 10 g of carboxylic acid obtained in Stage A (63.6 mmol) in 65 mL of dichloroethane are successively added 13.4 g of tosyl chloride (70.4 mmol),

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

The reaction medium is then diluted with methylene chloride, washed successively

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-13with IN HCl solution, saturated NaHCO3 solution, then saturated NaCl solution until neutral pH is obtained. The organic phase is then dried over MgSO4, 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 (400 MHz; CDCl 3; 300 ° K): 6.55-6.40 (d, 2H, tetrahydroindolizine); 3.91 (t, 3H methyl ester); 3.78 (s, 3H tetrahydroindolizine); 3.08 (t, 2H, tetrahydroindolizine);

1.95-1.85 (m, 4H, tetrahydroindolizine)

IR: v:> C = O 1692 cm ' ¹ ester

Stage C - methyl 3- (6-Formyl-1,3-benzodioxol-5-yl) -5,6,7,8-tetrahydro-l-lndolizine carboxyate

To a solution of 6.4 g of the ester obtained in Stage B (35.7 mmol) in 12 mL of Ν, Ν dimethylacetamide, 12.3 g of 6-bromo-1,3-benzodioxole-5carbaldehyde are successively added (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 PdCl ₂ (PPhj) 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 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: Ô: (400 MHz; dmso-d6; 353 ° K): 9.65 (s, 1H, H aldehyde); 7.3-7.15 (2s, 2H,

Aromatic H); 6.45 (s, 1H tetrahydroindolizine); 6.20 (s, 2H methylenedioxy); 3.70 (s,

3H methyl ester); 3.5-4.0 (m, 2H tetrahydroindolizine); 3.05 (m, 2H tetrahydroindolizine); 1.85 (m, 4H tetrahydroindolizine)

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

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- 14 Stage D: 6- [1- (Methoxycarborty 1) -5,6,7,8-tetrahydro-3-indolizinylj-1,3benzodioxo! E-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 NaC10 ₂ (36.05 mmol) and 3.6 g of Na ₂ PO4 (25.75 mmol) are added dropwise. The whole is then stirred at room temperature for 7 hours. Then, the reaction medium is concentrated in order to remove the acetone. The solid thus obtained is filtered, washed with water and then dried under vacuum at 40 ° C. overnight. The title product is obtained in the form of a solid, which is used for the following without further purification.

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

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

Preparation 2 4-Bromo-2- [1- (niethoxycarbonyl) -5,6,7,8-tetrahydro-3Indoliziny I] benzoic acid

The procedure is carried out according to the process of Preparation 1, replacing the 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C by 2,4-dibromobenzaldehyde. A mixture of two regioisomers is obtained which are separated by chromatography.

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

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

Preparation 4: 4-Fluoro-2- | 1- (methoxycarbony |) -5,6,7,8-tetrahydro-3indollzinyl] benzoic acid

We proceed according to the method of Preparation 1, replacing 6-bromo-l, 3DUPL1CATA

-15benzodioxole-5-carbaldehyde used in Stage C by 2-bromo-4-fluorobenzaldehyde.

Preparation 5: 8- [1- (Methoxycarbonyl) -5,6,7,8-tetrahydro-3-indolizinylj-3,4dihydro-2 // - 1,5-benzodioxepin-7-carboxylic acid

The procedure of Preparation 1 is carried out by replacing the 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C by 8-bromo-3,4-dihydro-2H-1,5benzodioxepine-7-carbaldehyde.

Preparation 6; 4-Methoxy-2- [1- (methoxycarbonyl) -5,6,7,8-tetrahydrO’3indolizinyljbenzoic 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-methoxybenzaldehyde.

Preparation 7: 7- [1 »(Methoxycarbonyl) -5,6,7,8-tetrahydro-3-indolizinylj-23 · dihydro-1,4-benzodioxin-6-carboxylic acid

The procedure is carried out according to the method of Preparation 1, replacing the 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C by 7-bromo-2,3-dihydro-1,4benzodio xine-6-carbal de hyde.

Preparation 81 4-Ethoxy-2 »[1- (methoycarbonyl) -5,6,7,8-tetrahydro-3indolizinylbenzoic acid

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

Preparation 9: 1 ^ -dideuterio-6-ll-imethoycarbonylI-Sjo ^^ - tetrahydro-Sindolizinyl] -13 * benzodioxole-5-carboxylic acid

Stage A; 2,2-Dideuterio-1,3-benzodioxole-5-carbaldehyde

To a solution of 30 g of 3,4-dihydroxy benzaldehyde (217 mmol) in 110 mL of anhydrous DMF, 114 g of cesium carbonate (347 mmol) and 22 mL of dideuterated methylene chloride (347 mmol) are successively added. The reaction medium is then stirred at ambient temperature overnight. After filtration through Celite of the insoluble matter, the filtrate

DUPLICATE

The residue is then hydrolyzed by adding 200 mL of water, then extracted with ethyl acetate. The organic phases are then combined, washed with a saturated solution of LÎC1, then dried over MgSO4. After concentration to dryness, the residue is purified by chromatography on silica gel (petroleum ether / AcOEt gradient). The title product is obtained as a solid.

1 H NMR: δ: (400 MHz; dmso-d6; 300 ° K): 9.8 (s, 1H, H aldehyde); 7.4-6.95 (m, 3H, aromatics)

IR: v: C = O aldehyde: 1670 cm ' ¹

Stage B. 6-Bromo-2,2-dideuterio-1,3-benzodioxole-5-carbaldehyde

To a solution of 10 g of the compound obtained in Stage A (65.7 mmol) in 100 mL of methanol cooled to 0 ° C, 3.7 mL of a bromine solution (1.1 molar equivalent) is added dropwise. in 10 mL of methanol. The whole is then stirred at room temperature overnight. The reaction medium is concentrated to dryness, then taken up in water. After stirring, the resulting solid is then filtered and then dried.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 10.2 (s, 1H, H aldehyde); 7.4 (s, 1H, aromatic H); 7.05 (s, IH, aromatic H)

IR: v: C = O aldehyde: 1670 cm- ¹ ; C = C aromatics: 1611 cm ' ¹

Stage C: 2,2-Dideuterio-6- [1- (methoxycarbonyl) -5,6,7,8-tetrahydro-3-indo! Izinyl] 1,3-benzodioxole-5-carboxylic acid

One proceeds according to the protocol described in Stages C and D of Preparation 1, replacing the 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Stage C by 6-bromo-2,2dideuteri ο-1,3 - benzodi oxole-5 -carbal dehyde.

Preparation 10; 2-] 1- (Methoxycarbonyl) -5,6,7,8-tetrahydro-3-indolizinyl] -4 (trifluoromethyl) benzoic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing 6-bromo-1,3benzodioxole-5-carbal dehyde used in Stage C by 2-bromo-4 (trifluoromethyl) benzaldehyde.

DUPLICATE

-17 Preparation 11: 2- [1- (methoxycarbony!> 5,6,7,8-tetrahydro-3-indo! Izinyl] -4 (trifluoromethoxy) benzoic acid

The procedure is carried out according to the protocol described in Preparation I, replacing 6-bromo-l, 3benzodioxole-5-carbaIdehyde used in Stage C by 2-bromo-4 (tri fluoro methoxy) benzal dehy.

Preparation ______ 12: 2- [1- (methoxycarhonyl) -5,6,7,8-tetrahydro-3indolizinyljhenzoic acid

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

Preparation 13; 6- [1- (Methoxycarhonyl) -3-indolizinyl] -13-henzodioxole-5carhoxylic acid

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

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

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

Stage B: Methyl 1-Indo! Izinecarboxylate

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 MnO2 (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.

DUPLICATE

-18 on silica get (heptane / AcOEt gradient: 0-10%) in the form of an oil which crystallizes in the cold.

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

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

Stage C: 6- [1- (methoxycarbonyl) -3-indolizinyl] -l, 3-benzodioxole-5-carboxylic acid

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

Preparation 14; 4-Chloro-2- | 1- (methoxycarbonyl) -3-indolizinyl] benzoic acid

Methyl 1-indolizinecarboxylate is formed according to the process described in Steps A and B of Preparation 13. The title product is then obtained according to the protocol described in Steps C and D of Preparation 1, replacing 6-bromo-1 , 3-benzodioxole-5carbaldehyde used in Stage C by 2-bromo-4-chlorobenzaldehyde.

Preparation 15 7- [1- (Methoxycarbonyl) -3-indolizinyl] -23-dihydro-1,4benzodioxlne-6-carboxylic acid

Methyl 1-indolizinecarboxylate is formed according to the process described in Steps A and B of Preparation 13. The title product is then obtained according to the protocol described in Steps C and D of Preparation 1, replacing 6-bromo-1 , 3-benzodioxole-5carbaldehyde used in Stage C by 7-bromo-2,3-dihydro-l, 4-benzodioxine-6carbaldehyde.

Preparation 16; 4-Methoxy-2- [1- (methoxycarbonyl) -3-Indolizinyl] benzoic acid

Methyl 1-indolizinecarboxylate is formed according to the process described in Steps A and B of Preparation 13. The title product is then obtained according to the protocol described in

Steps C and D of Preparation 1, replacing the 6-bromo-1,3-benzodioxote-5carbaldehyde used in Step C by 2-bromo-4-methoxybenzaldehyde.

DUPLICATE

- 19Preparation 17: Acid 6-I2 - (/ ert-butoxycarbonyl) -8- (methoxycarbonyl) -133,4tetra hy dropy rro lo [1,2-a] py razin -6-y I] -13-benzodioxo le- 5-ca r boxy lîque

Stage A - 1-tert-butyl 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 successively added in portions and 12 mL of formic acid (312 mmol). The whole is stirred at room temperature for 2 hours. Then a mixture of 32 g of 1-rerr-butyl and 3-methyl 1,3-piperazinedicarboxylate (130 mmol) and 18 mL of triethylamine (130 mmol) in solution in 520 mL of CH2Cl2 is added. 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 saturated aqueous NaHCCh solution, then with saturated aqueous NaCl solution until neutral. After drying over MgSOi, 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 as an oil.

IR. V: C = O: 1674-1745 cm ¹ m / z (C ₁₂ H2oN ₂ O _s ): 272.1 (M +); 295,121 (M + Na) ⁺ ; 567.253 (2M + Na) ⁺

Stage B: lithium 4- (tert-Butoxycarbonyl) -1-formyl-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 H ₂ O are added. 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 in the form of a solid and is used directly for the next cyclization step.

¹³ C NMR: δ (500 MHz; dmso-d6; 300 ° K): 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

DUPLICATE

-20stage C; 3,4-Dihydropyrrolo [1,2-a [pyrazine-2,8 (1H) -dicarboxylate 2-tert-butyl 8-methyl

To a suspension of 29 g of the compound obtained in Stage B (103 mmol) in 800 mL of dichloroethane, 24 g of tosyl chloride (124 mmol), 12.6 mL of methyl 2-chloroacrylate (124 mmol) are added successively, then 35 mL of triethylamine (247 mmol). The whole is stirred at reflux for 2 hours. After cooling, the reaction medium is diluted with ethyl acetate and the organic phase is washed with saturated NaCl solution until neutral. After drying over MgSO4, 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.

H NMR: δ (400 MHz; dmso-d6; 300 ° K): 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 'Bu).

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

Stage D: Acid 6- [2- (tert-butoxycarbonyl) -8- (methoxycarbonyl) -l, 2,3 _y 4tetrahydropyrrolo [1,2-a [pyrazin-6-yl [-l, 3-benzodioxole-5- carboxylic

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

Preparation 18; 6- [7- (Methoxycarbonyl) -23-dihydro-177-pyrroIizin-5-yl] -13benzodioxole-5-carboxylic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing the 2-piperidine carboxylic acid used in Stage A by the proüne.

Preparation 19; 4-Chloro-2- [7- (methoxycarbonyi) -23-dihydro-1H-pyrrolizin- acid

5-yl | benzoic

The procedure is carried out according to the protocol described in Preparation 1, replacing the 2-piperidine carboxylic acid used in Stage A by proline, while the 6-bromo-l, 3-benzodioxole-5carbaldehyde used in Stage C is replaced by 2 -bromo-4-chlorobenzaldehyde.

DUPLICATE

-21 Preparation 20: 4-Chloro-2- [8- (inethoxycarbonyl) -3,4-dihydro-1H ^: -pyrrolo [2, lc] 11,4] oxazin-6-y I] benzoic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing 2-piperidine carboxylic acid with 3-morpholinecarboxylic acid, while 6-bromo-1,3-benzodioxole-5-carbaldehyde used in Stage C is replaced by 2-bromo-4chlorobenzaldehyde.

Preparation 21: 6- [8- (Methoxycarbonyl) -3,4-dihydro-1H-pyrrolo | 2, lc] | 1,4 | oxazin-6-yl | -13-benzodioxo! E-5-carboxylic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing 2-piperidine carboxylic acid with 3-morpholinecarboxylic acid.

Preparation 22: 4-Chloro-2- | 1- (methoxycarbonyl) -6,7,8,9-tetrahydro-5 / Jpyrrolo] 1,2-a | azepin-3-yl] benzoic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing 2-piperidine carboxylic acid with 2-azepanecarboxylic acid, while the 6-bromo-l, 3-benzodioxole-515 carbaldehyde used in Stage C is replaced by the 2-bromo-4-chlorobenzaldehyde.

Preparation 23 - 6- | 1- (Methoxycarbonyl) -6,73,9-tetrahydro-5 // - pyrrolo | l ^ a] azepin-3-yl] -13-benzodioxol-5-carboxylic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing 2-piperidine carboxylic acid with 2-azepanecarboxylic acid.

Preparation 24: 4-Chloro-2-I3- (methoxycarbonyl) -5,6,7,8-tetrahydro-lindolizinyl acid | benzoic

Stage A: methyl l ~ (4-bromobutyl) -1H-pyrrole ~ 2-carboxy! Ate

To a suspension of 6.7 g (241.7 mmol) of NaH (60%) in 400 mL of anhydrous THF placed at 0 ° C, 20 g (161.13 mmol) of 1 // - pyrrole-2-carboxy! Ate are added. methyl (see

Tetrahedron 2008, 64, 7745). The whole is stirred at room temperature for one hour. Then, 95 mL of 1,4-dibromobutane is added. After addition, the reaction is heated at reflux for 12 h. The precipitate obtained is filtered off and then washed with THF. The

DUPLICATE

-22filtrate is then concentrated to dryness. The compound is then isolated by chromatography on silica gel (cyclohexane / ethyl acetate gradient: 0 to 20%) in the form of an oil.

Elemental microanalysis:

%VS % H %NOT % Br Calculated 46.17 5.42 5.38 30.72 Find 46.76 5.56 5.29 30.77

IR: v. · -C = O: 1700 cm- ¹ ; v: COC: 1238 cm ⁴

Stage B: 5,6,7,8-Tetraltydro-3-indolizinecarboxylate methyl

A solution of 8 g (30.8 mmol) of the brominated derivative obtained in Stage A in 700 mL of acetonitrile is brought to reflux. To this is added a solution of a mixture of 25 g of azobisisobutyronitriïe (151 mmol) and 30 g of BujSnH (100 mmol) in 500 mL of toluene. The whole is brought to reflux for 120 h. The reaction medium is then concentrated to dryness. The compound is then isolated by chromatography on silica gel (gradient of cyclohexane / ethyl acetate 5 to 10%) in the form of an oil.

1 H NMR: δ (400 MHz; CDCl ₃ ; 300 ° K): 6.90 (d, 1H, H pyrrole); 5.85 (d, 1H, H pyrrole); 4.30 (t, 2H, CH2 indolizine); 3.80 (s 3H, Me); 2.80 (t, 2H, CH2 indolizine); 1.95 (m, 2H, CH ₂ indolizine); 1.80 (m, 2H, CH2 indolizine)

IR: v: -C = O: 1695 cm ⁴

Stage C: 4-Chloro-2- [3- (methoxycarbonyl) -5,6,7,8-tetrahydro-1-indolizinylJ benzoic acid

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

Preparation 25: 2- [I- (Methoxycarbonyl) -5,6 »7,8-tetrahydroindolizin-3-yl] -4methylbenzoic acid

The procedure is carried out according to the process of Preparation i, replacing the 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C with 2-bromo-4-methylbenzaldehyde.

DUPLICATE

-23 Preparation 26: 4-Flnoro-2- [8- (methoxycarbonyl) -3,4-dihydro-1H-pyrrolo [2, lcj [1,4] oxazin-6-y 1] benzoic acid

The procedure is carried out according to the protocol described in Preparation 1, replacing 2-piperidine carboxylic acid with 3-morpholinecarboxylic acid, while the 6-bromo-1,3benzodioxole-5-carbaldehyde used in Stage C is replaced by 2 -bromo-4fluorobenzaldehyde.

Preparation 27; 4-Fluoro-2- [r- (methoxycarbonyl) -5 ', 6 * -dihydro-8'H-spiro [13dioxolan-2,7'-indolizin] -3'-yl] benzoic acid

Stage A: Methyl 8-Formyl-1,4-dioxa-8-azaspirol4.5Jdecane-7-carboxylate g of methyl 1,4-dioxa-8-azaspiro [4.5] decane-9-carboxylate (111 mmol) are solubilized 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 h. 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, then with a saturated NH ₄ C1 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.

NMR: δ (400 MHz; dmso-d6; 300 ° K): 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, Me); 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 [4.5] decane-7-carboxylic acid

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 add 125 mL of HCl

IM and extract the compound with dichloromethane. The organic phase is dried over

MgSO ₄ , filtered and concentrated to dryness. The title product is obtained in the form of a

DUPLICATE

-24powder.

1 H NMR: 5 (400 MHz; dmso-d6; 300 ° K) 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, H aliphatic 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-spirofl, 3-dioxolane-2 _t 7'-indolizine] -I '-methylcarboxylate

To a solution of 13.5 g (62.7 mmol) of the acid obtained in Stage B in 380 mL of dichloroethane, 39.5 mL (238.4 mmol) of triethylamine are successively added, then by shoveling 12.5 g (65.6 mmol) of para-toluene sulfonyl chloride and 23.7 mL (238.4 mmol) of methyl chloroacrylate. The whole is stirred at 80 ° C. for 18 h. The reaction medium is then filtered through Celite. The filtrate is then washed with a saturated solution of NaHCO ₃ then with a saturated solution of NH4Cl. 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; 300 ° K) 6.70 (d, 1H, pyrrol); 6.40 (d, 1H, pyrrole); 4.05 (t, 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

Stage D: 3 - (5-Fluoro-2-formylphenyl) -5 6 '-dihydro-8' H-spirof1,3-dloxolane-2,7 lndolizinej-l '-carboxylate

The procedure of Stage C of Preparation 1 is carried out, replacing 6-bromo-1.3benzodioxole-5-carbaldehyde with 2-bromo-4-fluorobenzaldehyde.

Stage E: 4-Fluoro-2- [l '- (methoxycarbonyll-S'tô'-dihydroS'ILspîroflfS-dioxolane2,7-lndolizin J-3-yl] benzoic acid

The procedure is carried out according to Stage D of Preparation I.

DUPLICATE

-25 Preparation 28 î 4-Fluoro-2 - [(2R) -2-hydroxy-7- (methoiycarbonyl) -23-diliydro1 H-py rrol ίζίη-5-y 1] benzoic acid

Stage A: (4R) -4 ~ [[tert ~ Butyl (dimethyl) silylJoxy} -L-methyl prolinate

The protection of the alcohol function of methyl (4Æ) -4-hydroxy- £ -prolinate with a rer-butyldimethylsilyl group is carried out according to the protocol described in document WO 2012040242.

Stage B: (4R) -4 - {[tert-Butyl (dimethyl) silyl] oxy} -l-formyl-L-prolinate

13.7 g (52.8 mmol) of Stage A compound are dissolved in 100 mL of acetonitrile. 13.2 g (79.3 mmol) of (4-nitrophenyl) formate and 39 mL (238 mmol) of diisopropylethylamine are added thereto. The whole is stirred at room temperature for 6 hours. The reaction medium is evaporated to dryness and taken up in ethyl acetate. The organic phase is then washed successively with a 1N solution of NaOH, with water and then with a saturated NH4Cl solution until neutral. It is then dried over magnesium sulfate, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (gradient: dichloromethane / ammoniacal methanol). The title product is obtained in the form of an oil.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 8.15 and 8.12 (s, 1H, formyl); 4.62 and 4.25 (t, 1H, H alpha ester); 4.40 (m, 1H, SiOCH,); 3.65 and 3.6 (s, 3H, OMe); 3.5 and 3.3 (m, 2H, 2H proline); 2.12 and 1.95 (m, 2H, 2H proline); 0.8 (s, 9H, Si'Bu); 0.05 (s, 6H, SiMe2). IR: v: C = O ester: 1749 cm- ¹ ; C = O formyl; 1659 cm ' ¹

Stage C: (2S, 4R) -4 - [[tert-Butyl (dimethyl) silylJoxy} -l-formylpyrrolidine-2-carboxylate of lithium

The compound of Stage B (26.2 g; 91.1 mmol) is dissolved in 450 mL of dioxane. A solution of lithine (4.2 g; 100 mmol) in water (90 mL) is added. The whole is stirred at room temperature for 7 hours. The reaction medium is evaporated to dryness and used as it is for the next step.

DUPLICATE

-26Stade D t (2R) -2- {ftert-Biityl (dimethyl) silyl] oxy} -2,3-dihydro-1H-pyrrolizine-7carboxylate methyl

To a solution of 22.4 g (80.2 mmol) of the lithium carboxylate obtained in Stage D in 640 mL of dichloroethane, is added successively 27 mL (192 mmol) of triethylamine, then, per portion, 18 g (96 mmol) of para-toluene sulfonic chloride and 9.7 mL (96.2 mmol) of methyl chloroacrylate. The reaction medium is heated at reflux for 18 h, then cooled and diluted in ethyl acetate. The organic phase is washed with water, brine, before being dried over MgSQ ". After filtration and concentration of the medium, the oil obtained is purified by flash chromatography (gradient: heptane / ethyl acetate). The title product is obtained in the form of an oil.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 6.7 (d, 1H, H pyrrole); 6.4 (d, 1H, H pyrrole); 5.0 (m, 1H, SiOCH,); 4.2-3.75 (ABx, 2H, 2H dihydropyrrolizine); 3.3 + 2.8 (ABx, 2H, 2H dihydropyrrolizine); 3.70 (s, 3H, CO ₂ CH ₃ ); 0.9 (s, 9H, 'Bu); 0.10 (ABx, 6H, SiMe ₂ ) IR: v: -OO (ester): 1701 cm- ¹ ; SiCHj: 1249 cm- ¹ ; Si-0: 1118-1090 cm- ¹ ; Si-C: 835777 cm ' ¹

Stage E: (2R) -2 - {[tert-biityl (dimethyl!) SUy!] Oxy} ~ 5- (5-fluoro-2-formylphenyl) -2,3dihydro-1H-pyrrolizine-7-carboxylate

The procedure is carried out according to the process of Stage C of Preparation 1, replacing 6-bromo-1.3benzodîoxole-5-carbaldehyde with 2-bromo-4-fluorobenzaldehyde.

Stage F: Acid 2 - [(2R) -2 - {[tert-buty! (Dimethyl) silyl] oxy} -7- (methoxycarbony!) - 2,3dihydro-1H-pyrrolizin-5-y!] - 4- fluorobertzoic

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

Preparation 29 • 4-Fluoro-2- | (2S) -2-hydroxy-7- (niethoxycarbonyl) -23'dlhydrolH-pyrrolizin-5-yl acid | benzoic

The procedure is carried out according to the process of Preparation 28, replacing the methyl (4Æ) -4-hydroxy-Lprolinate used in Stage A by methyl (4S> 4-hydroxy-L-prolinate.

DUPLICATE

-27 Preparation 30: 4-Fluoro-2- [7-hydroxy-1- (methoxycarbony!) - 5,6,7,8tetrahydroindo! Izin-3-yl] benzoic acid

The procedure is carried out according to the process of Preparation 27, replacing the 2-bromo-4fluorobenzaldehyde used in Stage D by 6-bromo-1.3-benzodioxole-5-carbaldehyde.

Preparation 31: 6- [8- (Methoxycarbony!) Pyrro! O [1,2-a] pyrazin-6-yl] -l, 3benzodioxol-5-carboxylic acid

Stage A: Pyrrolo [1,2 ~ ajpyrazine ~ methyl 8-carboxylate

To a solution of 10 g (65.7 mmol) of methyl pyrazin-2-ylacetate in 263 mL of anhydrous acetone (4 mL / mmol), 5.7 g of lithium bromide (65.7 mmol) are successively added, 22, 1 g of sodium bicarbonate (263 mmol), then 9.4 mL of chloroacetaldehyde (50% solution in water) (72.6 mmol). The whole is then heated at reflux overnight. The reaction medium is then concentrated to dryness, then taken up in ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness. An oil is obtained which is purified by chromatography on silica gel (CH ₂ Cl ₂ / ethyl acetate gradient). After concentration, the title product is obtained in the form of a solid.

1 H NMR: δ (400 MHz; dmso-d6; 300 ° K): 9.36 (m, 1H, H pyrazine); 8.50 (dd, 1H, H pyrazine)); 7.8 (m, 2H, 1H pyrazine, 1H pyrrole); 7.31 (m, 1H, H pyrrole). 3.88 (s, 3H, OCHj)

IR: v: -C = O (conjugated ester): 1686 cm ' ¹

Stage B: 6 ~] 8- (methoxycarbonyl) pyrroloJI, 2-a] pyrazin-6-yi] -l, 3-benzodioxole-5carboxylic acid

The procedure is carried out according to the methods of Steps C and D of Preparation 1.

Preparation 32: 4-Fluoro-2- [1- (methoxycarbony!) - 3-indoiizinyl] benzoic acid

Methyl l-indolizinecarboxy) ate is formed according to the process described in Steps A and B of Preparation 13. The title product is then obtained according to the protocol described in

DUPLICATE

-28Stages C and D of Preparation 1, replacing the 6-bromo-l, 3-benzodioxole-5carbaldehyde used in Stage C by 2-bromo-4-fluorobenzaldehyde.

Preparation Γ: (3S) -3- (4-Morpholinylméthy!) - 133t4-tetrahydroisoquinoline

Stage A: (3S) -3- (4-Morpholinylcarbonyl) -3,4-dihydro-2 (lII) -isoquinoline carboxylate benzyl

To a solution of 5 g of (3S) -2 - [(benzyloxy) carbonylj-1,2,3,4-tetrahydro-3isoquinolinecarboxylic acid (16 mmol) in 160 mL of dichloromethane are added 1.5 mL of morpholine ( 17.6 mmol), then 9 mL of N, N, JV-triethylamine (64 mmol), 3.3 g of 1ethyl-S-O'-dimethylaminopropylJ-carbodiiniide (EDC) (19.2 mmol), and 2, 6 g of hydroxybenzotriazole (HOBT) (19.2 mmol). The reaction medium is stirred at room temperature overnight, then it is poured into an 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 (dichloromethane / methanol gradient). The product is obtained in the form of a foam.

1 H NMR: δ (400 MHz; dmso-d6; 353 ° K): 7.30 (m, 5H benzyl); 7.15 (m, aromatic 4H); 5.2-5.0 (m, 3H, 2H benzyl, 1H dihydroisoquinoline); 4.75-4.5 (2d, 2H dihydroisoquinoline); 3.55-3.3 (m, 8H morpholine); 3.15-2.9 (2dd, 2H dihydroisoquinoline)

IR: v:> C = O: 1694; 1650cm * ¹

Stage B i (3S) -3- (4-Morpholinyhnethyl) -3,4-dihydro-2 (1H) -lsoquinoline carboxylate benzyl

To a solution of 5.3 g of the product obtained in Stage A (13.9 mmol) in 278 mL of tetrahydrofuran are added 14 mL of BH ₃ Me ₂ S (27.8 mmol) at room temperature. The whole is heated for 4 hours at 80 ° C. Allowed to warm to room temperature and then 7 ml (14 mmol) of BHjMe ₂ S. The reaction mixture is again heated at 80 ° C for 2 hours. The tetrahydrofuran is then evaporated off, then methanol is slowly added, then 5.6 ml of 5N hydrochloric acid (27.8 mmol). The mixture is stirred at

DUPLICATE

-29 room temperature overnight, then at 80 ° C for 1 hour. A saturated NaHCO ₃ solution is then added to the reaction medium at 0 ° C. until a pH = 8 is reached, then extraction is carried out with ethyl acetate. The organic phase is then dried over magnesium sulfate, then filtered and evaporated to dryness. The title product is obtained as an oil.

1 H NMR: δ (400 MHz; dmso-d6; 353 ° K): 7.43-7.30 (solid, 5H benzyl); 7.19 (m, aromatic 4H); 5.16 (m, 2H, 2H benzyl); 4.79-4.29 (d, 2H dihydroisoquinoline); 4.58 (m, 1H dihydroisoquinoline); 3.50 (m, 4H morpholine); 3.02-2.80 (dd, 2H dihydroisoquinoline); 2.42-2.28 (solid, 5H, 4H morpholine, 1H morpholine); 2.15 (dd, 10 1H morpholine)

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

Stage C; (3S) -3- (4-MorphoHnylmethyl) -l, 2,3,4-tetrahydroisoquinoline

To a solution of 4.9 g of the compound of Stage B (13.4 mmol) in 67 mL of ethanol is added 0.980 g of palladium dihydroxide (20% by mass) at room temperature. The reaction medium is placed under 1.2 bard of hydrogen at room temperature for 4 hours. It is then passed through a Wathman filter, then the palladium is rinsed several times with ethanol. The filtrate is evaporated to dryness. The title product is obtained in the form of an oil.

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

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

Preparation 2 ': (3Æ) -3- (4-MorphoIinylmethyl) -1 ^ 3f4-tetrahydroisoquinoline

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

DUPLICATE

-30 Preparation 3 '(3S> 3 - [(4-Methyl-1-piperazinyl) methyl | -U3,4tetrahydroisoquinoline

The procedure is carried out according to the method of Preparation Γ, replacing the morpholine used in Stage A by 1-methyl-piperazine.

Preparation 4 ’; (35) -3- (1.4-Oxazenan-4-vlmethvl) -1 ^ 23.4-tetrahvdroisoQuinoline

The procedure is carried out according to the method of Preparation 1 *, replacing the morpholine used in Stage A by 1,4-oxazepane.

Preparation 5 *: (3S) -3 - {[(3R) -3-Methylmorpholinyl] inethyl} -1 »23i4tetrahydroisoquinoline

The procedure is carried out according to the method of Preparation Γ, replacing the morpholine used in Stage A by (3Æ) -3-methylmorpholine.

Preparation _________ 6 ’; (35) -3 - {[(35) -3-Methylmorpholinyl | niethyl) -1 ^ 3ï4tetrahydroisoquinoline

The procedure is carried out according to the method of Preparation 1 ’, replacing the morpholine used in Stage A by (3S) -3-methylmorpholine.

Preparation T. · (35) -3-Π (3 $, & 9) -3,5-ΟΐπιέίΙιγΙιηοΓρΙιοΗηγΙ] ιηέΙΙιγΙ} -1,23ι4tétrahydroisoquinoline

The procedure is carried out according to the method of Preparation 1 *, replacing the morpholine used in Stage A by (3S, 5S) -3,5-dimethylmorpholine.

Preparation 8 ’: ArjV-Dimethyl (3S) -U3,4-tetrahvdrO-3-isoquinolinyl | methanamine The procedure of Preparation Γ is carried out by replacing the morpholine used in Stage A by MW-dimethylamine.

Preparation ______ 9 ′: (35) -3 - {[4- (2-Methoxyethyl) piperazin-1-yl] methyi) -l "23i4tetrahydroisoquinoline

The procedure of Preparation Γ is carried out by replacing the morpholine used in

DUPLICATE

-31 Stage A by 1- (2-methoxyethyl)) piperazine.

Preparation __________ 10 * î 1-Methyl-4 - [(3S) -1 ^ 3.4-tetrahydroisoquinolin-3ylmethyl] piperazîn-2-one

The procedure is carried out according to the process of Preparation Γ, replacing the morpholine used in Stage A by 1-methylpiperazin-2-one.

Preparation 11 *; 2-Methoxy-JV-methyl-JV - [(3S) -l, 2,3,4-tetrahydroisoquinolin-3ylmethyljethanamine

The procedure of Preparation I ’is carried out by replacing the morpholine used in Stage A with 2-methoxy-JV-methylethanamine.

Preparation 12 ’; / V-Ethyl · 2-methoxy- / V - [(3S) -1 ^ 3,4-tetrahydroisoquinolin-3ylmethyljethanamine

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

Preparation 13 ’; (3S) -3 - ([4- (Methylsulfonyl) piperazin-1-yl] methyl} -1 ^ 3,4tetrahydroisoquinoline

The procedure is carried out according to the method of Preparation Γ, replacing the morpholine used in Stage A by 1- (methylsulfony)) piperazine.

Preparation 14 *; (3S) -3 - ([4- (2 ^, 2-Trifluoroethyl) piperazin-1-yl] methyl} -1 ^ 3,4tetrahydroisoquinoüne

The procedure is carried out according to the method of Preparation 1 ’, replacing the morpholine used in Stage A by 1- (2,2,2-trifluoroethyl) piperazine.

Preparation _______ 15 *; (3S) -3 - [(1,1-Dioxidothiomorpholin-4-yl) methyl] -1 ^ 3,4tetrahydroisoquinoline

The procedure is carried out according to the method of Preparation 1 ’, replacing the morpholine used in Stage A by thiomorpholine 1,1-dioxide.

DUPLICATE

-32 Preparation ________ 16 ’; (3S) -3-K3-Methoxypyrrolidin-1-yl) methyl | -133i4tetrahydroisoquinoline

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

Preparation ________ 17 ’: (3S) -3 - [(33-Difluoropyrrolidin -’yl) methyl] -133" 4tetrahydroisoquinoline

The procedure of Preparation Γ is carried out by replacing the morpholine used in Stage A by 3,3-dIfluoropyrrolidine.

Preparation __________ 18 ': (3S) -3 - [(3-methoxyazetidin-1-yl) methyl] -133 "4tetrahydroisoquinoline

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

Preparation ____________ 19 ': (3S) -3 - [(3-fluoroazetidin-1-yl) methyl] -133 _t 4tetrahydroisoquinoline

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

Preparation 1 ”: 4 - {[/ er / -Butyl (dlmethyl) siiyl] oxy) -iV-phenylaniline

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 tertbutyl (chloro) dimethylsilane (77.64 mmol). The whole is stirred at 70 ° C for 4 hours. Then, the reaction medium is poured into water and extracted with ether. The organic phase is then dried over magnesium sulfate, then filtered and evaporated to dryness. The crude product thus obtained is then purified by chromatography on silica gel (petroleum ether / dichloromethane gradient). The title product is obtained in the form of a powder.

DUPLICATE

-33RMN * H: δ (400 MHz; dmso-d6; 300 ° K): 7.84 (s, 1H NH); 7.17 (t, 2H aniline); 6.98 (d, 2H phenoxy); 6.94 (d, 2H aniline); 6.76 (d, 2H phenoxy); 6.72 (t, 1H aniline); 0.95 (s, 9H ferf-butyl); 0.15 (s, 6H dimethyl)

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

The amines NHR3R4 in which Rj and R4 represent, independently of one another, an aryl or heteroaryl group are obtained according to the methods described in the literature (Surry DS et al., Chemical Science, 2011,2,27-50, Charles MD et al., Organic Letters, 2005, 7, 3965-3968). The reaction for protecting the hydroxy function of 4anilinophenol described in Preparation 1 ”can be applied to various secondary amines NHR3R4 (as defined above), comprising one or more hydroxy functions, when these are commercially available. Alternatively, the secondary amines comprising at least one hydroxy substituent can be synthesized directly in a protected form, i.e. from reagents whose hydroxy function has been protected beforehand. Among the protective groups, fo / -butylsilyloxy 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 Zfindol-6-yl) amino] phenyl} methanol , 4- (2,3-dihydro-1H-indol-6-ylamino) phenol, 4 [(1 -methyl 1-2,3-dihydro-1 H-indo! -6-yl) amino] phenol, 4 - [(1 -methyl-1 H-indol-6y!) Amino] phenol, 4 - [(1-methyl-1H-indol-6-yl) amino] cyclohexanol, 4 - [(1-methyl- 1,2,3,4-tetrahydro-6-quinolinyl) amino] phenol, 4 - [(4-methyl-3,4-dihydro-2W-1,4benzoxazin-7-yl) amino] phenol, 4- [4- (diethylamino) anilino] phenol, 4- (2,3-dihydrolH-inden-5-ylamino) phenol, 4 - [(1-methyl-1 / f-indazol-5-yl) amino] phenol , 4 - [(Γmethyl! -r, 2'-dihydrospiro [cyclopropane-1,3 * -indol] -5'-y!) amino] phenol, 4 - [(1, 3,3trimethyl-2,3 -dihydro-1W-indol-5-yl) amino] phenol, 4- [4-methoxy-3 (trifluoromethyl) anilino] pheno l, 4- [4- (methylsulfanyl) -3- (trifluoromethyl) anilino] phenol, 2-fluoro-4 - [(1-methyl-1H-indol-5-yl) amino] phenol,

4 - [(1-ethyl-1 W-indol-5-yl) amino] phenol, 4 - [(1-ethyl-2,3-dihydro-1H-indol-5yl) amino] phenol, 4- [ (1-isopropyl-2,3-dihydro-1W-indol-5-yl) amino] phenol, 4DUPLICATA

-34 (butylamino) phenol, 3 - ((1-methyl-l / 7-indol-5-yl) amino] -l-propanol, 4 - ((1-methyll // - indol-5-yl) amin] -1-butanol, 4 - ((3-fluoro-4-methylphenyl) amino] phenol, 4 - ((3chloro-4-methylphenyl) amino] phenol, 4 - [(4-fluorophenyl) amino] phenol, 4 - ((1-methyl-1 / 7pyrrolo [2,3-6] pyridin-5-yl) aminoJphenol, 4 - ((4-fluorophenyl) amino] phenol, 4 - ((25 fluorophenyl) amino] phenol, 4 - [(3-fluorophenyl) amino] phenol, 4 - ((2,4-difluorophenyl) aminojphenol, 4 - [(3,4-difluorophenyl) amino] phenol, 3 - [(4-hydroxyphenyl) amino] benzonitrile, 4 - [(3-methoxyphenyl) amino] phenol, 4 - ((3,5-difluorophenyl) amino] phenol, 4 [(3-methylphenyl) aminoJphenol, 4 - [(4-hydroxyphenyl) amino] benzonitrile, 4- ((3chlorophenyl) amino] phenol, 4- (pyrimidin-2-ylamino) phenoI, 4 - ((cyclobutylmethyl) 10 aminojphenol, 2 - ((4-hydroxyphenyl) amino] benzonitrile, 4 - {((l-methyl-l) / 7-pyrazol-4yl) methyl] amino} phenol, 4 - [(cyclopropylmethyl) amino] phenol, 4 - {[(1 -methyl-1H ~ pyrazol-3-yl) methyl] amino) phenol, 4- (but -2-yn-1-ylamino) phenol, 4- (pyrazin-2-yiamîno) phenol, 4 - (pyridin-2-ylamino) phenol, 4- (pyridazin-3-ylamino) phenol, 4- (pyrimidin-5ylamino) phenol, 4- (pyridin-3-yiamino) phenol, 4 - ((3,5-difluoro -4-methoxyphenyl) aminojphenol, 4- (pyridin-4-ylamino) phenol, 4 - [(3-fluoro-4-methoxyphenyl) amino] phenol, 2- (phenylamino) pyrimidin-5-ol, 5 - [(4 -hydroxyphenyl) amino] -2-methoxy benzonitrile, 4 - {[3- (trifluoromethyl) phenyl] amino} 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 the previous general process.

Example 1: 2V- (4-Hydroxyphenyl) -3- {6 - [((35) -3- (4-morphoIinyl methyl) -3,4-dihydro-2 (lf /) - Îsoquinolinyl) carbonyl] - hydrochloride 1,3-Benzodioxol-5-yl} -jV-phenyl-

5,6,7,8-tetrahydro-l-indolizine carboxamid

Stage Λ. 3- {6 - [((3S) -3 '(4-Morpholinylmethyl) ~ 3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl [-l, 3-benzodioxol-5-y! J Methyl -5,6,7,8-tetrahydro-1-indolizine 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, N, N-triethylamine (6.96 mmol), 2.12 g of compound of Preparation 1 '(6.96 mmol), then 0.94 g of hydroxybenzotriazole (HOBT) and

1.34 g of 1-ethyl-3- (3'-dimethylaminopropy!) - carbodiimide (EDC) (6.96 mmol). The middle

DUPLICATE

The reaction mixture is then stirred at room temperature overnight, then i) 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). The title product is obtained in the form of an oil.

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

IR: v:> C = O 1695 cm ' ¹ ester; v:> C = O 1625 cm ⁴ amide; v:> COC <1214-1176-1115 cm ⁴ ;> CH-Ar 772-744 cm ⁴

Stage B: 3- [6 - [(3S) -3- (MorphoUnometh yl) -3,4-dih vdro-1H-isoquinoIine-2-carbonyll-1 _f 3benzodioxol-5-yll-5,6,7,8 -tetrahydro ~ lithium l-indolizine carboxylate

To a solution of 4.6 g of the compound of Stage A (8.26 mmol) in 24 mL of dioxane is added a solution of lithium hydroxide (675 mg, 16.1 mmol). The whole is placed in a microwave oven at 140W, 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 O _S.

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

DUPLICATE

-36stage C; N- (4 - {[tert-Butyl (dimethyl) sHylloxy} phenyl) -3- [6 - [((3S) -3- (4morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl} -l, 3-benzodioxol-5-yl} N-phenyl-5,6,7,8-tetrahydro-l-indolizirte carboxamide

To a solution of 2.6 g of the compound of Stage B (4.73 mmol) in 47 mL of dichloromethane are added, dropwise, 1.2 mL of oxalyl chloride 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 of 2.1 g of the compound obtained in Preparation 1 ”(7.1 mmol) in 10 mL of dichloromethane in the presence of 0.6 10 mL of pyridine (7.1 mmol). The whole is stirred at room temperature overnight.

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

1H NMR: δ (500MHz; dmso-d6; 300 ° K): 6.9-7.3 (9H aromatics); 6.88 (2H aromatics); 6.72-6.87 (aromatic 2H); 6.64 (aromatic 2H); 6.13 (2H 15 methylenedioxy); 5.05-4.74 (1H dihydroisoquinoline); 4.25-4.13 (2H dihydroisoquinoline); 3.44-3.7 (4H morpholine); 3.62-3.52 (2H tetrahydroindolizine);

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

IR: v:> C = O: 1632 cm- ¹ ; v:> COC <: 1237 cm '¹; v: -Si-OC-: 1035 cm- ¹ ; -If-C-: 910 cm- ¹ ; > CH-Ar: 806 cm ' ¹

Stage D1 N- (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholiny! Methyl) -3,4dihydro-2 (1H) -lsoquinolinyl) carbonylJ-l, 3- hydrochloride benzodioxol-5-yl} -N-phenyl-S, 6,7,8tetrahydro-l-indolizine carboxamide

0.646 g (11.5 mmol) of potassium hydroxide dissolved in 8 mL of methanol is added to a solution of 1.9 g of the compound obtained in Stage C (2.3 mmol) in 4 mL of methanol. The whole is stirred at room temperature for 30 min. The reaction medium is then diluted in dichloromethane and washed successively with 1N HCl solution, saturated NaHCO 3 solution, then saturated NaCl solution until a neutral pH is reached. The organic phase is then dried over sulphate of

DUPLICATE

-37magnesium, filtered and evaporated. The crude product thus obtained is purified 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.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 69.11 5.8 7.5 4.74 Find 68.95 5.46 7.51 4.48

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

Example 2: 7V- (4-Hydroxyphenyl) -A- (4-methylphenyl) - 3- {6 - [((3S) - hydrochloride

3- (4-morpholinylmethyl) -3,4-dihydro-2 (ltf) -isoquinolinyl) carbony! [- 13-benzodioxol-

5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide

The procedure of Example 1 is carried out, replacing the compound of Preparation

1 ”used in Stage C by 4 - {[/ er / -butyl (dimethyl) silyl] oxy) -A /’ - (4-methylphenyl) aniline.

Elemental microanalysis:

% C% H% n% ci% cr

Calculated 69.42 5.96

7.36 4.66 4.66

Found 69.19 5.76

7.19 4.62 4.48

Example 31 JV '(4-Chlorophenyl) -jV- (4-hydroxyphenyl) -3- (6 - [((3S) - hydrochloride

3- (4-morpholinylmethyl) -3,4-dihydro-2 (1/7) -isoquino! Inyl) carbonyl] -13 * benzodioxol-

5-y l} -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure of Example 1 is carried out, replacing the compound of Preparation

1 ”used in Stage C by 4 - {[feri-butyl (dimethyl) silyl] oxy} -N- (4-chlorophenyl) anylin.

DUPLICATE

-38 Elemental microanalysis:

%VS % H %NOT % Cl % CF Calculated 66.07 5.42 7.17 9.07 4.54 Find 65.74 5.14 7.08 9.02 4.48

Optical rotation: (a) d ^{20 =} + 80.9 ° (c = 2.5 mg / mL, MeOH)

Example 4 / V- (3-Nuoro-4-methylphenyl) JV- (4-hydroxyphenyl) -3 {6- | ((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 hydrochloride. (lff) -isoquinolinyl) carbon)] - 13benzodioxol-5-yl} -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure is carried out according to the process of Example 1, replacing the compound of Preparation 10 i ”used in Stage C by 4 - {[ter / -butyl (dimethyl) sîtyt] oxy} - / V- (3-fluoro- 4methylphenyl) aniline.

High resolution mass (ESI +):

Molecular Formula: C44H43FN4O6 [M + H] ⁺ Calculated: 743.3245 [M + H] ⁺ Measured: 743.3250

Optical rotation: (a) d ²⁰ = + 40.7 ° (c = 2.5 mg / mL, MeOH) '

Example 5 JV- (4-Hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinyl methyl) -3,4-dihydro-2 (1 //) - isoquino) inyl) hydrochloride carbonyl) -13-benzodioxol-5-y)) - / V- [4 (trifluoromethoxy) phenyl] -5,6,7,8-tetrahydro-1-indolizine carboxamide

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation

1 ”used in Stage C by 4 - {[/ er / -butyl (dimethyl) silyl] oxy} - / V- (4trifluoromethoxyphenyl) aniline.

DUPLICATE

-39 Elemental microanalysis:

%VS % H %NOT % Cl- Calculated 63.57 5.09 6.74 4.26 Find 63.38 4.95 6.88 4.23

Example 6: 7V // - bis (4-hydroxyphenyl) -3- {6 - [((35) -3- (4morpholinylmethyl) -3,4-dihydro-2 (1JJ) -isoquinolinyl) carbonyl] -13 hydrochloride -benzodioxol-5yl) -5,6,7,8-tetrahydro-l-indollzine carboxamide

The procedure of Example 1 is carried out by replacing the compound of Preparation 1 ”used in Stage C by 4 - {[fert-butyl (dîmethyl) silyl] oxy} -7V- (4 - {[/ erfbutyl ( dimethyl) silyl] oxy} phenyl) aniline.

Elemental microanalysis:

%VS %NOT % Cl- Calculated 67.66 5.68 7.34 4.64 Find 67.11 5.49 7.31 4.74

Optical rotation t (a) p ² ° ⁼ + 50.8 ° (c - 6 mg / mL, MeOH)

Example 7: 7V- [4- (hydroxymethyl) phenyl] - 7V- (1-methyl-1H-indob hydrochloride)

5-yl) -3- (6 * | ((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1ZO-isoquiiiolinyl) carbonyll13-benzodioxol-5-yl} -5,6,7 , 8-tetrahydro-l-indolizine carboxamide

The procedure of Example 1 is carried out by replacing the compound of Preparation 1 ”used in Stage C by 7V- [4 - ({[feri-butyl (dimethyl) silyl] oxy} methyl) phenyl] -lmethyl 1 -1 // - indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 69.32 5.94 8.6 4.35 Find 69.63 5.75 8.59 4.13

DUPLICATE

Example 8: Bis (hydrochloride) of JV- (23 * dihydro-1H-indol-5-yl) - jV- [4 (hydroxy) phenyl] -3- {6- | ((35) -3- (4 -morpholinylmethyl) -3,4-dihydro-2 (1H) isoquinolinyl) carbonyl] -13-benzodioxol-5-yl} -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure of Example 1 is carried out, replacing the compound of Preparation 1 ”used in Stage C by A- (4 - {[/ er / -butyl (dimethyl) silyl] oxy} phenyl) -5-indolinamine .

Elemental microanalysis:

% C% H% N% Cl

Calculated 65.53 5.74

8.49 8.60

Found 65.47 5.69

8.43

7.82

Optical rotation t (a) d ²⁰ = + 40.9 ° (c = 3.5 mg / mL, MeOH)

Example 9: JV- [4- (hydroxy) phenyl] - / V- (1-methyl-23- <1Hydro-1Windol-5-yl) -3- {6 - [((35) -3- ( 4-MorpliolÎnylmethyl) -3,4-dihydro-2 (l / f) -isoquinolinyl) carbonyl] -13-benzodioxol-5-yl} -5,6,7,8-tetrahydro-l-indolizine carhoxamide

The procedure of Example 1 is carried out by replacing the compound of Preparation 1 ”used in Stage C by JV- (4 - {[ter / -butyl (dimethyl) silyl] oxy} phenyl) -l-methyl- 5indolinamine.

High resolution mass (ESI +):

Molecular Formula: C46H47N5O6 [M + Hf Calculated: 766.3605 [M + H] ⁺ Measured: 766.3601

DUPLICATE

Example 10: JV- | 4- (hydroxy) phenyl] -7V- (1-methyl-1 // - indol-5-yl) -3 [6 -) ((35) - 3- (4- hydrochloride) niorpho! inylmethyl) -3,4-dihydro-2 (1À /) - isoquinolinyl) carbonyl] -l3benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide

The procedure of Example 1 is carried out, replacing the compound of Preparation

1 ”used in Stage C by the A ^r - (4 - {[/ err-butyl (dimethyl) silyl] oxy} phenyl) -l-methyl-1 // indol-5-amine.

Elemental microanalysis: (theory for 1.1 HCl)

%VS % H %NOT % cr Calculated 68.72 5.78 8.71 4.85 10 Find 68.39 5.55 8.66 4.33

Rotating power ; (a) _D ^{20 =} + 37.6 ° (c = 7 mg / mL, MeOH)

Example 11; 7V- (4-Hydroxyphenyl) -3- {6 - [((3 / î) -3- (4-morpholinyl methyl) -3,4-dihydro-2 (1 //) - isoquinolinyl) carbonyl] - hydrochloride 13-benzodioxol-5-yl} - / V-phenyl-

5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure of Example 1 is carried out, replacing the compound of Preparation 1 * used in Stage A by the compound of Preparation 2 *.

Elemental microanalysis:

% C% H% N% cr

Calculated 69.11 5.80

7.50 4.74

Found 68.89 5.23

7.41

4.62

Optical rotation: (a) _D ²⁰ = - 45.Γ (c = 9 mg / mL, MeOH)

DUPLICATE • 42Example 12; JV- (4-Hydroxycyclohexyl) - / V- (1-ethyl-1H-indol-5-yl) hydrochloride -

3- {6 - {((35) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1 //) - isoquinolinyl) carbonyl] -13benzodioxol-5-yl} -5,6,7, 8-tetrahydro-l-indolizine carboxamide

The procedure of Example 1 is carried out by replacing the compound of Preparation 5 1 ”used in Stage C by N- (4- {perr-butyl (dimethyl) silyl] oxy} cyclohexyl) -l-méthyIl // -indol-5-amine.

High resolution ground (ESI +);

Molecular formula: CîôHsiNsOô [M + H] ⁺ calculated: 770.3918 [M + H] ⁺ measured: 770.3928

Example 13: Bls (hydrochloride) of N- (4-hydroxyphenyl) -N- (1-methyl-1 £ f-indol-5-yl) 3- {6 - [((3S) -3 - [(4- methyl-1-piperazinyl) methyl-3,4-dihydro-2 (lZ /) - isoquinolinyl) carbonyl | -13-benzodioxol-5-yl} -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compound of Preparation Γ used in Stage A by the compound of Preparation 3 ', and on the other hand the compound of Preparation 1 ”used in Step A. Stage C by M (4 - {[ierfbutyl (dimethyl) silyl] oxy} phenyl) -l-methyl-1 / Aindol-5-amine.

Elemental microanalysis;

%VS % H %NOT % Cl % cr 20 Calculated 66.43 5.93 9.89 8.34 8.34 Find 66.36 5.79 9.83 8.11 7.67

Rotating power ; (a) d ²⁰ = + 60.1 ° (c = 6 mg / mL, MeOH)

DUPLICATE

-43 Example 14; 7V- (4-Hydroxyphenyl) -jV- (1-methyl-1H-indol-5-yl) -3- {6] ((3S) -3- (1,4-oxazepan-4-ylmethyl) - hydrochloride 3,4-dihydro-2 (1/0-isoquinoIinyl) carbonyl] -13benzodioxol-5-yI} -5,6,7,8-tetrahydro-1-indolizine carboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compound of Preparation Γ used in Stage A by the compound of Preparation 4 ', and on the other hand the compound of Preparation 1 "used in Stage C by / V- (4 - ([/ er / butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1Z7-indol-5-amine.

Elemental microanalysis i% C% H% N% Cl% CL '

Calculated 69.32 5.94

8.60 4.35

4.35

Found 69.24 5.56

8.52 4.47 4.44

Example 15: 7V- (4-Hydroxyphenyl) -jV- (1-methyl-1H-indol-5-yl) -3- {6 (((3SJ-3 - {[(3Æ) -3-methyImorpholinyl] hydrochloride) methyl} -3,4-dibydro-2 (l //) - isoquinoIinyI) carbonyl] -13-benzodioxol-5-ylJ-5,6,7,8-tetrahydro-l-indoiizîne carboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compound of Preparation Γ used in Stage A by the compound of Preparation 5 ′, and on the other hand the compound of Preparation 1 ”used in Stage C by ZV- (4 - {[/ er / butyI (dimethyl) silyI] oxy} phenyI) -1-methyl-1 // - indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 69.32 5.94 8.60 4.35 Find 69.10 5.68 8.52 4.29

DUPLICATE

Example 16: JV- (4-Hydroxyphenyl) -7V- (1-methyl-1 / Z-indol-5-yl) -3- {6 [((35) -3 - {[(3S) - hydrochloride 3-methylmorpholinyl | methyl} -3,4-dihydro-2 (lf /) - isoquinolinyl) carbonyl | -13-henzodioxol-5-yl} -5,6,7,8-tetrahydro-l-indolizine carhoxamide

The procedure of Example I 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 JV- (4 - {[terfbutyl (dimethyl) silyl] oxy} pheny 1) -1 -methyl-1 // - indo! -5-amine.

Elemental microanalysis:

% C% H% N% cr

Calculated 69.32 5.94

8.60

4.35

Found 68.97 5.55

8.44 3.73

Example 17 t 3- {6 - [((35) -3 - {[(3 $, 5 * 5) “33 ^ · ηιέίΙη4ιηοι · ρΙϊο1 ^ 1] methyl} -3,4-dihydro-2 (l //) - isoquinoIinyl) carhonyl | -13-henzodioxol-5-yl} -A ^r - (4hydroxyphenyl) -JV- (1-methyl-1 / Z-indol-5-yl) -5,6,7,8 -tetrahydro-l-indolizine carhoxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compound of Preparation Γ used in Stage A by the compound of Preparation 7 ′, and on the other hand the compound of Preparation I ”used in Stage C by A- (4 - {[/ eributyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 Å / -indo! -5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 69.59 6.08 8.45 4.28 Find 69.29 5.52 8.46 4.09

DUPLICATE

-45 Example 18: 3- {5-Bromo-2- | ((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (17 /) - isoquinolinyl) carbonyl | phenyl) -7V- (4) hydrochloride -hydroxyphenyl) -jV- (l-methyl-l // indo l-5-y 1) -5,6,7,8-tet rahyd ro-1 -in dolîzine carboxamide

The procedure of ΓExample 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 A- (4 - ([/ er / buty 1 (dimethyl) sil 1] ox y} phenyl) -1 -methyl-!? / - indol-5-amine.

High resolution ground (ESI +).

Molecular formula: C4jH44 ⁷⁹ BrNiO4 [M + H] ⁺ calculated: 798.2655 [M + H] ⁺ measured: 798.2626

Example 19 3- {S-bronio-2-f ((3S) -3- (4-niorpholinylmethy)) - 3,4dihydro-2 (I //) - isoqulnolinyl) carbonyl | phenyl} -A ^r - hydrochloride (4-hydroxyphenyl) -A ^r - (1-methyl-23dihydro-17J-indo! -5-yl) -5,6,7,8-tetrahydro-1-indolizine carboxamide

The procedure of ΓExample 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 A- (4 - {[teributy! (Dimethyl) silyl] oxy} phenyl) -1-methyl-5-indo! Inamine.

High resolution mass (ESI +) t

Molecular formula: C45H46 ⁷⁹ BrN1O4 [M + Hf calculated: 800.2811 [M + H] ⁺ measured: 800.279!

DUPLICATE

-46 Example 20: 3- {5-chloro-2 - [((3S) -3- (4-morphoIinylmethyl) -3,4dihydro-2 (17 /) - isoquinolinyl) carbonyl] phenyl} -jV- (4) hydrochloride -hydroxyphenyl) -7V-phenyl

5,6,7,8-tetrahydro-1-indolizîne carboxamide

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation 1 used in Stage A by the compound of Preparation 3.

Elemental microanalysis.

%VS % H %NOT % cr Calculated 68.38 5.74 7.59 4.81 Find 67.89 5.71 7.72 4.68

Optical rotation: (a) d ^{20 =} + 53.7 ° (c = 6 mg / mL, MeOH)

Example 21: 3- {5-chloro-2 - [((35) -3- (4-morphoIinylmethyl) -3,4dihydro-2 (lZZ) -isoquinolinyl) carbonylJphenyl} - / V- (23) bis (hydrochloride) -dihydro-l / Z-indol-5-yl) -jV- (4hydroxyphenyl) -5,6,7,8-tetrahydro-l-indolizine 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 7V- (4- {£ / erZbuty! (dimethyl) silyl] oxy} phenyl) -5-indolinamine.

High resolution ground (ESI +)

Molecular formula: C44H44 ^3S ClNsO4 [M + H] ⁺ calculated: 742.3160 [M + H] ⁺ measured: 742.3120

DUPLICATE

-47 Example 22; 3- {5-Chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1 £ 0-isoquinolinyl) carbonyl] pheny |} -JV- (4-hydroxyphenyl) hydrochloride -7V- (1-methyl-1 / findol-5-yl) -5,6,7,8-tetrahydro-1-indo! Izine 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by M (4 - {[rertbutyl (dimethyl) siIylJoxy} phenyl) -1-methyl-1 // - indol-5-amine.

Elemental microanalysis;

% C% H% n% cr

Calculated 68.04 5.72

8.82

4.91

Found 67.84 5.46

8.64

5.21

Optical rotation. (A) q ²⁰ = + 55.9 ° (c = 7 mg / mL, MeOH)

Example 231 3- {5-chloro-2 - [((3S) -3- (4-morpho! Inylmethyl!) - 3,4dihydro-2 (1fO-isoquinolinyl) carbony!] Phenyl} -JV bis (hydrochloride) - (4-hydroxyphenyl) -7V- (l-methyl-23dihydro-l // - indol-5-yl) -5,6,7,8-tetrahydro-l-indolizine 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by M (4 - ([feributyl (dimethyl) silyl] oxy} phenyl) -1 -methyl-5-indolinamine.

Micro elemental analysis:

% C% H% n% ci% cr

Calculated 65.18 5.83

8.45 12.83 8.55

Found 65.75 5.45

8.39 11.71

7.54

Optical rotation. (A) p ²⁰ = + 56.6 ° (c = 6 mg / mL, MeOH)

DUPLICATE

Example 24: 3- (5-Fluoro-2- | ((35) -3- (4-morpholinylméthy]) - 3,4dihydro-2 (1H) -13oquinoliny!) Carbony]] phenyl} -7V- hydrochloride (4-hydroxyphenyl) - / V- (1-niethyl-1 // indol-5-yl) -5,6,7,8-tetrahydro-1-indolizine 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 4, and on the other hand the compound of Preparation 1 "used in Stage C by AT- (4 - {[/ errbutyl (dimethyl) slyl] oxy} phenyl) -1 -methyl-1 H-indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 69.80 5.86 9.04 4.58 Find 69.57 5.62 8.76 4.47

Rotary power. · (A) _D ^{20 =;} + 55.0 ° (c = 5 mg / mL, MeOH)

Example 25 i 3- {5-Fluoro-2- | ((35) -3- (4-morpho! Iny! Methy 1) -3,4dihydro-2 (1 //) - isoquinoliny!) Carbonyl] pheny hydrochloride !} - jV- (4-hydroxypheny!) - A ^r -phenyl-

5,6,7,8-t ét rahy dro-1 - in do lizine ca r bo xami de

The procedure is carried out according to the process of Example 1, replacing the compound of Preparation 1 used in Stage A by the compound of Preparation 4.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 69.94 5.87 7.77 4.92 Find 69.70 5.32 7.72 4.80

DUPLICATE

Example 26: 3- {5-ch! Oro-2 - [((3S) -3- (4-morpholinylmethyl> 3,4dihydro-2 (1/7) -isoquinolmyl) carbonyl] phenyl} -A ^r hydrochloride - (4-hydroxyphenyl) -ZV- (1-methyl1 ^ 3,4-tetrahydro-6-quinolinyl) -5,6,7,8-tetrahydro-1-indolizine carboxamide

The procedure is carried out according to the method of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by jV- (4- {[zerzbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1,2,3,4-tetrahydro-6-quinolinamine.

Elemental microanalysis: (theory for 1.5 HCl)

%VS %NOT % cr Calculated 66.97 6.05 8.49 6.45 Find 66.80 5.55 8.32 6.23

Example 27; 3- [5-Chloro-2- | ((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1 / Z) -isoquinolinyl) carbonyl] phenyl] -7V- (4-hydroxyphenyl) hydrochloride -A / - (4-niethyl-3,4dihydro-2 / M, 4-benzoxazin-7-yl) -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure is carried out according to the process of ['Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by JV- (4 - ([zerzbutyl (dimethyl) silyl] oxy) phenyl) -4-methyl-3,4-dihydro-2 // - 1,4-benzoxazin-7-amine.

Elemental microanalysis: (theory for 1.1 HCl)

%VS % H %NOT % cr Calculated 66.53 5.84 8.62 4.80 Find 66.59 5.39 8.47 4.80

DUPLICATE

Example 28: 3- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (I //) - isoquinolinyl) carbonyl] phenyl} -j'V hydrochloride -14- (diethylamino) phenyl] -j'V- (4hydroxyphenyl) -5,6,7,8-tetrahydro-1-indolizine 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by N ^} - (4 - {[tertbutylCdimethynsilylJoxyJphenylJ-A ^ JV ^ diethyl-1/1-benzenediamine.

Elemental microanalysis î (theory for 1.6 HCl)

%VS % H %NOT % cr Calculated 66.51 6.26 8.43 6.83 Find 66.71 5.58 8.39 7.08

Example 29; 3- {5-Chloro-2 - [((3S) -3- (4-inorpholinylmethyl) -3,4dihydro-2 (1/7) -isoquinolinyl) carbonyl] phenyl} - / V- (23- < lihydro-1 // - Indén-5-yl) -jV- (4hydroxyphenyl) -5,6,7,8-tetrahydro-l-indolizine carhoxamide

We proceed according to the method of the Example! by replacing on the one hand the compound of Preparation 1 used in Stage A with the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by N- (4 - ([tertbutyl (dimethyl) silyl] oxy} phenyl) -5-indanamine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 69.49 5.96 7.20 4.56 Find 69.47 5.43 7.21 4.21

DUPLICATE

-51 Example 30: 3- {5-chloro-2 - [((3S) -3 - [(4-methyl-lpiperazinyl) methyl] -3,4-dihydro-2 (1 //) bis (hydrochloride) -isoquinolinyl) carbonyl | phenyl} -7V- (4hydroxyphenyl) -? / - (1-methyl-1 // - indol-5-yl) '5,6,7,8-tetrahydrt> -l-indolizîne carboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compounds of Preparations 1 and Γ used in Stage A by the respective compounds of Preparations 3 and 3 ', and on the other hand the compound of Preparation 1 ” used in Stage C by jV- (4 - {[ferfbutyl (dimethyl) silyl] oxy} phenyl) -l -methyl-1 Jf-indol-5-amine.

High resolution mass (ESI +):

Molecular formula: C4ôH47 ³⁵ C1N6O3 [M + H] ⁺ calculated: 767.3476 [M + H] ⁺ measured: 767.3476

Example 31: Ar- (4-Hydroxyphenyl) -3- {8 - [((3i5) -3- (4morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinoliny!) Carbonyl] -3,4 hydrochloride -dihydro-2 // - l, 515 benzodioxepin-7-yl) -. / V-phenyl-5,6,7,8-tetrahydrt> -l-indolizîne carboxamide

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation 1 used in Stage A by the compound of Preparation 5.

High resolution mass (ESI +):

Molecular Formula: C45H46N4O6 [M + H] ⁺ Calculated: 739.3496 [M + H] ⁺ Measured: 739.3479

Example 32; A44-Hydroxyphenyl) - / V- (1-methyl-1W-iiidol-5 "yl) -3- {8 [((35) -3- (4-inorpholinylmethyl) -3,4-dihydro-2 ( lZ7) -isoquinolinyl) carbonyl] -3,4 · dihydro-2ZM, 5-benzodioxepin-7-yl} -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure of Example I is carried out, on the one hand replacing the compound of

DUPLICATE

-52Preparation 1 used in Stage A by the compound of Preparation 5, and on the other hand the compound of Preparation 1 ”used in Stage C by 7V- (4 - {[rerrbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 // - indol-5-amine.

Elemental microanalysis:

% C% N% cr

Calculated 69.59 6.08

8.45

4.78

Found 69.23 5.46

8.41

4.16

Example 33 I JV- (4-Hydroxyphenyl) -3- {5-Inethoxy-2 - [((3S) -3- (4morpholinylmethyl) -3,4-dihydro-2 (1 //) - isoqulnolinyl) carbonyl hydrochloride ] phenyl} -7V- (1-methyl10 l // - Indol-5-yl) -5,6,7,8-tetrahydro-l-indoIizine carboxamide

The procedure of Example I 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 7V- (4- {[tertbuty! (dimethyl) sily!] oxy} phenyl) -1-methyl-1/7-indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 70.26 6.15 8.91 4.51 Find 69.78 5.36 8.90 4.29

Optical rotation: (a) p ²⁰ = + 42.1 ^q (c = 6 mg / mL, MeOH)

Example 34: 7V- (4-Hydroxyphenyl) -3- {7 - [((35) -3- (4morphoIinylmethyl) -3,4-dihydro-2 (1H) isoquinolinyl) carbonyl] -23-dihydro-1 hydrochloride , 4benzodioxin-6-yl) -7V-phenyl-5,6,7,8-tetrahydro-l-indolizin carboxamide

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation 1 used in Stage A by the compound of Preparation 7.

DUPLICATE

-53 Elemental microanalysis t

%VS % H %NOT % cr Calculated 69.42 5.96 7.36 4.66 Find 69.39 5.56 7.30 4.49

Rotating power ; (a) _D ²⁰ = + 34.5 ° (c = 6 mg / mL, MeOH)

Example 35: / V- (4-hydroxyphenyl) -? V- (1-methyl-1/7-indol-5-yl) -3- (7 - (((35) -3- (4morpholinylmethyl) -3, 4-dihydro-2 (lJ ^t /) - isoquinolinyl) carbonyl) -23-dihydro-l, 4henzodioxin-6-yl} -5,6,7,8-tetrahydro-l-indolizine carhoxamide

The procedure is carried out according to the process of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 7, and on the other hand the compound of Preparation 1 ”used in Stage C with N- (4 - {[tertbutyl (dimethyl) silyl] oxy} phenyl) -l-methyl-1H-indol-5-amine, it being understood that the product thus obtained is not subjected to a salification step in presence of hydrochloric ether.

Elemental microanalysis.

%VS % H Calculated 72.57 6.09 9.00 Find 73.11 5.70 8.95

Optical rotation: (a) d ^{20 = +} 88.2 ° (c = 7 mg / mL, MeOH)

Example 36; 3- {5-Ethoxy-2 - (((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1ZD'isoqulno! Inyl) carbonylJphenyl} - / V- (4-hydroxyphenyl) - / V- (1-methyl-lHindol-5-y 1) -5,6,7,8-tetrahydro-l-indolizine 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 8, and on the other hand the compound of Preparation 1 ”used in Stage C by V- (4 - ([iron / butyl (dimethyl) silyl] oxy} phenyl ) -1 -methyl-1 H-indol-5-amine.

DUPLICATE

-54 Elemental microanalysis;

%VS % H %NOT % Cl Calculated 70.53 6.30 8.75 4.43 Find 70.77 5.59 8.66 4.22

Example 37; 7V- (4-Hydroxyphenyl) -jV- (1-methyl-1H-indol-5-yl) -3 (2 ^ -dideuterio-6 - [((35) -3- (4-morpholïnyImethyl) -3 hydrochloride , 4-dihydrO-2 (1H) isoquinolinyI) carbonyl) -13-benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine 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 9, and on the other hand the compound of Preparation Γ 'used in Stage C by N- (4 - {[tertbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 / Z-indol-5-amine.

High resolution mass (ESI +):

Molecular Formula: C46H43N5O6D2 [M + H] ⁺ Calculated: 766.3573 [M + H] ⁺ Measured: 766.3533

Rotating power ; (a) _D ²⁰ = + 35.5 ° (c = 3.5 mg / mL, MeOH)

Example 38; A / - (4-Hydroxyphenyl) -3- {23-dideuterio-6 - [((35) -3- (4morpholinylmethyl) -3,4-dihydro-2 (1 //) - isoquinoIinyl) carbonyl] - hydrochloride 13-benzodioxol-5yl} -jV-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide

Stage A: N ~ (4-hydroxyph enyl) -3- {2,2-dideuterlo-6 - [((3S) -3- (4-morpholinylmethyl) 3,4-άϋφάΓθ-2 (1Η) -1 $ οηαΙηοϋηγΙ ) € α ^ οηγΙ] -Ι, 3 ^ οηζοάίοχοΙ-5γΙ} -Ν-ρ1 ^ ηγΙ-5,6,7,8 ~ tetrahydro-1 -indolizine carboxamide

The procedure of Example 1 is carried out, replacing the compound of Preparation 1 used in Stage A by the compound of Preparation 9, it being understood that the step of

DUPLICATE

-55salification in the presence of hydrochloric ether is carried out only in the following Stage B.

Stage B: N- (4-hydroxyphenyl) -3- {2,2-dideuterio-6 - [((3S) -3- (4 ~ morpltolinylmethyl) -3,4-dihydro-2 (1H) -isoquinoiinyl hydrochloride ) carbonyl / -l _t 3-benzodioxol-5-yl} -Nphenyl-5,6,7,8-tetrahydro-l-indolizlne carboxamide

The product obtained in Stage A is 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:

% C ° / oH% N% ci% cr

Calculated 68.93 5.80

7.48 4.73 4.73

Found 68.45 5.49

7.57 4.63 4.54

Example 39:? / - (4-hydroxyphenyl) -? / - (l-methyl-1 // - indazol-5-yl) -3 {7-f ((3A ^r ) -3- (4-morpholinylmethyl) hydrochloride ) -3,4-dihydro-2 (lJ /) - lsoquinolinyl) carbonyl] -2315 dihydro-1,4-benzodioxin-6-yl} -5,6,7,8-tetrahydro-l-indoIizine 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 by // - (4- {[tertbuty 1 (dimethyl) if there is 1] ox y} pheny I) -1-methyl 1-1 // - indazol-5-amine.

Elemental microanalysis:

% C% H% N% cr

Calculated 67.76 5.81

10.31 4.35

Found 67.82 5.25

9.87

4.18

Optical rotation. (A) d ^{20 =} + 42.6 ° (c = 5 mg / mL, MeOH)

DUPLICATE

Example 40: A- (4-Hydroxyphenyl) -. / V- (1-methyl-1,2,3 »4-tetrahydro- hydrochloride

6-quinolinyl) -3- (7 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) isoquinolinyl) carbonyl] -23 * <iihydro-1,4-benzodioxin- 6-yl} -5,6,7,8-tetrahydro-lindolizine carboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compound of Preparation I used in Stage A by the compound of Preparation 7, and on the other hand the compound of Preparation 1 ”used in Stage C by butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1,23 »4-tetrahydro-6-quinolinamine.

Micro elemental analysis:

10 %VS % H %NOT % Cl % cr Calculated 66.51 6.16 8.08 8.18 8.18 Find 66.85 5.88 8.04 6.47 6.25

Example 41? 7V (4-Hydroxyphenyl) -JV (4-methyl3,4-dihydro-2 £ fl, 4benzoxazin-7-yl) -3- (7 - [((3S) -3- (4-morpholinylmethyl) hydrochloride ) -3,4-dihydro-2 (1 //) 15 isoquinolinyl) carbonyl] -23-dihy ^< iro-13'benzodioxin-6-yl} -5,6,7,8-tetrahydro-lindolizine carboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compound of Preparation I used in Stage A by the compound of Preparation 7, and on the other hand the compound of Preparation 1 ”used in Stage C by N- (4 - {[fo / butyl (dimethyl) silyl] oxy} phenyl) -4-methyl-3,4-dihydro-2if-1,4-benzoxazin-7-amine.

High resolution mass (ESI +):

Molecular Formula: C47H49N5O7 [M + H] ⁺ Calculated: 796.3710 [M + H] ⁺ Measured: 796.3687

DUPLICATE

-57 Example 42; 3- {5-Chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (l //) - isoqui ⁿ oli ⁿ yl) carbonyl] phenyl} -7V- ( 4-hydroxyphenyl) -2V- (1-methyl-17 / indazol-5-yl) -5,6,7,8-tetrahydro-l-indolizine 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by A- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl} -l-methyl-1 / Aindazol-5-amine.

Elemental microanalysis:

%VS % H %NOT % Cl % cr Calculated 66.75 5.60 10.61 8.96 4.48 Find 66.63 5.06 10.42 8.83 4.46

Example 43: 1- {5-Chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1A /) - isoquinolinyl) carbonyl] phenyl} -JV- (4-) hydrochloride hydroxyphenyl) -A ^r - (l-methyl-23dihydro-l / Z-indol-5-yl) -5,6,7,8-tetrahydro-3-indolizine 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 24, and on the other hand the compound of Preparation 1 ”used in Stage C by M (4 - {[iron / butyl (dimethyl) silyl] oxy} phenyl) -1 -methyl-1 H-indol-5-amine.

Elemental microanalysis t

%VS % H %NOT % Cl Calculated 68.35 5.74 8.86 8.97 Find 68.29 5.21 8.76 9.04

DUPLICATE

-58 Example 44; 3- {5-Fluoro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1 //) - isoquinolinyl) carbonyl] phenyl} -A- (4-hydroxyphenyl) hydrochloride -jV- (1-methyl-1 // indazol-5-yl) -5,6,7,8-tetrahydro-1-indolizine carhoxamide

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 4, and on the other hand the compound of Preparation 1 ”used in Stage C by jV- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1W-indazol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 68.16 5.72 10.84 4.57 Find 67.93 5.01 10.89 4.24

Example 45: 3- {5-Chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) ·

isoquinolinyl) carbonyl] phenyl} -A ^r - (4-hydroxyphenyl) -A ^r - (l * -methyl-r, 2'-dihydrospiro [cyclopropane-13 ** lndol] -5'-yl) -5,6, 7,8-tetrahydro-l-indolizine carhoxamide

The procedure of Example I is carried out by replacing, on the one hand, the compound of Preparation I used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by A / - (4 - {[iron / butyl (dimethyl) silyl] oxy} phenyl) - (r-methyl-r, 2'-dihydrospiro [cyclopropane-1,3'-indol] 5'-yl) amine .

Elemental microanalysis.

Calculated

Find

%VS % H %NOT 72.15 6.18 8.95 71.86 5.76 8.85

DUPLICATE

Example 46: 3- {5-chioro-2 - [((3S) -3- (1,4-oxazepan-4-ylmethyl) -3,4dihydro-2 (1W) -isoquinolinyl) carbonyl] phenyl} hydrochloride - / V- (4-hydroxyphenyl) - / V- (1-methyl-lffindol-5-yl) -5,6,7,8-tetrahydro-1-indolizine carboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compounds of Preparations 1 and 1 * used in Stage A by the respective compounds of Preparations 3 and 4 \ and on the other hand the compound of Preparation 1 ” used in Stage C by 7V- (4 - {[rerfbutyl (dimethyl) silyl] oxy} phenyl) -1 -methyl-1 H-indol-5-amine.

Elemental microanalysis:

%VS %NOT Calculated 68.65 5.89 8.70 Find 68.33 5.45 8.54

Optical rotation: (a) d ^{20 =} + 13.6 ° (c - 4 mg / mL, MeOH)

Example 47: / V- (4-Hydroxyphenyl) -? / - (1-methyl-1 / f-indol-5-yl) -3- [2 [((3S) -3- (4-morpholinylmethyl) hydrochloride -3,4-dihydro-2 (12Z) -isoquinolÎnyl) carbonyl] -5 (trifluoromethyl) phenyl] -5,6,7,8-tetrahydro-1-indolizine 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 10, and on the other hand the compound of Preparation 1 ”used in Stage C by JV- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) -! - methyl- 1 / Z-indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 67.02 5.50 8.50 4.30 Find 67.01 5.11 8.47 4.21

DUPLICATE

Example 48 i JV- (4-Hydroxyphenyl) -AT- (1-methyl-17f-indol-5-yl) -3- [2f ((3S) -3- (4-morpholinylmethyl) -3,4 hydrochloride -dihydro-2 (17 /) - l ^s ° qi ¹ > nolinyl) carbonyl] -5 (trifluoromethoxy) phenyl] -5,6,7,8-tetrahydro-l-indolîzine 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 11, and on the other hand the compound of Preparation 1 ”used in Stage C by A- (4- {[terfbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1/7-indol-5-amine.

Elemental microanalysis:

% C% H% N% Cl% cr

Calculated 65.75 5.40

8.33

4.22

4.22

Found 65.78 5.00

8.35

4.33

4.50

Example 49 3- {5-Chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (10isoquinolinyl) carbonyl] phenyl} -jV- (4-hydroxyphenyl) -jV - (13 »3 * tri ^nl ethyl-23-dihydrolH-indol-5-yl) -5,6,7,8-tetrahydro-1-indolizine 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C with A- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) -1,3,3-trimethyl-5-indolinamine, it being understood that the product thus obtained is not subjected to a salification step in presence of hydrochloric ether.

Elemental microanalysis.

%VS % H %NOT Calculated 71.97 6.42 8.93 Find 71.87 6.22 8.94

DUPLICATE

-61 Example 50: N- (4-Hydroxyphenyl) -A ^r - (1-methyl-17 / -indazol-5-y!) - 3 {2,2-dideuterio-6 - [((3S ') hydrochloride -3- (4-morpholinylmethyl) -3,4-dihydro-2 (l //) isoquinolinyl) carhonyl] -13-benzodioxol-5-yl) -5,6,7,8-tetrahydro-l-indolizine 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 9, and on the other hand the compound of Preparation 1 ”used in Stage C by AT- (4 - {[terrbutyl (dimethyl) silyl] oxy} phenyl) -1 -methyl-1 H-indazol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 67.28 5.66 10.46 4.41 Find 66.77 5.07 10.25 3.92

Example 51; Hydrochloride of A ^r - (3-fluoro-4-methylphenyl) -A ^r - (4-hydroxyphenyl) -3 (2 _t 2-dideuterio-6 - [((35) -3- (4-morpholinylniethyl) -3, 4-dîhydro-2 (lZ0isoquInolinyl) carbonyl] -13-benzodioxol-5-y)} - 5,6,7,8-tetrahydro-l-indolizine 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 9, and on the other hand the compound of Preparation 1 ”used in Stage C by jV- (4- {[terfbutyl (dimethyl) siIyl] oxy) phenyl) -3-fluoro-4-methylaniline.

Elemental microanalysis î

%VS % H %NOT % cr Calculated 67.64 5.69 7.17 4.54 Find 67.08 5.18 7.04 4.28

DUPLICATE

-62 Example 52; 3- {5-Chloro-2 - [((35) -3 - [(dimethylamino) methyl] -3,4dihydro-2 (1H) -isoquinolinyl) carbonyl] phenyl} - / V- (4-hydroxyphenyl) hydrochloride -A ^r - (1-methyl-lHindol-5-yl) -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure of PExample 1 is carried out by replacing, on the one hand, the compounds of Preparations 1 and Γ used in Stage A by the respective compounds of Preparations 3 and 8 ', and on the other hand the compound of Preparation 1 ”used in Stage C by ^ - (4 - ((/ ^ / buty 1 (dimethyl) if there is 1] oxy} pheny)) - 1 -methyl-1 H-indo 1-5-amine.

High resolution mass (ESI +):

^Molecular formula: C4 ₃ H42 ^3Î C1N5O ₃ [M + H] ⁺ calculated: 712.3054 [M + H] ⁺ measured: 712.3060

Optical rotation: (a) d ^{20 =} + 35.8 ° (c = 6 mg / mL, MeOH)

Example 53: 3- [5-Chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1H) -isoquinolinyl) carbonyl] phenyl} - / V- (4-) hydrochloride hydroxyphenyl) -A ^r - [4-methoxy-3 (trifluoromethyl) phenyI] -5,6,7,8-tetrahydro-1-indolizine 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 3, and on the other hand the compound of Preparation 1 "used in Stage C by / V- (4 - ([ter / butyl (dimethyl) silyl] oxy} phenyl) -4-methoxy-3- (trifluoromethy)) aniline.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 63.23 5.19 6.70 4.24 Find 63.08 4.68 6.79 3.92

DUPLICATE

-63 Example 54: 3- {5-Chloro-2 - [((35) -3- (4-morpholinylmethyl) -3.4 * dihydro-2 (177) -isoquinolinyl) carbonyl] phenyl} -A ^r - hydrochloride (4-hydroxyphenyl) - / V- [4 (methylsulfanyl) -3- (trifluoromethyl) phenyl] -5,6,7,8-tetrahydro-1-indolizine carboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compound of Preparation I used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation I ”used in Stage C by λ- (4 - ([rer / butyl (dimethyl) silyl] oxy} phenyl) -4- (methylsulfanyl) -3- (trifluoromethyl) aniline.

Elemental microanalysis:

% C% H% N% S% cr

Calculated 62.04 5.09

6.58 3.76 4.16

Found 62.10 4.90

6.61

3.37 3.99

Example 55: 3- {5-Chloro-2 - [((35) -3- (4-morpholinylmethyl) -3,4dihydro-2 (177) -isoquinolinyl) carbonyl] phenyl} -jV- (3-fluoro) hydrochloride -4-hydroxyphenyl) -A ^r - (l15 methyl-177-lndol-5-yl) -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compound of Preparation I used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation I ”used in Stage C by 2V- (4 - {[rerfbutyl (dimethyl) s ily l] oxy} -3-fluorophenyl) -1 -methyl-17f-indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % CT Calculated 66.83 5.48 8.66 4.38 Find 66.84 4.92 8.68 3.63

DUPLICATE

-64 Example 56; / V- (4-Hydroxyphenyl) - / V- (1-methyl-1H-indol-5-yl) -3- {2 [((35) -3- (4-morpholinyImethyl) -3,4- hydrochloride dihydro-2 (l //) - isoquinolinyl) carbonyl] phenyl} -lIndoüzine 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 your Preparation 12, and on the other hand the compound of your Preparation I ”used in Stage C is N- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 W-indol-5-amine.

Elemental microanalysis;

% C% H% n% cr

Calculated 71.84 5.63

9.31

4.71

Found 71.74 5.25

9.24 4.38

Example 57: Bis (hydrochloride) of A ^r - (4-hydroxyphenyl) -A ^r - (1-methyl-17 / -indol-5-yl) 3- {6 - [((3S) -3 - [(4 -methyl-1-piperazinyl) methyl] -3,4-dihydro-2 (l / Z) isoqu in olinyl) carbonyl] -l 3benzodioxol-5-yl} -l-indolizine carboxamide

The procedure of Example 1 is carried out by replacing on the one hand your compounds of Preparations 1 and Γ used in Stage A by the respective compounds of Preparations 13 and 3 ', and on the other hand the compound of Preparation 1 ” used in Stage C by jV- (4 - {[tertbutyl (d imethyl) si ty t] oxy} pheny t) -1 -methyl-1 Hi ndot-5 -amine.

Elemental microanalysis:

% C% H% N% cr

Calculated 66.74 5.48

9.94

8.38

Found 66.69 5.25

9.80 8.03

Rotating power ; (a) o ²⁰ = + 113.2 ° (c = 6 mg / mL, MeOH)

DUPLICATE

-65 Example 58; IV- (4-Hydroxyphenyl) -3- {6 - [((35) -3- (4morpho] inyIméthy]) - 3,4-dihydro-2 (I //) - isoquinoliny]) carbonyl]] - hydrochloride 13-benzodjoxol-5yl} -7V-phenyl-1-indo! Izine carboxamide

The procedure of Example 1 is carried out, on the one hand replacing the compound of Preparation 1 used in Stage A by the compound of Preparation 13.

Elemental microanalysis:

% C% H% N% Cr

Conducted 69.49 5.29

7.54 4.77

Found 69.41 5.00

7.61

4.45

Optical rotation: (a) d ^{20 =} + 111.4 ° (c = 6 mg / mL, MeOH)

Example 59:! V- (4-Hydroxyphenyl) -jV- (1-methyl-1H-Indol-5-yl) -3- {6 [((3S) -3- (4-morpholinylmethyl) -3 hydrochloride, 4-dihydro-2 (liO-isoquinolinyI) carbonyl] -13benzodioxol-5-yl} -l-indo1izine 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 13, and on the other hand the compound of Preparation 1 ”used in Stage C by Af- (4 - {[Zer / butyl (dimethyl) silyl] oxy} phenyl) -1 -methyl-1 W-indol-5-amine.

Elemental microanalysis;

% C ° ÂH% n ° / _o cr

Calculated 69.38 5.32

8.79

4.45

Found 68.95 5.12

8.57 3.92

Optical rotation: (a) d ^{20 =} + 116.8 ° (c = 5 mg / mL, MeOH)

DUPLICATE

-66 Example 60: / V- (1-Ethyl-1H-indol-5-yl) -7V- (4-hydroxyphenyl) -3- {6 [((3S) -3 * (4-morpholinylmethyl) -3 hydrochloride , 4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -13 * benzodioxol-5-y 1} -1 -în do lizin e car hoxamlde

The procedure of Example 1 is carried out by replacing, on the one hand, the compound of Preparation I used in Stage A by the compound of Preparation 13, and on the other hand the compound of Preparation 1 used in Stage C by jV- (4 - {[/ er / butyl (dimethyl) silyl] oxy) phenyl) -1-ethyl-1W-indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr 10 Calculated 69.66 5.47 8.64 4.38 Find 69.81 5.13 8.64 4.30

Example 61: Hydrochloride of A ^r - (4-Hydroxyphenyl) -A ^r - (1-methyl! -2,3-dihydro-1Hindol-5-y!) - 3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) isoqulnolînyl) carbony!] - 13-benzodioxo! -5-yl} -l * indo! Izine carboxamide

Î5 The procedure of Example l is carried out by replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 13, and on the other hand the compound of Preparation 1 ”used in Stage C by W- (4 - {[ferfbutyl (dimethyl) silyl] oxy) phenyl) -1-methyl-5-indolinamine.

High resolution mass (ESI +):

Molecular Formula: C46H43N5O6 [M + H] ⁺ Calculated: 762.3292 [M + H] ⁺ Measured: 762.3284

DUPLICATE

Example 62: JV- (4-Hydroxyphenyl> JV- {1-isopropyl-1W-indoI-5-yI) -3 {6 -] ((3S) -3- (4-niorpho! Inylmethyl) -3 hydrochloride ₍ 4-dihydro-2 (1H) -isoquino! Inyl) carbony!] - 13benzodioxoL5-y!} - l-indo! Izine carboxamide

The procedure is carried out according to the method of Example i, replacing on the one hand the compound of Preparation I used in Stage A by the compound of Preparation 13, and on the other hand the compound of Preparation 1 ”used in Stage C by 7V- (4 - {[terfbuty l (d imethyl) si ly 1 Joxy} phenyl) -1 -isopropyl-1 H-indol-5-amine.

Elemental microanalysis: (theory for 1.3 HCl)

%VS % H %NOT % cr Calculated 69.94 5.62 8.50 4.30 Find 69.66 5.50 8.42 4.28

Example 63; JV- (1-Ethy! -23-dihydro-1/7-indoI-5-yI) -JV- (4hydroxypheny)) - 3- {6 - [((3S) -3- (4-morpholinylmethyl) hydrochloride! ) -3,4-dihydro-2 (l £ 0isoquinolinyl) carbonyI] -13 * benzodioxol-5-yl} -l-lndolizine carboxamide

The procedure is carried out according to the process of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 13, and on the other hand the compound of Preparation 1 ”used in Stage C by A- (4 - ([rerfbutyl (dimethyl) silyl] oxy} phenyl) -1-ethyl-5-indolinamine.

Elemental microanalysis: (theory for 1.3 HCl)

%VS % H %NOT % CT Calculated 68.57 5.67 8.51 5.60 Find 68.11 5.23 8.36 5.65

DUPLICATE

Example 64: A / - (4-Hydroxyphenyl) -2V- (1-isopropyl-23-dihydro-1Zfindol-5-yl) -3- {6 - [((35) -3- (4-morpholinylmethyl) hydrochloride ) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -13-benzodioxol-5-yl) -l-indolizine 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 13, and on the other hand the compound of Preparation 1 ”used in Stage C by JV- (4 - {[/ er / butyl (dimethyl) siIyl] oxy} phenyl) -1-isopropyl-5-indoIinamine.

Elemental microanalysis: (theory for 1.3 HCl)

%VS % H %NOT % cr Calculated 68.85 5.81 8.36 5.50 Find 68.58 5.68 8.49 5.10 Example 65 t Bis (hydrochloride) of 3- {5-chloro-2 - [((33) -3 - [(4-methy 1-1

piperazinyl) methyl] -3,4-dihydro-2 (lJ /) - isoquino! inyl) carbonyl] phenyl} -7V- (4hydroxypheny!) - A- (1-methyl-lW-indol-5-yl) -l -indolizine carboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compounds of Preparations 1 and Γ used in Stage A by the respective compounds of Preparations 14 and 3 ', and on the other hand the compound of Preparation 1 ” used in Stage C by 7V- (4- {[/ erfbutyl (dimethyl) silyl] oxy} phenyl) -i-methyM / Aindol-5-amine.

Elemental microanalysis: (theory for 1.9 HCl)

%VS % H %NOT % cr Calculated 66.36 5.44 10.09 8.09 Find 66.35 5.38 9.86 7.70

DUPLICATE

Example 66: Bis (hydrochloride) of 3- {5-chloro-2 - [((3S) -3- (4-inorpholiiiyIinethyl) -3,4dihy dro-2 (17 /) - isoqu inoliny l) ca rhony I ] ph ény l} -7V- (4-hy d roxyph ény!) - / V- (1 -mé thy 1-2 3 * dihydro-lH-indol-5-yl) -l-indolîzine 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 14, and on the other hand the compound of Preparation 1 ”used in Stage C by / V- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) -I-methyl-5-indolinamine.

Elemental microanalysis:

%VS % H %NOT % Cl 10 Calculated 65.50 5.37 8.49 12.89 Find 66.02 4.91 8.50 12.11

Optical rotation: (a) d ^{20 =} + 142.2 ° (c = 3.5 mg / mL, MeOH)

Example 67; 3- {5-Chloro-2 - [((35) -3- (4-morphoinin! Methyl) -3,4dihydro-2 (1/7) -isoquinolinyl) carbonyI] phenyl) -jV- (4-) hydrochloride hydroxyphenyl} - / V- (l-methyl-lH15 indol-5-yI) ~ l-indoIizine 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 14, and on the other hand the compound of Preparation 1 ”used in Stage C by ^ - (4- ([ter / · butyl (dimethyl) silyl] oxy} phenyl) -I-methyl-1 // - indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 68.70 5.25 8.90 4.51 Find 68.43 4.88 8.83 4.13

Optical rotation: (a) d ²⁰ = + 133.3 ° (c = 3.5 mg / mL, MeOH)

DUPLICATE

-70 Example 68; 3- {5-Chloro-2 - [((35) -3- (4-morphoIinyImethyl) -3,4dihydro-2 (1 //) - isoquinoIinyl) carbonyl] phenyI} -A ^r - (4-nuorophényI) hydrochloride ) -jV- (1-methyl-17 / indoI-5-yI) -l-indolizine carboxamide

The procedure of Example 1 is carried out, on the one hand replacing the compound of

Preparation I used in Stage A by the compound of Preparation 14, and on the other hand the compound of Preparation I ”used in Stage C by A ^r - (4-fluorophenyl) -l-methyl-l / A indol- 5-amine, it being understood that Stage D is then limited to a step of forming the hydrochloride.

Elemental microanalysis:

10 %vs % H %NOT % cr Calculated 68.53 5.11 8.88 4.49 Find 68.48 4.71 9.09 4.28

Example 69; A ^r - (4-Hydroxyphenyl) 'A- (1-methyl-1 ^ 3J-tetrahydro15 6-quinolinyI) -3- {7 - [((35) -3- (4-morpholinylmethyl) -3,4 hydrochloride -dihydro-2 (lf /) isoquinolinyl) carbonyl] -23-dihydro-l, 4-benzodioxin-6-yl} -l-indolizine 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 15, and on the other hand the compound of Preparation 1 ”used in Stage C by A ^r - (4 - {[/ eri20 butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1,2,3,4-tetrahydro-6-quinolinamine.

High resolution ground (ESI +);

Molecular Formula: C48H47NSO6 [M + H] ⁺ Calculated: 790.3605 [M + H] ⁺ Measured: 790.3591

DUPLICATE

Example 70: 2V- (4-Hydroxyphenyl) -JV- (1-methyl-1H-indol-5-yl) -3- {7 [((35) -3- (4-morpho! Inylmethyl) - hydrochloride 3,4-dihydro-2 (1H) -isoquinoIinyl) carbonyl] -23dihy dro-1,4-benzo dioxin-6-y 1} - 1-in do lizine 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 15, and on the other hand the compound of Preparation Γ * used in Stage C by V- (4 - ([rer / butyl (dimethyl) silyl] oxy} pheny!) - 1-methyl-1 // - indol-5-amine.

Elemental microanalysis;

%VS % H %NOT % Cl % cr 10 Calculated 69.66 5.47 8.64 4.38 4.38 Find 69.45 4.68 8.56 4.64 4.21

Example 71; 2V- (4-Hydroxyphenyl) -3- [5-methoxy-2 - [((3S) -3- (4morphoIinylmethyl) -3,4-dihydro-2 (1 / Z) -Îsoquinolinyl) carbonyl] phenyl-hydrochloride 2V- (1-methyll / 7-indol-5-yl) -l-indolizine carboxamide

The procedure is carried out according to the method of Example 1, replacing on the one hand the compound of Preparation I used in Stage A by the compound of Preparation 16, and on the other hand the compound of Preparation 1 ”used in Stage C by jV- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1W-indol-5-amine.

High resolution ground (ESI +).

Molecular Formula: C46H43N5O5 [M + H] * Calculated: 746.3342 [M + H] * Measured: 746.3348

DUPLICATE

-72Example 72: 8 - {[4-Hydroxy (1-methyl-1H-indoI-5-yI) anilino] carbonyl} -6- {6 - [((35) -3 (4-morpho! Inylmethyl!) - 3,4-dihydro-2 (1H) -isoquinoliny!) Carbonyl] -13-beiizodÎoxo! -5yl} -3,4-dihydropyrrolo [13-u] pyrazine-2 (1 //) - / erf-butyl carboxylate

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 17, and on the other hand the compound of Preparation 1 ”used in Stage C by 7V- (4 - {[forfbutyl (dimethyl) silyl] oxy} pheny]) - 1-methyl-1/7-indol-5-amine, it being understood that the product thus obtained is not subjected to a salification step in the presence of hydrochloric ether.

Elemental microanalysis.

10 %VS % H %NOT Calculated 69.43 6.06 9.72 Find 69.41 5.84 9.68

Example 73: 8 - {[4-Hydroxy (1-methyl-23-dihydro-1H-indol-5-y!) Anilino] carbonyl} -6 {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -i ^s oq ^u > ⁿ ol> ⁿ yl) carbonyI] -1315 benzodioxo! -5-yl} -3,4-dihydropyrro! O [l, 2-a] pyrazine -2 (lZ /) - tert-butyl carboxylate

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 17, and on the other hand the compound of Preparation 1 ”used in Stage C by // - (4 - {[iron / butyl (dimethyl) silyl] oxy} pheny]) - 1-methyl-5-indolinamine, it being understood that the product thus obtained is not subjected to a salification step in the presence of hydrochloric ether.

Elemental microanalysis;

%VS % H %NOT Calculated 69.27 6.28 9.69 Find 69.20 6.11 9.77

DUPLICATE

Example 74: Bis (hydrochloride) of M (4-hydroxyphenyl) -2V- (1-methyl-1/7-indol-5-y)) ^ • {i »* [((3 * S) -3- (4-mon> holinylméthy]) - 3,4 * <l> hy <lr (> - 2 (lZZ) -isoquÎno! Inyl) carbonyl] -13 · benzodioxol-5-y!) - 133> 4-tetrahydrOpyrrolo [ 13 - <* lpyrazine-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 17, and on the other hand the compound of Preparation 1 ”used in Stage C with N- (4 - {[tertbutyl (dimethyl) silyl] oxy} phenyl) -l-methyl-1H-indol-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.

Elemental microanalysis: (theory for 1.9 HCl)

%VS % H %NOT % cr Calculated 64.80 5.55 10.08 8.08 Find 64.48 5.41 9.85 7.84

Example 75: / V- (4-hydroxyphenyl) - / V- (1-methyl-23-dihydrO '1H-indoI-5-yl) -6- {6 - [((35) -3 tris (hydrochloride) - (4-morpholinyImethyl) -3,4-dihydro-2 (1 //) - lsoquino! Inyl) carbonyl] -13-benzodioxol-5-yl} -l, 23 _t 4-tetrahydropyrrolo [1,2-a] pyrazine-8carboxamide

The procedure of Example 1 is carried out, on the one hand replacing the compound of

Preparation 1 used in Stage A by the compound of Preparation 17, and on the other hand the compound of Preparation I ”used in Stage C by / 7- (4- ([ter / butyl (dimethyl) silyl] oxy) phenyl) -1-methyl-5-indolinamine, 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! .. The compound thus obtained is deprotected in the presence of 10 equivalents of trifluoroacetic acid in dichloromethane (10

DUPLICATE

-74mL / 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 t

5 %VS % H %NOT % cr Calculated 61.68 5.64 9.59 12.14 Find 61.65 5.35 9.45 11.72

Example 76 B is (chl or hydrate) of 7V- (4-hydroxyphenyl) -7V- (1-methylHH-indol-5′yl) -

5- {6 - [((3S) -3-I (4-methyl-1-piperazinyl) methyl] -3,4-dihydro-2 (1/7) -isoquinolinyl) carbonyl] -13-benzodioxol-5- yl} -23-dihydro-1H-pyrrolizine-7-carboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compounds of Preparations I and Γ used in Stage A by the respective compounds of Preparations 18 and 3 ', and on the other hand the compound of Preparation 1 ” used in Stage C by M (4 - {[tertbutyl (dimethyl) silyl] oxy) phenyl) -1-methyl-1W-indol-5-amine.

High resolution ground (ESI +);

Molecular Formula: C46H46N6O5 [M + H] ⁺ Calculated: 763.3608 [M + H] ⁺ Measured: 763.3594

Example 77: Bls (hydrochloride) of 5- {5-chloro-2 - [((3S) -3 - [(4-methyl-120 piperazinyl) methyl] -3,4-dihydro-2 (1 W) -isoquinoIinyl ) ca ^r bonyl] phenyl} -A- (4hydroxyphenyl) -7V- (1-niethyl-1H-indol-5'yl) -23-dihydro-1H-pyrrolizine'7carboxamide

The procedure is carried out according to the process of ('Example 1 by replacing on the one hand the compounds of

Preparations 1 and Γ used in Stage A by the respective compounds of Preparations 19 and

3 ', and on the other hand the compound of Preparation 1 ”used in Stage C by? / - (4 - {[teributyl (dimethyl) silyl] oxy} phenyl) -i-methyl-i // - indol- 5-amine.

DUPLICATE

-75 Elemental microanalysis: (theory for for 1.9 HCl)

%VS % H %NOT % cr Calculated 65.70 5.75 10.22 8.19 Find 65.46 5.55 10.68 7.65

Example 78; 6- {5-Chloro-2 - [((3S) -3- (4-morphoIinyImethyl) -3,4dihydro-2 (1H) -ÎsoquinoIinyI) carbonyIlphenyl} -7V- (4-hydroxyphenyl) -7V-phenyl hydrochloride -3,4dihydro-17 / -pyrrolo [2, lc] [1,4] oxazine-8-carboxamide

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation 1 used in Stage A by the compound of Preparation 20.

Elemental microanalysis:

% C% H% N% cr

Calculated 66.57 5.45

7.57 4.79

Found 66.22 5.23

7.53 4.57

Example 79 t Bis (hydrochloride) of 6- {5-chloro-2 - [((3 <S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (177) -isoquinolinyl) carbonyI] phenyl} -7V - (23-dIhydro-1/7-indol-5-yI) - / V- (4hydroxyphenyl) -3,4-dihydro-1H-pyrroIo [2, 1-cJ [1,4] oxazine-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 20, and on the other hand the compound of Preparation 1 ”used in Stage C by 7V- (4 - {[tertbutyl (dimethyl) silyl] oxy) phenyl) -5-indolinamine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 63.20 5.43 8.57 8.68 Find 62.64 5.19 8.39 8.03

DUPLICATE

-76 Example 80; 7V- (4-Hydroxyphenyl) -jV- (1-methy 1-1 H-indol-5-y 1) -6- {6 - [((35) -3- (4morpholinylmethyl) -3,4-dihydro- 2 (1H) '* soquinolinyl) carbonyl] -1,3-benzodioxol-5yl} -3,4-dihydro-1 H-py rrolo [2,1 -c] [1,4] oxazine-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 21, and on the other hand the compound of Preparation 1 ”used in Stage C with V- (4 - ([forfbutyl (dimethyl) silyl] oxy} phenyl) -l-methyl-1 // - indol-5-amine, it being understood that the product thus obtained is not subjected to a step of salification in the presence of hydrochloric ether.

Elemental microanalysis:

%VS % H %NOT Calculated 70.57 5.66 9.14 Find 69.99 5.53 9.04

Example 81: A / '- (4-Hydroxyphenyl) -2V- (1-methyl-23' <lihydro-1Hindol-5-yl) -6- {6 - [((35) -3- (4-) hydrochloride morpholinylmethyl)) - 3,4-dihydro-2 (li /) - isoquinolinyl) carbonyl] -13-benzodioxol-5-yl} -3,4-dihydro-l // - pyrrolo [2, lc] [l, 4 ] oiazine-8carboxamide

The procedure of Example i is carried out by replacing, on the one hand, the compound of Preparation 1 used in Stage A by the compound of Preparation 21, and on the other hand the compound of Preparation 1 ”used in Stage C by 7 / - (4- {[teributyl (dimethyl) silyl] oxy} phenyl) -1-methyl-5-indolinamine.

Elemental microanalysis;

%VS % H %NOT % cr Calculated 67.20 5.76 8.71 4.41 Find 66.67 5.60 8.66 5.10

DUPLICATE

Example 82: 6- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (lZ /) - i3oquinoIinyl) carbonyl] phenyl} -A ^r - ( 3-fluoro-4-methylphenyl) -7V- (4hydroxyphenyl) -3,4-dihydro-1H-pyrrolo [2, lc [[[l, 4 [oxazine-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 20, and on the other hand the compound of Preparation 1 ”used in Stage C by? / - (4 - {[terrbutyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4-methylaniline.

Elemental microanalysis î

%VS % H %NOT % Cl % cr Calculated 65.37 5.35 7.26 9.19 4.59 Find 65.49 4.67 7.45 9.18 4.40

Optical rotation: (a) d ²⁰ = + 35.0 ° (c = 6 mg / mL, MeOH)

Example 83; 3- {5-Chloro-2 - [((35) -3- (4-morphoIinylmethyl) -3,4dihydro-2 (1H) -isoquinolinyl) carbonyl] phenyl} -2V- (4-hydroxyphenyl) -Ar hydrochloride - (1-methyl-1H in dol-6-yl) -6,7,8,9-tetrahydro-5 / f-pyrrolo | 13-uIazepine-1-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 22, and on the other hand the compound of Preparation 1 ”used in Stage C by? 7- (4 - {[ter / buty 1 (dimethyl) sily l] ox y} phenyl) -1 -methyl-1 W-indol-5-amine.

High resolution ground (ESI +);

Molecular ^formula : C4eH46 ^3î ClNsO4 [M + Hf calculated: 768.3317 [M + H] ⁺ measured: 768.3254

Example 84: JV- (4-Hydroxyphenyl) -2V- (1-methyl-1W-indol-6-yl) -3- {6 | ((3S) -3- (4-morpholinylmethyl) -3,4 hydrochloride -dihydro-2 (lJ7) -i3oquinolinyl) carbonyI] -l, 3benzodioxol-5-yl} -6,7,8,9-tet rahy dro-5H-py rrolo [1,2-a] azepine-1-ca rboxamide

DUPLICATE

The procedure is carried out according to the process of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 23, and on the other hand the compound of Preparation 1 "used in Stage C by JV- (4 - ([ierf · butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1W-indol-5-amine.

Elemental microanalysis t

%VS % H %NOT % cr Calculated 69.32 5.94 8.60 4.35 Find 69.42 5.52 8.74 4.05

Rotating power ; (a) _D ^{20 =} + 86.6 ”(c = S mg / mL, MeOH)

Example 85: 3- {5-Chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1Z /) 'isoquinolinyl) carbonyl] phenyl) -7V- (4-) hydrochloride hydroxyphenyl) -jV- (3-thienyl) -

5,6,7,8-tetrahydro-l-indolizine carhoxamide

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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 7V- (4- {per / butyl (dimethyl) silyl] oxy} phenyl) -3-thiophenamine.

Elemental microanalysis.% C% H% N

% cr

Calculated 64.60 5.42

7.53 4.31

4.77

Found 64.67 5.05

7.37 3.90 4.19

Example 86; 6- {5-Chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (1 //) - isoquinolinyl) carbonyl] phenyl) -7V- (4-hydroxyphenyl) hydrochloride -A ^f - (1-methyMHindol-5-yl) -3,4-dihydro-1H-pyrrolo [2, lc] [l, 4] oxazine-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 20, and on the other hand the

DUPLICATE

-79compound of Preparation 1 ”used in Stage C by buty! (Dimethyl) silyl] oxy} phenyl) -1-methyl-1 // - indol-5-amine.

High resolution ground (ESÏ +):

Molecular formula: C ^ Hn ^ ClNjOi [M + H] ⁺ calculated: 756.2953 [M + H] ⁺ measured: 756.2936

Example 87: AM> utyWV- (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4morpholiny! Methyl) -3,4-dihydro-2 (170-isoquinolinyl) carbonyll-13 'hydrochloride benzodioxol-5-yl} -5,6,7,8-tetrahydro-l-indolizine carboxamide

The procedure of Example 1 is carried out, replacing the compound of Preparation

1 ”used in Stage C by 7V-butyl-4 - {[/ err-butyl (dimethyl) slyl] oxy} aniline.

Elemental microanalysis.

%VS % H %NOT % cr Calculated 67.71 6.51 7.70 4.87 Find 67.48 6.30 7.74 5.01

Example 88: Mbutyl-jV hydrochloride - [(3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4dihydro-2 (I //) - isoquinolinyl) carbonyll-13-benzodioxol-5 -yl} -5,6,7,8-tetrahydro-lindolizinyl) methyl [-l-butanamine

The procedure of Example 1 is carried out, replacing the compound of Preparation 1 ”used in Stage C by ΛζΎ-dibuty laminamine, it being understood that Stage D is then limited to a step of forming the hydrochloride.

High resolution mass (ESI +):

Molecular Formula: C39H50N4O5 [M + Hf Calculated: 655.3859 [M + H] ⁺ Measured: 655.3826

DUPLICATE

Example 89: 3- {5-Chloro-2 - [((35) -3- (4-morpho! Iny! Methyl) -3,4dihydro-2 (1/7) -Îsoquinolinyl) carbonylIphenyl} -j hydrochloride ^/ V- (3-hydroxypropy!) - J'V- (l-methyl-l // lndol-5-yl) -5,6,7,8-tetrahydro-l-indolizine 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by JV- (3 - {[rerrbutyl (dimethyl) silyl] oxy} propyl) -1 -methyl-1 H-indol-5-amine.

Elemental microanalysis:

% C% H% N% Cl% Cr

Calculated 66.66 6.26

9.25

9.37 4.68

Found 66.51 5.87

9.25

9.12

4.21

Example 90: 3- {5-Chloro-2 - [((3S) -3- (4-morpholiny! Methy!) - 3,4dihydro-2 (1ZO-isoquinolinyl) carbonyl] phenyl} -AT- (4 -hydroxybutyl) -N- (1-methyl-l Wlndol-5-yl) -5,6,7,8-tetrahydro-l-indolizine 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by N- (3- {[tertbutyl (dimethyl) silyl] oxy} butyl) -1-methyl-1 // - indol-5-amine.

Elemental microanalysis:

% C% H% n% cr

Calculated 67.01 6.41

9.09 4.60

Found 66.93 5.88

9.23 4.30

Example 91: AT- (3-fluoro-4-methylphenyl) -3- (5-fluoro-2 - {[(3S) -3 (morpholin-4-ylmethyl)) - 3,4-dihydroisoquinolin-2 ( l //) - yl] carbonyl} phenyl) -A ^r - (4hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-l-carboxamide

DUPLICATE

The procedure is carried out according to the method of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 4, and on the other hand the compound of Preparation 1 ”used in Stage C by A- (4 - {[iron / butyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4-methylaniline.

Elemental microanalysis.% C% H% n% cr

Calculated 68.56 5.75

7.44 4.71

Found 68.57 5.23

7.53 4.74

Example 92: 7V- (3-Fluoro-4-methylphenyl) -A '' - (4-hydroxyphenyl) -6 (6 - {[(35) -3- (morpholin-4-ylmethyl) -3,4 hydrochloride -dihydroisoqulnolin-2 (lZ /) - yl] carbonyI} -13benzodioxoI-5-yI) -3,4-dihyd ro-l // - py rrolo [2,1 -c] [1,4] oxazine-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 21, and on the other hand the compound of Preparation 1 ”used in Stage C by A- (4- (per / butyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4-methylaniline.

Elemental microanalysis:

% C% H% n% cr

Calculated 66.11 5.42

7.17 4.54

Found 66.02 4.92

7.13 4.26

Example 931 3- (5-Chloro-2 - ([(3R) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinoIin-2 (1 //) - yllcarbonyI} phenyl) -7V- (4- hydrochloride) hydroxyphenyl) -7V- (1-methyl-1 / 7indol-5-y 1) -5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure of Example 1 is carried out, on the one hand replacing the compounds of

Preparations I and Γ used in Stage A by the compounds of Preparations 3 and 2 ', and on the other hand the compound of Preparation 1 ”used in Stage C by A- (4 - {[/ erfbutyl (dimethyl) silyl] oxy) phenyl) -1-methyl-1/7-indol-5-amine.

DUPLICATE

-82 Elemental microanalysis:

%vs % H %NOT % Cl % cr Calculated 68.35 5.74 8.86 8.97 4.48 Find 68.27 5.14 8.92 8.70 4.08

Example 94: A- (4-Hydroxyphenyl) -jV- (1-methyl-1 // - indazol-5-yl) -3 (6 - {[(3S) -3- (morphonn-4-ylmethyl) hydrochloride -3,4-dihydroisoqulnoIin-2 (l //) - yI] carbonyl} -13benzodioxol-5-yl) -5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure of Example 1 is carried out by replacing the compound of Preparation 1 ”used in Stage C by N- (4 - {[terZ-butyl (dimethyl) silyl] oxy} phenyl) -l-methyl-1Hindazol -5-amine.

Elemental microanalysis:

% C% H% n% cr

Calculated 67.45 5.66

10.49 4.42

Found 67.40 5.19

10.40 4.11

Example 95; 7V- (4-Hydroxyphenyl) -7V- (1-methyl-1 // - indol-5-yl) -3- (5methyl'2 - {] (35) -3- (morpholin-4-ylmethyl) hydrochloride -3,4-dihydroisoquinonn-2 (1H) -yi] carbonyl} phenyl) -5,6,7,8-tetrahydroindoiizine-1-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 25, and on the other hand the compound of Preparation 1 ”used in Stage C by N- (4 - ([terfbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 // - indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 71.72 6.28 9.09 4.60 Find 71.17 5.66 8.85 4.47

DUPLICATE

-83 Example 96; / V- (4-Hydroxyphenyl) -A '- (1-methyl! -LH-indol-5-yl) -5- (6 {[(35) -3- (morpholÎn-4-ylmethyl) -3 hydrochloride , 4-dihydroÎsoquîno! In-2 (1Zf) -yl) carhonyl} -13henzodioxol-5-yl) -23-dîhydro-lZ / -pyrrolîzine-7-carboxamide

The procedure is carried out according to the method of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 18, and on the other hand the compound of Preparation Γ * used in Stage C by N- (4 - {[zerZbutyl (dimethyl) silyl] oxy} pheny 1) -1 -methyl-1 H-indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 68.74 5.64 8.91 4.51 Find 68.41 4.96 8.84 4.31

Example 97; 2V- (3-Chloro-4-methylphenyl) -3- (5-chloro-2 - {[(35) -3 (morpholin-4-ylmethyl) -3,4-dihydroisoquinolÎn-2 (lZ /) - hydrochloride yl] carbonyl} phenyl) -A ^r - (4hy droxypheny 1) -5,6,7,8-tetrahyd roindolizin-1 -ca rhoxam id e

The procedure is carried out according to the method of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by jV- (4 - {[ZerZbutyl (dimethyl) silyl] oxy) phenyl) -3-chloro-4-methylaniline.

Elemental microanalysis:

% C% H% n% cr

Calculated 65.69 5.51

7.13 4.51

Found 65.58 5.03

7.05 4.25

Example 98; / V- (3-Fluoro-4-methylphenyl) -6- (5-fluoro-2 - {[(35) -3 (morph olin-4-y! M ethy l) -3,4-d ihy hydrochloride droisoqu inol in-2 (1 ZQ-y I] carbonyl} ph enyl) -JV- (4hydroxyphenyl) -3,4-dihydro-1 // - pyrro! o [2, lc] [1,4] oxazine-8 -carboxamide

DUPLICATE

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 26, and on the other hand the compound of Preparation 1 ”used in Stage C is 7V- (4 - {[feributyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4-methylaniline.

High resolution ground (ESI +);

Molecular formula: C42H40F2N4O5 [M + H] ⁺ calculated: 719.3045 [M + Hf measured: 719.3030

Example 99: 6- (5'fluoro-2 "{[(35) -3- (morpholin-4-ylmethyl) -3,410 dihydroisoquinolin-2 (1 //) - yl] carbonyl} phenyl) -j'V hydrochloride - (4-nuorophenyl) -jV- (4hydroxyphenyl) -3,4-dihydro-1H-pyrrolo [2, lc] [1,4] oxazine-8-carhoxamide

The procedure is carried out according to the process of ['Example 1, replacing on the one hand the compound of Preparation t used in Stage A by the compound of Preparation 26, and on the other hand the compound of Preparation t ”used in Stage C by 4 - {[/ err-butyl (dimethyl) silyl] oxy} 15 7V- (4-fluorophenyl) aniline.

High resolution ground (ESI +) î

Molecular Formula: C41H38F2N4O5 [M + H] ⁺ Calculated: 705.2889 [M + H] ⁺ Measured: 705.2882

Example 100: 3- (5-Fluoro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4d ihydroisoquînolin-2 (1 //) - yl] carbonyl) phenyl) -7 hydrochloride -hyd roxy-JV- (4-hyd roxy phenyl> JV · phenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

Stage A: 3 '- (5-Fluoro-2 - [[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin2 (1H) -yl] carbonyl} pltenyl) -5', 6 ' methyl-dihydro-8'H-spiro [1,3-oxolane-2,7'-indolizineJ-1 carboxylate

DUPLICATE

The procedure is carried out according to Stage A of Example 1, replacing the compound of Preparation 1 with the compound of Preparation 27.

Stage B r 3- (5-Fluoro-2 - {[(3S) -3- (morpholin'4-ylmethyl) -3,4 ~ dlhydroisoquinolin2 (lH) -yl] carbonyl} phenyl) -7- (prop ~ 2 -en ~ l ~ yloxy) -5,6,7,8-tetrahydrolndolizine-methylcarboxylate

The procedure is carried out in Steps B, C and D of Example 113.

Stage C; N- (4 - {[tert-Butyl (dimethyl) silyl] oxy} ph enyl) -3- (5-fluoro-2 - {[(3S) -3 (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin -2 (! H) -yl / carbonyl} phenyl) -N-phenyl-7 (prop-2-en-I-yloxy) -5,6,7,8-tetraliydroindolizine-1-carboxamide

The procedure is carried out according to the methods of Steps B and C of Example 1.

Stage D i N- (4 - {[tert-Biityl (dimethyl) silylJoxy} phenyl) -3- (5-fliioro-2 - {[(3S) -3 (morpholin-4-ylmétltyl) -3,4-dihydrolsoquinolin -2 (1H) -yl / carbonyl} phenyl) -N-plienyl-7hydroxy-5,6,7,8-tetrahydroindolizine-I-carboxamide

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

Stage E ΐ 3- (5-Fluoro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroÎsoquinolin-2 (1H) -ylJcarbonyl} phenyl) -7-hydroxy-N- hydrochloride (4-hydroxyphenyl) -Nphenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

The deprotection of the ferf-butylsilyloxy group is carried out according to the method of Stage D of Example 1.

Elemental microanalysis:

%VS % H %NOT Calculated 71.98 5.90 7.99 Find 71.18 5.98 7.18

DUPLICATE

-86 High resolution mass (ESI +):

Molecular formula: C42H42FN4O5 [M + Hf calculated: 701.3139 [M + Hf measured: 701.3134

Example 101; 6- (5-Chloro-2 - {[(3S) -3- (morphoIin-4-ylm £ thyï) -3,4dihydroisoquinolin-2 (1/7) -yllcarbonyI} phenyl) -7V- (4-) hydrochloride hydroxyphenyl) -7V- (1-methyl-1Hindazol-5-yl) -3,4-dihydro-17 / -pyrrolo | 2, lc] [1,4] oxazine-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 20, and on the other hand the compound of Preparation 1 ”used in Stage C by jV- (4- {[rerrbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-17 / -indazo [-5-amine.

Elemental microanalysis.

%VS % H %NOT Calculated 65.07 5.33 10.59 Find 65.54 4.86 10.57

Example 102! (2Jî) -5- (5-fluoro-2 - {[(3S) -3- (morpholiii-4-ylmethyl) - hydrochloride

3,4-dihydroisoquino! In-2 (170-yl] carbonylJphenyl) -2-hydroxy-7V- (4-hydroxyphenyI) 7V-phenyl-23 * dihydro-1H-pyrro! Izine-7-carhoxamide

Stage A: (2R) -2 - {[tert-Butyl (dimethyl!) Silyl] oxy} -5- (5-fluoro-2 - {[(3S) -3- (morpholin4-ylmétliyl) -3,4- methyl diliydroisoquinolin-2 (1H) -y!] carbonyl} phenyl) -2,3-dihydro-IHpyrrolizine-7-carboxylate

The procedure is carried out in Stage A of Example 1, replacing the compound of Preparation I with the compound of Preparation 28.

Stage B: (2R) -5- (5-Fluoro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-diltydro isoquinolin-2 (1H) -ylJcarbonyl} phenyl) -2 -hydroxy-2 _t 3-dihydro ~ methyl lH-pyrrolizine-7carboxylate

DUPLICATE

-87A a solution of the compound of Stage A (1g; 1.54 mmol) in THF (8 mL) is added a 1 M solution of tetrabutylammonium fluoride (1.7 mL; 1.7 mmol). The reaction medium is stirred for 3 h at room temperature, then the THF is evaporated off and replaced with ethyl acetate. The organic phase is washed with water, brine, before being dried over MgSCh, filtered and concentrated to dryness. The crude product obtained (830 mg) is used as it is in the next step.

1 H NMR: δ (500 MHz; dmso-d6; 300 ° K) 7.55-6.9 (m, 7H, aromatic Hs); 6.55-6.35 (m, 1H, H aromatic dihydropyrrolizine); 5.5-5.3 (m, 1H, alcohol); 5.25-4.6 (m, 1H, tertiary H tetrahydroisoquinoline); 5.0-4.2 (m, 2H, aliphatic H tetrahydroisoquinoline);

4.95-4.62 (m, 1H, HCOH); 3.7-3.6 (bs, 3H, OMe); 3.6-3.2. (m, 2H, 2H, H aliphatic dihyropyrrolizine); 3.7-3.5 (m, 4H, H morpholine); 3.0-2.4 (m, 2H, aliphatic H tetrahydroisoquinoline); 2.6-1.96 (m, 4H, H morpholine); 2.6-1.96 (m, 2H, H aliphatic dihydropyrrolizine)

Stage C t (2R) -5- (5-Fluoro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydro isoquinolin-2 (1H) -yl] carbonyl} phenyl) Methyl -2- (prop-2-en-1-yloxy) -2,3-dihydro-1Hpyrrolizine-7-carboxylate

To a suspension of 62 mg (1.54 mmol) of sodium hydride in 8 mL of anhydrous THF cooled to 0 ° C, a solution of the compound of Stage B (820 mg; 1.54 mmol) in THF (6 mL). This suspension is stirred for 15 minutes at 0 ° C. Then 0.15 mL (1.69 mmol) of allyl bromide is added dropwise. The reaction medium is stirred for 5 h at room temperature, then hydrolyzed with a saturated aqueous solution of sodium bicarbonate, and extracted with dichloromethane. The organic phase is dried over MgSOi, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (gradient: dichloromethane / ammoniacal methanol) to yield the title product in solid form.

1 H NMR: δ (500 MHz; dmso-d6; 300 ° K): 7.5-6.8 (m, 7H, aromatic Hs); 6.55-6.3 (m,

1H, H aromatic dihydropyrrolizine); 5.9 (s, 1H, H allyl); 5.3-5.2 (m, 2H, H allyl);

5.2-5.0 (m, 1H, tertiary H tetrahydroisoquinoline); 5.0-4.2 (m, 2H, aliphatic H tetrahydroindolizine); 4.7-4.42 (m, 1H, HCOallyl); 4.6-3.85 (m, 2H, aliphatic H

DUPLICATE

-88dihydropyrrolizine); 4.6-3.85 (m, 2H, allylic CH2); 3.7-3.5 (m, 3H, OMe); 3.65-3.5 (m, 4H, morpholine); 3.3-2.4 (m, 4H, morpholine and H aliphatic dihydropynolidine);

2.4-1.7 (m, 6H, morpholine and CH2N)

Stage D: (2R) ~ N- (4 - {] tert-butyl (dîmethyl) sîlyl] oxy} phenyl) -5- (5-fluoro ~ 2 - {] (3S) -3 (morpho! In-4- ylmethyl) ~ 3,4-dihydroisoquinolin-2 (IH) -yl / carbonyl} pérty!) - N-plienyl-2 ~ (prop-2-en-1-yloxy) -2,3-dihydro-1H-pyrrolizine- 7-carboxamide

We proceed according to the procedures of Steps B and C of Example 1.

Stage E: (2R) -N- (4 - {] tert-biityl (dimethyl) silyl] oxy} phenyl) -5- (5 ~ fluoro-2- {I (3S) -3 (morpholin-4-y! methyl) -3,4-dihydroisoquinolin-2 (1H) -yl / carbonyl} phenyl) -2-hydroxy-Nphenyl-2,3-diliydro-1H-pyrrolizine-7 ~ carboxamide

A deprotection reaction of the allyl group is then carried out in the presence of 1,3dimethylpyrimidine-2,4,6 (1 //, 3H, 5H) -trione (also called dimethylbarbiturate) and tetrakis (triphenylphosphine) palladium (Synlett, 2007, 21, p 3136).

Stage F: (2R) -5- (5-fluoro-2 - {/ (3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1H) -yl / carbonyl} plienyl) hydrochloride - 2-hydroxy ~ N- (4-hydroxyphértyl) -Nphenyl-2,3-dihydro ~ 1H-pyrrolizine-7-carboxamide

The deprotection of the fert-butylsilyloxy group is carried out according to the method of Stage D of Example 1.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 68.09 5.57 7.75 4.90 Find 67.73 5.10 7.54 4.84

High resolution ground (ESI +); Molecular Formula: C41FHJ9N4O5 [M + H] ⁺ Calculated: 687.2983 [M + H] ⁺ Measured: 687.2958

DUPLICATE

-89 Example 103: 3-f5-Chloro-2- {1 (35) -3- (morphoIin-4-yImethyl) -3,4-dihydroisoquinoIin2 (1ZO-yl] carbonyl] phenyl) -JV- (4-hydroxyphenyl) -JV- (1-Niethyl-1/7-pyrTolo [23 '6] pyridin-5-yl) -5.6 _t 7' 8-tetrahydroindolizine-1-carboxaniide

The procedure of Example I is carried out by replacing, on the one hand, the compound of Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by A- (4 - {[/ errbutyl (dimethyl) silyl] oxy} phenyl) -1-methylI-1W-pyrrolo [2,3-]] pyridin-5-amine.

High resolution mass (ESI +):

Molecular Formula: C44CIH44N6O4 [M + H] ⁺ Calculated: 755.3113 [M + H] ⁺ Measured: 755.3088

Example 104 JV- (4-Hydroxyphenyl) -3- (5-methoxy-2 - ([(3> S) -3 (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1 // ) -yllcarbonyl} phenyl) -A ^r - (lmethyl] -lH-indazol-5-yl) -5,6,7,8-tetrahydroindolizine-l-carboxainide

The procedure of Example I 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 jV- (4 - {[/ er / butyl (dimethyl) silyl] oxy} phenyl) -! -methyl-1 H-indazol-5-amine.

Elemental microanalysis t

20 %VS % H %NOT % cr Calculated 68.65 6.02 10.67 4.50 Find 67.91 5.52 10.53 4.08

Example 105: Bis (hydrochloride) of JV- (4-hydroxyphenyl) -3- (6 - {[(35) -3 - {[4- (2 · methoxyethyl) piperazin-1-yl] niethyl} -3,4 -dihydroisoquinolin-2 (l / 0-ylIcarbonyl} -13benzodioxol-5-yl) -JV-phenyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

DUPLICATE

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation 1 ’used in Stage A with the compound of Preparation 9’.

Elemental microanalysis;

%VS % H %NOT 5 Calculated 65.71 6.11 8.33 Find 66.57 6.16 8.44

Example 106: (2S) -5- (5-fluoro-2 - {[(35) -3- (inorpholin-4-ylinethyl) - hydrochloride

3,4-dihydroisoquinolin-2 (1H> yl] carbonyl} phenyl) -2-hydroxy- / V * (4-hydroxyphenyl) jV-phenyl-23-dihydro-1/7-pyrrolizine-7-carboxamide

The procedure is carried out according to the method of Example 102, replacing the compound of Preparation used in Stage A by the compound of Preparation 29.

Elemental microanalysis:

%VS % H %NOT ° / _o cr Calculated 68.09 5.57 7.75 4.90 15 Find 68.16 5.13 7.74 4.97

Example 107: 3- (5-Chloro-2 - ([(3S) -3 - [(4-methyl-3-oxopiperazin-lyl) methyl] -3,4-dihydroisoquinolin-2 (l £ /) - hydrochloride yl] carbonyl} phenyI) -7V- (4-hydroxyphenyl) jV- (1 -methyl-1 / Z-indoI-5-yl) -5,6,7,8-tetrahydroindoIizine-1 -carboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Stage A by the respective compounds of Preparations 3 and

10 ', and on the other hand the compound of Preparation 1 ”used in Stage C by M (4 - {[/ er / buty 1 (dimethyl) sil y 1] oxy} phenyl) -1 -methyl-1 H -indoI-5-amine.

Elemental microanalysis:

%VS % H %NOT % Cl % cr Calculated 67.56 5.67 10.28 8.67 4.34 Find 67.31 5.14 10.18 8.27 3.76

DUPLICATE

Example 108: 3- (5-Chloro-2 - {[(3S) -3 - {[(2-methoxyethyl) (methyl) amino] methyl} -3,4-dihydroisoquinolin-2 (1W) -yl hydrochloride ] carbonyl} phenyl) -A / - (4hydroxyphenyl) -7V- (1-methyl-1 // - indol-5-yl) -5,6,7,8-tetrahydrOindoli2ine-lcarboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compounds of Preparations I and 1 'used in Stage A by the respective compounds of Preparations 3 and 1Γ, and on the other hand the compound of Preparation 1 ” used in Stage C by A ^ - (4 - ([/ er / butyl (dimethyl) silyl] oxy} phenyl) -l-methyl-1 // - indol-5-amine.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 68.18 5.98 8.83 4.47 Find 68.30 5.61 8.78 4.46

Example 109: / V- (4-Hydroxyphenyl) -3- (6 - {[(3S> 3 - [(4-oxidomorpholin-4-yl) methyl] -

3,4-dihydroisoquinolin-2 (1W) -yllcarbonyl} -13-benzodioxol’5-yl) -JV-phenyl-5,6,7,8tetrahydroindolizine-1-carboxamide

To a solution of the compound of Example I, taken as the free base, in 10 mL of CH2Cl2, is added portionwise me / o-chloroperbenzoic acid (0.242 mg; 1.4 mmol). The whole is then stirred at room temperature overnight. The reaction medium is then concentrated to dryness, then the residue is purified by reverse phase flash chromatography (gradient: acetonitrile / water / trifluoroacetic acid). After concentration, the title product is obtained in the form of a solid.

Elemental microanalysis:

%VS % H %NOT Calculated 71.06 5.82 7.71 Find 70.59 5.36 7.69

DUPLICATE

-92 High resolution mass (ESI +):

Molecular Formula: C43H42N4O7 [M + Hf Calculated: 727.3132 [M + H] ⁺ Measured: 727.3110

Example______110: 3- (5-Chloro-2 - {[(3S) -3 - {[ethyl (2methoxy ethyl) amîno] methyl 1} -3,4-dihy droisoquinolin-2 (1H) -y I hydrochloride] carbonyl] phenyl) -JV (4-hydroxyphenyl) -? V- (1-methyl-1 // - indol-5-yl) -5,6,7,8-tetrahydroindolizine-lcarboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compounds of Preparations 1 and Γ used in Stage A by the respective compounds of Preparations 3 and 12 ', and on the other hand the compound of Preparation Γ * used in Stage C by the jV- (4 - {[tertbutyl (dimethyl) si lyl] oxy} ph enyl) -1-methyl 1-1 // - indol-5-amine.

Elemental microanalysis;

%VS % H %NOT % cr Calculated 68.48 6.12 8.68 4.39 Find 68.40 5.78 8.61 4.23

Example 111: 3- (5-Chloro-2 - {[(3S) -3- (morphoHii-4-ylmethyl) -3,4dihydroisoquinolin-2 (lED ^- yll ^car honyl) phenyl) - / V- (4 -fluorophenyl) -7V- (4hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-1-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 3, and on the other hand the compound of Preparation 1 “used in Stage C by 4 - {[fert-butyl (dimethyl) silyl] oxy} W- (4-fluorophenyl) aniline.

High resolution mass (ESI +):

Molecular Formula: C42H40CIN4O4 [M + H] ⁺ Calculated: 719.2722

DUPLICATE

-93 [M + H] ⁺ measured: 719.2806

Example 112 JV- (4-Hydroxyphenyl) -3- (5-methoxy-2 - {[(3S) -3 (morpholin-4-ylmethyl) -3,4-dihydroisoquinolm-2 (1/7) - hydrochloride yl] carbonyl} phenyl) -JV-phenyl-

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

The procedure of Example 1 is carried out, replacing the compound of Preparation 1 used in Stage A by the compound of Preparation 6.

Elemental microanalysis:

%VS % H %NOT % CT Calculated 70.43 6.19 7.64 4.83 Find 70.17 5.79 7.60 4.69

Example 113: 7-Hydroxy-JV- (4-hydroxyphenyl) -3- (6 - {[(3S) -3 '(morphoIin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1/7) hydrochloride -yl] carbonyl} -13-benzodioxol-

5-yl) -7V-phenyl-5,6,7,8-tetrahydroindolizin-1-carboxamide

Stage A. 3 ^, - (6 - {[(3S) -3- (Morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) ylJcarbonyl / -l, 3-benzodoxol-5-yl) - 5 ', 6'-dihydro-8 ^, H-sp! Ro [I, 3-dioxolane-2,7'-indolizineJ -1' -methylcarboxylate

The procedure is carried out in Stage A of Example 1, replacing the compound of Preparation 1 with the compound of Preparation 30.

Stage B: 3 '(6 - {[(3S)' 3 '(Morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (lH) -ylJ οα ^ οη} Ί} -1.3 ^ ηζοάίοχοΙ · 5 -} Ί) -7-οχο-5,6,7,8 ^ ίΓαΙΐ) 'άΓθΜοϋζίηε-1 ^ α ^ οχ)' Ιαί € methyl

2.75 g of the compound of Stage A (4.47 mmol) 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. The product

DUPLICATE

-94 of the title is obtained in the form of an oil.

1 H NMR: δ (500MHz; dmso-d6; 300 ° K): 7.9-7.2 (m, 4H, aromatic Hs); 7.02 (m, 1H, aromatic Hs); 6.88 (m, 1H, aromatic Hs); 6.44-5.87 (m, 1H, H aromatic tetrahydroindolizine); 6.17 (d, 2H, CH ₂ methylene dioxy); 5.07 / 4.85 / 3.79 (m, 1H, tertiary H tetrahydroisoquinoline); 4.88 / 4.27 / 4.24 (m, 2H, aliphatic H tetrahydroisoquinoline); 4.22-3.43 (m, 4H, aliphatic H tetrahydroindolizine); 3.59-3.49 (m, 4H, aliphatic H morpholine); 3.75-3.52 (s, 3H, Me); 2.93-2.49 (m, 2H, aliphatic H tetrahydroindolizine); 2.75-2.28 (m, 2H, aliphatic H tetrahydroindolizine);

2.68-1.68 (m, 6H, morphoiin aliphatic H + CH ₂ )

Stage C: 7-Hydroxy-3- (6- {f (3S) -3- (morpholbt-4-ylmethyl) -3,4 ~ dihydrolsoquinolin 2 (1H) -yl] carbonyl} -l, 3-benzodîoxol-5 -yl) -5,6,7,8-tetrahydroindolizine-1-methyl carboxylate

To a solution of 2.55 g of the compound obtained in Stage B (4.47 mmol) 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 H ₂ O, dried over MgSO ₄ , filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (dichloromethane / ethanol-ammonia gradient). The title product is obtained in the form of a solid.

1 H NMR: δ (500MHz; dmso-d6; 300 ° K): 7.22-6.97 (m, 4H, H aromatic tetrahydroisoquinoline); 7.05 (s, 1H, aromatic H); 6.89 (s, 1H, aromatic H); 6.37 / 6.3 / 6.07 (m, 1H, aromatic H tetrahydroindolizine); 6.16 (d, 2H, CH ₂ methylene dioxy); 5.09 (m, 1H, tertiary H tetrahydroisoquinoline); 4.87-4.21 (m, 2H, aliphatic H tetrahydroindolizine); 4.20-3.67 (m, 2H, aliphatic H tetrahydroindolizine); 4.10-3.86 (m, 1H, tertiary H tetrahydroindolizine); 3.69-3.58 (s, 3H, Me); 3.69-3.52 (m, 4H, morpholine aliphatic H); 2.96 + 2.43 (m, 2H, aliphatic H tetrahydroisoquinoline); 2,552.0 (m, 6H, aliphatic H morpholine + CH ₂ ); 2.4-1.5 (m, 4H, H aliphatic tetrahydroi ndol izi ne)

DUPLICATE

-95IRI OH: 3239 cm * ¹ ; -C = O (ester): 1696 cm * ¹ ; -C = O (amide): 1624 cm * ¹ ; CC-OH (secondary alcohol): 1034 cm ¹

Stage D: 3- (6 - {[(3S) -3- (Morpholin-4-ylmethyl) -3,4-dihydroisoquino! In-2 (1H) ylJcarbonyl} -1, 3-benzodÎoxo! -5-yl) Methyl -7- (prop-2-en-1-yloxy) -5,6,7,8-tetrahydrolndolizin-l5 carboxylate

To a suspension of 331 mg (8.26 mmol) of sodium hydride in 15 mL of anhydrous THF cooled to 0 ° C., 2.37 g (4.13 mmol) of the compound obtained in Stage C. are added. This suspension is added. 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 10 reaction mixture is stirred for lh at 0 ^q 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). The title product is obtained in the form of a solid.

1 H NMR: δ (500 MHz; dmso-d6; 300 ° K): 7.2-6.9 (m, 4H, H aromatic tetrahydroisoquinoline); 7.2-6.8 (m, 2H, aromatic Hs); 6.4-6.0 (m, 1H, H aromatic tetrahydroindolizine); 6.10 (d, 2H, CH ₂ methylene dioxy); 5.9 (m, 1H, allyl); 5.35-5.10 (m, 2H, allyl); 5.1 + 4.75 (m, 1H, tertiary H tetrahydroisoquinoline); 4.15-3.9 (m, 2H, CH ₂ allyl); 3.9-3.6 (m, 1H, tertiary H tetrahydroindolizine); 4.1-3.4 (m, 4H, morpholine aliphatic H); 4.9-3.4 (m, 4H, 2H aliphatic tetrahydroindolizine + 2H aliphatic tetrahydroisoquinoline); 3.8-3.6 (s, 3H, Me); 2.55-1.6 (m, 6H, aliphatic H morpholine + CH ₂ ); 3.3-1.5 (m, 6H, 4H aliphatic tetrahydroindolizine + 2H aliphatic tetrahydroisoquinoline)

Stage E: N- (4 - {[tert-Butyl (dimethyl) si! Yljoxy} phenyl) -3- (6 - {[(3S) -3- (morpholin-425 ylmethyl) -3,4-dUiydroisoquînolin-2 (lH) -yl] carbonyl} -l _f 3-benzodioxol-5-yl) ~ N-phenyl-7 (prop-2-en-I-yloxy) -5,6,7,8-tetrahydrolndolizine-I- carboxamide

The procedure is carried out according to the methods of Steps B and C of Example 1.

DUPLICATE

-96 Stage F: N- (4 - {[tert-Butyl (dimethyl) silyl [oxy} phenyl) -7-hydroxy-3- (6 - [[(3S) -3 (morpholin-4-ylmétliyl) -3 _t 4-dihydroisoquinolin-2 (1H) -yl [carbonyl} -l, 3-benzodioxol-5yl) -N-ph enyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

A deprotection reaction of the allyl group is then carried out in the presence of 1,35 dimethylpyrimidin-2,4,6 (1H, 3H, 5W) -trione (also called dimethylbarbiturate) and of tetrakis (triphenylphosphine) palladium in a mixture of methanol and of dichloromethane.

Stage G; 7-Hydroxy-N- (4-hydroxyphenyl) -3- (6 - {[(3S) -3 (morphoHn-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) -yllcarbonyl} -l hydrochloride, 3-benzodioxol-510 yl) -N-phenyl-5 _t 6,7,8-tetrahydroindoUzine-1-carboxamide

The deprotection of the silyloxy group is carried out according to the method of Stage D of Example 1.

Elemental microanalysis i

%VS % H %NOT % cr 15 Calculated 67.66 5.68 7.34 4.64 Find 67.02 5.27 7.36 4.61

High resolution mass (ESI +):

Molecular Formula: C43H43N4O7 [M + H] ⁺ Calculated: 727.3132 [M + H] ⁺ Measured: 727.3121

Example 114: Hydrochloride of A ^r - (3-fluoro-4-methylphenyl) -7V- (4-hydroxyphenyl) -3 (5-methoxy-2 - {[(3S) -3- (morpholin-4-ylmethyl) - 3,4-dihydroisoquinolin-2 (lZ /) - yl] carbonyl} phenyl) -5,6,7,8-tetrahydroindolizine-l-carboxamide

The process is carried out according to the method of Example I, 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 H- (4 - {[/ er / butyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4-methylaniline.

DUPLICATE

-97Elemental microanalysis;

%VS % H %NOT % cr Calculated 69.05 6.06 7.32 4.63 Find 68.90 5.56 7.33 4.41

Example 115 - 3- (5-Chloro-2 - [[(3S) -3- (morpholin-4-ylniethyl) -3,4dihydroisoquinolin-2 (1Z /) - yl] carbonyl} phenyl) -7V- ( 2-fluorophenyl) -jV- (4hydroxyphenyl) -5,6,7,8-tetrahydroindollzine-1-carboiamide

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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 4- {per / -butyl (dimethyl) silyl] oxy} Ar- (2-fluorophenyl) aniline.

High resolution ground (ESI +);

Molecular Formula: C42H40CIN4O4 [M + Hf Calculated: 719.2722 [M + H] ⁺ Measured: 719.2802

Example 116; 3- (5-Chloro-2 - (] (3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1F /) - yl] carbonyl) phenyl) -jV- (3-fluorophenyl) hydrochloride ) -7V- (4hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-1-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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 4 - {[ter / -butyl (dimethyl) silyl] oxy} AL (3-fluorophenyl) aniline.

High resolution mass (ESI +):

Molecular Formula: C42H40CIN4O4 [M + H] ⁺ Calculated: 719.2722 [M + H] ⁺ Measured: 719.2819

DUPLICATE

-98 Example 117; 3- (5-Chloro-2 - {[(35) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1 //) - yl] carbonyl} phenyl) -jV- (2, 4-difluorophenyl) -jV- (4hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-1-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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 2V- (4- {per / -butyl (dimethyl) silyl] oxy} phenyl) -2,4-difluoroanilin.

High resolution mass (ESI +):

Molecular Formula: C42H39CIF2N4O4 [M + H] ⁺ Calculated: 737.2628 [M + H] ⁺ Measured: 737.2660

Example 118; 3- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoqulnolin-2 (1 / Z) -yI] cai'bonyl} phenyl) -JV- ( 3,4-Difluorophenyl) -Ar- (4hydroxypheny 1) -5,6,7,8-tetrahydroindolizine-1-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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by ZV- (4 - {[teributyI (dimethyl) silyl] oxy} phenyl) -3,4-difluoroaniline.

Elemental microanalysis:

20 %VS % H %NOT % cr Calculated 65.20 5.21 7.24 4.58 Find 65.26 5.01 6.90 4.57

Example 119; 3- (5-Chloro-2 - ([(3iS) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1 //) - yl] carbonyl) phenyl) -jV- (3- cyanophenyl) -jV- (425 hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-l-carboxainlde

DUPLICATE

The procedure of Example 1 is carried out by replacing on the one hand the compound of your Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of your Preparation 1 ”used in Stage C by 3 - [(4 - {[/ er / butyl (dimethyl) silyl] oxy} phenyl) amino] benzonitrile.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 67.71 5.42 9.18 4.65 Find 67.00 5.20 8.89 4.54

Example 120; 2V- (4-Hydroxyphenyl) -6- (6 - {[(3S) -3- (morpholin-410 ylmethyl) -3,4-dihydroisoquinolin-2 (1Λ /) - yl] carbonyI} hydrochloride 4.3 ' 'benzodioxol 5-y)) - 2Vpheny Ipy rrolo [1 * 2 * a] py razin-8-ca rboxamide

The procedure is carried out according to the method of Example I, replacing the compound of Preparation i used in Stage A by the compound of Preparation 31.

High resolution mass (ESI +):

Molecular Formula: C42H37NSO6 [M + H] ⁺ Calculated: 708.2822 [M + H] ⁺ Measured: 708.2788

Example 121; / V- (3-Fluorophenyl) -Ar- (4-hydroxypheny)) - 6- (6 - {[(3S) 3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolîn-2 (l / 7) -ylJcarbonyl} -1320 benzodioxol * 5 * y)) pyrrolo [1,2-a] pyrazine-8-carboxamide

The procedure of Example I is carried out, on the one hand replacing the compound of

Preparation 1 used in Stage A by the compound of Preparation 31, and on the other hand the compound of Preparation 1 ”used in Stage C by 4 - {[ter / -butyl (dimethyl) silyl] oxy} 7V- ( 3-fluorophenyl) aniline.

DUPLICATE

-100 High resolution mass (ESI +):

Molecular Formula: C42H36FN3O6 [M + H] ⁺ Calculated: 726.2728 [M + H] ⁺ Measured: 726.2723

Example 122; IV- (3-Fluorophenyl) -JV- (4-hydroxyphenyl) -3- (6 - {[(35) 3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) -yl hydrochloride ] carbonyl} -13-benzodioxol -5-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure of Example 1 is carried out by replacing the compound of Preparation 1 ”used in Stage C by 4 - {[/ er / -butyl (dimethyl) silyl] oxy} -2V- (3-fluorophenyl) aniline .

High resolution mass (ESI +):

Molecular formula: C43H41FN4O6 [M + H] ⁺ calculated: 729.3088 [M + H] ⁺ measured: 729.3068

Example 123 I JV- (4-Hydroxyphenyl) -3- (6 - {[(3S ') - 3 - {[4 (methylsulfonyl) piperazin-1-yl] methyl]} - 3,4-dihydroisoquinolln-2 hydrochloride (1H) -y]] carbonyl} 13-benzodioxol-5-y]) - / V-pheny] -5,6,7,8-tetrahydrolndolizine-1-carhoxamide

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation 1 * used in Stage A by the compound of Preparation 13 '.

Elemental microanalysis î

%VS % H %NOT % S % CT Calculated 64.11 5.62 8.50 3.89 4.30 Find 64.19 5.07 8.52 3.87 4.02

Example 124; 3- (5-Chloro-2 - {[(35) -3- (morpholin-4-ylmethyl) -3,4dihydrolsoq uino I ln-2 (1 £ f) -y I] carbony 1} ph ény l hydrochloride ) -JV- (4-hy d roxyph enyl) - / V- (3methoxyphenyl) -5,6,7,8-tetrahydroindolizin-1-carboxamide

DUPLICATE

- 101 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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 77- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) -3-methoxyaniline.

Elemental microanalysis:

% C% H% N% cr

Calculated 67.27 5.78

7.30 4.62

Found 67.54 5.35

7.32 4.62

Example 125; 3- (5-Chloro-2- {| (3S) -3- (morpholin-4-ylmethyl) -3,4dihydrolsoquinolin-2 (1J /) - yllcarbony!) Phenyl) -jV- (3,5-) hydrochloride difluorophenyl) - / V- (4hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-l-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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 77- (4 - {[rertbutyl (dimethyl) silyl] oxy} phenyl) -3,5-difluoroaniline.

Elemental microanalysis;

%VS % H %NOT % cr Calculated 65.20 5.21 7.24 4.58 Find 65.85 4.93 7.04 4.76

Example 126: 3- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquino! Iii-2 (1 / Z) -yl] carbony!} Pheny hydrochloride! ) -A7- (4-hydroxypheny!) - A7- (3-methyl phenyl) -5,6,7,8-tetrahydroindolizine-1-carboxainide

The procedure of Example 1 is carried out, on the one hand replacing the compound of

Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 "used in Stage C by 77- (4- {[tertDUPLICATA

-102buty! (Dimethyl) silyl] oxy} phenyl) -3-methylaniline.

Elemental microanalysis t% C% N% cr

Calculated 68.70 5.90

7.45 4.72

Found 68.94

5.72

7.21

4.84

Example 127 2V- (4-Hydroxyphenyl) -2V-phenyl-3- (6 - {[(3S) -3 - {[4 (2,2t2 * trifliioroethyl) piperazin-1-yl] methyl!} - hydrochloride 3,4-dihydroisoqiiino! In-2 (lJ7) -y!] Carbonyl} -13 * benzodloxoL5-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure of Example I is carried out, replacing the compound of Preparation 1 'used in Stage A by the compound of Preparation 14'.

Elemental microanalysis:

% C% H% n% cr

Calculated 65.25 5.48

8.45

4.28

Found 64.91 5.23

8.37 4.96

Example 128 2V- (4-Hydroxyphenyl) -3- (6 - ([(3S) -3 - [(4-methyl-3 oxopiperazin-1-yl) methyl] -3,4-dihydroisoquinolin-2 ( l //) - yl] carbony!) - 13benzodioxo! -5-yl) -7V-phenyl-5,6,7,8-tetrahydroindolizlne-l-carboxamide

The procedure is carried out according to the process of Example 1, replacing the compound of Preparation Γ used in Stage A by the compound of Preparation 10 ’.

Elemental microanalysis.

%VS % H %NOT % cr Calculated 68.25 5.73 9.04 4.58 Find 68.04 5.09 8.82 4.64

DUPLICATE

-103 Example 129: 3- (5-Chloro-2 - {[(3S) -3- (inorpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (17 /) - yl] carbonyl} phenyl) -A ^r hydrochloride - (4-cyanophenyl) - / V- (4hydroxyphenyl) -5,6,7,8-tetrahydroindoIizine-1 -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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 4 - [(4 - {[tertbutyl (dimethyl) silyl] oxy} phenyl) amino] benzonitrile.

Elemental microanalysis:

%VS % H %NOT Calculated 67.71 5.42 9.18 Find 68.17 5.15 8.71

Example 130: 3- (5-Chloro-2- {1 (35) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinoIin-2 (I //) - yl] carbonyI} phenyl) -A ^r hydrochloride fV-diphenyl-5,6,7,8tetrahydroindolizine-1-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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 2V-phenylaniline.

High resolution ground (ESI +);

Molecular Formula: C42H40Cl2N4O4 [M + H] ⁺ Calculated: 735.2427 [M + H] ⁺ Measured: 735.2524

Example 131: 3- (5-chIon> -2 - {[(3S) -3- (morphoIin-4-ylmethyl) -3,4dihydroisoquinolin-2 (li /) - yllcarbonyl) phenyl) -2V- (3 hydrochloride) -chIorophényI) -N- (4hydroxyphenyl) -5,6,7,8-tetrahydroindoIizine-1-carboxamide

The procedure of Example 1 is carried out, on the one hand replacing the compound of

DUPLICATE

-104 Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by jV- (4 - {[/ £ t / butyl (dimethyl) silyl] oxy} phenyl) -3-chloroaniline.

Elemental microanalysis.% C% H% N% cr

Calculated 65.33 5.35

7.26 4.59

Found 64.08 5.29

6.92

4.59

Example 132: 3- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (177) -yl] carbonyl} phenyl) -7V- (4) hydrochloride -hydrOxyphenyl) -7V- (pyrimidin-2yI) -5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure of Example 1 is carried out by replacing on the one hand the compound of your Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by the // - (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) pyrimidin-2-amine.

Elemental microanalysis i

%VS %NOT Calculated 64.95 5.45 11.36 Find 64.62 5.07 10.92

Example 133: 3- (5-ch! Oro-2 - {[(3S) -3- (niorpholin-4-ylmethyl) -3,4dihydroisoquino! In-2 (lZI) -yI] carbonyl} phenyiy> M hydrochloride (cyc! obutylmethyl) -A / - (4hyd roxy ph ény l) -5,6,7,8-tet rahy droin dolizine-1 -carboxa mide

The procedure of Example 1 is carried out, on the one hand replacing the compound of

Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 4 - {[teri-butyl (dimethyl) sily [] oxy} 7V- ( cyclobutylmethyl) aniline.

DUPLICATE

-105 Elemental microanalysis:

% C% H% N% cr

Calculated 68.16 6.39

7.76 3.93

Found 68.69 5.93

7.45 3.81

Example 134: 3- (5-Chloro-2- {J (3S) -3- (morpholin * 4-ylmethyl) -3 _t 4dihydroisoquinolin-2 (1 //) - yl] carbonyl) phenyl) -A ^r hydrochloride - (2-cyanophenyl) -7V- (4hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-1-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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 2 - [(4- {[ter / butyl (dimethyl) silyl] oxy) phenyl) amino] benzonitrile.

Elemental microanalysis i

Calculated %VS 67.71 ° / oH 5.42 %NOT 9.18 15 Find 67.34 4.95 8.73

Example 135: 3- (5-ChIoro-2 - {[(35) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (1 //) - yl] carbonyl} phenyl) -7V- hydrochloride (4-hydroxyphenyl) - V- (l-methyl-l // pyrazol-4-yl> 5,6,7,8-tetrahydroindolizine-l-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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by N- (4 - {[/ errbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 / Apyrazol-4-amine.

Elemental microanalysis t% C% H% N% Cr

Calculated 64.77 5.71

11.33 4.78

Found 64.62 5.33

10.71 4.10

DUPLICATE

-106 Example 136; 3- (5 "chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4 dihydroisoqulnolin-2 (1 / 0'yl] carbonyl} phenyl) - / V- (cyclopropylmithyl) hydrochloride ) -JV- (4hydroxyphenyl) -5,6,7,8-titrahydroindolizine-1-carboxamide

The procedure is carried out according to the process of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation Γ * used in Stage C by 4 - {[terZ-butyl (dimethyl) silyl] oxy} JV- (cyclopropylmethyl) aniline.

Elemental microanalysis:

% C% H% N% cr

Calculated 67.13

6.20

7.83 4.95

Found 67.58 5.79

7.36 4.16

Example 137; 3- (5-Chloro-2 - ([(3S) -3- (morphoIiii-4-ylmethyl) -3,4dihydroisoquinolin-2 (l /) - yl] carbonyl} phenyl) -7V- (4-hydrOxyphényI hydrochloride) ) -A ^r - (1-methyl-1Z / pyrazol-3-yl) -5,6,7,8-tetrahydroindolÎzine-1-carboxamide

The procedure is carried out according to the method of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by A / - (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 // - pyrazol-3-amine.

Elemental microanalysis:

20 %VS % H %NOT % cr Calculated 64.77 5.71 11.33 4.78 Find 64.20 5.47 10.78 5.27

DUPLICATE

Example 138: AT- (but-2-yn-1-yl) -3- (5-chloro-2 - {[(35) -3- (morpholîn-) hydrochloride

4-ylmethyl) -3,4-dihydroÎsoquÎnolÎn-2 (1 //) - yl] carbonyl) phenyl) -jV- (4-hydroxyphenyl) -

5,6,7,8-tetra hy droin do lizin e- 1-ca rboxam i de

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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 4 - {[fert-butyl (dimethyl) silyl] oxy} W- (but-2-yn-1 -yl) aniline.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 64.95 5.45 11.36 4.79 Find 65.53 5.19 10.88 5.38

Example 139 - 3- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmithyl) -3,4dihydroisoquinolin-2 (177) -yl] carbonyl} phinyl) -Ar- (4) hydrochloride -hydroxyphinyl) -Ar- (pyridin-2-yl) -

5,6,7,8-tet rahyd roin dolizin-1 -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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by M (4- {[terZbutyl (dimethyl) silyl] oxy} phenyl) pyridin-2-amine.

Elemental microanalysis:

%VS % H <% N Calculated 66.66 5.59 9.48 Find 67.12 5.37 9.11

DUPLICATE

Example 140: 3- (5-chlo ro-2 - {[(35) -3- (m orpholin-4-ylm ethy 1) -3,4dihydroîsoquinolin-2 (lZf) -yl] carbonyl) phenyl hydrochloride) -A- (4-hydroxyphenyl) -7 / - (pyridazÎn-3y I) -5,6,7,8-té trahy d rolndolizine-1 -ca rhoxa mide

The procedure is carried out according to the method of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by Λ ^ζ - (4 - {[terfbuty l (di meth yl) sîly I] ox y} phenyl) pyr idazin-3 -ami ne.

High resolution mass (ESI +):

Molecular Formula: C42H39CIN6O4 [M + H] ⁺ Calculated: 703.2721 [M + H] ⁺ Measured: 703.2783

Example 141: 3- (5-Chloro-2 - ([(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (17 /) - yl] carbonyl} phenyl) -jV- ( 4-hydroxyphenyl) -jV- (pyrimidin-5yl) -5,6,7,8-tetrahydroindolizine-1-carhoxamide

The procedure is carried out according to the method of Example 1, replacing on the one hand the compound of Preparation 1 used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation Γ * used in Stage C by A- (4- {[tertbutyI (dimethyl) siIyl] oxy} phenyl) pyrimidin-5-amine.

Elemental microanalysis t %VS ° / ₀ H %NOT % cr Calculated 68.32 5.59 11.95 5.04 Find 68.05 5.52 11.83 5.50

DUPLICATE

-109 Example 142; 3- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) - bis (chlo r hydrate) -

3,4-dihydroisoquinolin-2 (lA /) - yl] carbonyl) phenyl) -A ^r - (4hydroxyphenyl) -A ^r - (pyridin3-yï) -5,6,7,8-té trahyd ro in do lizine-1 -carboxam ide

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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by N- (4 - {[tertbutyl (dimethyl) siIyl] oxy} phenyl) pyridin-3-amine.

High resolution mass (ESIF):

Molecular Formula: C41H40CIN5O4 [M + H] * Calculated: 702.2769 [M + H] * Measured: 702.2858

Example 143 3- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinoiin-2 (1J /) - yl] carbonyl} phenyl) -A ^r - hydrochloride (3,5-difluoro-4-niethoxyphenyl) -A ^r (4-hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-l-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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by M (4 - ([ter / butyl (dimethyl) silyl] oxy} phenyl) -3,5-difluoro-4-melhoxyaniline.

High resolution mass (ESI +):

Molecular Formula: C43H41CIF2N4O5 [M + H] * Calculated: 767.2734 [M + H] * Measured: 767.2804

DUPLICATE

-110 Example 144; 3- (5-chloro-2 - [[(35) -3- (morphonn-4-ylinethyl) - bis (hydrochloride)

3,4-dihydroisoquinolin-2 (1/0-yl] carhonyl} phenyl> JV- <4-hydroxyphenyl) - / V- (pyridin-

4-yl) -5,6,7,8-tetrahydroindo! Îzine-1-carhoxamlde

The procedure of Example 1 is carried out by replacing, on the one hand, the compound of Preparation I used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by jV- (4- {[tertbutyl (dimethyl) silyl] oxy} phenyl) pyridin-4-amine.

High resolution mass (ESI +):

Molecular Formula: C41H40CIN5O4 [M + H] ⁺ Calculated: 702.2842 [M + H] ⁺ Measured: 702.2842

Example 145; 3- (5-ChIoro-2- {K3S) -3- (morpholin-4-ylinethyl) -3,4dÎhydroisoquinolin-2 (1 //) - yl] carbonyl} pheny hydrochloride!) - jV- (3-nuoro -4-niethoxypheny!) - jV- (4hydroxyphenyl) -5,6,7,8-tetnihydroindolizine-1-carboiamide

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 3, and on the other hand the compound of Preparation 1 ”used in Stage C by // - (4- {[/ erZbutyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4-methoxyaniline.

High resolution mass (ESI +):

Molecular Formula: C43H42CIFN4OS [M + H] ⁺ Calculated: 749.2828 [M + H] ⁺ Measured: 749.2878

DUPLICATE

-111 Example 146: N- (4-hydroxyphenyl) -3- (6 - {[(3S) -3 - {[(2methoxyethyl) (methyl) amino] methyl) -3,4-dihydroisoquinolin-2 (lZ / ) -yl] carbonyl} -13benzod ioxo l-5-y lj-TV-ph ény 1-5,6,7,8-tetra hyd roindol izine-1 -ca r boxamide

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation 1 ’used in Stage A by the compound of Preparation 1’.

Elemental microanalysis.% C% H% n% cr

Calculated 68.93 6.05

7.48 4.73

Found 68.84 5.85

7.56 4.60

Example 147 - 3- (6- {| (3S) -3- | (1,1-dioxidothiomorpho! In-4yl) methyl] -3,4-dihydroisoquinoIin-2 (1H) -yl] carbonyl} -13 hydrochloride -benzodioxol-5-yl) -jV- (4hydroxyphenyl) -jV-phenyl-5,6,7,8-tetrahydroindolizin-l-carboxainide

The procedure of Example 1 is carried out, replacing the compound of Preparation 1 ’used in Stage A with the compound of Preparation 15’.

Elemental microanalysis;

% C% H% N% S% cr

Calculated 64.94 5.45

7.04 4.03

4.46

Found 65.27 5.13

7.14 3.90 4.30

Example 148: JV- (5-Hydroxypyrimidin-2-yl) -3- (6 - {[(35) -3 (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (I //) - trifluoroacetate yl] carbonyl} -13-benzodioxol-

5-yl) -Ar-phenyl-5,6,7,8-tetrahydroindoIizin-1-carboxainide

Stage A: N- [5- (benzyloxy) pyrimldin-2-ylJ-3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolln-2 (1H) -ylJcarbonyl} - 1,3-benzodioxol-5-yl) -N-phenyl-5,6,7,8 ~ tetrahydroindolizine-l-carboxamide

DUPLICATE

The procedure is carried out according to Stages A, B and C of the process of Example 1, replacing the compound of Preparation 1 ”used in Stage C by 5 * (benzyloxy) -jV-phenylpyrimidin2-amine.

Stage B. N- (5-Hydroxypyrimidin-2-yl) -3- (6 - {[(3S) -3- (morpholin-45 ylmethyl) -3,4-dihydroisoquinolin-2 (1H) -yl trifluoroacetate ] carbonyl} ~ 1,3-benzodioxol-5-yl) -N-phenyl5,6,7,8-tetrahydroindolizine-1-carboxamide

The compound of Stage A (150 mg; 0.2 mmol) is dissolved in 8 mL of methanol, and 30 mg of Pd / C (10% by mass of palladium) are added. The reaction medium is left under stirring under a hydrogen atmosphere (1.2 bar) for 15 h, then filtered through 10 Whatman, concentrated in vacuo and purified by reverse phase chromatography (gradient:

acetonitrile / water in the presence of trifluoroacetic acid). The desired product is obtained in the form of a trifluoroacetate salt.

High resolution mass (ESI +):

Molecular formula: C4iH4oN ₆ O6 [M + Hf calculated: 713.3082 [M + H] ⁺ measured: 713.3080

Example 1491 2V- (4-Hydroxypheny 1) -3- (6- {| (3S) -3 - [(3methoxypyrroIidin-1-yl) methyl] -3,4-dihydroisoquinolin-2 (lJ7) -yl] hydrochloride carbonyl} -1,3benzodioxol-5-yl) -A-phenyl-5,6,7,8-tetrahydro-indolizine-1-carboxamide

The procedure of Example 1 is carried out, replacing the compound of Preparation Γ used in Stage A by the compound of Preparation 16 ’.

Elemental microanalysis:

%VS % H %NOT % cr Calculated 69.42 5.96 7.36 4.66 25 Find 70.19 5.48 7.22 4.53

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Example 150: 3- (5-Chloro-2 - ([(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolÎn-2 (lJ7) -yl] carbonyl} phenyl) -7V- ( 3-cyano-4-methoxyphenyl) -jV- (4hydroxyphenyl) -5,6,7,8-tetrahydroindolizine-1-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 3, and on the other hand the compound of Preparation Γ 'used in Stage C by 5 - [(4 - {[tertbutyl (dimethyl) si [yl] oxy} phenyl) amino] -2-methoxybenzonitrile.

High resolution mass (ESI +):

Molecular formula: C44H42CIN10s [M + H] * calculated: 756.2874 [M + H] * measured: 756.2917

Example 151 - M (4-Hydroxyphenyl) -3- (5-inethoxy-2 - {[(3 £) -3 (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1ZD-yl] carbonyl) hydrochloride ) phenyl) -7V- (lmethyl-1/7-pyrazol-4-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure of Example 1 is carried out by replacing, on the one hand, the compound of your 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 77- (4 - {[tertbutyl (dimethyl) silyl] oxy) phenyl) -1-methyl-1 W-pyrazol-4-amine.

High resolution mass (ESI +):

Molecular Formula: C41H44N6O5 [M + H] ⁺ Calculated: 701.3446 [M + H] * Measured: 701.3446

Example 152; 3- (5-Chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (177) -yl] carbonyl) phenyl) -7V- (4-hydroxyphenyl) hydrochloride -7V- [3 (trifluoromethyl) phenyl] -5,6,7,8-tetrahydroindolizine-1-carboxamlde

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The procedure of Example 1 is carried out by replacing, on the one hand, the compound of Preparation I used in Stage A by the compound of Preparation 3, and on the other hand the compound of Preparation 1 ”used in Stage C by 7V- (4- {t / errbutyl (dimethyl) silyl] oxy} phenyl) -3- (trifluoromethyl) aniline.

High resolution mass (ESI +):

Molecular Formula: C43H40CIF3N4O4 [M + H] ⁺ Calculated: 769.2690 [M + Hf Measured: 769.2718

Example 153: 3- (6 - {{(3S) -3 - [(3,3-dIfluoropyrro! Idin-ly!) Methyl] 10 3,4-dihydroisoquinolin-2 (ltf) -yl] carbonyl} - hydrochloride 13 * benzodioxol-5-yl) -M (4hydroxyphenyl) -Mphenyl-5,6,7,8-tetrahydroindolizine-l-carboxamide

The procedure of Example I is carried out, replacing the compound of Preparation 1 'used in Stage A by the compound of Preparation 17'.

Elemental microanalysis:

15 %VS % H %NOT Calculated 67.31 5.39 7.30 Find 68.07 5.60 7.23

Example 154 ·. A ^r - (4-Hydroxyphenyl) -A ^r - (1-niethyl-1Z / -pyrazol-4-yl) 3 '(7 - {[(35) -3- (morpholin-4-ylmethyl)' 3 hydrochloride , 4-dihydroisoquinolin-2 (Lz0 ^_ yllcarbonyl} -2320 dihydro-4-benzodioxin-6-yl) -5,6,7,8-tetrahydroindolizine-l-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 by jV- (4 - {[/ cr / butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 Z7-pyrazol-4-amine.

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-115 Example 155; JV- (4-Hydroxyphenyl) -3- (7 - {{(3S) -3- (morpholin-4ylmethyl) -3,4-dihydroisoquinolin-2 (lZ /) - yl] carbonyl} -23 * dihydro- hydrochloride 1,4-Benzodioxin-6yl) -j ^/ V- (pyrimidin-5-yl) -5,6,7,8-tetrahydroindolizine-1-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 used in Stage C by W- (4 - {[iron / butyl (dimethyl) silyl] oxy} phenyl) pyrimidin-5-amine.

Example 156; A- (4-Hydroxyphenyl) -3- (6 - {[(3S) -3 - [(3-methoxyazetidin-1-yl) methyl] -

3,4-dihydroisoquinolin-2 (l / 7) -yl | carbonyl} -13-benzodioxol-5-yl) -j'V-phenyl-5,6,7,8tetrahydroindolizine-l-carboxamide

The procedure is carried out according to the method of Example 1, replacing the compound of your Preparation 1 ’used in Stage A by the compound of Preparation 18’.

Elemental microanalysis:

%VS % H %NOT Calculated 72.66 5.96 7.88 Find 72.32 5.51 7.96

High resolution mass (ESI +):

Molecular Formula: C43H42N4O6 [M + H] ⁺ Calculated: 711.3177 [M + H] ⁺ Measured: 711.3178

Example 157; 3- (6 - {[(3S) -3 - [(3-fluoroazetidin-1-yl) methyl] -3,4dihydroisoqulnolin-2 (l / 7) -ylIcarbonyl} -13-benzodioxol-5-yl) hydrochloride -jV- (4-hydroxyphenyl) -jVphenyl-5,6,7,8-tetrahydroindolizine-1-carboxamide

The procedure is carried out according to the method of Example 1, replacing the compound of Preparation Γ

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- 116used in Stage A by the compound of Preparation 19 '.

Example 158; 3- (5-nuoro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (17 /) - yI] carbonyl} phenyI) -jV- (4-hydroxyphenyl) hydrochloride ) -iV- (1-methyl | -lJ / pyrazoI-4-yI) -5,6,7,8-tetrahydroindolizinc-1-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 4, and on the other hand the compound of Preparation 1 ”used in Stage C by N- (4 - {[teributyl (di methy l) silyl] oxy} phenyl) -! -methyl-1H-pyrazol-4-amine.

Example 159; 3- (5-Fluoro-2 - ([(3S) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (17 /) - yl] carbonyl} phenyl) - / V- (4-) hydrochloride hydroxyphenyl) -jV- (1-methyl-17 / pyrazol-4-yl) indolizin-1-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 32, and on the other hand the compound of Preparation 1 ”used in Stage C by N- (4- {[ferfbutyl (dimethyl) silyl] oxy} phenyl) · 1-methyl-1 W-pyrazol-4-amine.

Example 160: 3- (5-Chloro-2 - ([(35) -3- (morpholin-4-ylmethyl) -3,4dihydroisoquinolin-2 (17 /) - yl] carbonyl} phenyl) -? / - hydrochloride (4-hydroxyphenyl) -jV- (l-methylI-1 // pyrazol-4-yI) indolizin-1-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 14, and on the other hand the compound of Preparation 1 ”used in Stage C by A ^r - (4 - {[rerfbutyl (dimethyl) silyl] oxy) phenyl) -1 -methyl-1 W-pyrazo 1-4-amine.

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-117 PHARMACOLOGICAL STUDY

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

The fluorescence polarization tests were carried out in microplates (384 wells). The Bcl-2 protein, at the final concentration of 2.50 × ¹⁰ −8 M, is mixed with a fluorescent peptide (Fluorescein-REIGAQLRRMADDLNAQY), at the final concentration of 1.00.

10 ' ⁸ 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 in IC10 (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 t 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. The cell viability is then quantified by a colorimetric assay, the Microculture Tetrazolium Assay (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.

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-118 Table 1: ÏC "o inhibition of Bcl-2 (fluorescence polarization test) and cytotoxicity for RS4 cells; 11

1C _M (nM) Bcl-2 FP IC _M (nM) MTTRS4.II IC ”(nM) Bcl-2 FP IC ”(nM) MTTRS4.il Example 1 18 60.1 Example 32 34 71.3 1 Example 2 20 49.8 Example 33 23 12.2 Example 3 20 44.7 Example 34 27 65.8 Example 4 19 27.1 Example 35 15 11.7 1 Example 5 51 98 Example 36 43 ¹³⁵ 1 Example 6 15 30 Example 37 19 ^11.6 1 Example 8 15 25.6 Example 38 21 61.8 Example 9 13 16.1 Example 39 16 ^14.1 1 Example 10 18 11 Example 40 15 ^32.2 1 Example 13 12 8.63 Example 41 26 44 1 Example 14 16 10.7 Example 42 13 53.6 Example 15 17 20.4 Example 43 110 142 Example 16 18 23.4 Example 44 14 45 Example 17 81 120 Example 45 47 76.8 Example 18 32 24.9 Example 46 21 56.8 Example 19 27 42.3 Example 47 58 194 Example 20 35 105 Example 48 130 229 Example 21 22 34.6 Example 49 45 169 Example 22 27 19.1 Example 50 13 4.01 Example 23 14 23 Example 51 32 26 Example 24 17 29.8 Example 52 16 19.8 Example 25 29 143 Example 53 180 ¹³⁸ 1 Example 26 17 40 Example 54 180 106 I Example 27 17 35.4 Example 55 34 19.4 Example 28 25 76.1 Example 56 20 25.9 Example 29 35 85.5 Example 57 12 8.62 Example 30 13 8.59 Example 58 22 40.1 Example 31 33 340 Example 59 13 8.13

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IC ”(nM) Bcl-2 FP ] C *> (nM) MTTRS4Jl IC ”(nM) Bcl-2 FP IC _e (nM) MTTRS4, ll Example 60 19 11.7 Example 98 12 ^73.5 Example 61 22 14.5 Example 99 25 213 Example 62 22 19.3 Example 100 22 856 Example 63 21 18.8 Example 101 5 22.1 Example 64 31 23.3 Example 103 6 16.8 Example 65 14 9.19 Example 104 7 21.6 Example 66 16 21.7 Example 105 10 ^28.9 1 Example 67 24 17.7 Example 107 7 8.29 J Example 69 26 16.7 Example 108 9 ^36.4 1 Example 70 19 14 Example 109 30 483 Example 71 21 24.4 Example 110 29 129 Example 72 220 270 Example 111 15 81.5 Example 74 24 241 Example 112 9 139 Example 76 17 49 Example 113 16 190 Example 77 23 70.4 Example 114 9 43.1 Example 78 31 101 Example 115 8 58.1 Example 79 31 67.5 Example 116 10 ^43.6 1 Example 80 18 18.8 Example 117 15 ¹⁹⁴ 1 Example 81 28 39.3 Example 118 15 ⁷¹ 1 Example 82 33 21.9 Example 119 9 ^31.6 1 Example 83 18 41.2 Example 121 34 445 Example 84 18 20.6 Example 122 16 43.5 Example 85 41 246 Example 123 22 92.1 Example 86 22 29.5 Example 124 28 101 Example 87 27 121 Example 125 38 81.8 Example 91 8 65.5 Example 126 26 115 Example 92 5 40.2 Example 127 26 ¹²⁹ 1 Example 94 3 8.16 Example 128 10 63.4 | Example 95 6 13.5 Example 129 9 ^46.7 1 Example 96 11 58.8 Example 131 30 ^88.4 1 | Example 97 20 45.4 Example 134 37 ³⁰⁵ 1

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-120-

ICw (nM) Bd-2 FP IC ”(nM) MTT RS4.I I IC ”(nM) Bd-2 FP ICw (nM) MTT RS4, ll Example 135 6 37.4 Example 144 n.d. 59.9 Example 141 n.d. 72.5 Example 145 n.d. 28.9 Example 142 n.d. 66.1 Example 146 n.d. 153 1 Example 143 n.d. 43.8 Example 147 n.d. 74.2

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 ⁷ RS4 cells; 11 are grafted subcutaneously in immunosuppressed mice (strain SC1D). 25 to 30 days after the transplant, the animals are treated orally with the different compounds. Sixteen hours after the treatment, the tumor masses are recovered, lysed and the caspase 3 activity is measured in the tumor lysates.

This enzymatic measurement is carried out by assaying 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 are presented in Table 2 and show that the compounds of the invention are capable of inducing apoptosis in RS4; 11 tumor cells in vivo.

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-121 Table 2 î Caspase activation factors (DEVDase activity in tumors of treated mice versus control mice) in vivo, after oral treatment (doses specified in brackets)

I Compound tested Activation factor 1 (versus control) | Example 1 29.3 (100 mg / kg) Example 2 27.8 (100 mg / kg) Examples 5.7 (50 mg / kg) Example 4 29.2 (50 mg / kg) Example 8 9.8 (50 mg / kg) | Example 9 20.6 (50 mg / kg) Example 10 13.8 (50 mg / kg) Example 22 11.3 (50 mg / kg) Example 23 22.7 (50 mg / kg) Example 58 23.3 (50 mg / kg) Example 59 23 (50 mg / kg) Example 66 24.7 (50 mg / kg) Example 67 18.9 (50 mg / kg)

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

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- 122 cleaved in the treated mice divided by the quantity of caspase 3 cleaved in the control mice.

The results obtained are presented in Table 3 and show that the compounds of the invention are capable of inducing apoptosis in RS4; 11 tumor cells in vivo.

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

Compound tested Activation factor (versus control) Example 78 10.4 (25 mg / kg) Example 87 18.3 (50 mg / kg) Example 122 17.4 (25 mg / kg) Example 135 60 (50 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 ⁷ RS4 cells; 11 are grafted subcutaneously in immunosuppressed mice (SCID strain). 25 to 30 days after the transplant, when the tumor mass has reached about 150 mm ³ , the mice are treated orally with the different compounds in 2 different schedules (daily treatment for five days per week for two weeks, or two treatments with week for two weeks). The tumor mass is measured twice a week from the start of treatment.

The compounds of the invention exhibit antitumor activities, by the oral route, in the RS4; 11 leukemia model (acute lymphoblastic leukemia) with ΔΤ / C (parameter for qualifying the activity of a product which is defined as tumor volume ratio of the treated group / tumor volume of the untreated control group) ranging from -15 to -56% in relation to tumor regression. The results obtained therefore show that the

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The compounds of the invention are capable of inducing significant tumor regression during the period of treatment.

EXAMPLE F: Pharmaceutical composition: Tablets

1000 tablets containing 5 mg of a compound chosen from Examples 1 to 160 ......... 5g

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

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

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

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

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

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

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Claims (22)

1- Compound of formula (I): in which : ♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they cannot simultaneously represent two carbon atoms or two nitrogen atoms, ZX ♦ the Het part of the Æ group represents an optionally substituted ring, aromatic or not, consisting of 5, 6 or 7 members, and may contain, in addition to the nitrogen represented by X or by Y, one to 3 heteroatoms chosen independently from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question can be substituted by a group representing a hydrogen atom, a linear or branched alkyl (C | -Ce) group or a -C (O) -O-Alk group in which Alk is an alkyl group (Cj-Ce) linear or branched, ♦ Ri and R ₂ represent, independently of one another, a hydrogen atom or a linear or branched alkyl group (Ct-Ce), or else R _t and R ₂ form with the atom of nitrogen which carries them, a heterocycloalkyl consisting of 4 to 7 members and which may contain, in addition to the nitrogen atom, another he teroatom chosen from oxygen, sulfur, SO ₂ and NR in which R represents a hydrogen atom, a linear or branched (Ci-C ₆ ) alkyl group, a DUPLICATE -125 (C _r C6) aIkylsulfonyl group, a linear or branched polyhaloalkyl (Ci-Ce) group, or a -C (O) -O-Alk group in which Alk is a linear or branched (C | -Cs) alkyl group, , ♦ Rj represents a linear or branched alkyl (Ci-Ce), alkenyl (C2-C3, alkynyl (Cî-Cs), cycloalkyl, cycloalkyI (C ₄ -Cto) alkyl (Ct-Cé) linear or branched, aryl or heteroaryl, ♦ R4 represents an aryl, heteroaryl, cycloalkyl or linear or branched alkyl (Cj-Ce) group, ♦ Rj represents a hydrogen or halogen atom, ♦ R ”, Rb, R“ and Rj independently represent each others a hydrogen atom, a halogen atom, a linear or branched alkyl (Ct-Ce) group, a linear or branched alkoxy (Cj-Ce) group, a hydroxy group, a polyhaloalkyl (Cj-Cè) group linear or branched, or a trifluoromethoxy group, or the substituents of one of the pairs (R ,, Rb), (Rb, RJ or (Rc, Rd) together with the carbon atoms which carry them form a ring consisting of 5 to 7 members, which may contain from one to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, an alkyl group (C | Linear or branched CJ or a -C (O) -O-Alk group in which Alk is a linear or branched (Ct-Ce) alkyl group, it being also understood that one or more carbon atoms of the previously defined ring can (wind ) be deuterated, it being understood that: - By aryl is meant a phenyl, naphthyl, biphenyl or indenyl group, - By heteroaryl is meant any mono or bi-cyclic group consisting of 5 to 10 members, having at least one aromatic part, and containing from 1 to 3 heteroatoms chosen from oxygen, sulfur or nitrogen, - By cycloalkyl is meant any non-aromatic carbocyclic group, mono or bi-cyclic, containing 4 to 10 members, the alkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined DUPLICATE -126 which can be substituted by 1 to 3 groups chosen from alkyl (C | -Ce) linear or branched optionally substituted, spiro (Cj-Ce), alkoxy (Cj-Ce) linear or branched, (CjCi) alkyl-S-, hydroxy , oxo (or A / -oxide where appropriate), nitro, cyano, -COOR ', NR'R ”, linear or branched polyhaloalkyl (C1-C6), trifluoromethoxy, (C1-C6alkylsulfonyl or halogen, provided that R 'and R ”represent, independently of one another, a hydrogen atom or a linear or branched alkyl group (Cj-Ce), the Het part of the group defined above possibly being substituted by a group chosen from among linear or branched (C1-C6) alkyl, hydroxy, NRt'Ri ”, or halogen, it being understood that Rf and Rf 'have the same definitions as the groups R' and R '' mentioned above, their enantiomers and diastereomers, as well as as their addition salts with a pharmaceutically acceptable acid or base. 2- Compound of formula (I) according to claim 1 wherein the group represents one of the following groups: 5,6,7,8-tetrahydroindolizine optionally substituted with a hydroxy, indolizine, l, 2,3,4-tetrahydropyrrolo [1,2-a] pyrazine, 3,4dihydropyrrolo [1,2-a] pyrazine-2 (17 /) - tert-butyl carboxylate, 3,4-dihydro-lWpyrrolo [2, lc] [l, 4] oxazine, 2,3-dihydro-1 // - pyrrolizine optionally substituted with a hydroxy, 6,7,8,9-tetrahydro-5 / Apyrrolo [1,2-fl] azepine or pyrrolo [1,2-n] pyrazine. 3- A compound of formula (I) according to claim 1 wherein R 1 and R 2 each represent an alkyl group optionally substituted with a methoxy, or R | and R2 form with the nitrogen atom which carries them a heterocycloalkyl chosen from the following groups: morpholine optionally substituted by one or more linear or branched (Ct-Cs) alkyl (s), oxidomorpholine, thiomorpholine 1,1-dioxide, 1,4-oxazepane, 3methoxypyrrolidine, 3,3-difluoropyrrolidine, 3-methoxyazetidine, 3-fluoroazetidine, oxopiperazine or piperazine, the last two groups being substituted by a linear alkyl group (C | -Ce) or branched, linear or branched polyhaloalkyl (C 1 -Ce) or methylsulfonyl. DUPLICATE -127- 4- A compound of formula (I) according to claim I wherein R _a and Rd each represent a hydrogen atom and (Rb, Rc) together with the carbon atoms which carry them a 1,3-dioxolane group of which l 'one of the carbon atoms is optionally deuterated, a 1,4-dioxane group, a 1,4-dioxepane group, or else Ra, Rc and Rd each represent a hydrogen atom and Rb represents a halogen, a methyl, a methoxy, ethoxy, trifluoromethyl or trifluoromethoxy. 5- A compound of formula (I) according to claim 1 wherein R4 represents a 4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl or 5-hydroxypyrimidine group. 6- A compound of formula (I) according to claim 1 wherein R3 represents a group selected from phenyl, indole, indoline, 1,2,3,4-tetrahydroquinoline, 3,4dihydro-2 // - i, 4-benzoxazine, indane, 1/7-indazole, l // - pyrrolo [2,3-6] pyridine, pyrimidine, cyclobutylmethyl, cyclopropylmethyl, l / Apyrazole, pyridine, pyridazine, these groups optionally comprising one or more substituents chosen from halogen, alkyl ( Ci-Ce) linear or branched, cyano or alkoxy (Ci-Cè) linear or branched. 7- A compound of formula (I) according to claim 1 chosen from the following group: - A- (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1/7) 'isoquinolinyl) carbonyl] -l, 3- benzodioxol-5-yl} -? / - phenyl-5,6,7,8-tetrahydro-lindolizine carboxamide, - 3 - {5 -chloro-2- [((3S) -3 - (4-morphol inylmethyl) -3,4-dihydro-2 (1 H) -i soquinol inyl) carbonyl] phenyl} -? / - (4-hydroxyphenyl) -A ^r - (1-methyl-1 // - indol-5-yl) -5,6,7,8tetrahydro-1-indolizine carboxamide, - N- (4-hydroxypheny 1) -7V- (1 -methyl 1-1 H- indazol-5-yl) -3 - {2,2-dideuterio-6- [((3S) -3 (4-morpholinylmethyl ) -3,4-dihydro-2 (1 //) - isoquinolinyl) carbony 1] -1,3benzodioxol-5 -y 1} -5,6,7,8 -tetrah ydro-1 -ï ndolizine carboxamide, -? / - (4-hydroxypheny!) -? / - (1 -methyl 1 -1 // - i ndazol-5 - yl) -3- (6- {[(3S) -3- (morpho li n- 4 ylmethyl) -3,4-dihydroisoquinolin-2 (lZ /) - yl] carbonyl} -l, 3-benzodioxol-5-yl) - 5,6,7,8-tetrahydroindol izine-1 -carboxamide, - AT- (4-hydroxyphenyl) -3- {7 - [((3S) -3 ’(4-morpholinylmethyl) -3,4-dihydro-2 (IH) DUPLICATA -128isoquinolinyl) carbonyl] -2,3-dihydro-1,4-benzodioxin-6-yl} W-phenyl-5,6,7,8tetrahydro-1-indolizine carboxamide, - A / - (4-hydroxyphenyl) -AT- (1-methylI-1H-indol-5-yl) -3- {6 - [((35) -3 - [(4-methylI-lpiperazinyl) methyl] - 3,4-dihydro-2 (l //) - isoquinoIînyl) carbonyl] -1, 3-benzodioxoI-5yl} -1-indolizine carboxamide, - AT- [4- (hydroxy) phenyl] -A ^ (1-methyl-1H-indol-5-yl) -3- {6 - [((3S) -3- (4-morphoIinyl methyl) -3, 4-dihydro-2 (1W) -isoquinoIinyl) carbonyl] -l, 3-benzodioxoI-5-yl} -5,6,7,8tetrahydro-1-indolizine carboxamide, - A / - (4-hydroxyphenyl) -3- {6- [((3S) -3 - (4-morpholinyImethyl) -3,4-dihydro-2 (1H) isoquinolinyl) carbonyl] -l, 3-benzodioxol- 5-yI) -A / -phenyl-1-indoIizine carboxamide, - 3 - {5-chloro-2 - [((35) -3 - (4-morpholinyImethyI) -3,4-dihydro-2 (1 H) isoquinolinyI) carbonyl] phenyl} -Ar- (4-hydroxyphenyl) - / V- (1-methyl-1 // - indoI-5-yI) 1-indolizine carboxamide, - 6- {5-chloro-2 - [((35) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (IW) -isoquinolinyI) carbonyl] phenyl} -N- (3-fluoro-4 -methylphenyl) -AT- (4-hydroxyphenyl) -3,4-dihydro1 H-pyrroIo [2,1 -c] [1,4] oxazine-8-carboxamide, - 3- (5-chIoro-2 - {[(35) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinoIin-2 (1H) yljcarbonyl} phenyl) -A ^r - (4-hydroxy ^, phenyl ) -N- (1 -methyl-1 H-pyrazol-4-yl) -5,6,7,8tetrahydroindol izine-1 -carboxami de, - jV- (3-fluoro-4-methylphenyl) -M (4-hydroxypheny!) - 3- {6 - (((35) -3- (4morphoIinylmethyl) -3,4-dihydro-2 (I //) -isoquinolinyl) carbonyl] -l, 3-benzodioxol-5yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide,. N- [4- (hydroxy) phenyI] -N- (1-methyl-2 , 3-dihydro-1W-indol-5-yI) -3- {6 - [((35) -3- (4morpholinyImethyl) -3,4-dihydro-2 (lf /) - isoquinolinyl) carbonyl] -l, 3-benzodioxol-5yi} -5,6,7,8-tetrahydro-1 -indolizine carboxamide, - 3- {5-chloro-2 - [((35) -3- (4-morpholinyImethyl) -3,4-dihydro-2 (1W) isoquinolinyI) carbonyl] phenyl} -A ^ - (4-hydroxyphenyl) - A / - (1-methyl-2,3-dihydro- 1 H-indoI-5-y 1) -5,6,7,8-tetrahydro-1-indolizine carboxamide, - 2V- (4-hydroxyphenyl) W- (1-methyl-1 H-indol-5-yl) -3- {6 - (((35) -3- (4morphoIinylmethyl) -3,4-dihydro-2 ( lZ /) - isoquinoIinyl) carbonyl] -1, 3-benzodioxoI-5yl} -l-indolizine carboxamide, - 3- {5-chloro-2 - [((35) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (lZ /) - isoquinolinyl) DUPLICATE -129carbonyl] phenyl} -y- (4-hydroxyphenyl) -N- (1-methyl-2,3-dihydro-1 H-indol-5-yl) -1 indolizine carboxamide, - 6- {5 -chloro-2- [((3S) -3 - (4-morphol iny Imethyl 1) -3,4-dihydro-2 (1 //) * i ^so qu * ⁿ ° l iny 0 carbony l] pheny 1} -N- (4-hydroxypheny l) -N-phenyl -3,4-dihydro-17 / -pyrrolo [2,1 - 5 c] [1,4] oxazine-8-carboxami, - jV- (3-fluorophény l) -N- (4-hydroxyphenyl) -3- (6- {[(3S) -3- (morpholin-4-ylmethyl) - 3,4-dihydroisoquinoIin-2 (1 //) * yI] carbonyl} -l, 3-benzodioxo] -5-yl) -5,6,7,8tetrahydroindolizine-1 -carboxamide, their enantiomers and diastereomers, as well as their addition salts with a pharmaceutically acceptable acid or base. 8- A compound of formula (I) according to claim 1 chosen from the following group: - A ^r - (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (Ii /) isoquinolinyl) carbonyl] -1,3-benzodioxol -5-yl} -N-phenyl-5,6,7,8-tetrahydro-1indolizîne carboxamide, 15 - 3- {5-chloro-2 - [((3S) -3- (4-morpholÎnylmethyl) -3,4-dihydro-2 (lfl) -> ^sot luinoIinyl) carbonyl] phenyl} -N- (4- hydroxyphenyl) -N- (1-methyl-1/7-indol-5-yl) -5,6,7,8tetrahydro-1 -indolizine carboxamide, - y- (4-hydroxyphenyl) -N- (1-methyl-1H-indazol-5-yl) -3- {2,2-dideuterio-6 - [((3S) -3 (4-morpholinylmethyl) -3 , 4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1, 3-benzodioxo! 20 -5-yl} -5,6,7,8-tetrahydro-l-indolizine carboxamide, - N- (4-hy droxypheny 1) -7 / - (1 -methyl-1 H-indazol-5-yl) -3 - (6- {[(3S) -3- (morpholin-4ylmethyl) -3, 4-dihydroisoquinolin-2 (lfl) -yl] carbonyl} -l, 3-benzodioxol-5-yl) - 5,6,7,8-tetrahydroindolizine-l-carboxamide, - jV- (4-hydroxyphenyl) -3- {7 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (l / 7) - 25 isoquinolinyl) carbon]] - 2,3-dihydro-1,4-benzodioxin-6-yl} -N-phenyl-5,6,7,8tetrahydro-1-indolizine carboxamide, - N- (4-Hydroxyphenyl) -2V- (l -methyl-1 H-indol-5-yl) -3- {6 - [((3S) -3 - [(4-methyl-lpiperazinyl) methyl] - 3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -l, 3-benzodioxol-5yl} -l-indolizine carboxamide, 30 - / V- [4- (hydroxy) phenyl] -A ^r - (1 -methyl-1 H-indol-5-yl) -3- {6 - [((3S) -3- (4morpholinylmethyl) -3 , 4-dihydro-2 (l / 7) -isoquinolinyl) carbonyl] -l, 3-benzodioxol-5DUPLICATA -130yl} -5,6,7,8-tetrahydro- 1-indolizine carboxamide, -? / - (4-hy dr oxyphé ny 1) - 3 - {6- [(¢ 35) -3 - (4-morphol inyl methyl) -3,4-dihydro-2 (1 //) isoquinolinyl) carbonyl ] -l, 3-benzodioxol-5-yl} -? / - phenyl-l-indoIizine carboxamide, - 3- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (17 /) - 5 isoquinoIinyl) carbonyl] pheny!} - iV- (4-hydroxyphenyl) -? / - (1-methyl-1 // - indol-5-yl) 1-indolizine carboxamide, - 6- {5 -chloro-2- [((3 S) -3 - (4-morphol i ny Imethyl 1) -3,4-dihydro-2 (17 /) - i soqui noliny I) carbonyl] phenyl} -? / - (3-fluoro-4-methylphenyl) -? / - (4-hydroxyphenyl) -3 ₎ 4-dihydro177-pyrrolo [2,1 -c] [1,4] oxazine-8-carboxamide, 10 - 3- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinoIin-2 (1W) yl] carbonyl} phenyl) -N- (4-hydroxyphenyl ) -Æ- (1-methyl-1 // - pyrazol-4-yl) -5,6,7,8tétrahydroin dolizi ne-1 -carboxami de, their enantiomers and diastereoisomers, as well as their addition salts with an acid or to a pharmaceutically acceptable base. 9- Process for the preparation of a compound of formula (I) according to claim 1, characterized in that the starting product is the compound of formula (II): Rc in which Ra, Rb, Rc and Rj are as defined in formula (I), compound of formula (II) which is subjected to a Heck reaction, in aqueous or organic medium, in the presence of a palladium catalyst , a base, a phosphine and the compound of formula (III): DUPLICATE -131 - in which the groups X, Y and Het are as defined in formula (I), to obtain the compound of formula (IV): \ ^R c in which Ra, Rb, Rc, Rj, X, Y and Het are as defined in formula (I), compound of formula (IV) in which the aldehyde function is oxidized to a carboxylic acid for 5 form the compound of formula (V): \ where R *. Rb, Rc, Rd, X, Y and Het are as defined in formula (I), DUPLICATE -132 a compound of formula (V) which then undergoes peptide coupling with a compound of formula (VI): (VI) in which R 1, R ₂ , and R _s are as defined in formula (I), to yield the compound of formula (VII): in which Ra, Rb, R ", Rj, R 1, R ₂ , Rs. X. Y and Het are as defined in formula (I), compound of formula (VII) in which the ester function is hydrolyzed to lead to the corresponding carboxylic acid or 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 that in formula 10 (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 addition salts with an acid or with a pharmaceutically acceptable base and from which the isomers are optionally separated according to a conventional separation technique, 15 it being understood that at any time deemed appropriate during the process described above, DUPLICATE -133certains groups (hydroxy, amino ..,) reagents or synthesis intermediates can be protected and then deprotected for the needs of the 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 hydroxy function characterized in that the amine NHR3R4 is subjected beforehand 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 resulting protected compound of formula (I) then undergoes a deprotection reaction, then is optionally converted into one of its addition salts with a pharmaceutically acceptable acid or base. 1_1- Pharmaceutical composition containing a compound of formula (I) according to any one of claims I to 8 or an addition salt thereof 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, immune and autoimmune diseases. 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, follicular lymphomas, melanomas, hematologic malignancies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. 15. Use of a pharmaceutical composition according to claim II for the manufacture of a medicament useful as a pro-apoptotic agent. DUPLICATE -134- 16- Use of a pharmaceutical composition according to claim 11 for the manufacture of a medicament for the treatment of cancers, immune and autoimmune diseases. 17- Use of a pharmaceutical composition according to claim 11 for 5 manufacture of a medicament for the treatment of cancers of the bladder, brain, breast, uterus, chronic lymphoid leukemia, colorectal cancer, cancer of the esophagus, liver, lymphoblastic leukemia, follicular lymphomas, melanomas, hematologic malignancies, myelomas, 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 a pharmaceutically acceptable acid or base, for its use in the treatment of cancers of the bladder, of the brain, breast, uterine, chronic lymphocytic leukemia, colorectal cancer, cancer of the esophagus, liver, 15 Lymphoblastic leukemias, follicular lymphomas, melanomas, hematologic malignancies, myelomas, ovarian cancer, 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 an addition salt thereof with a pharmaceutically acceptable acid or base, for the 20 manufacture of a medicament for the treatment of cancers of the bladder, brain, breast, uterus, chronic lymphoid leukemias, colorectal cancer, cancers of the esophagus, liver, lymphoblastic leukemias, follicular lymphomas, melanomas, hematologic malignancies, myelomas, 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 anticancer agent chosen from genotoxic agents, poisons DUPLICATE -135mitotics, anti-metabolites, proteasome inhibitors, kinase inhibitors or antibodies. 21. 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. 5 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 (1) according to any one of claims 1 to 8 for its use in combination with radiotherapy in the treatment of cancer.