NEW MACROCYCLIC DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Description

[0001] The present invention relates to novel macrocyclic derivatives, their preparation process and the pharmaceutical compositions that contain them.

[0002] The compounds of the present invention are novel and exhibit very interesting pharmacological characteristics in the field of apoptosis and oncology.

[0003] Apoptosis, or programmed cell death, is a crucial physiological process for embryonic development and the maintenance of tissue homeostasis.

[0004] Apoptotic cell death involves morphological changes, such as nuclear condensation and DNA fragmentation, as well as biochemical phenomena, such as the activation of caspases that degrade key structural components of the cell to induce its disassembly and death. The regulation of the apoptosis process is complex and involves the activation or repression of several intracellular signaling pathways (Cory S. et al., Nature Review Cancer, 2002, 2, 647-656).

[0005] Dysregulation of apoptosis is implicated in certain pathologies. Increased apoptosis is linked to neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and ischemia. Conversely, deficiencies in the execution of apoptosis play an important role in the development of cancers and their chemoresistance, autoimmune diseases, inflammatory diseases, and viral infections. Thus, apoptotic escape is one of the phenotypic signatures of cancer (Hanahan D. et al., Cell 2000, 100, 57-70).

[0006] Anti-apoptotic proteins of the Bcl-2 family are associated with numerous pathologies. The involvement of Bcl-2 proteins is described in many types of cancer, such as colorectal cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, bladder cancer, ovarian cancer, prostate cancer, chronic lymphocytic leukemia, follicular lymphoma, and myeloma. Overexpression of Bcl-2 proteins is implicated in tumorigenesis, chemotherapy resistance, and the clinical prognosis of cancer patients. Therefore, there is a therapeutic need for compounds that inhibit the anti-apoptotic activity of Bcl-2 proteins.Among the Bcl-2 inhibitors known in the literature, WO2015 / 011397 describes derivatives of 3-[2-(3,4-dihydroisoquinoline-2(1H)-carbonyl)phenyl]-5,6,7,8-tetrahydroindolizine-1-carboxamide and their pharmacological properties of interest for cancer treatment. Furthermore, WO2014 / 022752 discloses PIM inhibitors, also useful in cancer treatment and exhibiting a macrocyclic structure.

[0007] The compounds of the present invention, in addition to their novelty, exhibit proapoptotic properties allowing them to be used in pathologies involving a defect in apoptosis, such as for example in the treatment of cancer, autoimmune diseases and the immune system.

[0008] The invention relates in the first embodiment (E1) to compounds of formula (I): in which: ◆ A1 and A2 each represent a methyl group, ◆ G represents an -NR7- group, a 1,2,3,4-tetrahydroisoquinoline group possibly substituted by a T group, a 2,3-dihydro-1 group H-isoindolylene possibly substituted by a T group, or a piperidinylene group, ◆ T represents a hydrogen atom, a linear or branched (C1-C6) alkyl possibly substituted by one to three halogen atoms, an alkyl(C1-C4)-NR1R2 group, or an alkyl(C1-C4)-OR6 group, ◆ X represents a (C2-C8)alkylene group, of which 1 to 3 members may be replaced by a heteroatom selected from oxygen, sulfur, and NR5, or by an arylene or heteroarylene group, ◆ Y represents a -CH2- or -CO- group, ◆ R1 and R2 independently represent a hydrogen atom or a linear or branched (C1-C6) alkyl group branched, or R1 and R2 form a heterocycloalkyl with the nitrogen atom to which they are attached, ◆ R3 and R4 are such that: one of them represents a phenyl group with the following formula: in which W represents a hydroxyl group or a phosphate group chosen from -OPO(OM)(OM'), -OPO(OM)(O -< M 1 +< ), -OPO(O -< M 1 +< )(O -< M 2 +< ), -OPO(O -< )(O -< )M 3 2+< , -OPO(OM)(O[CH 2 CH 2 O]nCH 3 ), and -OPO(O -< M 1 +< )(O[CH 2 CH 2 O]n CH 3 ), in which M and M' independently represent a hydrogen atom, a linear or branched (C 1 - C 6) alkyl group, a linear or branched (C 2 - C 6) alkenyl group, a linear or branched (C 2 - C 6) alkynyl group, a cycloalkyl group, or a heterocycloalkyl group, both consisting of 5 with 6 links, while M 1 +< and M 2 +< independently represent a pharmaceutically acceptable monovalent cation, M 3 2+< represents a pharmaceutically acceptable divalent cation and n is an integer between 1 and 5, while the other represents a linear or branched aryl, heteroaryl, heterocycloalkyl, cycloalkyl or alkyl (C 1 -C 6) group,it being understood that one or more carbon atoms of the preceding groups, or of their possible substituents, may be deuterated, ◆ R 5 represents a hydrogen atom or a linear or branched (C 1 - C 6) alkyl group, ◆ R 6 and R 7 independently represent a hydrogen atom or a linear or branched (C 1 - C 6) alkyl group, ◆ Ra , R c and R d each represent a hydrogen atom and R b represents a hydrogen or halogen atom, , It being understood that: by "aryl" is meant a phenyl, naphthyl, biphenyl, or indenyl group; by "heteroaryl" is meant any mono- or bicyclic group consisting of 5 to 10 members, possessing at least one aromatic portion, and containing 1 to 4 heteroatoms selected from oxygen, sulfur, nitrogen, and quaternary nitrogen; by "cycloalkyl" is meant any non-aromatic carbocyclic, mono- or bicyclic group containing 3 to 10 members; by "heterocycloalkyl" is meant any non-aromatic mono- or bicyclic group, fused or spiral, consisting of 3 to 10 members, and containing 1 to 3 heteroatoms selected from oxygen, sulfur, SO₄²⁻, SO₂²⁻, or nitrogen; by arylene, heteroarylene, 1,2,3,4-tetrahydroisoquinoline, 2,3-dihydro-1 H-isoindolylene or piperidinylene, means an aryl, heteroaryl, 1,2,3,4-tetrahydroisoquinoline or divalent piperidine group, the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl, alkenyl, alkynyl, alkoxy groups, which may be substituted by 1 to 3 groups chosen from: alkyl (C1-C6) linear or branched possibly substituted by a hydroxy, morpholinyl, 3,3-difluoropiperidinyl or 3,3-difluoropyrrolidinyl group; spiro (C3-C6); alkoxy (C1-C6) linear or branched possibly substituted by a morpholinyl group; (C1-C6)alkyl-S-; hydroxy; oxo; A-oxide; nitro; cyano; -COOR'; -OCOR'; NR'R"; linear or branched (C1-C6) polyhalogenoalkyl; trifluoromethoxy; (C1-C6)alkylsulfonyl; halogen; aryl possibly substituted by one or more halogen atoms; heteroaryl; aryloxy; arylthio; cycloalkyl;heterocycloalkyl possibly substituted by one or more halogen atoms or linear or branched (C1-C6) alkyl groups; it being understood that R' and R" represent, independently of each other, a hydrogen atom or a linear or branched (C1-C6) alkyl group possibly substituted by a methoxy group, its enantiomers, diastereomers, or its addition salts to a pharmaceutically acceptable acid or base.

[0009] Pharmaceutically acceptable acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulfonic, camphoric acids, etc.

[0010] Pharmaceutically acceptable bases include, but are not limited to, sodium hydroxide, potassium hydroxide, triethylamine, andtert butylamine, etc.

[0011] Various specific embodiments of the invention (E) are detailed below. It should be noted that the characteristics of the different embodiments can be combined to generate new embodiments: E2. Compound of formula (I) according to E1 in which Y represents a -CO- group. E3. Formula composition (I) according to E1 or E2 in which G represents a group chosen from the following groups: where T represents a methyl group or a (4-morpholinyl)methyl group. E4. Formula composition (I) according to one of the modes E1 to E3 in which X represents a group chosen from the following groups: E5. Compound of formula (I) according to one of the modes E1 to E4 in which one of the groups R3 or R4 represents a 4-hydroxyphenyl group while the other represents a group chosen from the following list: a phenyl group possibly substituted by a cyano group, a pyrazolyl group, a 1-methyl-1 group H- pyrazolyl, a 1-(tetrahydrofuran-3-yl)-1 group H -pyrazolyl, a 5-methyl-2-cyano-1 group H -pyrrolyl, a 1-methyl-2-cyano-1 group H -pyrrolyl, a 1,2-dimethyl-1 group H -pyrrolyl, a 1,5-dimethyl-2-cyano-1 group H -pyrrolyl, a pyrimidinyl group, an ethyl group, a pyridinium group. In some embodiments of the invention, R 3 or R 4 represents a 4-[(NaO) 2 OPO]phenyl group. E6. Compound of formula (I) according to mode E5 in which R 4 represents a 4-hydroxyphenyl group. E7. Compound of formula (I) according to mode E5 in which R3 represents a 4-hydroxyphenyl group. E8. Compound of formula (I) according to mode E7 in which R3 represents a 4-hydroxyphenyl group and G represents a piperidinylene group. E9. Compound of formula (I) according to embodiment E1 selected from the following group: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-20,23-dioxa-1,10,14-triazahexacyclo[26.3.1.1-9,12-.1-15,19-.0-3,8-.0-24,29-]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-17-carbonitrile, 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-4,16,17,23,24,25-hexahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrazolo[4,3-p][1,6,11,15]oxatriazacycloicosine-5,14(8H)-dione, 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-23-oxa-1,10,14-triazahexacy clo[26.3.1.1-9,12-. 1-15,19~.0~3,8~.0-24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-17-carbonitrile, 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-5,14-dioxo-4,5,8,16,17,23,24,25-octahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrrolo[3,2-p][1,6,11,15]oxatriazacycloicosine-2-carbonitrile, 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-5,14-dioxo-1,4,5,8,16,17,23,24-octahydro-14H-15,18-methano-6,9-(metheno)dibenzo[l,r]pyrrolo[2,3-d][1,6,10,15]oxatriazacyclononadecine-2-carbonitrile, 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,16,21,22,23-hexahydro-14H-15,21-methano-6,9-(metheno)dibenzo[j,o]pyrazolo[3,4-b][1,4,8,13]oxatriazacyclononadecine-5,14(8H)-dione, (16S or R)-11-chloro-4-(4-hydroxyphenyl)-1,7,8,16-tetramethyl-5,14-dioxo-4, 5,8,16,17,23,24,25-octahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrrolo[3,2-p][1,6,11,15]oxatriazacycloicosine-2-carbonitrile, 4-[16-chloro-3-hydroxy-19,20-dimethyl-13,22-dioxo-6,7,8,9,10,11,19,22-octahydro-13H,23H-8,12-methano-21,18-(metheno)dibenzo[b,j][1,4,8,13]oxatriazacyclononadecin-23-yl]-1,5-dimethyl-1H-pyrrole-2-carbonitrile, 10-fluoro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,27,30-trioxa-2,6,15,32,35-pentaazahexacyclo[29.2.2.1~4,7~.1~15,19~.0~8,13~.0~18,23~]heptatriaconta-1(33),4,7(37),8,10,12,18,20,22,31,34-undecaene-3,14-dione, 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,30-dioxa-2,6,15,32,35-pentaazahexacyclo[29.2.2.1~4,7~.1-15,19~.0~8,13~.0~18,23~]heptatriaconta-1(33),4,7(37),8,10,12,18,20,22,31,34-undecaene-3,14-dione, 10-chloro-2-(4-hydroxyphenyl)-5,6,27-trimethyl-24,30-dioxa-2,6,15,27,32,35-hexaazahexacyclo[29.2.2.1~4 ,7~.1~15,19~.0~8,13~.0~18,23~]heptatriaconta-1(33),4,7(37),8,10,12,18,20,22,31,34-undecaene-3,14-dione, 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,16,17,23,24-hexahydro-14H-15,18-methano-6,9-(metheno)dibenzo[l,r]pyrazolo[3,4-d][1,6,10,15]oxatriazacyclononadecine-5,14(8H)-dione. , E10. A process for preparing a compound of formula (I) according to embodiment E1, characterized in that the compound of formula (II) is used as the starting product: in which A1, A2, Ra, Rb, Rc, Rd, Y, and G have the same meaning as in formula (I) defined in E1, and Alk represents a linear or branched (C1-C6)alkyl group, compound of formula (II) whose ester function -OAlk is hydrolyzed to give the corresponding carboxylic acid or carboxylate, which can be converted to the corresponding acyl chloride or anhydride, before being coupled with an amine NHR3A R4, in which R4 has the same meaning as in formula (I), and R3A represents: an R3 group as defined in formula (I) or an R3-O-Alk'-Z, R3-Alk'-Z, or R3-Z group in which Alk' represents a linear or branched (C1-C6)alkyl group, and Z represents a halogen atom or a -OH group, to form the compound of formula (III): in which A 1 , A 2 , R a , R b , R c , R d , R 4 , Y and G have the same meaning as in formula (I), which is subjected to a deprotection reaction of the alcohol function, followed by either an intramolecular nucleophilic substitution, or a Mitsunobu reaction, or an aromatic nucleophilic substitution, to give the compound of formula (I), compound of formula (I) which can be purified by a conventional separation technique, which can be transformed into its addition salts to a pharmaceutically acceptable acid or base and from which the isomers are possibly separated by a conventional separation technique, it being understood that at any time deemed appropriate during the process described above, the hydroxy and amino groups of the reagents or synthetic intermediates can be protected and then deprotected for the purposes of the synthesis. E11.A process for preparing a compound of formula (I) according to embodiment E1, characterized in that the compound of formula (IV) is used as the starting product: in which R3, R4 and X have the same meaning as in formula (I), and GA represents a group chosen from the following list: compound of formula (IV) which is then coupled to a compound of formula (V): in which A 1 , A 2 , R a , R b , R c , and R d have the same meaning as in formula (I), to lead to the compound of formula (VI): in which A 1 , A 2 , R a , R b , R c , R d , R 3 , R 4 and X have the same meaning as in formula (I), which is subjected to a deprotection reaction followed by intramolecular coupling to give the compound of formula (I), compound of formula (I) which can be purified by a conventional separation technique, which can be transformed into its addition salts to a pharmaceutically acceptable acid or base and from which the isomers are possibly separated by a conventional separation technique, it being understood that at any time deemed appropriate during the process described above, the hydroxy and amino groups of the reagents or synthetic intermediates can be protected and then deprotected for the purposes of the synthesis. E12. Pharmaceutical composition containing a compound of formula (I) according to one of the modes E1 to E9, or one of its addition salts with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients. E13. Pharmaceutical composition according to embodiment E12 for its use as a pro-apoptotic agent. E14. Pharmaceutical composition according to embodiment E12 for use in the treatment of cancers, autoimmune diseases and the immune system. E15. Pharmaceutical composition according to embodiment E14 in which the cancer is selected from the following list: bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, non-Hodgkin lymphoma, melanoma, hematological malignancy, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. E16. Use of a compound of formula (I) according to one of the modes E1 to E9 for the manufacture of a drug useful as a pro-apoptotic agent. E17. Use of a compound of formula (I) according to one of modes E1 to E9 for the manufacture of a drug for the treatment of cancers, immune and autoimmune diseases. E18. Use of a compound of formula (I) according to embodiment E17 wherein the cancer is selected from the following list: bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukemia, colorectal cancer, esophageal cancer, liver cancer, lymphoblastic leukemia, non-Hodgkin lymphoma, melanoma, hematological malignancy, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer. E19. Association of a compound of formula (I) according to one of the modes E1 to E9 with an anticancer agent chosen from among genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, kinase inhibitors or antibodies. E20. Pharmaceutical composition containing an association according to embodiment E19 in combination with one or more pharmaceutically acceptable excipients. E21. Association according to embodiment E19 for its use in the treatment of cancers. E22. Use of an association according to embodiment E19 for the manufacture of a medicinal product useful in the treatment of cancers. E23. Compound of formula (I) according to one of modes E1 to E9 for use in association with radiotherapy in the treatment of cancers.

[0012] Among the pharmaceutical compositions according to the invention, one may mention, more particularly, those which are suitable for oral, parenteral, nasal, percutaneous or transcutaneous, rectal, sublingual, ocular or respiratory administration and in particular plain or coated tablets, sublingual tablets, sachets, packets, capsules, lozenges, tablets, suppositories, creams, ointments, dermal gels, and oral or injectable ampoules.

[0013] 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 from 0.01 mg to 1 g per 24 hours in one or more doses.

[0014] Finally, the compounds of the invention can be linked to monoclonal antibodies or fragments thereof, or can be linked to framework proteins that may or may not be related to monoclonal antibodies.

[0015] Antibody fragments are understood to mean fragments of the type Fv, scFv, Fab, F(ab')2, F(ab'), scFv-Fc, or diabodies, which generally have the same binding specificity as the antibody from which they are derived. According to the present invention, the antibody fragments of the invention can be obtained from antibodies by methods such as digestion with enzymes such as pepsin or papain, and / or by cleavage of disulfide bonds by chemical reduction. Alternatively, the antibody fragments included in the present invention can be obtained by genetic recombination techniques also well known to those skilled in the art, or by peptide synthesis using automated peptide synthesizers, for example, such as those supplied by Applied Biosystems, etc.

[0016] By framework proteins, which may or may not be related to monoclonal antibodies, we mean a protein that may or may not contain an immunoglobulin fold and that provides a binding capacity similar to that of a monoclonal antibody. Those skilled in the art know how to select framework proteins. More specifically, it is known that, to be selected, such a framework should exhibit several characteristics, such as the following (Skerra A., J. Mol. Recogn. 13, 2000, 167-187): good phylogenetic conservation, a robust architecture with a well-known three-dimensional molecular organization (such as crystallography or NMR, for example), small size, no or few post-translational modifications, and ease of production, expression, and purification.Such a scaffold protein may be, but not limited to, a structure chosen from the group consisting of fibronectin and preferably the tenth type III domain of fibronectin (FNfn10), lipocalin, anticalin (Skerra A., J. Biotechnol., 2001, 74(4):257-75), protein Z derived from the B domain of staphylococcal protein A, thioredoxin A or any protein with a repeated domain such as an "ankyrin repeat" (Kohl et al., PNAS, 2003, vol.100, no.4, 1700-1705), an "armadillo repeat", a "leucine-rich repeat" or a "tetratricopeptide repeat". We could also mention a framework derived from toxins (such as toxins from scorpions, insects, plants or molluscs, for example) or from nitric oxide synthase (PIN) inhibitory proteins.

[0017] The following Preparations and Examples illustrate the invention and do not limit it in any way. Preparation 1a: 4-chloro-2-[4-(ethoxycarbonyl}-1,5-dimethyl-1H-pyrrol-2-yl]benzoic acid Stage A: ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate

[0018] A solution of 2-methyl-1 H ethyl pyrrole-3-carboxylate (10 g; 65.3 mmol) and methyl iodide (8.95 mL; 130.6 mmol) in the N,N Dimethylformamide (70 mL), placed at 0°C, is mixed with 60% sodium hydride (2.61 g; 65.3 mmol) in three portions. The mixture is then stirred at 0°C for 1 hour. The reaction mixture is hydrolyzed by the addition of ice-cold water (420 mL) and then diluted with ethyl acetate. After settling, the organic phase is washed successively with 0.1 N hydrochloric acid, saturated lithium chloride, and saturated sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titration.

[0019] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 6.65 (d, 1H), 6.3 (1d, 1H), 4.1 (1q, 2H); 3.5 (s, 3H), 2.4 (s, 3H), 1.5 (1t, 3H).

[0020] IR: v: >C=O: 1688 cm -1< ; COC: 1172 cm -1<. Stage B: 5-(5-chloro-2-formylphenyl)-1,2-dimethyl-1H-pyrrole-3-ethyl carboxylate

[0021] A solution of the compound obtained at Stage A (10 g; 62.8 mmol) in the N,N-Dimethylacetamide (65 mL) is successively mixed with 2-bromo-4-chlorobenzaldehyde (15.2 g; 69 mmol) and potassium acetate (12.3 g; 125.6 mmol), and the mixture is stirred under argon for 20 minutes. Dichlorobis(triphenylphosphine)palladium(II) (2.2 g; 3.14 mmol) is then added. The reaction mixture is heated overnight at 130 °C. After cooling to room temperature, the reaction mixture is diluted with dichloromethane, and then bone black (2 g) is added. The mixture is stirred at room temperature for 1 hour and then filtered. The organic phase is washed with water, dried over magnesium sulfate, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ethanol as eluents to obtain the titration product.

[0022] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 9.8 (s, 1H), 7.91-7.69-7,61 (d, 3H), 6.5 (s, 1H), 4.2 (q, 2H,), 3.4 (s, 3H), 2.55 (s, 3H), 1.28 (t, 3H). Stage C: 4-chloro-2-[4-(ethoxycarbonyl)-1,5-dimethyl-1H-pyrrol-2-yl]benzoic acid

[0023] The compound obtained in Stage B (12.85 g; 42 mmol) and 2-methyl-2-butene (35.7 mL; 336 mmol) are dissolved in a mixture of acetone (20 mL) and tetrahydrofuran (20 mL). 200 mL of an aqueous solution containing a mixture of sodium chlorite (13.3 g; 147 mmol) and sodium hydrogen phosphate (14.5 g; 105 mmol) are added dropwise. The mixture is then vigorously stirred at room temperature for 7 hours. The reaction mixture is concentrated to remove the acetone and then diluted with ethyl acetate. After settling, the organic phase is washed with water and concentrated to dryness. The residue is then resuspended in a minimum of ethyl ether. The resulting solid is filtered, washed with ethyl ether, and then dried under vacuum at 40 °C overnight. The proceeds from the title are used for the remainder without further purification.

[0024] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 13 (m, 1H), 7.85 (d, 1H), 7.60 (dd, 1H), 7.41 (d, 1H), 6.3 (s, 1H), 4.15 (q, 2H), 3.25 (s, 3H), 2.5 (s, 3H), 1.25 (t, 3H).

[0025] IR: v : -OH : 3100-2500 cm -1< ; >C=O : 1681 cm -1< . Preparation 2a: 5-(5-chloro-2-formylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid Stage A: ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate

[0026] A solution of ethyl acetoacetate (1000 g; 7.68 mol) in tetrahydrofuran (3 L) at -10 °C is to which a 50 wt. aqueous solution of chloroacetaldehyde (1206 g; 7.68 mol) is added over a period of 1 hour. A 40 wt. aqueous solution of methylamine (1495 g; 19.2 mol) is then added over a period of 3 hours at -10 °C. The reaction mixture is then heated to 30 °C for 1.5 hours and stirred at this temperature for 16 hours. After returning to room temperature, the mixture is diluted in ethyl acetate (3 L) and the phases are separated. The basic aqueous phase is retained for extraction. The organic phase is cooled to 10°C and a 1 N aqueous hydrochloric acid solution (2.5 L) is added over a period of 15 minutes. The phases are separated and the organic phase is washed again with a 1 N aqueous hydrochloric acid solution (2.5 L), then with a saturated aqueous sodium chloride solution (1 L).The basic and acidic aqueous phases are combined and washed with ethyl acetate (1.5 L). The organic phases are combined and washed with a saturated aqueous solution of sodium chloride (1 L), dried over sodium sulfate, filtered, and concentrated to dryness. The product is purified by vacuum distillation to obtain the product of the titer.

[0027] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.50 (d, 1 H), 6.45 (d, 1 H), 4.25 (q, 2 H), 3.51 (s, 3 H), 2.49 (s, 3 H), 1.33 (t, 3 H). Stage B: 1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0028] Lithium hydroxide monohydrate (251 g; 5.98 mmol) is added to a solution of the compound obtained in Stage A (500 g; 2.99 mol) in water (5 L), and the mixture is heated at 100°C for 2 hours. After returning to room temperature, the reaction mixture is washed with toluene (1 L) and methyl- tert-butyl ether (1 L). The aqueous phase is acidified with an aqueous hydrochloric acid solution (530 mL) at pH=1 at a temperature between 10 and 15 °C, stirred for 1 hour, and then filtered. The resulting solid is washed three times with water and dried under vacuum at a temperature between 60 and 65 °C for 36 hours.

[0029] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 11.52 (s, 1 H), 6.62 (d, 1 H), 6.29 (d, 1 H), 3.50 (s, 3 H), 2.41 (s, 3 H). Stage C: 5-(5-chloro-2-formylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0030] The compound of titration is obtained according to the process described in Stage B of Preparation 1a using 2-bromo-4-chlorobenzaldehyde acid and the compound obtained in the previous stage.

[0031] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.8 (s, 1 H), 7.91 (d, 1 H), 7.69 (dd, 1 H), 7.61 (d, 1 H), 6.5 (s, 1 H), 4.2 (quad., 2 H), 3.4 (s, 3 H), 2.55 (s, 3 H), 1.28 (t, 3 H). Preparation 1a': 5-(prop-2-en-1-yloxy)-1,2,3,4-tetrahydroisoquinoline, hydrochloride (1:1) Stage A: tert-butyl 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0032] To a solution of 5-hydroxyisoquinoline (20 g; 137 mmol) in acetic acid (120 mL), platinum dioxide (2 g; 8.8 mmol) is added. The mixture is placed under a hydrogen atmosphere (2 bar) for 24 hours. The reaction mixture is filtered, and the catalyst is washed with toluene. The resulting filtrate is concentrated to dryness. The residue obtained is used for subsequent steps without further purification.

[0033] To a solution of the residue obtained (1.95 g; 13 mmol) in dichloromethane (110 mL), diisoprolylethylamine (9.7 mL; 57 mmol) and di- tert-Butyl dicarbonate (3.69 g, 16.9 mmol) is added, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with a saturated aqueous solution of ammonium chloride. After settling, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate, then with a saturated aqueous solution of sodium chloride. It is then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of titration.

[0034] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.41 (m, 1 H), 6.97 (t, 1 H), 6.64 / 6.54 (2d, 2 H), 4.42 (m, 2 H), 3.53 (t, 2 H), 2.59 (t, 2 H), 1.42 (s, 9 H).

[0035] IR: v: -OH: 3294 cm -1< ; >C=W: 1652 cm -1<. Stage B: 5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0036] To a solution of the compound obtained in Stage A (10 g; 40.1 mmol) in acetonitrile (110 mL), allyl bromide (6 mL; 60.2 mmol) and potassium carbonate (14.6 g; 120.3 mmol) are added, and the mixture is stirred for 20 hours at room temperature. The reaction mixture is diluted with ethyl acetate. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of titration.

[0037] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.8 (d, 1 H), 7.12 (t, 1 H), 6.75 (d, 1 H), 6.05 (m, 1 H), 5.41 (dquad, 1 H), 5.28 (dquad, 1 H), 4.58 (dt, 2 H), 4.49 (s, 2 H), 3.55 (t, 2 H), 2.68 (t, 2 H), 1.43 (s, 9 H).

[0038] IR:v: >C=O: 1691 cm -1< ; >COC<: 1162 cm -1<. Stage C: 5-(prop-2-en-1-yloxy)-1,2,3,4-tetrahydroisoquinoline, hydrochloride (1:1)

[0039] A solution of the compound obtained in Stage B (9.7 g; 33.4 mmol) in dioxane (30 mL) is combined with a solution of 4 N hydrochloric acid in dioxane (33.4 mL; 133.5 mmol), and the mixture is stirred for 48 hours at room temperature. The reaction mixture is concentrated to dryness, and the resulting residue is resuspended in ethyl acetate and then filtered.

[0040] The product of the titration is obtained in the form of a solid, which is used without further purification.

[0041] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.4 (s, 2 H), 7.21 (t, 1 H), 6.92 (d, 1 H), 6.8 (d, 1 H), 6.08 (m, 1 H), 5.41 (dt, 1 H), 5.29 (dt, 1 H), 4.62 (m, 2 H), 4.25 (s, 2 H), 3.35 (t, 2 H), 2.86 (t, 2 H).

[0042] IR: v: >NH 2 +: 3250-2250 cm -1<. Preparation 2a': 1,2,3,4-Tetrahydroisoquinoline-4-ylmethanol Stage A: methyl 1,2,3,4-tetrahydroisoquinoline-4-carboxylate

[0043] To a solution of 1,2,3,4-tetrahydro-4-isoquinolinecarboxylic acid (5 g; 28.2 mmol) in methanol (40 mL), trimethylchlorosilane (5.4 mL; 42.3 mmol) is added, and the mixture is stirred for 16 hours at room temperature. After a second addition of trimethylchlorosilane (4 mL; 31.35 mmol), the reaction mixture is stirred for another 16 hours at room temperature. The reaction mixture is then concentrated to dryness, and the residue is reconstituted in methanol, followed by further concentration. This process is repeated twice to obtain the titration product, which is used without further purification.

[0044] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.75-9.6 (massive, 2H), 7.4-7.25 (massive, 4H), 4.3 (s, 2H), 4.29 (m, 1H), 3.72 (s, 3H), 3.65 / 3.55 (ABx, 2H).

[0045] IR: v: -NH2+: 3200-2150 cm -1<; >C=W: 1731 cm -1<. Stage B: 1,2,3,4-tetrahydroisoquinoline-4-ylmethanol

[0046] To a mixture of lithium aluminum hydride (1.24 g; 32.7 mmol) in tetrahydrofuran (50 mL) at 0 °C, the compound obtained in Stage A (3.47 g; 18.1 mmol) in tetrahydrofuran (50 mL) solution is added dropwise at the same temperature. The reaction mixture is stirred for 2 hours at 0 °C, then hydrolyzed with a mixture of water (11 mL) and 1 N aqueous sodium hydroxide solution (15 mL). After the addition of ethyl acetate, the mixture is stirred for 16 hours at room temperature. The insoluble material is then filtered, and the filtrate is extracted with ethyl acetate. The organic phases are combined and washed with saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness to provide the titration product, which is used thereafter without further purification.

[0047] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.2-6.95 (m, 4 H), 3.8 (s, 2 H), 3.6 (d, 2 H), 3.3 (m, 2 H), 3.18 / 2.85 (2dd, 2 H), 2.65 (m, 1 H).

[0048] IR : v: -NH / -OH+: 3295 cm -1< ; >C=C<: 1626 cm -1<. Preparation 1a" N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-(2-chloroethoxy)aniline Stage A: 1-bromo-3-(2-chloroethoxy)benzene

[0049] A solution of 3-bromophenol (5 g; 18.9 mmol) and bromochloroethane (3.7 mL; 43.3 mmol) in acetonitrile (80 mL) is mixed with potassium carbonate (12 g; 86.7 mmol), and the mixture is stirred at 80 °C for 24 hours. The reaction mixture is diluted with a mixture of ethyl acetate and water. After settling, the organic phase is washed with water and a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of titration.

[0050] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.15 (m, 2 H), 7.09 (m, 1 H), 6.85 (dt, 1 H), 4.21 (t, 2 H), 3.8 (t, 2 H).

[0051] IR: v: Ar: 1588 cm -1<; >COC<: 1227 cm -1< ; γ: >CH-Ar: 764 and 678 cm -1<. Stage B: 4-{[tert-butyl(dimethyl)silyl]oxy}aniline

[0052] The compound of the titration is obtained from 4-aminophenol in tetrahydrofuran in the presence of imidazole and tert-butyl(dimethyl)silyl chloride according to the protocol described in the literature (S. Knaggs et al, Organic & Biomolecular Chemistry, 3(21), 4002-4010; 2005 ) .

[0053] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 6.45-6.55 (dd, 4H), 4.60 (m, 2H), 0.90 (s, 9H), 0.10 (s, 6H).

[0054] IR: v: -NH 2 +<: 3300-3400 cm -1< Stage C: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-3-(2-chloroethoxy)aniline

[0055] A solution of the compounds obtained in Stage A (4.8 g; 20.8 mmol) and Stage B (5.6 g; 24.9 mmol) in toluene (70 mL) is degassed by bubbling with argon for 10 minutes. The following are added: tert -sodium butoxide (2.4 g; 24.9 mmol) and chloro(2-di- tert- butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (0.7 g; 1 mmol). The mixture is then stirred at 80 °C for 1 hour. The reaction mixture is filtered through Celite®. After rinsing with ethyl acetate, the filtrate is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0056] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.88 (s, 1 H), 7.08 (t, 1 H), 7 (d, 2 H), 6.79 (d, 2 H), 6.54 (dd, 1 H), 6.49 (t, 1 H), 6.32 (dd, 1 H), 4.19 (t, 2 H), 3.91 (t, 2 H), 0.95 (s, 9 H), 0.2 (s, 6 H) IR: v: >NH: 3393 cm -1< ; δ: Si-CH 3: 1250 cm -1<. Preparation 2a" : N-(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)-3-(3-chloropropoxy) aniline

[0057] The compound of the titer is obtained according to the process of Preparation 1a" by replacing bromochloroethane with bromochloropropane in Stage A.

[0058] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.85 (s, 1 H), 7.05 (t, 1 H), 6.99 (d, 2 H), 6.77 (d, 2 H), 6.52 (dd, 1 H), 6.48 (t, 1 H), 6.31 (dd, 1 H), 4.02 (t, 2 H), 3.8 (t, 2 H), 2.13 (quint., 2 H), 0.95 (s, 9 H), 0.2 (s, 6 H).

[0059] IR: v: >NH: 3398 cm -1< ; δ: NH: 1504 cm -1<; δ: Si-CH 3: 1250 cm -1<. Preparation 3a" : N-(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)-3-(4-chlorobutoxy)aniline

[0060] The compound of the titer is obtained according to the process of Preparation 1a" by replacing bromochloroethane with bromochlorobutane in Stage A.

[0061] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.81 (m, 1 H), 7.05 (m, 1 H), 7 (m, 2 H), 6.77 (m, 2 H), 6.5 (m, 1 H), 6.47 (m, 1 H), 6.3 (m, 1 H), 3.92 (m, 2 H), 3.7 (m, 2 H), 1.8 (m, 4 H), 0.97 (m, 9 H), 0.2 (m, 6 H).

[0062] IR: v : >NH : 3401 cm -1< . Preparation 4a" : 3-[(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)anùno]-5-(2-chloroéthoxy) benzonitrile Stage A: (3-bromo-5-methoxyphenyl)methanol

[0063] To a solution of 3-bromo-5-methoxybenzoic acid (10 g; 43.3 mmol) in tetrahydrofuran (280 mL), boranedimethylsulfide complex (32.5 mL; 64.9 mmol) is added dropwise, and the mixture is stirred for 2 hours. The reaction mixture is acidified dropwise with 2 N aqueous hydrochloric acid until pH 1 is reached. After ether extraction, the organic phase is washed with 1 N aqueous sodium hydroxide and saturated aqueous sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as an oil, which is used in the next stage without purification.

[0064] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.08 (m, 1 H), 6.99 (m, 1 H), 6.89 (m, 1 H), 5.3 (br. s, 1 H), 4.47 (s, 2 H), 3.75 (s, 3 H). “br.” means "wide".

[0065] IR: v: -OH: 1588 cm -1< ; >CO: 1268 and 1038 cm -1<; γ: >CH-Ar: 811 cm -1<. Stage B: 3-bromo-5-methoxybenzaldehyde

[0066] To a solution of the compound obtained in Stage A (8.6 g; 39.8 mmol) in dichloromethane (400 mL), Dess Martin's reagent (20.3 mL; 47.8 mmol) is added, and the mixture is stirred for 2 hours. After the addition of ether, the reaction mixture is filtered through a silica gel bath. The filtrate is concentrated, resuspended in a mixture of heptane and ethyl acetate, and then filtered again through a silica gel bath. After concentration of the filtrate, the product of the titration is obtained as a pale yellow solid, which is used in the next stage without purification.

[0067] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.5 (s, 1 H), 7.69 (t, 1 H), 7.5 (t, 1 H), 7.42 (t, 1 H), 3.85 (s, 3 H).

[0068] IR: v : >C=O : 1691 cm -1< . Stage C: (E)-1-(3-bromo-5-methoxyphenyl)-N-hydroxymethanimine

[0069] To a solution of the compound obtained in Stage B (7.8 g; 36.4 mmol) in ethanol (10 mL), hydroxylamine hydrochloride (12.6 g; 182 mmol) and pyridine (6.27 mL; 87.4 mmol) are successively added, and the mixture is stirred at 65 °C for 1 hour. After returning to room temperature, the reaction mixture is diluted with a mixture of ethyl acetate and water. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as a white solid, which is used in the next stage without purification.

[0070] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 11.45 (s, 1 H), 8.1 (s, 1 H), 7.35 (t, 1 H), 7.16 (d, 2 H), 3.8 (s, 3 H).

[0071] IR: v: -OH: 3300-3000 cm -1<; Ar: 1600 and 1564 cm -1<; >CO: 1220 and 1059 cm -1<; -NO: 960 cm -1< ; γ: >CH-Ar: 831 cm -1<. Stage D: 3-bromo-5-methoxybenzonitrile

[0072] To a solution of the compound obtained in Stage C (8.1 g; 35.2 mmol) in dioxane (70 mL), pyridine (22 mL; 211 mmol) and trifluoroacetic anhydride (1.4 mL; 70.4 mmol) are added dropwise at 0 °C, and the mixture is stirred at room temperature for 24 hours. The reaction mixture is then placed at 0 °C, and a second portion of trifluoroacetic anhydride (1.4 mL; 70.4 mmol) is added dropwise. The mixture is then stirred at room temperature for 24 hours. The reaction mixture is again placed at 0 °C, and a third portion of trifluoroacetic anhydride (1.4 mL; 70.4 mmol) is added dropwise. The mixture is then stirred at 60 °C for 1 hour. After returning to room temperature, the reaction mixture is diluted with a mixture of dichloromethane and water.After settling, the organic phase is washed with a 1 N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as a pale yellow solid, which is used in the next stage without purification.

[0073] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.69 (t, 1 H), 7.53 (dd, 1 H), 7.5 (dd, 1 H), 3.82 (s, 3 H).

[0074] IR: v: -CN: 2232 cm -1< ; Ar: 1597 and 1562 cm -1<; >COC<: 1278 and 1051 cm -1<; γ: >CH-Ar: 848, 814 and 671 cm -1<. Stage E: 3-bromo-5-hydroxybenzonitrile

[0075] Lithium iodide (11.2 g; 83.7 mmol) is added to a solution of the compound obtained in Stage D (5.9 g; 27.9 mmol) in 2,4,6-collidin (55 mL), and the mixture is stirred at 150 °C for 16 hours. After cooling to room temperature, the reaction mixture is poured into ice-cold water. Following extraction with dichloromethane, the organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as an orange-brown solid, which is used in the next stage without purification.

[0076] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 10.7 (br. s, 1 H), 7.51 (t, 1 H), 7.3 (t, 1 H), 7.18 (dd, 1H).

[0077] IR: v: -OH: 3283 cm -1< ; -CN: 2245 cm -1<. Stadium F : 3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-(2-chloroethoxy) benzonitrile

[0078] The compound of the titration is obtained according to the processes of Stages A and C of Preparation 1a" using the compound obtained in the previous stage and bromochloroethane as starting materials.

[0079] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 8.29 (s, 1 H), 7.04 (d, 2 H), 6.82 (d, 2 H), 6.79 / 6.75 / 6.67 (3 ∗< m, 3 H), 4.24 (dd, 2 H), 3.91 (dd, 2 H), 1.19 (s, 6 H), 0.95 (s, 9 H).

[0080] IR: v: >NH: 3332 cm -1< ; -CN: 2232 cm -1< ; Ar: 1595 and 1504 cm -1< ; >COC< : 1250 cm -1< ; γ: -Si-C: 828 cm -1< . Preparation 5a" : 3-[(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)amino]-5-(3-chloropropoxy)benzonitrile

[0081] The compound of the titer is obtained according to the process of Preparation 4a" by replacing bromochloroethane with bromochloropropane at Stage F.

[0082] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 8.3 (m, 1 H), 7.05-6.85 (m, 4 H), 6.8-6.6 (m, 3 H), 4.1 (m, 2 H), 3.8 (m, 2 H), 2.05 (m, 2 H), 0.95 (m, 9 H), 0.2 (m, 6 H).

[0083] IR:v: >NH: 3345 cm -1< ; -CN: 2229 cm -1<. Preparation 6a" N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-(3-chloropropyl)-1-methyl-1H-pyrazol-4-amine Stage A: 5-(3-{[tert-butyl(dimethyl)silyljoxy}propyl)-1-methyl-1H-pyrazole

[0084] A solution of the N -methylpyrazole (3.2 g; 39 mmol) in tetrahydrofuran (65 mL) is added dropwise at -78 °C to a solution of n-butyllithium in hexane (26.8 mL; 42.9 mmol), and the mixture is stirred for 1 hour until it reaches 0 °C. The reaction mixture is then placed at -78 °C, and (3-bromopropoxy)- is added tert-butyldimethylsilane (10.6 mL; 46.8 mmol). The mixture was stirred at room temperature for 16 hours and poured into a mixture of ice-cold water and ethyl acetate. After extraction with ethyl acetate, the organic phase was washed with a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0085] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.35 (d, 1 H), 7 (d, 1 H), 3.8 (s, 3 H), 3.65 (t, 2 H), 2.7 (m, 2 H), 1.85 (m, 2 H), 0.9 (s, 9 H), 0.5 (s, 6 H).

[0086] IR: γ: CH 3: 1254 cm -1< ; v: -Si-O-: 1098 cm -1< ; -Si-C-: 834 and 772 cm -1< . Stage B: 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)propan-1-ol

[0087] Pyridinium tribromide (6.6 g; 20.8 mmol) is added at 0 °C to a solution of the compound obtained in Stage A (4.8 g; 18.9 mmol) in methanol (200 mL). The mixture is stirred for 1 hour at 0 °C, then for 16 hours at room temperature. After concentration of the reaction mixture, the residue is resuspended in a mixture of a 10% aqueous solution of potassium carbonate and dichloromethane. After extraction with dichloromethane, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ammoniacal methanol as eluents to obtain the product of the titer.

[0088] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.45 (s, 1 H), 4.59 (t, 1 H), 3.79 (s, 3 H), 3.4 (quad, 2 H), 2.7 (t, 2 H), 1.65 (m, 2 H).

[0089] IR: v : -OH : 3348 cm -1< . Stage C: 4-bromo-5-(3-chloropropyl)-1-methyl-1H-pyrazole

[0090] Thionyl chloride (2.6 mL; 36.4 mmol) is added dropwise at 0 °C to a solution of the compound obtained in Stage B (3.9 g; 17.2 mmol) in tetrahydrofuran (40 mL), and the mixture is stirred for 1 hour at 50 °C. After concentration of the reaction mixture, the residue is resuspended in a mixture of water and ethyl acetate. Following extraction with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ammoniacal methanol as eluents to obtain the titer product.

[0091] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.48 (s, 1 H), 3.8 (s, 3 H), 3.69 (t, 2 H), 2.8 (t, 2 H), 1.95 (m, 2 H). Stage D: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-(3-chloropropyl)-1-methyl-1H-pyrazol-4-amine

[0092] A solution of the compounds obtained at Stage C (3.6 g; 15.2 mmol) and Stage B (3.4 g; 15.2 mmol) of Preparation 1a" in a mixture of toluene (25 mL) and tetrahydrofuran (25 mL) is degassed by bubbling with argon for 10 minutes. The following are added: tert -sodium butoxide (1.75 g; 18.2 mmol) and chloro(2-di- tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (0.5 g; 0.76 mmol), then the mixture is stirred at room temperature for 2 hours. The reaction mixture is filtered through Celite®, then concentrated after rinsing with tetrahydrofuran. The residue is resuspended with a mixture of water and dichloromethane, then extracted with dichloromethane, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by first silica gel chromatography using heptane and ethyl acetate as eluents, and then by second chromatography using dichloromethane and ethyl acetate as eluents to obtain the product of the titer.

[0093] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.21 (s, 1 H), 6.59 (d, 2 H), 6.45 (d, 2 H), 3.72 (s, 3 H), 3.55 (t, 2 H), 2.89 (quint, 2 H), 2.65 (t, 2 H), 0.91 (s, 9 H), 0.1 (s, 6 H). Preparation 7a" : 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-(4-chlorobutyl)-5-methyl-1H-pyrrole-2-carbonitrile Stage A: 5-methyl-1H-pyrrole-2-carbonitrile

[0094] A solution of ethyl acetamidocyanoacetate (50.0 g; 0.29 mol) in ethanol (1.25 L) is mixed with sodium acetate (100 g; 1.47 mol), and the mixture is stirred for 10 minutes at 30 °C, then for 10 minutes at 50 °C. At this temperature, a solution of 1,4-dichloro-2-butyne (72.3 g; 0.587 mol) in ethanol (250 mL) is added dropwise over a period of 2 hours, and the mixture is then refluxed for 100 minutes. After returning to room temperature, an aqueous solution of 2 N hydrochloric acid (588 mL) is added, and the ethanol is concentrated. After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The resulting residue is distilled under vacuum to obtain the product of the titer.

[0095] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 8.76 (br. s, 1 H), 6.76 (t, 1 H), 5.93-5.96 (m, 1 H), 2.3 (s, 3 H). Stage B: 4-bromo-5-methyl-1H-pyrrole-2-carbonitrile

[0096] A solution of the compound obtained in Stage A (40.7 g; 0.341 mol) in a mixture of acetic acid (325 mL) and dichloromethane (122 mL) is added at 10°C for 75 minutes to a solution of bromine (59.9 g; 0.374 mol) in acetic acid (163 mL). The mixture is then stirred for 30 minutes at this temperature, followed by a further stir at room temperature for 1 hour. The reaction mixture is hydrolyzed (200 mL) and the dichloromethane is concentrated. After returning to room temperature, water (400 mL) is added and the resulting suspension is stirred for 2 hours at 0°C. The precipitate is filtered and dried under vacuum to obtain the product of the titration without purification.

[0097] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 9.37 (br. s, 1 H), 6.78 (d, 1 H), 2.27 (s, 3 H). Stage C: 4-bromo-1-(4-chlorobutyl)-5-methyl-1H-pyrrole-2-carbonitrile

[0098] A 60% sodium hydride mixture in oil (0.95 g; 23.8 mmol) in a minimum of N,N The compound obtained in Stage B (4 g; 21.6 mmol) is added to N,N-dimethylformamide (120 mL), and the mixture is stirred for 15 minutes at room temperature before adding 1,4-dichlorobutane (4.7 mL; 43.2 mol). The reaction mixture is allowed to act at room temperature for 3 days before being diluted with water (1.5 L). The product is then extracted with ethyl acetate. The organic phases are washed with saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0099] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.76 (s, 1 H), 4.05 (t, 2 H), 3.56 (t, 2 H), 2.27 (s, 3 H), 1.87-1.95 (m, 2 H). Stage D: 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)anùno]-1-(4-chlorobutyl)-5-methyl-1H-pyrrole-2-carbonitrile

[0100] The compound of the titration is obtained according to the process described in Stage C of Preparation 1a" from the compound obtained in the previous stage.

[0101] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.64-6.69 (m, 3 H), 6.46-6.51 (m, 2 H), 4.67 (br. s, 1 H), 4.04 (t, 2 H), 3.57 (t, 2 H), 2.15 (s, 3 H), 1.89-1.99 (m, 2 H), 1.79-1.88 (m, 2 H), 0.96 (s, 9 H), 0.15 (s, 6 H). Preparation 8a" : 4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-(3-chloropropyl)-5-methyl-1H-pyrrole-2-carbonitrile

[0102] The compound of the titer is obtained according to the process of Preparation 7a" by replacing 1,4-dichlorobutane with bromochloropropane at Stage C.

[0103] NMR 1< H (400 MHz, CDCl 3, 300 K) δ ppm: 6.68 (s, 1 H), 6.67 (d, 2 H), 6.48 (d, 2 H), 4.67 (br. s, 1 H), 4.18 (t, 2 H), 3.56 (t, 2 H), 2.26 (quint., 2 H), 2.18 (m, 3 H), 0.96 (s, 9 H), 0.15 (s, 6 H). Preparation 9a": 3-[(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)amino]-5-(3-chloropropyl)benzonitrile Stage A: (3-bromo-5-iodophenyl)methanol

[0104] To a solution of 3-bromo-5-iodobenzoic acid (10 g; 30.58 mmol) in tetrahydrofuran (70 mL), a 1 M boranetetrahydrofuran complex in tetrahydrofuran (61.1 mL; 61.1 mmol) is added dropwise at 0 °C, and the mixture is stirred for 16 hours at room temperature. The reaction mixture is diluted in methanol (10 mL) and hydrolyzed with a 1 M aqueous sodium hydroxide solution (100 mL). After extraction with dichloromethane, the organic phase is washed with a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as a pale brown solid, which is used in the next step without purification.

[0105] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.76-7.79 (m, 1 H), 7.63-7.66 (m, 1 H), 7.47-7.50 (m, 1 H), 4.64 (s, 2 H). Stage B: 3-bromo-5-iodobenzaldehyde

[0106] A solution of the compound obtained in Stage A (7.89 g; 25.2 mmol) in dichloromethane (80 mL) is to which pyridinium dichromate (12.3 g; 32.8 mmol) is added, and the mixture is stirred for 16 hours at room temperature. The reaction mixture is filtered through silica gel, and the filtrate is concentrated to provide the product of the titer without purification.

[0107] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 9.87 (s, 1 H), 8.12 (t, 1 H), 8.10 (t, 1 H), 7.96 (t, 1 H). Stage C: 3-bromo-5-iodobenzonitrile

[0108] A solution of the compound obtained in Stage B (6.95 g; 22.3 mmol) in tetrahydrofuran (60 mL) is combined with an aqueous solution of 28% ammonium hydroxide (30 mL) and iodine (6.81 g; 26.8 mmol), and the mixture is stirred until the initial compound disappears. The reaction mixture is then diluted with an aqueous solution of sodium sulfite until the orange color disappears. After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, filtered, and concentrated to dryness with silica. The product deposited on silica is purified by silica gel chromatography using dichloromethane and heptane as eluents to obtain the product of titration.

[0109] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 8.10 (s, 1 H), 7.92 (s, 1 H), 7.76 (s, 1 H). Stage D: 3-bromo-5-(3-oxopropyl)benzonitrile

[0110] A solution of the compound obtained at Stage C (6.05 g; 19.6 mmol) in the N,N- Dimethylformamide (85 mL) is mixed with allyl alcohol (2.78 mL; 39.3 mmol), benzyltriethylammonium chloride (4.47 g; 19.6 mmol), and sodium bicarbonate (3.30 g; 39.3 mmol). After purging with nitrogen, palladium(II) acetate (0.13 g; 0.59 mmol) is added, and the mixture is heated to 40 °C for 16 hours. The reaction mixture is diluted in a mixture of water (200 mL) and ethyl acetate (100 mL). After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using ethyl acetate and heptane as eluents to obtain the titer product.

[0111] 1H NMR(400 MHz, CDCl 3, 300 K) δ ppm: 9.81 (t, 1 H), 7.64 (t, 1 H), 7.59-7.61 (m, 1 H), 7.44 (t, 1 H), 2.93-3.02 (m, 2 H), 2.81-2.88 (m, 2 H). Stage E: 3-bromo-5-(3-hydroxypropyl)benzonitrile

[0112] Sodium borohydride (0.62 g; 16.27 mmol) is added in portions to a solution of the compound obtained in Stage D (2.98 g; 12.52 mmol) in methanol (30 mL). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is then diluted with a 1 M aqueous sodium hydroxide solution (50 mL). After extraction with dichloromethane, the organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate, filtered, and concentrated to dryness to obtain the product of the titer without purification.

[0113] NMR 1< H (400 MHz, CDCl 3, 300 K) δ ppm: 7.61-7.64 (m, 1 H), 7.59-7.61 (m, 1 H), 7.44 (t, 1 H), 3.68 (t, 2 H), 2.72-2.79 (m, 2 H), 1.83-1.93 (m, 2H). Stage F: 3-bromo-5-(3-chloropropyl)benzonitrile

[0114] To a solution of the compound obtained in Stage E (2.57 g; 10.7 mmol) and triethylamine (3.43 mL; 24.6 mmol) in dichloromethane (30 mL) at 0 °C, methanesulfonyl chloride (1.65 mL; 21.4 mmol) is added. The mixture is stirred at room temperature for 2 hours, and then tetrabutylammonium chloride (8.92 g; 32.1 mmol) is added. The reaction mixture is stirred for 16 hours and then diluted with a mixture of water and dichloromethane. After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using ethyl acetate and heptane as eluents to obtain the titer product.

[0115] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.65 (t, 1 H), 7.60 (s, 1 H), 7.44 (s, 1 H), 3.53 (t, 2 H), 2.78-2.86 (m, 2 H), 2.04-2.14 (m, 2 H). Stage G: 3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-(3-chloropropyl)benzonitrile

[0116] The compound of the titration is obtained according to the process described in Stage C of Preparation 1a" from the compound obtained in the previous stage.

[0117] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.78-7.07 (m, 7 H), 5.60 (br. s, 1 H), 3.52 (t, 2 H), 2.71 (t, 2 H), 2.00-2.10 (m, 2 H), 0.99 (s, 9 H), 0.27 (s, 6 a.m.). Preparation 10a" N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-amine Stage A: 5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-methyl-1H-pyrazole

[0118] The titration compound is obtained according to the process described in Stage A of Preparation 6a, replacing the (3-bromopropoxy)- tert -butyldimethylsilane by (2-bromoethoxy)- tert- butyldimethylsilane.

[0119] 1H NMR (400 / 500 MHz, CDCl 3, 300 K) δ ppm: 7.35 (d, 1 H), 7 (d, 1 H), 3.8 (s, 3 H), 3.65 (t, 2 H), 2.7 (m, 2 H), 1.85 (m, 2 H), 0.9 (s, 9 H), 0.5 (s, 6 H) IR: v: -Si-O-: 1098 cm -1<; -Si-C-: 834 and 772 cm -1<. Stage B: 2-(4-bromo-1-methyl-1H-pyrazol-5-yl)ethanol

[0120] The compound of the title is obtained according to the process described in Stage B of Preparation 6a".

[0121] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.45 (s, 1 H), 4.59 (t, 1 H), 3.79 (s, 3 H), 3.4 (quad, 2 H), 2.7 (t, 2 H), 1.65 (m, 2 H).

[0122] IR: v : -OH : 3348 cm -1< . Stage C: 4-bromo-1-methyl-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazole

[0123] To a solution of the compound obtained in the previous stage (5.34 g; 2.4 mmol) in dichloromethane (40 mL), 3,4-dihydro-2H-pyran (7 mL; 6 mmol) and para-toluenesulfonic acid (4.6 g; 2.4 mmol) are added, and the mixture is stirred for 16 hours. The reaction mixture is diluted in a saturated aqueous solution of sodium bicarbonate. After extraction with dichloromethane, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0124] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.42 (s, 1 H), 4.55 (t, 1 H), 3.8-3.3 (m, 4 H), 3.8 (s, 3 H), 2.71 (m, 2 H), 1.78 (m, 2 H), 1.7-1.4 (m, 6 H). Stage D: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl-1H-pyrazol-4-amine

[0125] The compound of the titration is obtained according to the process described in Stage D of Preparation 6a" from the brominated compound of the previous stage.

[0126] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.2 (s, 1 H), 6.6 (s, 1 H), 6.55 (d, 2 H), 6.45 (d, 2 H), 4.4 (t, 1 H), 3.7 (s, 3 H), 3.65-3.2 (4m, 4 H), 2.58 (m, 2 H), 1.68 (m, 2 H), 1.6-1.3 (m, 6 H), 0.92 (s, 9 H), 0.1 (s, 6 H).

[0127] IR: v: >NH: 3356 cm -1< ; ->CCO-: 1240 cm -1<. Preparation 11a" : Stage A: 4-(prop-2-en-1-yloxy)aniline

[0128] A solution of the N-(allyloxyphenyl)acetamide (4 g; 20.9 mmol) in ethanol (30 mL) is mixed with concentrated sodium hydroxide solution (7 mL; 83.6 mmol). The mixture is stirred at 100 °C for 24 hours. After cooling to room temperature, the ethanol in the reaction mixture is concentrated, and the residue is reconstituted in water (100 mL). After extraction with dichloromethane, the organic phases are dried over magnesium sulfate, filtered, and concentrated to dryness to obtain the product of the titer without purification.

[0129] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 6.66 (d, 2 H), 6.49 (d, 2 H), 6 (m, 1 H), 5.34 (dq, 1 H), 5.2 (dq, 1 H), 4.59 (s, 2 H), 4.4 (dt, 2 H).

[0130] IR: v: -NH2: 3428, 3354 and 3220 cm -1< . Stage B: 4-fluoro-3-{[4-(prop-2-en-1-yloxy)phenyl]amino}benzonitrile

[0131] The titer compound is obtained according to the Stage C process of Preparation 1a" using the compound obtained in the previous stage and 3-bromo-4-fluorobenzonitrile.

[0132] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 8.08 (s, 1 H), 7.36 (dd, 1 H), 7.24 (dd, 1 H), 7.19 (m, 1 H), 7.12 (d, 2 H), 6.96 (d, 2 H), 6.05 (m, 1 H), 5.4 (ddt, 1 H), 5.26 (ddt, 1 H), 4.56 (dt, 2 H).

[0133] IR: v: -NH: 3327 cm -1<; >CN: 2235 cm -1<. Preparation 1b : 5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1 2-dimethyl-1H-pyrrole-3-carboxylic acid Stage A: ethyl 1,2-dimethyl-1H-pyrrole-3-carboxylate

[0134] The procedure is identical to that described in Stage A of Preparation 1a.

[0135] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.50 (d, 1 H), 6.45 (d, 1 H), 4.25 (q, 2 H), 3.51 (s, 3 H), 2.49 (s, 3 H), 1.33 (t, 3 H). Stage B: 1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0136] The procedure is identical to that described in Stage B of Preparation 1a.

[0137] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 11.52 (s, 1 H), 6.62 (d, 1 H), 6.29 (d, 1 H), 3.50 (s, 3 H), 2.41 (s, 3 H). Stage C: tert-butyl 2-bromo-4-chlorobenzoate

[0138] To a solution of magnesium sulfate (1431 g; 11.9 mol) in dichloromethane (10.5 L), sulfuric acid (287 g; 2.97 mol) is added over a period of 30 minutes, followed by 2-bromo-4-chlorobenzoic acid (700 g; 2.97 mol) and 700 mL of tert- butanol. The reaction mixture is stirred for 4 days at room temperature, then filtered. The filtrate is washed with a 5% aqueous solution of potassium bicarbonate, then the organic phase is dried with sodium sulfate and concentrated to dryness, then reconcentrated in heptane (1 L) to obtain the product of the titration.

[0139] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.65 (d+d, 2 H), 7.30 (dd, 1 H), 1.65 (s, 9 H). Stage D: 5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0140] A degassed solution (by bubbling nitrogen for 15 minutes) of the residue obtained in Stage C (187.5 g; 0.643 mol) and of the compound obtained in Stage B (89.6 g; 0.643 mol) in the N,N-dimethylformamide (1.87 L) is mixed with potassium carbonate (178 g; 1.29 mol; previously pulverized using an Ultra-Turrax® grinder) suspended in ethyl acetate. The suspension is then degassed for an additional 15 minutes. Palladium(II) acetate (7.2 g, 0.003 mol) is added, and the suspension is heated to 100 °C and stirred for 18 hours. After returning to room temperature, the reaction mixture is diluted with water (950 mL). This same operation is repeated with the same quantity of the compound obtained in Stage C.

[0141] The two solutions are combined and washed with methyl- tert-butyl ether. The aqueous phases at pH 10 are acidified to pH 2 with a 12 N aqueous hydrochloric acid solution at a temperature between 10 and 20 °C. The resulting suspension is cooled to 0 °C, stirred for 1 hour, and then filtered. The solid is washed with water (2 L) and then drained for 1 hour. To a solution of the residue in methanol (12 L), activated charcoal (375 g) is added. The suspension is heated to 40 °C and stirred for 2 hours. The mixture is filtered through Celite® (375 g), and the solid is washed with methanol. The filtrate is concentrated to dryness, and the resulting residue is diluted in a mixture of ethanol (1.3 L) and methanol (400 mL). The suspension is distilled; 400 mL of distillate are collected. One liter of ethanol is added to continue the distillation until one liter of distillate is collected. After returning to room temperature, the suspension is stirred for 16 hours, then cooled to 0 °C and stirred again for 2 hours.The product is filtered and washed with cold ethanol, then dried under vacuum at 60 °C for 16 hours. The titration product is obtained as a white solid.

[0142] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 10.87-12.20 (s, 1 H), 7.77 (d, 1 H), 7.57 (dd, 1 H), 7.44 (d, 1 H), 6.25 (s, 1 H), 3.25 (s, 3 H), 2.51 (s, 3 H), 1.25 (t, 9 H). Preparation 2b: 5-[2-(tert-butoxycarbonyl)-5-fluorophenyl]-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0143] The compound of titration is obtained according to the process of Preparation 1b using 2-bromo-4-fluorobenzoic acid in Stage C.

[0144] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 12.18 (s, 1 H), 7.93 (dd, 1 H), 7.14 (td, 1 H), 7.03 (dd, 1 H), 6.52 (s, 1 H), 3.27 (s, 3 H), 2.60 (s, 3 H), 1.33 (t, 9 H). Preparation 1b' : 5-(3-hydroxypropyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: (2E)-3-(isoquinoline-5-yl)prop-2-methyl enoate

[0145] In a sealed tube containing a solution of methyl acrylate (5.4 mL; 60.2 mmol), triphenylphosphine (0.63 g; 2.4 mmol), triethylamine (13.4 mL; 96.0 mmol), and palladium(II) acetate (0.27 g; 1.2 mmol) in N,N-dimethylformamide (30 mL), 5-bromoisoquinoline (5 g; 24.1 mmol) is added. Nitrogen is bubbled through the mixture for 10 minutes, then the tube is sealed and immersed in an oil bath at 120 °C. The reaction mixture is stirred for 1.5 hours and then hydrolyzed after returning to room temperature. The product is extracted with ethyl acetate, and the organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titer product.

[0146] 1H NMR(400 MHz, CDCl 3, 300 K) δ ppm: 9.29 (s, 1 H), 8.62 (d, 1 H), 8.42 (d, 1 H), 8.03 (d, 1 H), 7.94-8.01 (m, 2 H), 7.64 (t, 1 H), 6.57 (d, 1 H), 3.88 (s, 3 H). Stage B: 5-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0147] A solution of the compound obtained in Stage A (7.24 g; 34 mmol) and sodium cyanoborohydride (9.6 g; 152.8 mmol) in methanol (200 mL) is placed at 45°C. Boron trifluoride diethyl etherate (18.9 mL; 152.8 mmol) is added dropwise, and then the reaction mixture is stirred for 20 minutes at this temperature. tert-Butylcarbonate (8.15 g; 37.4 mmol) and then triethylamine (14.2 mL; 101.9 mmol) are added. The reaction mixture is stirred for 15 minutes at 45 °C. After returning to room temperature, it is hydrolyzed with water and a 1 N aqueous sodium hydroxide solution. The product is extracted with ethyl acetate, then the organic phases are washed with an aqueous hydrochloric acid solution and water, dried over magnesium sulfate, filtered, and concentrated to dryness to obtain the product of titration.

[0148] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.94 (d, 1 H), 7.44 (d, 1 H), 7.21 (t, 1 H), 7.11-7.17 (m, 1 H), 6.35 (d, 1 H), 4.58 (s, 2 H), 3.81 (s, 3 H), 3.67 (t, 2 H), 2.93 (t, 2 H), 1.49 (s, 9 H). Stage C: 5-[(1E)-3-hydroxyprop-1-en-1-yl]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0149] A 25 wt. diisobutylaluminum hydride solution in toluene (50 mL; 74.7 mmol) is slowly added at -78 °C to a solution of diisobutylaluminum hydride (50 mL; 74.7 mmol). The reaction mixture is stirred for 20 minutes at this temperature, and then methanol is slowly added. After returning to room temperature, the reaction mixture is hydrolyzed with water and a 1 N aqueous sodium hydroxide solution. The product is extracted with ethyl acetate, and the organic phases are washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness to obtain the product of the titer.

[0150] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.33 (d, 1 H), 7.17 (t, 1 H), 7.03 (d, 1 H), 6.80 (d, 1 H), 6.24 (dt, 1 H), 4.54-4.60 (m, 2 H), 4.35 (d, 2 H), 3.65 (t, 2 H), 2.84 (t, 2 H), 1.49 (s, 9 H). Stage D: 5-(3-hydroxypropyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0151] A solution of the compound obtained in Stage C (9.82 g; 34.0 mmol) in methanol (300 mL) is to which palladium on carbon (1 g; 10 wt%) is added. The reaction mixture is hydrogenated for 16 hours and then filtered through Celite®. The filtrate is concentrated to dryness to obtain the product of the titer.

[0152] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.32 (d, 1 H), 7.16 (t, 1 H), 7.02 (d, 1 H), 6.79 (d, 1 H), 6.24 (dt, 1 H), 4.57 (s, 2 H), 4.34 (d, 2 H), 3.62-3.67 (m, 2 H), 3.49 (s, 2 H), 2.84 (t, 2 H), 1.49 (s, 9 H). Preparation 2b': 5-(4-hydroxybutoxy)-3,4-dihydroisoquinoléine-2(1H)-carboxylate de tert-butyle Stage A: tert-butyl 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0153] To a solution of 5-hydroxyisoquinoline (20 g; 137 mmol) in acetic acid (120 mL), platinum dioxide (2 g; 8.8 mmol) is added. The mixture is placed under a hydrogen atmosphere (2 bar) for 24 hours. The reaction mixture is filtered, and the catalyst is washed with toluene. The resulting filtrate is concentrated to dryness. The product of the titration is obtained as an oil, which is used without further purification.

[0154] To a solution of the residue obtained (1.95 g; 13 mmol) in dichloromethane (110 mL), diisoprolylethylamine (9.7 mL; 57 mmol) and di-tert-butyl dicarbonate (3.69 g; 16.9 mmol) are added, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with a saturated aqueous solution of ammonium chloride. After settling, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0155] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.41 (m, 1 H), 6.97 (t, 1 H), 6.64 / 6.54 (2d, 2 H), 4.42 (m, 2 H), 3.53 (t, 2 H), 2.59 (t, 2 H), 1.42 (s, 9 H).

[0156] IR:v: -OH: 3294 cm -1< ; >C=W: 1652 cm -1<. Stage B: 5-[4-(tetrahydro-2H-pyran-2-yloxy)butoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0157] To a solution of the compound obtained in Stage A (1 g; 4 mmol) in acetonitrile (15 mL), 2-(4-bromobutoxy)-tetrahydropyran (0.77 mL; 4.2 mmol) and cesium carbonate (1.4 g; 4.2 mmol) are added, and the mixture is stirred for 18 hours at 70 °C. The reaction mixture is diluted with ethyl acetate and water. After settling, the organic phase is washed with a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and countersunk to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titration product.

[0158] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.12 (dd, 1 H), 6.79 (d, 1 H), 6.72 (d, 1 H), 4.55 (t, 1 H), 4.45 (s, 2 H), 3.98 (t, 2 H), 3.74 / 3.42 (2*m, 2 H), 3.68 / 3.41 (2*m, 2 H), 3.54 (t, 2 H), 2.63 (t, 2 H), 1.79 (m, 2 H), 1.74-1.4 (m, 6 H), 1.68 (m, 2 H), 1.42 (s, 9 H).

[0159] IR: v: >C=O: 1693 cm -1< ; >COC<: 1033 cm -1<. Stage C: 5-(4-hydroxybutoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0160] To a solution of the compound obtained in Stage B (1.29 g; 3.18 mmol) in methanol (50 mL), is added the paraPyridinium toluenesulfonate (0.16 g; 0.64 mmol) was added, and the mixture was stirred for 8 hours at 60 °C. The reaction mixture was diluted with dichloromethane and a saturated aqueous solution of ammonium chloride. After settling, the organic phase was washed with water, then dried over magnesium sulfate, filtered, and countersunk to dryness. The residue was purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titer product.

[0161] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.12 (dd, 1 H), 6.78 (d, 1 H), 6.72 (d, 1 H), 4.45 (s, 2 H), 4.42 (t, 1 H), 3.96 (t, 2 H), 3.54 (t, 2 H), 3.45 (m, 2 H), 2.62 (t, 2 H), 1.75 (m, 2 H), 1.58 (m, 2 H), 1.42 (s, 9 H).

[0162] IR: v: -OH: 3600-3100 cm -1<; >C=W: 1693 cm -1<. Preparation 3b': 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0163] To a solution of 5-hydroxyisoquinoline (20 g; 137 mmol) in acetic acid (120 mL), platinum dioxide (2 g; 8.8 mmol) is added. The mixture is placed under a hydrogen atmosphere (2 bar) for 24 hours. The reaction mixture is filtered, and the catalyst is washed with toluene. The resulting filtrate is concentrated to dryness. The product of the titration is obtained as an oil, which is used without further purification.

[0164] To a solution of the residue obtained (1.95 g; 13 mmol) in dichloromethane (110 mL), diisoprolylethylamine (9.7 mL; 57 mmol) and di-tert-butyl dicarbonate (3.69 g; 16.9 mmol) are added, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with a saturated aqueous solution of ammonium chloride. After settling, the organic phase is washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0165] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.41 (m, 1 H), 6.97 (t, 1 H), 6.64 / 6.54 (2d, 2 H), 4.42 (m, 2 H), 3.53 (t, 2 H), 2.59 (t, 2 H), 1.42 (s, 9 H).

[0166] IR:v: -OH: 3294 cm-1; >C=O: 1652 cm-1. Preparation 4b': 5-hydroxy-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: Methyl 3-methoxy-2-methylbenzoate

[0167] Thionyl chloride (17.5 mL; 0.24 mol) is added dropwise at 0 °C to a solution of 2-methyl-3-methoxybenzoic acid (20 g; 0.12 mol) in methanol (200 mL). The reaction mixture is refluxed for 2 hours. After cooling to room temperature, the reaction mixture is concentrated and then diluted in a mixture of ethyl acetate and 1 N aqueous sodium hydroxide solution. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as an oil, which is used in the next stage without purification.

[0168] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.39 (dd, 1 H), 7.19 (t, 1 H), 6.98 (d, 1 H), 3.89 (s, 3 H), 3.84 (s, 3 H), 2.42 (s, 3 H).

[0169] IR: v : >C=O : 1719 ; >COC 1254 and 1066 cm -1< . Stage B: methyl 2-(bromomethyl)-3-methoxybenzoate

[0170] To a solution of the compound obtained in Stage A (19.8 g; 0.11 mol) in carbon tetrachloride (100 mL), the following are added N -bromosuccinimide (19.56 g; 0.18 mol) and azoisobutyronitrile (2 g; 0.012 mol). The reaction mixture is refluxed for 3 hours. After returning to room temperature, the reaction mixture is diluted in a mixture of dichloromethane and water. After settling, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, filtered, and concentrated to dryness. The residue is resuspended in dichloromethane to provide the titration product as a white solid, which is used in the next step without purification.

[0171] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.51 (d, 1 H), 7.31 (t, 1 H), 7.08 (d, 1 H), 5.05 (s, 2 H), 3.91 (2s, 6 H).

[0172] IR: v : >C=O : 1713 cm -1< . Stage C: (acetylamino)[2-methoxy-6-(methoxycarbonyl)benzyl]diethyl propanedioate

[0173] A sodium hydride suspension (3.42 g; 85.6 mmol) in the N,N- dimethylformamide, is added, drop by drop, at a temperature below 30 °C, a solution of diethyl acetamidomalonate (16.9 g; 77.8 mmol) in the N,N-dimethylformamide (100 mL). The reaction mixture is stirred for 15 minutes, and then a solution of the compound obtained in Stage B (21.2 g; 81.67 mmol) is added dropwise at room temperature. After 18 hours of contact, the reaction mixture is concentrated and then diluted in a mixture of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. After extraction with ethyl acetate, the organic phases are combined, washed with water and a saturated aqueous solution of lithium chloride, then dried over sodium sulfate, filtered, and concentrated to dryness. The residue is resuspended in diisopropyl ether to give the titration product as an off-white solid, which is used in the next stage without purification.

[0174] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.68 (s, 1 H), 7.3 (t, 1 H), 7.1 (2d, 2 H), 4.15 / 4.05 (2m, 4 H), 3.81 (s, 2 H), 3.71 / 3.7 (2s, 6 H), 1.79 (s, 3 H), 1.15 (t, 6 H).

[0175] IR: v: -NH: 3367; >C=O: 1755, 1732 and 1707; >C=O: 1668; >C=C<: 1600 cm -1<. Stage D: 5-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0176] Acetic acid (40 mL) is added to a solution of the compound obtained in Stage C (8.1 g; 20 mmol) in an aqueous solution of 5 N hydrochloric acid. The reaction mixture is refluxed for 18 hours and then filtered after returning to room temperature. The precipitate is rinsed with an aqueous solution of 5 N hydrochloric acid and toluene. After drying under vacuum, the titration product is obtained as a creamy solid, which is used in the next stage without purification.

[0177] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 12.75 (s, 1 H), 7.98 (d, 1 H), 7.48 (d, 1 H), 7.3 (t, 1 H), 7.15 (d, 1 H), 4.2 (m, 1 H), 3.8 (s, 3 H), 3.28 / 3.05 (m, 2H).

[0178] IR: v: -NH / OH: 3215 and 3000 to 2000; >C=O: 1715 and 1627 cm -1< . Stage E: 5-methoxy-3-(morpholin-4-ylcarbonyl)-3,4-dihydroisoquinoline-1(2H)-one

[0179] To a solution of the compound obtained in Stage D (11.1 g; 50 mmol) in dichloromethane (150 mL), morpholine (4.4 mL; 50 mmol), 1-hydroxybenzotriazole (6.7 g; 50 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (9.6 g; 50 mmol), and diisopropylethylamine (20 mL; 115.2 mmol) are successively added. The mixture is then stirred overnight at room temperature. The reaction mixture is diluted with a mixture of dichloromethane and water. After settling, the organic phase is washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is taken up in dichloromethane, filtered and rinsed with hot isopropanol to obtain the titration product, which is used in the next stage without purification.

[0180] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 7.71 (d, 1 H), 7.45 (d, 1 H), 7.29 (t, 1 H), 7.11 (d, 1 H), 4.7 (m, 1 H), 3.81 (s, 3 H), 3.65-3.3 (massif, 8 H), 3.05 / 2.95 (2*dd, 2 H). IR: v : -NH : 3284 ; >C=O : 1676 ; >C-O-C< : 1268 et 1248 cm -1< . Stage F: 5-methoxy-3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline

[0181] A solution of the compound obtained in Stage E (5 g; 17.2 mmol) in tetrahydrofuran (300 mL) is dropwise supplemented with a 2 M solution of the borane / dimethylsulfide complex in tetrahydrofuran (43 mL; 86 mmol). The mixture is then refluxed for 5 hours and left at room temperature overnight. A 5 N aqueous hydrochloric acid solution is added dropwise, and the reaction mixture is refluxed for 8 hours. Finally, an aqueous sodium hydroxide solution is added at 0 °C until a basic pH is reached, and the reaction mixture is diluted with dichloromethane. After extraction, the organic phases are washed with water, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ammoniacal ethanol as eluents to obtain the product of the titer.

[0182] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 7.61 (d, 1 H), 7.09 (t, 1 H), 6.72 (d, 1 H), 3.9 (s, 2 H), 3.75 (s, 3 H), 3.6 (t, 4 H), 2.9 (m, 1 H), 2.62 / 2.05 (2dd, 2 H), 2.5-2.3 (m, 6 H). IR: v : -NH : 3203 cm -1< . Stage G: 3-(morpholin-4-ylmethyl)-1,2,3,4-tetrahydroisoquinoline-5-ol

[0183] A solution of the compound obtained in Stage F (5.6 g; 21 mmol) in dichloromethane (60 mL) is dropwise added at -10 °C to a 1 M solution of tribromoborane in dichloromethane (100 mL; 100 mmol). The mixture is then stirred at this temperature for 3 hours and subsequently warmed to 10 °C over 1 hour. The reaction mixture is diluted to 0 °C with dichloromethane and a saturated aqueous solution of sodium bicarbonate, and then filtered to obtain a white solid. After settling, the aqueous phase is extracted with ethyl acetate, and the organic phases are concentrated. The resulting residue and the white precipitate are combined to obtain the titration product, which is used in the next stage without purification.

[0184] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.2 (br. s, 1 H), 6.89 (t, 1 H), 6.59 (d, 1 H), 6.48 (d, 1 H), 3.81 (s, 2 H), 3.6 (t, 4 H), 2.89 (m, 1 H), 2.6 / 2.02 (2dd, 2 H), 2.5-2.25 (m, 6 H).

[0185] IR: v : -NH / OH : 3412 and 3000 to 2500 ; >C=C< : 1615 cm -1< . Stage H: 5-hydroxy-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0186] To a solution of the compound obtained in Stage G (4.1 g; 16.5 mmol) in dichloromethane (100 mL), diisoprolylethylamine (7.4 mL; 72.6 mmol) and di- tert-butyl dicarbonate (7.9 g, 36.3 mmol) is added, and the mixture is stirred for 18 hours at room temperature. The reaction mixture is diluted with a saturated aqueous ammonium chloride solution. After settling, the organic phase is washed with a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is diluted in a 1 M potassium hydroxide solution in methanol. After a 2-hour contact at room temperature, the reaction mixture is diluted with dichloromethane and a saturated aqueous ammonium chloride solution. After dichloromethane extraction, the organic phases are washed with water, dried over magnesium sulfate, filtered, and concentrated. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titer.

[0187] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm : 9.41 (br. s, 1 H), 6.97 (t, 1 H), 6.62 (d, 1 H), 6.55 (d, 1 H), 4.7-4.4 (d+m, 2 H), 4.08 (m, 1 H), 3.52 (m, 4 H), 2.75-2.2 (m, 7 H), 2.08 (dd, 1 H), 1.42 (br. s, 9 H).

[0188] IR: v : -OH : 3295 ; >C=O : 1689 et 1656 cm -1< . Preparation 5b': 4-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 4-(prop-2-en-1-yl)isoquinoline

[0189] A solution of 4-bromoisoquinoline (25 g; 0.12 mol) and potassium carbonate (50 g; 0.36 mol) in a mixture of water (125 mL) and dimethoxyethane (375 mL) is degassed with a stream of nitrogen. Tetrakis(triphenylphosphine)palladium(0) (7 g; 0.006 mol) and allylboronic pinacolate (35 mL; 0.18 mol) are then added. Nitrogen is bubbled through the mixture for 30 minutes, after which it is refluxed and stirred for 18 hours. After returning to room temperature, the reaction mixture is hydrolyzed. The product is extracted with ethyl acetate, and the organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titer product.

[0190] 1H NMR(400 MHz, CDCl 3 , 300 K) δ ppm : 9.15 (s, 1 H), 8.39 (s, 1H), 7.98 (d, 2 H), 7.71 (ddd, 1 H), 7.60 (ddd, 1 H), 6.08 (dddd, 1 H), 5.05-5.15 (m, 2 H), 3.78 (d, 2 H). Stage B: 2-(isoquinoline-4-yl)ethanol

[0191] The compound obtained in Stage A (14 g; 78 mmol) is dissolved in a mixture of dichloromethane (180 mL) and methanol (180 mL). Ozone is bubbled into the resulting solution using a gas diffuser at -78 °C for 1.5 hours, followed by air for 10 minutes, and finally nitrogen for the same duration. The reaction mixture is maintained at 0 °C, and sodium borohydride (8.83 g; 233 mmol) is added incrementally. After a contact time of 18 hours at room temperature, the mixture is diluted in a mixture of water and saturated aqueous ammonium chloride solution. The product is extracted with ethyl acetate, and the organic phases are washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using ethyl acetate and methanol as eluents to obtain the product of the titer.

[0192] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 9.00 (s, 1 H), 8.37 (s, 1 H), 8.03 (d, 1 H), 7.92 (d, 1 H), 7.74 (ddd, 1 H), 7.61 (ddd, 1 H), 4.01 (t, 2 H), 3.29 (t, 2 H), 2.35 (s, 1 H). Stage C: 4-(2-hydroxyethyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0193] The compound of the titer is obtained according to the process described in Stage B of Preparation 1b' using the compound from the previous stage as the starting material.

[0194] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.16-7.22 (m, 3 H), 7.07-7.13 (m, 1H), 4.87 (d, 1 H), 4.32 (d, 1 H), 4.19 (s, 1 H), 3.73-3.87 (m, 2 H), 3.19 (d, 1 H), 2.97-3.04 (m, 1 H), 1.81 (q, 2 H), 1.65 (s, 1 H), 1.50 (s, 9 H). Preparation 6b': tert-butyl 4-hydroxy-1,3-dihydro-2H-isoindole-2-carboxylate Stage A: 2,2-furan-2-yl dimethylpropanoate

[0195] A solution of 2-(5H)-furanone (22 g; 0.26 mol) and trimethylacetyl chloride (38 g; 0.31 mol) in acetonitrile (50 mL) is added to a solution of triethylamine (43.5 mL; 0.31 mol) in acetonitrile (11 mL). The reaction mixture is stirred for 3 days at room temperature, and the resulting suspension is then filtered and rinsed with methyl tert-butyl ether. The organic phase is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride solutions, then dried over magnesium sulfate, filtered, and concentrated under vacuum. The resulting oil is distilled under vacuum (15 Torr, fractions collected at 76–78 °C) to obtain the product of the titer.

[0196] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.05 (dd, 1 H), 6.36 (dd, 1 H), 5.86 (dd, 1 H), 1.34 (s, 9 H). Stage B: 1,3-dioxo-3,3a,7,7a-tetrahydro-4,7-epoxy-2-benzofuran-4(1H)-yl 2,2-dimethylpropanoate

[0197] The compound obtained in Stage A (38.76 g; 0.23 mol) is added to a solution of freshly ground maleic anhydride (24.9 g; 0.25 mol) in diethyl ether (207 mL). The reaction mixture is stirred at room temperature for 16 hours. The resulting beige suspension is filtered, and the filtrate is concentrated to approximately 50 mL and then filtered again. The solids thus obtained are combined and dried under vacuum to give the titration product.

[0198] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 6.77 (dd, 1 H), 6.69 (d, 1 H), 5.33 (d, 1 H), 3.66 (s, 2 H), 1.22 (s, 9 H). Stage C: 4-hydroxy-2-benzofuran-1,3-dione

[0199] To a solution of concentrated sulfuric acid (80 mL) cooled to -15 °C, the compound obtained in Stage B (36.5 g; 0.16 mol) is added in portions. The mixture is stirred for 15 minutes at -15 °C, then poured onto ice-cold water. The resulting solid is then filtered, rinsed with water, and dried under vacuum to give the titration product.

[0200] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 11.72 (s, 1 H), 7.77 (dd, 1 H), 7.45 (d, 1 H), 7.33 (d, 1 H). Stage D: 4-hydroxy-2-(4-methoxybenzyl)-1H-isoindole-1,3(2H)-dione

[0201] To a solution of the compound obtained in Stage C (24.76 g; 0.15 mol) in acetic acid (150 mL), 4-methoxybenzylamine (21.7 mL; 0.17 mol) is added, and the mixture is refluxed for 5 hours. After returning to room temperature, water (200 mL) is added to the mixture, which is stirred for another hour. The suspension is filtered, and the solid is rinsed with water. The crude product is dissolved in ethyl acetate, and the organic phase is washed with saturated aqueous sodium bicarbonate solution, saturated aqueous ammonium chloride solution, and finally with saturated aqueous sodium chloride solution. The mixture is then dried over sodium sulfate, filtered, and concentrated under vacuum to give the titration product.

[0202] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.54 (t, 1 H), 7.32-7.40 (m, 3 H), 7.12 (d, 1 H), 6.84 (d, 2 H), 4.73 (s, 2 H), 3.77 (s, 3 H). Stage E: 2-(4-methoxybenzyl)-2,3-dihydro-1H-isoindol-4-ol

[0203] To a suspension of lithium aluminum hydride (11.9 g; 0.31 mol) in tetrahydrofuran (150 mL) at 0 °C, a solution of the compound obtained in Stage D (35.5 g; 0.13 mol) in tetrahydrofuran (250 mL) is added dropwise, while maintaining the internal temperature of the mixture below 20 °C. Once the addition is complete, the mixture is heated under reflux. The mixture is stirred for 2 hours under reflux and then cooled to 0 °C. Ethyl acetate is added slowly, while maintaining the internal temperature of the mixture below 20 °C. When no exothermic effect is observed upon the addition of ethyl acetate, the mixture is diluted with ethyl acetate and a 1.5 N aqueous solution of Rochelle salt. The mixture is stirred vigorously for 2 hours at room temperature. After decantation, the aqueous phase is washed with ethyl acetate.The organic phases are combined and washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum to give the product of the titer.

[0204] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.27-7.34 (m, 2 H), 6.95 (t, 1 H), 6.81-6.90 (m, 2 H), 6.68 (d, 1 H), 6.39 (d, 1 H), 3.89 (d, 4 H), 3.83 (s, 2 H), 3.80 (s, 3 H). Stage F: tert-butyl 4-hydroxy-1,3-dihydro-2H-isoindole-2-carboxylate

[0205] To a solution of the compound obtained in Stage E (18.2 g; 71.3 mmol) in methanol (325 mL) and acetic acid (8.2 mL), palladium on carbon (10 wt%) is added. The reactor is sealed, purged with nitrogen, and then with hydrogen. The reaction mixture is subjected to a hydrogen pressure of 45 psi and stirred for 4 hours at room temperature. The reaction mixture is filtered and rinsed with methanol, and the filtrate is concentrated under vacuum. To a solution of the crude product in methanol (200 mL), triethylamine (40 mL; 0.29 mol) and di-tert-butyl dicarbonate (15.6 g; 71.3 mmol) are added. The mixture is stirred at room temperature for 16 hours. The solvent is evaporated under vacuum, and the residue is diluted in ethyl acetate. The organic phase is washed with a 2 N aqueous solution of hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and with a saturated aqueous solution of sodium chloride.Then, it is dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titration product.

[0206] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.11-7.17 (m, 1 H), 7.02 (s, 0.5 H), 6.68-6.84 (m, 2 H), 5.98 (s, 0.5 H), 4.63-4.85 (m, 4 H), 1.51-1.55 (m, 9 a.m.). Preparation 7b': 5-hydroxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 3-(benzyloxy)-2-(prop-2-en-1-yl)benzaldehyde

[0207] To a solution of 2-allyl-3-hydroxybenzaldehyde (20 g; 0.12 mol) in acetonitrile (400 mL), benzyl bromide (16 mL; 0.13 mol) and potassium carbonate (18 g; 0.13 mol) are added. The reaction mixture is stirred for 3 days at room temperature, then poured into a mixture of ice and a saturated aqueous solution of sodium bicarbonate. After extraction with ethyl acetate, the organic phases are dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography using dichloromethane as the eluent to obtain the product of the titer.

[0208] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 10.2 (s, 1 H), 7.5-7.3 (m, 8 H), 6 (ddt, 1 H), 5.2 (s, 2 H), 5-4.85 (m, 2 H), 3.85 (dt, 2 H).

[0209] IR: v : >C=O : 1681 cm -1< . Stage B: N-benzyl-1-[3-(benzyloxy)-2-(prop-2-en-1-yl)phenyl]methananun

[0210] To a solution of the compound obtained in Stage A (20 g; 0.078 mol) in dichloromethane (800 mL), benzylamine (10 mL; 0.078 mol) and, in portions, sodium triacetoxyborohydride (25 g; 0.118 mol) are added. The reaction mixture is stirred for 16 hours at room temperature, and then an aqueous solution of 1 N sodium hydroxide and ice is added. After extraction in dichloromethane, the organic phases are washed with an aqueous solution of 1 N sodium hydroxide, then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography using dichloromethane and ammoniacal ethanol as eluents to obtain the product of titration.

[0211] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.48-7.22 (m, 10 H), 7.14 (t, 1 H), 6.99 (d, 1 H), 6.95 (d, 1 H), 5.85 (m, 1 H), 5.09 (s, 2 H), 4.85 (m, 1 H), 4.76 (m, 1 H), 3.7 (s, 2 H), 3.61 (s, 2 H), 3.44 (d, 2 H), 2.35 (br. s, 1H). Stage C: 2-benzyl-5-(benzyloxy)-3-methyl-1,2,3,4-tetrahydroisoquinoline

[0212] A solution of the compound obtained in Stage B (18.9 g; 0.055 mol) in tetrahydrofuran (1 L) is added dropwise at 60 °C to a solution of n -butyllithium 1.5 N in hexane (40 mL; 0.06 mol). After the addition, the reaction mixture is cooled to room temperature and then neutralized with water. Following ether extraction, the organic phases are washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography using heptane and ammoniacal ethanol as eluents to obtain the titer product.

[0213] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.5-7.2 (m, 5 H), 7.5-7.2 (m, 5 H), 7.03 (t, 1 H), 6.83 (d, 1 H), 6.58 (d, 1 H), 5.1 (s, 2 H), 3.76 (d, 1 H), 3.53 (d, 1 H), 3.58 (d, 1 H), 3.49 (d, 1 H), 3.05 (m, 1 H), 2.8 (dd, 1 H), 2.49 (dd, 1 H), 1.09 (d, 3 H). Stage D: 3-methyl-1,2,3,4-tetrahydroisoquinoline-5-ol

[0214] A solution of the compound obtained in Stage C (13.47 g; 39.22 mmol) in methanol (250 mL) is combined with an aqueous solution of 1 N hydrochloric acid (58.8 mL; 58.8 mmol) and then palladium on carbon (10 wt%). The flask is pressurized with hydrogen, and the reaction mixture is stirred for 48 hours at room temperature. The reaction mixture is filtered and rinsed with methanol, and the filtrate is concentrated under vacuum. The residue is resuspended in ethanol and filtered to obtain the product of the titration.

[0215] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 9.75 (s, 1 H), 9.3 (br. s, 1 H), 7.05 (t, 1 H), 6.75 (d, 1 H), 6.65 (d, 1 H), 4.21 (m, 2 H), 3.48 (m, 1 H), 2.95 (dd, 1 H), 2.47 (dd, 1 H), 1.4 (d, 3 H).

[0216] IR: v : -OH : 3226 cm -1< ; -NH 2 +< : 3300-3400 cm -1< . Stage E: tert-butyl 5-hydroxy-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0217] To a solution of the compound obtained in Stage D (5 g; 25.2 mmol) in dichloromethane (250 mL), triethylamine (7.38 mL; 52.9 mmol) and di-tert-butyl dicarbonate (5.5 g; 25.2 mmol) are added at 0 °C. The reaction mixture is stirred at this temperature for 3 hours, then at room temperature for 20 hours. The solvent is evaporated under vacuum, and the residue is diluted in ethyl acetate. The organic phase is washed with saturated aqueous ammonium chloride solution, water, and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography using cyclohexane and ethyl acetate as eluents to obtain the product of titration.

[0218] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 9.4 (br. s, 1 H), 6.98 (t, 1 H), 6.67 (d, 1 H), 6.6 (d, 1 H), 4.59 (d, 1 H), 4.15 (d, 1 H), 4.45 (m, 1 H), 2.65 (d, 2H), 1.42 (s, 9H), 0.99 (d, 3H).

[0219] IR: v: -OH: 3308 cm -1< ; >C=W: 1655 cm -1<. Preparation 8b': 5-(3-iodopropoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 5-(3-chloropropoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0220] To a solution of the compound obtained in Preparation 3b' (1 g; 4 mmol) in acetonitrile (20 mL), bromochloropropane (0.48 mL; 4.8 mmol) and potassium carbonate (1.1 g; 8 mmol) are added, and the mixture is stirred for 18 hours at 70 °C. The reaction mixture is diluted with ethyl acetate and water. After settling, the organic phase is washed with water, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of titration.

[0221] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.14 (t, 1 H), 6.82 (d, 1 H), 6.75 (d, 1 H), 4.46 (s, 2 H), 4.08 (t, 2 H), 3.82 (t, 2 H), 3.55 (t, 2 H), 2.64 (t, 2 H), 2.18 (fifth, 2 H), 1.42 (s, 9 H).

[0222] IR: v: >C=O: 1692 cm -1< ; >COC<: 1241 / 1164 / 1112 cm -1<. Stage B: 5-(3-iodopropoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0223] Sodium iodide (2.3 g; 15.3 mmol) is added to a solution of the compound obtained in Stage A (1 g; 3.07 mmol) in acetone (30 mL), and the mixture is stirred under reflux for 24 hours. The reaction mixture is concentrated and then diluted with ethyl acetate and water. After extraction with ethyl acetate, the organic phases are washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness to obtain the titration product.

[0224] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.12 (t, 1 H), 6.8 (d, 1 H), 6.72 (d, 1 H), 4.45 (s, 2 H), 4 (t, 2 H), 3.55 (t, 2 H), 3.41 (t, 2 H), 2.63 (t, 2 H), 2.2 (m, 2 H), 1.41 (s, 9 H). IR: v : >C=O : 1692 cm -1< . Preparation 9b': 5-[2-(2-hydroxyethoxy)ethoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0225] A solution of the compound obtained in Preparation 3b' (5 g; 20 mmol) in the N,N- Dimethylformamide (20 mL) is mixed with 2-(2-chloroethoxy)ethanol (6.25 mL; 60 mmol) and potassium carbonate (8.3 g; 60 mmol), and the mixture is stirred for 5 hours at 125 °C. The reaction mixture is diluted with ethyl acetate and water. After settling, the organic phase is washed with a saturated aqueous solution of lithium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of titration.

[0226] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.13 (t, 1 H), 6.81 (d, 1 H), 6.75 (d, 1 H), 4.58 (m, 1 H), 4.46 (s, 2 H), 4.09 (m, 2 H), 3.75 (m, 2 H), 3.54 (t, 2 H), 3.51 (massive, 4 H), 2.63 (t, 2 H), 1.42 (s, 9 H).

[0227] IR : v: -OH: 3450 cm -1< ; >C=O: 1690 cm -1<. Preparation 10b' : 5-(but-3-yn-1-yl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 5-(3-methoxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0228] A solution of the compound obtained in Stage B of Preparation 1b' (19.74 g; 62.3 mmol) in methanol (150 mL) is supplemented with palladium on carbon (10 wt%). Hydrogen is bubbled through the suspension for 10 minutes, and then the mixture is stirred under a hydrogen atmosphere (1 bar) for 18 hours. The reaction mixture is filtered through a Celite® bed, and the filtrate is concentrated to dryness to give the titration product, which is used thereafter without purification.

[0229] 1H NMR(400 MHz, CDCl 3 , 300 K) δ ppm : 7.10 - 7.16 (m, 1 H), 7.04 (d, 1 H), 6.98 (d, 1 H), 4.56 (s, 2 H), 3.68 (s, 3 H), 3.66 (br. s, 2 H), 2.90 - 2.96 (m, 2 H), 2.80 (t, 2 H), 2.55 - 2.61 (m, 2H), 1.48 (s, 9 H). Stage B: 5-(but-3-yn-1-yl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0230] A solution of the product obtained in Stage A (10 g; 31.3 mmol) in dichloromethane (100 mL) at -78 °C is slowly added to a 25 wt% diisobutylaluminum hydride solution in toluene (25.2 mL; 37.6 mmol) over a period of 45 minutes. The addition rate is determined to maintain the temperature of the reaction mixture below -75 °C. At the end of the addition, the mixture is stirred at -78 °C for 30 minutes, and then methanol (50 mL) is slowly added to the reaction. The mixture is then gradually warmed to 0 °C. More methanol (50 mL) is added, followed by potassium carbonate (8.65 g; 62.6 mmol) and then dimethyl-(1-diazo-2-oxopropyl)phosphonate (7.22 g; 37.6 mmol). The mixture is stirred at room temperature for 48 hours and diluted with methyl tert-butyl ether (400 mL). Then, a 1 N aqueous solution of potassium sodium tartrate tetrahydrate (250 mL) is added.The phases are separated, and the aqueous phase is washed with methyl-. tert -butyl ether. The organic phases are combined and washed with a saturated aqueous sodium chloride solution, dried with sodium sulfate, filtered, and evaporated under vacuum. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0231] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.12 - 7.18 (m, 1 H), 7.09 (d, 1 H), 7.00 (d, 1 H), 4.57 (s, 2 H), 3.61 - 3.73 (m, 2 H), 2.78 - 2.89 (m, 4 H), 2.44 (td, 2 H), 1.98 (t, 1 H), 1.49 (s, 9 H). Preparation 1b": 5-(3-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyanophenoxy}propyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A : 5-[3-(3-bromo-5-cyanophenoxy)propyl]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0232] A solution of the compound obtained in Preparation 1b' (9.89 g; 34.0 mmol) and 3-bromo-5-fluorobenzonitrile (27.2 g; 135.8 mmol) in N , N-dimethylformamide (80 mL) is adducted with 60% sodium hydride in oil (1.77 g; 44.1 mmol). The mixture is then stirred for 45 minutes at room temperature and subsequently hydrolyzed slowly. After extraction with ethyl acetate, the organic phases are washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of titration.

[0233] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.36 (t, 1 H), 7.26-7.28 (m, 1 H), 7.12-7.17 (m, 1 H), 7.06-7.09 (m, 1 H), 6.98-7.05 (m, 2 H), 4.58 (s, 2 H), 3.98 (t, 2 H), 3.62-3.68 (m, 2 H), 2.76-2.82 (m, 4 H), 2.02-2.09 (m, 2 H), 1.49 (s, 9 H). Stage B: 4-{[tert-bbutyl(dimethyl)silyl]oxy}aniline

[0234] The compound of the titration is obtained from 4-aminophenol in tetrahydrofuran in the presence of imidazole and tert-butyl(dimethyl)silyl chloride according to the protocol described in the literature (S. Knaggs et al, Organic & Biomolecular Chemistry, 3(21), 4002-4010; 2005 ). 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 6.45-6.55 (dd, 4H), 4.60 (m, 2H), 0.90 (s, 9H), 0.10 (s, 6H). IR: v: -NH 2 +<: 3300-3400 cm -1< Stage C : 5-(3-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyanophenoxypropyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0235] A solution of the compounds obtained in Stage A (8.11 g; 17.2 mmol) and Stage B (4.23 g; 17.2 mmol) in toluene (110 mL) is degassed with argon for 10 minutes. The tert -sodium butoxide (1.82 g; 18.9 mmol), 2-di- tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (0.73 g; 1.72 mmol) and tris(dibenzylidene acetone)dipalladium(0) (0.86 g; 0.86 mmol) were added, and the mixture was stirred at 80°C for 30 minutes. The reaction mixture was filtered through Celite®. After rinsing with ethyl acetate, silica was added to the filtrate, and the mixture was concentrated and purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0236] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.13 (t, 1 H), 6.95-7.06 (m, 4 H), 6.83 (d, 2 H), 6.69 (br. s, 1 H), 6.51-6.59 (m, 2 H), 5.59 (br. s, 1 H), 4.57 (s, 2 H), 3.92 (t, 2 H), 3.58-3.68 (m, 2 H), 2.61-2.83 (m, 4 H), 2.02 (quint., 2 H), 1.49 (s, 9 H), 1.00 (s, 9 H), 0.21 (s, 6 H). Preparation 2b" : 5-(4-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl ) tert-butyl amino]-1H-pyrazol-1-yl}butoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate Stage A: 5 -[4-(4-bromo-1H-pyrazol-1-yl)butoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0237] A solution of the compound from Preparation 2b' (0.786 g; 2.44 mmol) and triphenylphosphine (0.768 mg; 2.93 mmol) in tetrahydrofuran (5 mL) is added dropwise to a solution of 4-bromopyrazole (0.359 mg; 2.44 mmol) and diisopropyl azodicarboxylate (0.58 mL; 2.93 mmol) in tetrahydrofuran (5 mL). The reaction mixture is stirred at room temperature for 2 hours and then diluted in a mixture of ethyl acetate and water. After extraction of the aqueous phase with ethyl acetate, the organic phases are combined, washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by Oasis® phase chromatography using acetonitrile and water as eluents to obtain the titer product.

[0238] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 8.02 (s, 1 H), 7.53 (s, 1 H), 7.12 (dd, 1 H), 6.81-6.68 (2*d, 2 H), 4.46 (s, 2 H), 4.16 (t, 2 H), 3.95 (t, 2 H), 3.54 (t, 2 H), 2.61 (t, 2 H), 1.93 (m, 2 H), 1.65 (m, 2 H), 1.41 (s, 9 H).

[0239] IR: v : >C=O : 1688 cm -1< . Stage B: 5-(4-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1H-pyrazol-1-yl}butoxy) - 3,4-dihydroisoquinoline-2(1H) - tert-butyl carboxylate

[0240] The compound of the titer is obtained according to the process described in Stage C of Preparation 1b" using the compound obtained in the previous stage, the compound from Stage B of Preparation 1b" and chloro(2-di- tert -butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) as a catalyst and ligand.

[0241] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.63 (d, 1 H), 7.26 (d, 1 H), 7.2 (s, 1 H), 7.11 (t, 1 H), 6.75 (dd, 2 H), 6.64 (m, 4 H), 4.45 (s, 2 H), 4.1 (t, 2 H), 3.96 (t, 2 H), 3.53 (t, 2 H), 2.62 (t, 2 H), 1.93 (m, 2 H), 1.68 (m, 2 H), 1.41 (s, 9 H), 0.93 (s, 9 H), 0.12 (s, 6 H).

[0242] IR: v: -NH: 3340 cm -1<; >C=O: 1690 cm -1<. Preparation 3b" : 5-(2-{ 4- [(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino] - 1-methyl-1H-pyrazol-5-yl(ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 5-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-methyl-1H-pyrazole

[0243] A solution of N -methylpyrazole (10.95 g; 133 mmol) in tetrahydrofuran (200 mL) is added dropwise at -78 °C to a solution of n -butyllithium in hexane (100 mL; 160 mmol), then the temperature was raised to 0 °C over 1 hour. The reaction mixture was cooled again to -78 °C, and a solution of (3-bromoethoxy)- was added tert-butyldimethylsilane (34.2 mL; 160 mmol) in tetrahydrofuran (50 mL). The reaction mixture is then stirred at room temperature for 18 hours and poured into a mixture of ice-cold water and ethyl acetate. After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0244] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.28 (d, 1 H), 6.04 (d, 1 H), 3.79 (t, 2 H), 3.74 (s, 3 H), 2.81 (t, 2 H), 0.84 (s, 9 H), 0.1 (s, 6 H). Stage B: 2-(4-bromo-1-methyl-1H-pyrazol-5-yl ) ethanol

[0245] Pyridinium tribromide (14 g; 43 mmol) is added to a solution of the compound obtained in Stage A (9.8 g; 41.1 mmol) in methanol (400 mL) at 0°C, and the mixture is stirred for 1 hour at 0°C, then for 2 hours at room temperature. The reaction mixture is then concentrated, and the residue is resuspended in a mixture of a 10% aqueous solution of potassium carbonate and dichloromethane. After extraction with dichloromethane, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ammoniacal methanol as eluents to obtain the product of the titer.

[0246] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.45 (s, 1 H), 4.88 (t, 1 H), 3.81 (s, 3 H), 3.55 (q, 2 H), 2.8 (t, 2 H).

[0247] IR:v: -OH: 3350 cm -1<; >CCO-: 1049 cm -1<. Stage C: 5-[2-(4-bromo-1-methyl-1H-pyrazol-5-yl)ethoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0248] The compound of the titration is obtained according to the process described in Stage A of Preparation 2b", using the alcohol obtained in the previous stage and the compound of Preparation 3b'.

[0249] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.49 (s, 1 H), 7.13 (t, 1 H), 6.82 (d, 1 H), 6.75 (d, 1 H), 4.45 (s, 2 H), 4.15 (t, 2 H), 3.87 (s, 3 H), 3.51 (t, 2 H), 3.16 (t, 2 H), 2.54 (t, 2 H), 1.41 (s, 9 H).

[0250] IR: v: >C=O: 1689 cm -1< . Stage D: 5-(2-{4-f ( 4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino] - 1-methyl-1H-pyrazol-5-yl(ethoxy)-3,4-dihydroisoquinoline-2 ( 1H)-tert-butyl carboxylate

[0251] The compound of the titer is obtained according to the process described in Stage C of Preparation 1b", using the compound obtained in the previous stage, the compound from Stage B of Preparation 1b", and chloro(2-di- tert -butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) as a catalyst and ligand.

[0252] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.28 (s, 1 H), 7.06 (t, 1 H), 6.71 / 6.67 (2*dd, 2 H), 6.7 (s, 1 H), 6.57 (d, 2 H), 6.48 (d, 2 H), 4.43 (s, 2 H), 4.05 (t, 2 H), 3.82 (s, 3 H), 3.48 (t, 2 H), 3.03 (t, 2 H), 2.5 (t, 2 H), 1.4 (s, 9 H), 0.9 (s, 9 H), 0.09 (s, 6 H).

[0253] IR: v: >NH: 3321 cm -1< ; >C=W: 1677 cm -1<. Preparation 4b" : N-(4-[[tert-butyl(dimethyl)silyl ) oxyphenyl)-1-methyl-5-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-1H-pyrazol-4-amine Stage A: 5-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-1-methyl-1H-pyrazole

[0254] The compound of the titer is obtained according to the process described in Stage A of Preparation 3b", using (3-bromopropoxy)- tert -butyldimethylsilane.

[0255] 1H NMR (400 / 500 MHz, CDCl 3, 300 K) δ ppm: 7.35 (d, 1 H), 7 (d, 1 H), 3.8 (s, 3 H), 3.65 (t, 2 H), 2.7 (m, 2 H), 1.85 (m, 2 H), 0.9 (s, 9 H), 0.5 (s, 6 H).

[0256] IR: v: -Si-O-: 1098 cm -1<; -Si-C-: 834 and 772 cm -1<. Stage B: 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)propan - 1-ol

[0257] The compound of the titer is obtained according to the process described in Stage B of Preparation 3b" using the compound from the previous stage.

[0258] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.45 (s, 1 H), 4.59 (t, 1 H), 3.79 (s, 3 H), 3.4 (quad, 2 H), 2.7 (t, 2 H), 1.65 (m, 2 H).

[0259] IR: v : -OH : 3348 cm -1< . Stage C: 4-bromo-1-methyl-5-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-1H-pyrazole

[0260] 3,4-dihydro-2 is added to a solution of the compound obtained in Stage B (5.34 g; 2.4 mmol) in dichloromethane (40 mL). H -pyrane (7 mL; 6 mmol) and acid paratoluenesulfonic acid (4.6 g; 2.4 mmol) is added, and the mixture is stirred for 16 hours. The reaction mixture is diluted in a saturated aqueous solution of sodium bicarbonate. After extraction with dichloromethane, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0261] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.42 (s, 1 H), 4.55 (t, 1 H), 3.8-3.3 (m, 4 H), 3.8 (s, 3 H), 2.71 (m, 2 H), 1.78 (m, 2 H), 1.7-1.4 (m, 6 H). Stage D: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-1-methyl-5-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-1H-pyrazol-4-amine

[0262] The compound of the titer is obtained according to the process described in Stage D of Preparation 3b" using the compound from the previous stage.

[0263] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm: 7.2 (s, 1 H), 6.6 (s, 1 H), 6.55 (d, 2 H), 6.45 (d, 2 H), 4.4 (t, 1 H), 3.7 (s, 3 H), 3.65-3.2 (4m, 4 H), 2.58 (m, 2 H), 1.68 (m, 2 H), 1.6-1.3 (m, 6 H), 0.92 (s, 9 H), 0.1 (s, 6 H).

[0264] IR: v: >NH: 3356 cm -1< ; ->CCO-: 1240 cm -1<. Preparation 5b" : 5-(3-{3-[(4-{[tert-butyl(diméthyl)silyl]oxy}phényl)amino]-5-cyano - 1-methyl-1H - pyrrol-2-yl}propoxy)-3,4-dihydroisoquinoline-2(1H ) tert-butyl carboxylate Stage A: (2E)-3-(1-methyl-1H-pyrrol-2-yl)prop-2-ethyl enoate

[0265] To a solution of triethyl phosphonoacetate (14.2 mL; 71.5 mmol) in tetrahydrofuran (300 mL), the following is added tert -potassium butoxide (9.25 g; 82.5 mmol), then the mixture is stirred at 0 °C for 45 minutes. A solution of N2-methyl-2-pyrrolecarboxaldehyde (6 g; 55.0 mmol) in tetrahydrofuran (20 mL) is added, and the mixture is stirred at room temperature for 16 hours. The solvent is then concentrated. The residue is diluted in water and ethyl acetate. After extraction with ethyl acetate, the organic phase is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of titration.

[0266] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.59 (d, 1 H), 6.73-6.76 (m, 1 H), 6.65 (dd, 1 H), 6.11-6.18 (m, 2 H), 4.23 (q, 2 H), 3.71 (s, 3 H), 1.32 (t, 3 H). Stage B: ethyl 3-(1-methyl-1H-pyrrol-2-yl)propanoate

[0267] A solution of the compound obtained in Stage A (8.1 g; 45.1 mmol) in ethanol (70 mL) is to which palladium on carbon (10 wt%) is added, and the mixture is then hydrogenated for 6 hours and 30 minutes. The reaction mixture is filtered through Celite® and the filtrate is concentrated to obtain the titration product, which is used for subsequent steps without purification.

[0268] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.52-6.56 (m, 1 H), 6.01-6.06 (m, 1 H), 5.87 (ddt, 1 H), 4.15 (q, 2 H), 3.55 (s, 3 H), 2.83-2.91 (m, 2 H), 2.60-2.68 (m, 2 H), 1.26 (t, 3 H). Stage C: ethyl 3-(5-cyano-1-methyl-1H-pyrrol-2-yl)propanoate

[0269] To a solution of the compound obtained in Stage B (12 g; 66.2 mmol) in acetonitrile (300 mL) at -20 °C, chlorosulfonyl isocyanate (6.92 mL; 79.5 mmol) is added dropwise while maintaining this temperature, then the mixture is stirred at -20 °C for 30 minutes. N , NDimethylformamide (10.3 mL; 132.4 mmol) and triethylamine (18.5 mL; 132.4 mmol) are added at -10 °C, and the mixture is stirred until it reaches room temperature. The reaction mixture is diluted in 500 mL of 1 M aqueous hydrochloric acid. After extraction with ethyl acetate, the organic phase is washed with 1 M aqueous hydrochloric acid, then with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0270] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.72 (d, 1 H), 5.93 (d, 1 H), 4.15 (q, 2 H), 3.68 (s, 3 H), 2.86-2.93 (m, 2 H), 2.63-2.69 (m, 2 H), 1.26 (t, 3 H). Stage D: 4-bromo-5-(3-hydroxypropyl)-1-methyl-1H-pyrrole-2-carbonitrile

[0271] A solution of the compound obtained at Stage C (9.74 g; 47.2 mmol) in the N,N- Dimethylformamide (125 mL) at 0 °C, is added in portions N -bromosuccinimide (8.82 g; 49.6 mmol), then the mixture is stirred at room temperature for 30 minutes. The reaction mixture is diluted in water and tert -butylmethyl ether. After extraction with tert -butylmethyl ether, the organic phase is washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated to dry to obtain the product, which is directly engaged in the next step.

[0272] A solution of this compound (3.13 g; 10.97 mmol) in tetrahydrofuran (30 mL) at 0 °C is to which a 2 M lithium borohydride solution in tetrahydrofuran (11 mL; 21.95 mmol) is added, and the mixture is stirred at room temperature for 6 hours. The reaction mixture is then slowly diluted with a 1 M aqueous sodium hydroxide solution (60 mL). After extraction with tert -butylmethyl ether, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of titration.

[0273] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.75 (s, 1 H), 3.73 (s, 3 H), 3.62-3.69 (m, 2 H), 2.78 (t, 2 H), 1.75-1.85 (m, 2 H), 1.38-1.45 (m, 1 H). Stage E: 5-[3-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)propoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0274] The compound of the titration is obtained according to the process described in Stage A of Preparation 2b", using the alcohol obtained in the previous stage and the compound of Preparation 3b'.

[0275] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.11 (t, 1 H), 7.06 (s, 1 H), 6.75 (2d, 2 H), 4.49 (s, 2 H), 3.99 (t, 2 H), 3.7 (s, 3 H), 3.55 (t, 2 H), 2.88 (t, 2 H), 2.61 (t, 2 H), 1.98 (m, 2 H), 1.41 (s, 9 H).

[0276] IR: v: >CN: 2218 cm -1< ; ->C=O: 1681 cm -1<. Stage F: 5-(3-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyano-1-methyl-1H-pyrrol-2-yl}propoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0277] The compound of the titer is obtained according to the process described in Stage D of Preparation 3b" using the compound from the previous stage.

[0278] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.05 (t, 1 H), 6.75 (s, 1 H), 6.75 (s, 1 H), 6.7 / 6.6 (2d, 2 H), 6.52 (d, 2 H), 6.45 (d, 2 H), 4.42 (s, 2 H), 3.88 (t, 2 H), 3.68 (s, 3 H), 3.5 (t, 2 H), 2.75 (t, 2 H), 2.51 (t, 2 H), 1.89 (m, 2 H), 1.41 (s, 9 H), 0.9 (s, 9 H), 0.1 (s, 6 H).

[0279] IR: v: >NH: 3364 cm -1< ; >CN: 2208 cm -1< ; >C=O: 1690 cm -1<. Preparation 6b" : 5-(2-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyano-1-methyl-1H-pyrrol-2-yl}ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: (1-methyl-1H-pyrrol-2-yl)(oxo)acetic acid

[0280] To a solution of oxalyl chloride (20.9 g; 0.25 mol) in dichloromethane at -10 °C, the following is added N -methylpyrrole (20 g; 0.25 mol) is added while maintaining a temperature below 0 °C, and the mixture is then stirred at 0 °C for 1 hour. The reaction mixture is diluted in a 25% aqueous potassium hydroxide solution at 0 °C. After settling, the aqueous phase is washed with dichloromethane and acidified to pH 1 with a 20% aqueous sulfuric acid solution. The precipitate is filtered and dried to obtain the titration product.

[0281] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 8.01 (dd, 1 H), 7.10 (t, 1 H), 6.27 (dd, 1 H), 3.99 (s, 3 H). Stage B: (1-methyl-1H-pyrrol-2-yl)acetic acid

[0282] To a 65% aqueous solution of hydrazine monohydrate (15.5 mL; 0.21 mol), the compound obtained in Stage A (29 g; 0.19 mol) is added, and the mixture is stirred for a few minutes. A 20% aqueous solution of sodium hydroxide (326 mL) is slowly added, and the mixture is refluxed for 4 hours. After returning to room temperature, a 6 N aqueous solution of hydrochloric acid (25 mL) is added. After extraction with dichloromethane, the organic phase is washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated to a volume of 100 mL. After the slow addition of heptane, the precipitate is filtered to obtain the titration product.

[0283] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.60-6.64 (m, 1 H), 6.04-6.12 (m, 2 H), 3.68 (s, 2 H), 3.59 (s, 3 H). Stage C: (1-methyl-1H-pyrrol-2-yl)methyl acetate

[0284] To a solution of the compound obtained in Stage B (10.2 g; 73.4 mmol) and potassium carbonate (15.2 g; 110.1 mmol) in dichloromethane (100 mL), dimethyl sulfate (7 mL; 73.4 mmol) is added, and the mixture is vigorously stirred at 30 °C for 4 hours. A 5% aqueous ammonium hydroxide solution (326 mL) is added. After settling, the organic phase is washed with a 5% aqueous ammonium hydroxide solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated to dryness to a volume of 100 mL. After the slow addition of heptane, the precipitate is filtered to obtain the titration product. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titration product.

[0285] 1H NMR(400 MHz, CDCl 3, 300 K) δ ppm: 6.58-6.62 (m, 1 H), 6.06-6.09 (m, 1 H), 6.03-6.06 (m, 1 H), 3.71 (s, 3 H), 3.64 (s, 2 H), 3.58 (s, 3 H). Stage D: (5-cyano-1-methyl-1H-pyrrol-2-yl)methyl acetate

[0286] The compound of the titer is obtained according to the process described in Stage C of Preparation 5b" using the compound from the previous stage.

[0287] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.74 (d, 1 H), 6.08 (d, 1 H), 3.73 (s, 3 H), 3.69 (s, 3 H), 3.66 (s, 2 H). Stage E: 5-(2-hydroxyethyl)-1-methyl-1H-pyrrole-2-carbonitrile

[0288] A solution of the compound obtained in Stage D (11.4 g; 10.97 mmol) in tetrahydrofuran (115 mL) at 0 °C is combined with a 2 M lithium borohydride solution in tetrahydrofuran (47.7 mL; 95.4 mmol) at a temperature below 5 °C, and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then slowly diluted with a saturated aqueous ammonium chloride solution (150 mL). After extraction at tert-butylmethyl ether, the organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of titration.

[0289] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 6.75 (d, 1 H), 6.02 (d, 1 H), 3.88 (t, 2 H), 3.69 (s, 3 H), 2.86 (t, 2 H). Stage F: 4-bromo-5-(2-hydroxyethyl)-1-methyl-1H-pyrrole-2-carbonitrile

[0290] A solution of the compound obtained at Stage E (4.25 g; 28.3 mmol) in the N,N- dimethylformamide (43 mL) at 0 °C, is added in portions N -bromosuccinimide (5.04 g; 28.3 mmol), then the mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted in water and tert -butylmethyl ether. After extraction with tert-butylmethyl ether, the organic phase is washed with water and a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness to obtain the titer product, which is used for the following without purification.

[0291] NMR 1< H (400 MHz, CDCl 3, 300 K) δ ppm: 6.76 (d, 1 H), 3.83 (t, 2 H), 3.75 (s, 3 H), 2.91 (t, 2 H), 1.64 (s, 1 H). Stage G: 5-[2-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)ethoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0292] The compound of the titration is obtained according to the process described in Stage A of Preparation 2b", using the alcohol obtained in the previous stage and the compound of Preparation 3b'.

[0293] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.12 (t, 1 H), 7.11 (s, 1 H), 6.8 (d, 1 H), 6.72 (d, 1 H), 4.45 (s, 2 H), 4.15 (t, 2 H), 3.78 (s, 3 H), 3.52 (t, 2 H), 3.18 (t, 2 H), 2.55 (t, 2 H), 1.41 (s, 9 H).

[0294] IR: v: >CN: 2215 cm -1< ; ->C=O: 1686 cm -1<. Stage H : 5-(2-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyano-l-methyl-1H-pyrrol-2-yl}ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0295] The compound of the titer is obtained according to the process described in Stage D of Preparation 3b" using the compound from the previous stage.

[0296] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.05 (t, 1 H), 6.82 (s, 1 H), 6.78 (s, 1 H), 6.7 (2d, 2 H), 6.55 (2d, 4 H), 4.4 (s, 2 H), 4.02 (t, 2 H), 3.7 (s, 3 H), 3.48 (t, 2 H), 3.05 (t, 2 H), 2.51 (t, 2 H), 1.41 (s, 9 H), 0.91 (s, 9 H), 0.12 (s, 6 H).

[0297] IR: v: >NH: 3315 cm-1; >CN: 2212 cm-1; >C=O: 1655 cm-1. Preparation 7b" : 5-[2-({4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H pyrazol5-yl}oxy)ethoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 5-{2-[(4-bromo-1-methyl-1H-pyrazol-5-yl)oxy]ethoxy}-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0298] To a solution of the compound obtained in Preparation 3b' (4.06 g; 16.28 mmol) in acetonitrile (75 mL), bromochloroethane (2 mL; 24.43 mmol) and potassium carbonate (3.35 g; 24.43 mmol) are added, and the mixture is stirred for 2 days at 70 °C. After concentrating the reaction mixture to two-thirds concentration, it is diluted with ethyl acetate and water. Following extraction with ethyl acetate, the organic phases are washed with a saturated aqueous solution of sodium bicarbonate, water, and then with a saturated sodium chloride solution, and dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane as the eluent to obtain a colorless oil.

[0299] Sodium iodide (21.15 g; 141.1 mmol) is added to a solution of the residue thus obtained (4.4 g; 14.1 mmol) in acetone (80 mL), and the mixture is then refluxed for 5 days. The reaction mixture is concentrated and then diluted with ethyl acetate and water. After extraction with ethyl acetate, the organic phases are washed with a saturated sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness to obtain a brown oil, which is used in the next stage without purification.

[0300] To a solution of the residue thus obtained (5.29 g; 13.13 mmol) in acetonitrile (100 mL), 5-hydroxy- N-methylpyrazole (1.29 g; 13.13 mmol), cesium carbonate (4.7 g; 24.43 mmol), and sodium iodide (0.39 g; 2.6 mmol) were added, and the mixture was stirred for 5 hours at 90 °C. After concentration of the reaction mixture, the residue was diluted with ethyl acetate and water. Following extraction with ethyl acetate, the organic phases were washed with a saturated aqueous solution of sodium bicarbonate, water, and a saturated sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain a colorless oil.

[0301] Pyridinium tribromide (2.4 g; 7.5 mmol) is added in portions at 0°C to a solution of the residue thus obtained (2.8 g; 7.5 mmol) in methanol (200 mL). The mixture is stirred for 1 hour at 0°C, then for 2 hours at room temperature. After concentration of the reaction mixture, the residue is resuspended in a mixture of water and dichloromethane. After extraction with dichloromethane, the organic phases are washed with a 1 M aqueous hydrochloric acid solution and water, then dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by RP-18 phase chromatography using acetonitrile and water as eluents to obtain the product of the titer.

[0302] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.41 (s, 1 H), 7.14 (m, 1 H), 6.88 (d, 1 H), 6.84 (d, 1 H), 4.56 / 4.28 (2t, 4 H), 4.45 (s, 2 H), 3.62 (s, 3 H), 3.52 (t, 2 H), 2.55 (t, 2 H), 1.42 (s, 9 H).

[0303] IR:v : >C=O : 1689 cm -1< . Stage B: 5-[2-({4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H-pyrazol-5-yl}oxy)ethoxy]-3,4-dihydroxyquinoline-2(1H)-tert-butyl carboxylate

[0304] A solution of the compound obtained in Stage A (2 g; 4.42 mmol) and the compound obtained in Stage B of Preparation 1b" (1.48 g; 6.63 mmol) in toluene (15 mL) is degassed with argon for 10 minutes. The tert -sodium butoxide (0.51 g; 5.3 mmol), 2-di- tert -butylphosphino-2',4',6'-triisopropylbiphenyl (0.187 g; 0.44 mmol) and chloro(2-di- tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (0.3 g; 0.44 mmol), then the mixture was stirred at 100 °C for 2 hours in a microwave oven (300 W). The reaction mixture was filtered through Celite®. After rinsing with ethyl acetate, the filtrate was washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography using heptane and ethyl acetate as eluents, and then by RP-18 phase chromatography using acetonitrile and water as eluents to obtain the titration product.

[0305] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.18 (s, 1 H), 7.1 (m, 1 H), 6.75 (d, 2 H), 6.7 (s, 1 H), 6.6 (d, 2 H), 6.48 (d, 2 H), 4.45 (s, 2 H), 4.42 / 4.15 (2t, 4 H), 3.53 (s, 3 H), 3.51 (t, 2 H), 2.52 (t, 2 H), 1.42 (s, 9 H), 0.92 (s, 9 H), 0.11 (s, 6 H).

[0306] IR:v: >NH: 3485-3182; >C=W: 1689 cm -1<. Preparation 8b" : 4-[2-({4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H-pyrazol-5-yl}oxy)ethyl]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 5-chloro-1-methyl-4-nitro-1H-pyrazole

[0307] A solution of 1-methyl-4-nitro-1 H Pyrazole (5 g; 39.34 mmol) in tetrahydrofuran (50 mL) is added dropwise at -78 °C to a 1.3 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (82 mL; 106.22 mmol) and hexachloroethane (14 g, 59.01 mmol), and the mixture is stirred for 1 hour at -78 °C. The reaction mixture is transferred to a saturated aqueous solution of ammonium chloride and ice. The product is extracted with dichloromethane, and the organic phases are dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ethyl acetate as eluents to obtain the product of titration.

[0308] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 8.41 (s, 1 H), 3.90 (s, 3 H).

[0309] IR: v: >CH: 3122; -NO 2: 1521+1312 cm -1<. Stage B: 4-{2-[(1-methyl-4-nitro-1H-pyrazol-5-yl)oxy]ethyl}-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0310] To a solution of the compound obtained in Preparation 5b' (2.8 g; 10.09 mmol) in tetrahydrofuran (50 mL), 60% sodium hydride (240 mg; 10.09 mmol) is added, and the mixture is stirred for 1 hour at room temperature. A solution of the compound obtained in Stage A (1.4 g; 8.66 mmol) in tetrahydrofuran (25 mL) is added, and the reaction mixture is stirred for 16 hours and then transferred to a saturated aqueous solution of ammonium chloride and ice. The product is extracted with ethyl acetate, and the organic phases are dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0311] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 8.15 (s, 1H), 7.20 (m, 4H), 4.80 (m, 1H), 4.51 (m, 2H), 4.30 (d, 1H), 4.08 (m, 1H), 3.71 (s, 3H), 3.25 (m, 1H), 3.10 (m, 1H), 2.03 (m, 1H), 1.90 (m, 1H), 1.40 (s, 9H).

[0312] IR: v: >C=O: 1687; -NO 2: 1567+1329 cm -1<. Stage C: 4-{2-[(4-amino-1-methyl-1H-pyrazol-5-yl)oxy]ethyl}-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0313] A solution of the compound obtained in Stage B (2.4 g; 5.96 mmol) in methanol (75 mL) is to which palladium on carbon (15 wt%) is added, and the mixture is then hydrogenated for 24 hours at room temperature under a pressure of 1 bar. The reaction mixture is filtered and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ammoniacal ethanol as eluents to obtain the titration product.

[0314] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.19 (m, 4 H), 6.88 (s, 1H), 4.76 (m, 1H), 4.39- 4.21 (m, 3H), 4.01 (dd, 1H), 3.52 (s, 3H), 3.40 (s, 2H), 3.24 (m, 1H), 3.04 (m, 1H), 1.91 (m, 1H), 1.82 (m, 1H), 1.42 (s, 9H).

[0315] IR: v: -NH 2 and -NH: 3390, 3327 and 3240; >C=W: 1684 cm -1<. Stage D: tert-butyl(4-iodophenoxy)dimethylsilane

[0316] A solution of the para -iodophenol (20 g; 90 mmol) in dichloromethane (50 mL), triethylamine (15.2 mL; 109 mmol) and chloride of tertbutyldimethylchlorosilane (16.4 g; 109 mmol) was added, and the mixture was stirred for 1 hour at room temperature. After hydrolysis, the product was extracted with ethyl acetate, and the organic phases were washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0317] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.5 (d, 2H), 6.67 (d, 2H), 0.95 (s, 9H), 0.20 (s, 6H).

[0318] IR: v: >COC<: 1252; -Si-OC-: 905; -Si-C-: 822 cm -1<. Stage E: 4-[2-({4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H-pyrazol-5-yl}oxy)ethyl]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0319] A solution of the compound obtained in Stage C (1.05 g; 2.81 mmol) and the compound obtained in Stage D (1.48 g; 3.14 mmol) in toluene (15 mL) is degassed with argon for 10 minutes. The tert-sodium butoxide (300 mg; 3.1 mmol) and chloro(2-di- tert -butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (387 mg; 0.56 mmol), then the mixture is stirred at 100 °C for 2.5 hours in a microwave oven (300 W). The reaction mixture is filtered through Celite®. After rinsing with dichloromethane, the filtrate is concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titration product.

[0320] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.2-7.20 (m, 5H), 6.60 (d, 2H), 6.5 (d, 2H), 6.4 (s, 1H), 4.65 (d, 1H), 4.25 (d, 1H), 4.20 (m, 2H), 3.60 (s, 3H), 3.30 (dd, 1H), 3.20 (dd, 1H), 2.88 (m, 1H), 1.80 (m, 2H), 1.40 (s, 9 H), 0.9 (s, 9H), 0.01 (s, 6H).

[0321] IR: v: >NH: 3328; >C=W: 1693 cm -1<. Preparation 9b" : 5-(2-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl}ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: tetrahydrofuran-3-yl methanesulfonate

[0322] To a solution of 3-hydroxytetrahydrofuran (14.8 g; 0.25 mol) and triethylamine (35 mL; 0.25 mol) in dichloromethane (200 mL), methanesulfonyl chloride (14.6 mL; 0.18 mol) is added, and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then diluted with water. After extraction with dichloromethane, the organic phases are washed with water, then dried over sodium sulfate, filtered, and concentrated to dryness to obtain the titer product, which is used in the next step without purification.

[0323] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 5.24-5.32 (m, 1 H), 3.81-4.04 (m, 4 H), 3.02 (s, 3 H), 2.17-2.26 (m, 2 H). Stage B: 1-(tetrahydrofuran) - methyl 3-yl)-1H-pyrazole-5-carboxylate

[0324] A solution of 1 H methyl -pyrazol-5-carboxylate (20 g; 0.16 mol) and the compound obtained in Stage A (28.9 g; 0.18 mol) in N , N-dimethylformamide (400 mL) is mixed with potassium carbonate (33 g; 0.24 mol), and the mixture is stirred at 80 °C for 48 hours. After returning to room temperature, the reaction mixture is filtered and the filtrate concentrated. The residue is resuspended in a 15% ethyl acetate in heptane mixture and then filtered through silica gel. The filtrate is concentrated, and the resulting residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0325] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.50 (d, 1 H), 6.83 (d, 1 H), 5.85-5.94 (m, 1 H), 4.08-4.20 (m, 2 H), 4.01 (dd, 1 H), 3.95 (td, 1 H), 3.86 (s, 3 H), 2.32-2.54 (m, 2 H). Stage C: [1-(tetrahydrofuran-3-yl)-1H-pyrazol-5 - yl]methanol

[0326] A suspension of lithium aluminum hydride (3.38 g; 86.0 mmol) in tetrahydrofuran (100 mL), cooled to 0°C, is added a solution of the compound obtained in Stage B (8.43 g; 49.0 mmol) in tetrahydrofuran (50 mL), and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then cooled to 0°C and slowly diluted with water (3.4 mL), a 15% aqueous sodium hydroxide solution (6.8 mL), and finally with water (6.8 mL). Magnesium sulfate is added to the mixture.

[0327] After filtration and concentration of the filtrate, the product of the titration is obtained, which is used for the following without purification.

[0328] NMR 1< H (400 MHz, CDCl 3, 300 K) δ ppm: 7.43 (s, 1 H), 6.17 (s, 1 H), 5.05-5.18 (m, 1 H), 4.69 (s, 2 H), 4.19 (q, 1 H), 4.06-4.13 (m, 1 H), 3.91-4.02 (m, 2 H), 2.32-2.50 (m, 2 H), 2.10-2.32 (m, 1 H). Stage D: [4 - bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl]methanol

[0329] N-bromosuccinimide (8.78 g; 49.3 mmol) is added to a solution of the compound obtained in Stage C (7.9 g; 47 mmol) in dichloromethane (100 mL) at 0 °C, and the mixture is stirred at room temperature for 1.25 hours. The reaction mixture is then diluted in 1 M aqueous sodium hydroxide solution (100 mL). After extraction with dichloromethane, the organic phases are combined, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titer product.

[0330] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.44 (s, 1 H), 5.08-5.19 (m, 1 H), 4.69 (d, 2 H), 4.19 (q, 1 H), 4.09 (dd, 1 H), 3.89-4.01 (m, 2 H), 2.32-2.48 (m, 3H). Stage E: 4-bromo-5-(chloromethyl)-1-(tetrahydrofuran-3-yl)-1H-pyrazole

[0331] A solution of the compound obtained in Stage D (8.93 g; 36.1 mmol) and triethylamine (7.5 mL; 54.2 mmol) in dichloromethane (100 mL) is mixed with methanesulfonyl chloride (2.85 mL; 36.1 mmol), and the mixture is stirred at room temperature for 16 hours. The reaction mixture is then diluted with water. After extraction with dichloromethane, the organic phases are combined, washed with water, dried over sodium sulfate, filtered, and concentrated to dryness to obtain the titer product, which is used without further purification.

[0332] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.49 (s, 1 H), 4.97-5.05 (m, 1 H), 4.64 (s, 2 H), 4.09-4.22 (m, 2 H), 3.93-4.05 (m, 2 H), 2.42 (q, 2 H). Stage F: [4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl]acetonitrile

[0333] A solution of the compound obtained in Stage E (7.92 g; 29.8 mmol) in a mixture of acetonitrile (80 mL) and water (80 mL) is supplemented with potassium cyanide (3.88 g; 59.7 mmol), and the mixture is stirred at 60 °C for 16 hours. The acetonitrile is evaporated, and the aqueous phase is extracted with ethyl acetate. The organic phases are combined, washed with water and a saturated aqueous solution of sodium chloride, then dried over sodium sulfate, filtered, and concentrated to dryness. The resulting residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0334] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.53 (s, 1 H), 4.92-5.00 (m, 1 H), 4.14-4.25 (m, 2 H), 4.03-4.10 (m, 1 H), 3.97 (td, 1 H), 3.85 (d, 2 H), 2.36-2.54 (m, 2 H). Stage G: 2-[4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl]ethanol

[0335] A solution of the compound obtained in Stage F (6.83 g; 26.7 mmol) in dichloromethane (133 mL) is added at -78 °C to a 1 M diisobutylaluminum hydride solution in dichloromethane (53.3 mL; 53.3 mmol), and the mixture is stirred at -78 °C for 3 hours. After the slow addition of methanol (10 mL) and sodium borohydride (3.04 g; 80.1 mmol), the reaction mixture is stirred at room temperature for 16 hours and then diluted with 1 N aqueous hydrochloric acid (50 mL). After 10 minutes of contact, the solvents are evaporated, and the product is extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue obtained is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titer.

[0336] 1H NMR(400 MHz, CDCl 3 , 300 K) δ ppm : 7.48 (s, 1 H), 5.04 (tt, 1 H), 4.13-4.21 (m, 1 H), 4.06-4.12 (m, 1 H), 3.91-4.00 (m, 2 H), 3.80-3.89 (m, 2 H), 2.96 (t, 2 H), 2.29-2.44 (m, 2 H). Stage H: 5-{2-[4-bromo-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl]ethoxy}-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0337] A solution of triphenylphosphine (2.64 g; 10.1 mmol) and diisopropyl azodicarboxylate (1.97 mL; 10.1 mmol) in tetrahydrofuran is prepared at 0 °C. After decolorization and the appearance of a whitish precipitate (after 5 minutes), a solution of the compound obtained in Stage G (2.02 g; 7.74 mmol) in tetrahydrofuran (10 mL) is added, and the mixture is stirred at room temperature for 1 hour. After adding the compound from Preparation 3b' (2.5 g; 10.1 mmol) in tetrahydrofuran (10 mL), the reaction mixture is stirred at room temperature for 4 hours and then diluted with dimethyl sulfoxide (10 mL). After concentration of the reaction medium, the residue is purified by RP-18 phase chromatography using methanol and water as eluents, then by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titer.

[0338] 1H NMR(400 MHz, CDCl 3, 300 K) δ ppm: 7.49 (s, 1 H), 7.12 (t, 1 H), 6.74 (d, 1 H), 6.66 (d, 1 H), 4.99-5.09 (m, 1 H), 4.54 (s, 2 H), 4.12-4.23 (m, 3 H), 4.09 (dd, 1 H), 3.93-4.02 (m, 2 H), 3.54-3.69 (m, 2 H), 3.21 (td, 2 H), 2.63-2.71 (m, 2 H), 2.28-2.47 (m, 2 H), 1.48 (s, 9 H). Stage I : 5-(2-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-(tetrahydrofuran-3-yl)-1H-pyrazol-5-yl}ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0339] The compound of the titer is obtained according to the process described in Stage B of Preparation 7b" using the compound from the previous stage.

[0340] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.48 (s, 1 H), 7.08 (t, 1 H), 6.73 (d, 1 H), 6.62-6.67 (m, 2 H), 6.56 (d, 1 H), 6.48-6.52 (m, 2 H), 4.96-5.04 (m, 1 H), 4.75 (s, 1 H), 4.54 (s, 2 H), 4.17-4.24 (m, 1 H), 4.02-4.15 (m, 4 H), 3.94-4.02 (m, 1 H), 6.61 (br. s, 1 H), 3.11 (t, 2 H), 2.67 (br. s, 2 H), 2.45-2.54 (m, 1 H), 2.31-2.42 (m, 1 H), 1.49 (s, 9 H), 0.96 (s, 9 H), 0.15 (s, 6 H). Preparation 10b" : 4-(2-[4-[(4-[[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H-pyrazol-5-yl}ethoxy)-1,3-dihydro-2H-isoindole-2-carboxylate of tert-butyl Stage A: 4-[2-(4-bromo-1-methyl-1H-pyrazol-5-yl)ethoxy]-1,3-dihydro-2H - isoindole -2- tert-butyl carboxylate

[0341] A solution of the compound obtained in Stage B of Preparation 3b" (1 g; 4.92 mmol) and the compound from Preparation 6b' (1.54 g; 6.54 mmol) in a mixture of tetrahydrofuran (10 mL) and toluene (10 mL) is degassed with argon for 10 minutes. Tri-cyanomethylene is added n -butylphosphorane (2.58 mL; 9.84 mmol), then the mixture is sealed and shaken at 110 °C for 48 hours. The reaction mixture is concentrated and then diluted in a mixture of ethyl acetate and water. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is triturated in cyclohexane to obtain the titration product.

[0342] 1H NMR (400 MHz, dmso-d6, 300K) δ ppm: 7.49 (s, 1 H), 7.24 (t, 1 H), 6.89 (m, 2 H), 4.55 (d, 2 H), 4.41 (m, 2 H), 4.19 (t, 2 H), 3.87 (d, 3 H), 3.16 (t, 2 H), 1.45 (d, 9 H).

[0343] IR:v : >C=C< : 1686 cm -1< . Stage B: 4-(2-{4-[(4-[[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1-methyl-1H-pyrazol-5-yl}ethoxy)-1,3-dihydro-2H-isoindole-2-carboxylate of tert-butyl

[0344] A solution of the compound obtained in Stage A (0.95 g; 2.25 mmol) and the compound obtained in Stage B of Preparation 1b" (0.74 g; 3.37 mmol) in tetrahydrofuran (50 mL) is degassed with argon for 10 minutes. Sodium tert-butylate (281 mg; 2.9 mmol) and chloro(2-di- tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (154 mg; 0.22 mmol), then the mixture is stirred at 50 °C for 3 hours. The reaction mixture is filtered through Celite®. After rinsing with ethyl acetate, the product is extracted with ethyl acetate, then the organic phases are washed with saturated aqueous ammonium chloride solution, water, and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ethyl acetate as eluents to obtain the product of titration.

[0345] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.28 (s, 1 H), 7.18 (t, 1 H), 6.88 (2d, 1 H), 6.75 (d, 1 H), 6.69 (2s, 1 H), 6.58 (d, 2 H), 6.49 (d, 2 H), 4.55 (d, 2 H), 4.41 (s, 2 H), 4.1 (t, 2 H), 3.81 (s, 3 H), 3.01 (t, 2 H), 1.48 (s, 9 H), 0.91 (s, 9 H), 0.11 (s, 6 H).

[0346] IR: v: >NH: 3308 cm -1< ; >C=W: 1681 cm -1< ; >C=C<: 1617 cm -1<. Preparation 11b" : (3R or 3S)-5-(3-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyano-1-methyl-1H-pyrrol-2-yl}propoxy)-3-methyl-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 5-[3-(3-bromo-5-cyano-1-methyl-1H-pyrrol-2-yl)propoxy]-3-methyl-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0347] A solution of the compound obtained in Stage D of Preparation 5b' (3.19 g; 13.12 mmol) and the compound obtained in Preparation 7b' (3.14 g; 11.93 mmol) in a mixture of tetrahydrofuran (30 mL) and toluene (30 mL) is degassed with argon. Tri-cyanomethylene is added n-butylphosphorane (6.26 mL; 23.86 mmol). The flask is sealed, and the reaction mixture is stirred at 110 °C for 20 hours, then concentrated. The resulting residue is diluted in a mixture of ethyl acetate and water. After extraction of the aqueous phase with ethyl acetate, the organic phases are combined, washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titer.

[0348] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.11 (t, 1 H), 7.09 (s, 1 H), 6.78 (t, 2 H), 4.55 (d, 2 H), 4.5 (m, 1 H), 3.95 (m, 2 H), 3.7 (m, 3 H), 2.85 (t, 2 H), 2.69 (d, 2 H), 1.95 (t, 2 H), 1.4 (s, 9 H), 1 (d, 3 H).

[0349] IR: v: -CN: 2215 cm -1< ; >C=W: 1686 cm -1<. Stage B: 5-(3-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyano-1-methyl-1H-pyrrol-2-yl}propoxy)-3-methyl-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0350] The compound of the titer is obtained according to the process described in Stage D of Preparation 3b" using the compound from the previous stage.

[0351] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.05 (t, 1 H), 6.8 (m, 2 H), 6.75 (d, 1 H), 6.65 (d, 1 H), 6.55 (d, 2 H), 6.5 (d, 2 H), 4.65 (d, 1 H), 4.15 (d, 1 H), 4.45 (m, 1 H), 3.88 (t, 2 H), 3.65 (s, 3 H), 2.75 (t, 2 H), 2.55 (d, 2 H), 1.9 (m, 2 H), 1.45 (s, 9 H), 0.98 (d, 3 H), 0.95 (s, 6 H), 0.1 (s, 9 H).

[0352] IR: v: >NH: 3400 cm -1< ; -CN: 2208 cm -1< ; >C=W: 1688 cm -1<. Stage C: (3R or 3S)-5-(3-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyano-1-methyl-1H-pyrrol-2-yl}propoxy)-3-methyl-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0353] The titration compound is obtained by chiral phase (S,S) Whelk-01 chromatography using heptane and isopropanol as eluents to obtain the titration product.

[0354] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 7.07 (t, 1 H), 6.77 (s, 1 H), 6.77 (m, 1 H), 6.73 (d, 1 H), 6.66 (d, 1 H), 6.56 (d, 2 H), 6.49 (d, 2 H), 4.62 (d, 1 H), 4.14 (d, 1 H), 4.46 (m, 1 H), 3.87 (t, 2 H), 3.66 (s, 3 H), 2.74 (t, 2 H), 2.57 (m, 2 H), 1.89 (m, 2 H), 1.43 (s, 9 H), 0.95 (d, 3 H), 0.92 (s, 9 H), 0.11 (s, 6 H). Preparation 12b" : ( 3S or 3R)-5-(3-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyano-1-methyl-1H-pyrrol-2-yl}propoxy)-3-methyl-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0355] Le composé du titre est obtenu selon le procédé de la Préparation 11b".

[0356] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm : 7.07 (t, 1 H), 6.77 (s, 1 H), 6.77 (m, 1 H), 6.73 (d, 1 H), 6.66 (d, 1 H), 6.56 (d, 2 H), 6.49 (d, 2 H), 4.62 (d, 1 H), 4.14 (d, 1 H), 4.46 (m, 1 H), 3.87 (t, 2 H), 3.66 (s, 3 H), 2.74 (t, 2 H), 2.57 (m, 2 H), 1.89 (m, 2 H), 1.43 (s, 9 H), 0.95 (d, 3 H), 0.92 (s, 9 H), 0.11 (s, 6 H). Preparation 13b" 4-(2-{5-(benzyloxy)-2-[(5-cyano-l,2-dimethyl-1H-pyrrol-3-yl)amino]phenoxy}ethyl)piperidine-1-carboxylate of tert-butyl Stage A: 4-(benzyloxy)-2-fluoro-1-nitrobenzene

[0357] To a solution of 3-fluoro-4-nitrophenol (12.76 g; 81.2 mmol) in acetone (165 mL), potassium carbonate (13.47 g; 97.5 mmol) and benzyl bromide (9.75 mL; 82.0 mmol) are added. The reaction mixture is stirred under reflux for 14 hours, and after returning to room temperature, it is diluted with water. After extraction of the aqueous phase with ethyl acetate, the organic phases are combined, washed with a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is resuspended in minimal amounts of ethyl acetate and pentane, and the resulting precipitate is filtered to obtain the titration product.

[0358] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 8.15 (t, 1 H), 7.25 (dd, 1 H), 7.05 (dd, 1 H), 5.25 (s, 2 H), 7.3-7.5 (m, 5 H).

[0359] IR: v: -NO2: 1510 and 1500 cm -1<; -NO2: 1329 cm -1<. Stage B: 4-{2-[5-(benzyloxy)-2-nitrophenoxy]ethyl}piperidine-1-tert-butyl carboxylate

[0360] A solution of 4-(2-hydroxyethyl)piperidine-1-carboxylate is added dropwise to a mixture of sodium hydride (1.52 g; 38.1 mmol) in tetrahydrofuran (30 mL) at 0 °C. tert -butyl (8 g; 35 mmol) in tetrahydrofuran (30 mL). The reaction mixture is stirred for 15 minutes at 0 °C, then for 30 minutes at room temperature. The reaction mixture is cooled again to 0 °C, and then a solution of the compound obtained in Stage A (7.86 g; 31.79 mmol) in tetrahydrofuran (30 mL) is added dropwise. The reaction mixture is stirred at room temperature for 17 hours and then hydrolyzed. After extraction of the aqueous phase with ethyl acetate, the organic phases are combined, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0361] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm : 7.95 (d, 1 H), 7.4 (m, 5 H), 6.9 (d, 1 H), 6.7 (dd, 1 H), 5.25 (s, 2 H), 4.2 (t, 2 H), 3.9 / 2.7 (m, 4 H), 1.7 (m, 3 H), 1.7 / 1.05 (m, 4 H), 1.4 (s, 9 H).

[0362] IR: v : ; >C=O : 1683 cm -1< ; -NO2 : 1513 et 1255 cm -1< . Stage C : 4-{2-[2-amino-5-(benzyloxy)phenoxy]ethyl} tert-butyl piperidine-1-carboxylate

[0363] A solution of the compound obtained in Stage B (9.4 g; 22 mmol) in a mixture of tetrahydrofuran (70 mL) and glacial acetic acid (70 mL) is to which iron (12.9 g; 23.1 mmol) is added, and the mixture is then heated at 65 °C for 18 hours. The reaction mixture is filtered through Celite®, and after the addition of 5 N aqueous sodium hydroxide solution to achieve pH 7, it is concentrated by half. After extraction of the aqueous phase with dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ethyl acetate as eluents to obtain the titration product.

[0364] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.4-7.3 (m, 5 H), 6.55 (m, 2 H), 6.35 (dd, 1 H), 4.95 (s, 2 H), 4.22 (m, 2 H), 3.95 (m, 4 H), 2.7 (m, 2 H), 1.65 (m, 3H), 1.65 / 1.05 (m, 4H), 1.4 (s, 9H).

[0365] IR:v: ; -NH2: 3450-3365 cm -1<; >C=W: 1669 cm -1<. Stage D: 4-bromo-1,5-dimethyl-1H-pyrrole-2-carbonitrile

[0366] A solution of 1,5-dimethyl-1 H -pyrrole-2-carbonitrile (15 g; 124.8 mmol) in glacial acetic acid (300 mL) is dropwise added to a bromine solution (24 mL; 457.74 mmol) in glacial acetic acid (60 mL). The reaction mixture is stirred for 16 hours at room temperature. After concentrating the reaction mixture by half, the same amount of water (180 mL) is added, and the resulting precipitate is filtered and then dissolved in dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0367] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.05 (s, 1 H), 3.65 (s, 3 H), 2.23 (s, 3 H). IR: v: ; >CH: 3131 cm -1< ; >CN: 2220 cm -1<. Stage E: 4-(2-{5-(benzyloxy)-2-[(5-cyano-l,2-dimethyl-1H-pyrrol-3-yl)amino]phenoxy}ethyl)piperidine-1-carboxylate of tert-butyl

[0368] The titer compound is obtained according to the process described in Stage B of Preparation 2b" using the compound from the previous stage.

[0369] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.4 (d, 2 H), 7.35 (t, 2 H), 7.3 (f, 1 H), 6.7 (s, 1 H), 6.6 (d, 1 H), 6.35 (dd, 1 H), 6.3 (d, 1 H), 5.85 (s, 1 H), 4.95 (s, 2 H), 4.05 (t, 2 H), 3.9 / 2.7 (m+m, 2+2 H), 3.6 (s, 3 H), 2.05 (s, 3 H), 1.7 (m, 5 H), 1.4 (s, 9 H), 1.05 (m, 2 H).

[0370] IR: v: ; >NH: 3404 cm -1< ; >CN: 2207 cm -1< ; >C=W: 1684 cm -1<. Preparation 14b" : 3-(2-{5-(benzyloxy)-2-[(5-cyano-1,2-dimethyl-1H-pyrrol-3 yl)amino]phenoxy}ethyl)piperidine-1-carboxylate of tert-butyl

[0371] The compound of the titration is obtained according to the process of Preparation 13b" using 3-(2-hydroxyethyl)-piperidine-1-carboxylate of tert -butyl at Stage B.

[0372] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 7.4 (d, 2 H), 7.35 (t, 1 H), 7.3 (t, 2 H), 6.75 (s, 1 H), 6.62 (d, 1 H), 6.35 (dd, 1 H), 6.25 (d, 1 H), 5.85 (s, 1 H), 4.95 (s, 2 H), 4.05-2.5 (m, 4 H), 4.05 (t, 2 H), 3.63 (s, 3 H), 2.1 (s, 3 H), 1.8-1.3 (m, 7 H), 1.35 (br. s, 9 H).

[0373] IR: v : ; >NH : 3400 cm -1< ; >CN : 2207 cm -1< ; >C=O : 1684 cm -1< . Preparation 15b" : iodide of ]-(3-{[2 - (tert-butoxycarbonyl)-1,2,3,4- t etrahydroisoquinoline-5-yl]oxypropyl)-3-{[4-(prop-2-en-1-yloxy)phenyl]aminopyridinium Stage A: 1-nitro-4-(prop-2-en-1-yloxy)benzene

[0374] To a solution of 4-nitrophenol (20 g; 0.144 mol) in acetonitrile (500 mL), allyl bromide (15 mL; 0.173 mol) and cesium carbonate (52 g, 0.158 mol) are added, and the mixture is stirred for 16 hours at room temperature and for 2 hours at 70 °C. After filtering out the insoluble matter and concentrating the filtrate, the residue is diluted with dichloromethane and water. After settling, the organic phase is washed with water, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using ethyl acetate and petroleum ether as eluents to obtain the product of the titer.

[0375] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 8.2 (d, 2 H), 7 (d, 2 H), 6 (m, 1 H), 5.45 (tdd, 1 H), 5.4 (tdd, 1 H), 4.6 (m, 2 H).

[0376] IR: v: >NO2: 1590 and 1331 cm -1< . Stage B: 4-(prop-2-en-1-yloxy)aniline

[0377] The titer compound is obtained according to the process described in Stage C of Preparation 13b" using the compound from the previous stage.

[0378] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 6.65 (d, 2 H), 6.49 (d, 2 H), 6 (m, 1 H), 5.34 / 5.2 (dd, 2 H), 4.59 (s, 2 H), 4.4 (d, 2 H).

[0379] IR: v: >NH2: 3429 and 3350 cm -1< . Stage C: N-[4-(prop-2-en-1-yloxy)phenyl]pyridin-3-amine

[0380] The titer compound is obtained according to the process described in Stage D of Preparation 3b" using 3-bromopyridine and the compound from the previous stage.

[0381] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 8.22 (d, 1 H), 8.05 (s, 1 H), 7.92 (dd, 1 H), 7.31-7.11 (2*dd, 2 H), 7.05 (d, 2 H), 6.91 (d, 2 H), 6.04 (m, 1 H), 5.46-5.19 (2*dd, 2 H), 4.52 (d, 2 H).

[0382] IR: v: >NH: 3250 and 3184 cm -1<. Stage D: 1-(3-{[2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl]oxy}propyl)-3-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyridinium iodide

[0383] To a solution of the compound obtained in Stage C (740 mg; 3.27 mmol) in dioxane (13 mL), the compound from Preparation 8b' (1.05 g; 2.5 mmol) is added, and the mixture is then stirred for 18 hours at 70 °C. After concentration, the residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the titer product.

[0384] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 9.1 (s, 1 H), 8.34 (m, 2 H), 7.81 (m, 2 H), 7.14 (t, 1 H), 7.12 (d, 2 H), 6.91 (d, 2 H), 6.78 (t, 2 H), 6.04 (m, 1 H), 5.4 / 5.27 (2*dd, 2 H), 4.67 (t, 2 H), 4.54 (d, 2 H), 4.46 (s, 2 H), 4.04 (t, 2 H), 3.5 (t, 2 H), 2.5 (d, 2 H), 2.37 (t, 2 H), 1.42 (s, 9 H).

[0385] IR: v: >NH: 3500-2700 cm -1< ; >C=W: 1686 cm -1<. Preparation 16b: 2 - methyl-N-[4-(prop-2-en-1-yloxy)phenyl]-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrimidin-5-amine Stage A: 4-chloro-2-methyl-6-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrimidin-5-amine

[0386] To a mixture of sodium hydride (1.5 g; 36.4 mmol) in tetrahydrofuran (10 mL) at 0 °C, a solution of 2-tetrahydropyran-2-yloxyethanol (4.6 mL; 33.6 mmol) in tetrahydrofuran (60 mL) is added dropwise. The reaction mixture is stirred for 15 minutes at 0 °C, then for 30 minutes at room temperature. The reaction mixture is cooled again to 0 °C, and then a solution of 5-amino-4,6-dichloro-2-methylpyrimidine (5 g; 28 mmol) in tetrahydrofuran (70 mL) is added dropwise. The reaction mixture is stirred at room temperature for 17 hours and then hydrolyzed. After extraction of the aqueous phase with ethyl acetate, the organic phases are combined, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0387] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 5.01 (s, 2 H), 4.66 (m, 1 H), 4.49 (m, 2 H), 3.94 (2*m, 2 H), 3.77 / 3.44 (2*m, 2 H), 2.34 (s, 3 H), 1.76-1.35 (m, 4 H), 1.61 / 1.45 (2*m, 2 H).

[0388] IR: v: -NH2: 3464 and 3340 cm -1< . Stage B: 2-methyl-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrimidin-5-amine

[0389] A solution of the compound obtained in Stage A (6.9 g; 24.0 mmol) in ethanol (120 mL) is added to palladium on carbon (10 wt.%), and the mixture is then hydrogenated for 6 hours at room temperature under 1 bar. The reaction mixture is filtered and concentrated to dryness. The residue is diluted in a mixture of a saturated aqueous solution of sodium bicarbonate and dichloromethane. After decantation and extraction with dichloromethane, the organic phases are combined and then dried over magnesium sulfate to give the titration product.

[0390] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 7.76 (s, 1 H), 4.76 (s, 2 H), 4.65 (m, 1 H), 4.46 (m, 2 H), 3.93 / 3.75 (2m, 2 H), 3.75 / 3.44 (2m, 2 H), 2.34 (s, 3 H), 1.75-1.35 (m, 6 H).

[0391] IR: v : -NH 2 : 3600-3100 cm -1< . Stage C: 1-bromo-4-(prop-2-en-1-yloxy)benzene

[0392] To a solution of 4-bromophenol (10 g; 57.8 mmol) in acetone (290 mL), allyl bromide (5.5 mL; 63.6 mmol) and potassium carbonate (16 g; 116 mmol) were added, and the mixture was stirred for 6 hours at 85 °C, then for 16 hours at room temperature. After filtering out the insoluble matter and concentrating the filtrate, the residue was diluted with ethyl acetate and water. After settling, the organic phase was washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography using ethyl acetate and petroleum ether as eluents to obtain the product of the titer.

[0393] 1H NMR (400 MHz, CDCl3, 300 K) δ ppm: 7.36 (d, 2 H), 6.79 (d, 2 H), 6.01 (m, 1 H), 5.4 (d, 1 H), 5.3 (d, 1 H), 4.5 (d, 2 H).

[0394] IR:v: >CH-Ar: 821 cm -1< ; >C=C<: 1590, 1578 and 1488 cm -1<. Stage D: 2-methyl-N-[4-(prop-2-en-1-yloxy)phenyl]-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrimidin-5-amine

[0395] The titer compound is obtained according to the process described in Stage B of Preparation 2b" using the compounds obtained in the preceding Stages B and C.

[0396] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 8.07 (s, 1 H), 7.17 (s, 1 H), 6.98 (d, 2 H), 6.86 (d, 2 H), 6.03 (m, 1 H), 5.38 / 5.24 (2*dd, 2 H), 4.62 (m, 1 H), 4.52 (m, 2 H), 4.5 (m, 2 H), 3.94 / 3.76 (2*m, 2 H), 3.74 / 3.4 (2*m, 2 H), 2.43 (s, 3 H), 1.61 (m, 2 H), 1.42 (m, 4 H).

[0397] IR: v: ; >NH: 3415 cm -1< ; >C=C<: 1649 cm -1<. Preparation 17b" : [ 2-(3-cyano-5-{[4-(prop-2-en-1-yloxy)phenyl]amino}phenoxy)ethyl] tert-butyl methylcarbamate Stage A: (3-bromo-5-methoxyphenyl)methanol

[0398] To a solution of 3-bromo-5-methoxybenzoic acid (10 g; 43.3 mmol) in tetrahydrofuran (280 mL), boranedimethylsulfide complex (32.5 mL; 64.9 mmol) is added dropwise, and the mixture is stirred for 2 hours. The reaction mixture is acidified dropwise with 2 N aqueous hydrochloric acid until pH 1 is reached. After ether extraction, the organic phase is washed with 1 N aqueous sodium hydroxide and saturated aqueous sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as an oil, which is used in the next stage without purification.

[0399] NMR 1< H (400 MHz, dmso-d6, 300 K) δ ppm: 7.08 (m, 1 H), 6.99 (m, 1 H), 6.89 (m, 1 H), 5.3 (br. s, 1 H), 4.47 (s, 2 H), 3.75 (s, 3 H).

[0400] IR: v: -OH: 1588 cm -1< ; >CO: 1268 and 1038 cm -1<; γ: >CH-Ar: 811 cm -1<. Stage B: 3-bromo-5-methoxybenzaldehyde

[0401] A solution of the compound obtained in Stage A (8.6 g; 39.8 mmol) in dichloromethane (400 mL) is mixed with Dess-Martin reagent (20.3 mL; 47.8 mmol), and the mixture is stirred for 2 hours. After the addition of ether, the reaction mixture is filtered through a silica gel bath. The filtrate is concentrated, resuspended in a mixture of heptane and ethyl acetate, and then filtered again through a silica gel bath. After concentration of the filtrate, the product of the titration is obtained as a pale yellow solid, which is used in the next stage without purification.

[0402] NMR 1< H (400 MHz, dmso-d6, 300 K) δ ppm: 9.5 (s, 1 H), 7.69 (t, 1 H), 7.5 (t, 1 H), 7.42 (t, 1 H), 3.85 (s, 3 H).

[0403] IR: v : >C=O : 1691 cm -1< . Stage C: (Z}-1-(3-bromo-5-methoxyphenyl)-N-hydroxymethanimine

[0404] To a solution of the compound obtained in Stage B (7.8 g; 36.4 mmol) in ethanol (10 mL), hydroxylamine hydrochloride (12.6 g; 182 mmol) and pyridine (6.27 mL; 87.4 mmol) are successively added, and the mixture is stirred at 65 °C for 1 hour. After returning to room temperature, the reaction mixture is diluted with a mixture of ethyl acetate and water. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as a white solid, which is used in the next stage without purification.

[0405] NMR 1< H (400 MHz, dmso-d6, 300 K) δ ppm: 11.45 (s, 1 H), 8.1 (s, 1 H), 7.35 (t, 1 H), 7.16 (d, 2 H), 3.8 (s, 3 H).

[0406] IR:v : -OH : 3300-3000 cm -1< ; At : 1600 and 1564 cm −1< ; >CO : 1220 and 1059 cm −1< ; -NO : 960 cm -1< ; γ : >CH-Ar : 831 cm −1< . Stage D: 3-bromo-5-methoxybenzonitrile

[0407] To a solution of the compound obtained in Stage C (8.1 g; 35.2 mmol) in dioxane (70 mL), pyridine (22 mL; 211 mmol) and trifluoroacetic acid anhydride (1.4 mL; 70.4 mmol) are added dropwise at 0 °C, and the mixture is stirred at room temperature for 24 hours. After returning to 0 °C, a second portion of trifluoroacetic acid anhydride (1.4 mL; 70.4 mmol) is added dropwise, and the mixture is stirred at room temperature for 24 hours. After returning to 0 °C, a third portion of trifluoroacetic acid anhydride (1.4 mL; 70.4 mmol) is added dropwise, and the mixture is stirred at 60 °C for 1 hour. After returning to room temperature, the reaction mixture is diluted with a mixture of dichloromethane and water.After settling, the organic phase is washed with a 1 N aqueous hydrochloric acid solution and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as a pale yellow solid, which is used in the next stage without purification.

[0408] NMR 1< H (400 MHz, dmso-d6, 300 K) δ ppm: 7.69 (t, 1 H), 7.53 (dd, 1 H), 7.5 (dd, 1 H), 3.82 (s, 3 H).

[0409] IR: v: -CN: 2232 cm -1< ; Ar: 1597 and 1562 cm -1<; >COC<: 1278 and 1051 cm -1<; γ: >CH-Ar: 848, 814 and 671 cm -1<. Stage E: 3-bromo-5-hydroxybenzonitrile

[0410] Lithium iodide (11.2 g; 83.7 mmol) is added to a solution of the compound obtained in Stage D (5.9 g; 27.9 mmol) in collidine (55 mL), and the mixture is stirred at 150 °C for 16 hours. After returning to room temperature, the reaction mixture is poured into ice-cold water. Following extraction with dichloromethane, the organic phases are combined, washed with water, dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as an orange-brown solid, which is used in the next stage without purification.

[0411] NMR 1< H (400 MHz, dmso-d6, 300 K) δ ppm: 10.7 (br. s, 1 H), 7.51 (t, 1 H), 7.3 (t, 1 H), 7.18 (dd, 1H).

[0412] IR: v: -OH: 3283 cm -1< ; -CN: 2245 cm -1<. Stage F: tert-butyl (2-hydroxyethyl)methylcarbamate

[0413] To a solution of 2-(methylamino)ethanol (30 g; 0.399 mol) in dichloromethane (800 mL), di- is added in portions at room temperature tert -butyl dicarbonate (87.3 g; 0.399 mol). The mixture is stirred at this temperature for 16 hours. The solvent is evaporated under vacuum and the residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0414] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 3.75 (t, 2 H), 3.39 (t, 2 H), 2.91 (s, 3 H), 2.85 (m, 1 H), 1.45 (s, 9 H).

[0415] IR: v : -OH : 3431 cm -1< ; >C=O : 1692 and 1668 cm -1< . Stage G: [2-(3-bromo-5-cyanophenoxy)ethyl]tert-butyl methylcarbamate

[0416] The titer compound is obtained according to the process described in Stage H of Preparation 9b" using the compounds obtained in the preceding Stages E and F.

[0417] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.7 (br. s, 1 H), 7.52 (br. s, 1 H), 7.5 (br. s, 1 H), 4.2 (m, 2 H), 3.5 (t, 2 H), 2.88 (br. s, 3 H), 1.35 (2br. s, 9 H).

[0418] IR: v: -CN: 2235 cm -1< ; >C=W: 1687 cm -1<. Stage H: 2-(3-cyano-5-{[4-(prop-2-en-1-yloxy)phenyl]amino}phenoxy)ethyl]tert-butyl methyl carbamate

[0419] The compound of the titer is obtained according to the process described in Stage B of Preparation 2b" using the compound from the previous stage and the compound obtained in Stage B of Preparation 15b".

[0420] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.07 (d, 2 H), 6.94 (d, 2 H), 6.73 (dd, 2 H), 6.63 (t, 1 H), 6.05 (m, 1 H), 5.4 (dd, 1 H), 5.26 (dd, 1 H), 4.54 (td, 2 H), 4.06 (t, 2 H), 3.5 (t, 2 H), 2.83 (s, 3 H), 1.34 (s, 9 H).

[0421] IR: v: -NH: 3344 cm -1<; -CN: 2231 cm -1< ; >C=W: 1741 cm -1< ; >C=W: 1673 cm -1< ; >C=C<: 1591 cm -1<. Preparation 18b": 4-(3-cyano-5-{[4-(prop-2-en-1-yloxy)phenyl]amino}phenoxy)butyl ]tert-butyl methylcarbamate

[0422] The compound of the titration is obtained according to the Preparation 17b process using 4-(methylamino)butanol at Stage F.

[0423] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 8.23 ​​(s, 1 H), 7.07 (d, 2 H), 6.94 (d, 2 H), 6.73 (t, 1 H), 6.68 (t, 1 H), 6.63 (t, 1 H), 6.05 (m, 1 H), 5.39 / 5.26 (2dquad, 2 H), 4.54 (dt, 2 H), 3.96 (t, 2 H), 3.19 (t, 2 H), 2.76 (br. s, 3 H), 1.59 (m, 4 H), 1.37 (br. s, 9 H).

[0424] IR: v: -NH: 3340 cm -1<; -CN: 2229 cm -1< ; >C=W: 1687 cm -1< ; >C=O: 1670 cm -1<. Preparation 19b" 5-(2-{2-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]ethoxy} ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 5-[2-(2-oxoethoxy)ethoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0425] Dimethyl sulfoxide (0.2 mL) is added to a solution of oxalyl chloride (0.2 mL; 2.22 mmol) in tetrahydrofuran (7 mL) at -78 °C. After 30 minutes of contact at this temperature, a solution of the compound obtained from Preparation 9b' (0.5 g; 1.48 mmol) in tetrahydrofuran (8 mL) is added dropwise at -78 °C, and triethylamine (0.77 mL; 5.93 mmol) is added under the same conditions. The mixture is stirred for 1 hour at -78 °C, then for 2 hours at 0 °C. The reaction mixture is diluted with a mixture of ethyl acetate and water. After settling, the organic phase is washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The product of the titration is obtained in the form of a brown oil, which is used in the next stage without purification.

[0426] NMR 1< H(400 MHz, dmso-d6, 300 K) δ ppm : 9.6 (s, 1 H), 7.13 (t, 1 H), 6.82 (d, 1 H), 6.75 (d, 1 H), 4.46 (br. s, 2 H), 4.29 (s, 2 H), 4.12 (m, 2 H), 3.85 (m, 2 H), 3.54 (m, 2 H), 2.64 (t, 2 H), 1.41 (s, 9 H).

[0427] IR: v : >C=O : 1689 cm -1< . Stage B: 5-(2-{2-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]ethoxy}ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0428] To a solution of the compound obtained in Stage A (0.5 g; 1.49 mmol) in dichloromethane (10 mL), the compound obtained in Stage B of Preparation 1b (0.4 g; 1.79 mmol) and sodium triacetoxyborohydride (0.63 g; 2.98 mmol) are added. The mixture is stirred for 16 hours at room temperature. The reaction mixture is diluted in a saturated aqueous solution of sodium bicarbonate. After extraction with dichloromethane, the organic phases are washed with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using ethyl acetate and petroleum ether as eluents to obtain the product of titration.

[0429] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.13 (t, 1 H), 6.81 (d, 1 H), 6.75 (d, 1 H), 6.59 (d, 2 H), 6.47 (d, 2 H), 5.05 (t, 1 H), 4.46 (s, 2 H), 4.1 (t, 2 H), 3.77 (t, 2 H), 3.62 (t, 2 H), 3.52 (t, 2 H), 3.13 (quad, 2 H), 2.63 (t, 2 H), 1.42 (s, 9 H), 0.92 (s, 9 H), 0.11 (s, 6 H).

[0430] IR: v: >NH: 3387 cm -1< ; >C=W: 1693 cm -1<. Preparation 20b" : 5-[2-(1-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyanophenyl}-1H-1,2,3-triazol-4-yl)ethyl]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 3-bromo-5-nitrobenzonitrile

[0431] A solution of tert-butyl nitrite (8.19 mL; 62 mmol) in the N,N- dimethylformamide (35 mL) at 50 °C, a solution of 2-amino-3-bromo-5-nitrobenzonitrile (10 g; 41.3 mmol) is added dropwise in N , N -dimethylformamide (85 mL). The mixture is stirred at 50 °C until gas evolution ceases. The crude mixture is then poured into a 0.5 N aqueous hydrochloric acid solution (1 L), and the mixture is extracted with methyl- tert-butyl ether. The organic phases are combined and washed with a saturated aqueous solution of sodium bicarbonate, then with a saturated aqueous solution of sodium chloride, dried with sodium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography using ethyl acetate and heptane as eluents to obtain the product of the titer.

[0432] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm 8.61 (t, 1 H), 8.47 (t, 1 H), 8.12 (t, 1 H). Stage B: 3-amino-5-bromobenzonitrile

[0433] To a solution of the compound obtained in Stage A (6.85 g; 30 mmol) in ethyl acetate (20 mL) and ethanol (82 mL), tin chloride dihydrate (33.85 g; 150 mmol) is added in portions. The reaction mixture is then heated to 70 °C for 30 minutes and concentrated to a volume of approximately 40 mL, then poured onto ice. The resulting mixture is alkalinized with 2 N aqueous sodium hydroxide solution, and the entire mixture is stirred for 20 minutes. The product is extracted with ethyl acetate. The organic phases are combined and washed with saturated aqueous sodium chloride solution, dried with sodium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography using ethyl acetate and heptane as eluents to obtain the product of titration.

[0434] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.12 (t, 1 H), 7.01 (t, 1 H), 6.80 - 6.83 (m, 1 H), 3.97 (br. s, 2 H). Stage C: 3-azido-5-bromobenzonitrile

[0435] To a solution of the compound obtained in Stage B (3.96 g; 20 mmol) in ethyl acetate (60 mL) at 0 °C, concentrated hydrochloric acid (12 mL) is added dropwise, maintaining the temperature below 5 °C, followed by a sodium nitrite solution (1.66 g; 24 mmol) in water (25 mL), also maintaining the temperature below 5 °C. After 1 hour of stirring at 0 °C, a sodium azidide solution (1.56 g; 24 mmol) in water (25 mL) is added dropwise, maintaining the temperature below 5 °C. The reaction mixture is stirred for 3 hours until it returns to room temperature, and then diluted with water. The product is extracted with ethyl acetate. The organic phases are combined and washed with a saturated aqueous solution of sodium chloride, dried with sodium sulfate, filtered and concentrated under vacuum to provide the compound of titer without purification.

[0436] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.55 (t, 1 H), 7.41 (t, 1 H), 7.20 - 7.24 (m, 1 H). Stage D: 5-{2-[1-(3-bromo-5-cyanophenyl)-1H-1,2,3-triazol-4-yl]ethyl}-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0437] A solution of the compound obtained in Stage C (1.56 g; 7 mmol) and the compound obtained in Preparation 10b' (2 g; 7 mmol) in tetrahydrofuran (30 mL) is supplemented with copper iodide (133 mg; 0.7 mmol) and triethylamine (1.16 mL; 8.4 mmol). The reaction mixture is stirred at room temperature for 16 hours. The reaction is then concentrated to a volume of approximately 15 mL, and the entire mixture is diluted with ethyl acetate. The organic phase is washed with 2 N aqueous hydrochloric acid, followed by saturated aqueous sodium chloride solution. The organic phase is dried with sodium sulfate, filtered, and concentrated under vacuum. The residue is purified by silica gel chromatography using ethyl acetate and heptane as eluents to obtain the product of titration.

[0438] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 8.17 (s, 1 H), 7.91 - 7.99 (m, 1 H), 7.79 - 7.86 (m, 1 H), 7.64 (br. s, 1 H), 7.09 - 7.20 (m, 1 H), 7.03 (dd, 2 H), 4.58 (s, 2 H), 3.65 (br. s, 2 H), 3.06 (br. s, 4 H), 2.82 (br. s, 2 H), 1.49 (s, 9 H). Stage E: 5-[2-(1-{3-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-5-cyanophenyl}-1H-1,2,3-triazol-4-yl)ethyl]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0439] The compound of the titer is obtained according to the process described in Stage B of Preparation 2b" using the compound from the previous stage and the compound from Stage B of Preparation 1b".

[0440] 1H NMR (400 MHz, CDCl 3, 300 K) δ ppm: 7.40 - 7.76 (m, 2 H), 7.19 (s, 1 H), 7.05 - 7.16 (m, 4 H), 6.95 - 7.05 (m, 2 H), 6.82 - 6.90 (m, 2 H), 6.67 (br. s, 1 H), 4.57 (s, 2 H), 3.58 - 3.67 (m, 2 H), 2.96 - 3.07 (m, 4 H), 2.70 - 2.81 (m, 2 H), 1.47 (s, 9 H), 1.00 (s, 9 H), 0.22 (s, 6 H). Preparation 21b": 4-(2-{2-[(5-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethoxy}ethoxy)-1,3-dihydro-2H-isoindole-2-carboxylate of tert-butyl Stage A: 5-bromo-2-[2-(2-chloroethoxy)ethoxy]pyrimidine

[0441] A solution of 5-bromo-2-chloropyrimidine (3.48 g; 18 mmol) and 2-(2-chloroethoxy)-ethanol (3.59 g; 28.8 mmol) in acetonitrile (50 mL) is mixed with cesium carbonate (11.73 g; 36 mmol), and the mixture is stirred for 14 hours at 60 °C. After cooling, the reaction mixture is filtered, and the filtrate is concentrated. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titration.

[0442] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 8.75 (s, 2 H), 4.41 (m, 2 H), 3.8 (m, 2 H), 3.72 (s, 4 H). Stage B: 4-{2-[2-({5-[(4-hydroxyphenyl)amino]pyrimidin-2-yl}oxy)ethoxy]ethoxy}1-1,3-dihydro-2H-isoindole-2-carboxylate of tert-butyl

[0443] A solution of the compound obtained in Stage A (2.81 g; 10 mmol) and the compound from Preparation 6b' (2.5 g; 10 mmol) in acetonitrile (100 mL) is combined with cesium carbonate (3.9 g; 12 mmol) and potassium iodide (0.35 g; 2.1 mmol), and the mixture is stirred for 14 hours at 60 °C. After returning to room temperature, the reaction mixture is concentrated. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents.

[0444] A solution of the residue thus obtained (3.3 g; 6.87 mmol) and the compound from Stage B of Preparation 15b" (1.44 g; 9.6 mmol) in tetrahydrofuran (60 mL) is degassed with argon for 10 minutes. Cesium carbonate (2.91 g; 8.9 mmol) and chloro(2-di- tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2-aminoethyl)phenyl]palladium(II) (180 mg; 0.26 mmol), then the mixture is stirred under reflux for 5 hours, followed by incubation at 50 °C for 15 hours. After cooling, the reaction mixture is concentrated. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the titration product.

[0445] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 9.00 (1H, s), 8.22 (1H, s), 8.21 (1H, s), 7.65 (1H, s), 6.90 (1H, d), 6.89 (1H, d), 7.24 (1H, t), 6.86 (2H, m), 6.68 (2H, m), 4.45 - 4.57 (4H, m), 4.33 (2H, m), 4.16 (2H, m), 3.81 (4H, m), 1.44 (9H, s). Stage C: 4-(2-{2-[(5-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethoxy}ethoxy)-1,3-dihydro-2H-isoindole-2-carboxylate of tert-butyl

[0446] The compound of the titration is obtained according to the process described in Stage C of Preparation 16b" using the phenol of Stage B.

[0447] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm: 8.29 / 8.28 (s, 2 H), 7.81 (brs, 1 H), 7.24 (t, 1 H), 6.93 (m, 2 H), 6.9 (m, 1 H), 6.88 (m, 1 H), 6.86 (m, 2 H), 6.03 (m, 1 H), 5.37 / 5.24 (m+m, 2 H), 4.57 / 4.55 (dc, 2 H), 4.48 / 4.45 (dc, 2 H), 4.38-3.78 (m, 8 H), 1.44 (s, 9 H). Preparation 22b" : 5-(2-{2-[(5-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethoxy}ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0448] The compound of the title is obtained according to the process of Preparation 21b" by replacing at Stage B the compound of Preparation 6b' with the compound of Preparation 3b'.

[0449] NMR 1< H (500 MHz, dmso-d6, 300 K) δ ppm: 8.29 (s, 2 H), 7.82 (s, 1 H), 7.12 (t, 1 H), 6.94 (m, 2 H), 6.86 (m, 2 H), 6.8 (d, 1 H), 6.73 (d, 1 H), 6.02 (m, 1 H), 5.37 / 5.23 (m+m, 2 H), 4.49 (m, 2 H), 4.45 (br., 2 H), 4.36 (m, 2 H), 4.1 (m, 2 H), 3.81 (m, 2 H), 3.81 (m, 2 H), 3.51 (t, 2 H), 2.61 (t, 2 H), 1.4 (s, 9 H). Preparation 23b: 5-({6-[(5-{[4-(prop-2-én-1-yloxy)phényl]amino}pyrimidin-2-yl)oxy]hexyl}oxy)-3,4-dihydroisoquinoléine-2(1H)-carboxylate de tert-butyle

[0450] The compound of the titer is obtained according to the process of Preparation 22b" by replacing 2-(2-chloroethoxy)-ethanol with 6-chlorohexanol at Stage A. High-resolution mass (ESI+):

[0451] Chemical formula: C33H42N4O5 [M+H]+ calculated 575.32, [M+H]+ measured 575.4. Preparation 24b": 5-({5-[(5-{[4-(prop-2-én-1-yloxy)phényl]amino}pyrimidin-2-yl)oxy]pentyl}oxy)-3,4-dihydroisoquinoléine-2(1H)-carboxylate de tert-butyle

[0452] The compound of the titer is obtained according to the process of Preparation 22b" by replacing 2-(2-chloroethoxy)-ethanol with 6-chloropentanol at Stage A.

[0453] 1H NMR (500 MHz, dmso-d6) δ ppm: 8.29 (s, 2 H), 7.79 (s, 1 H), 7.12 (t, 1 H), 6.93 (m, 2 H), 6.86 (m, 2 H), 6.79 (d, 1 H), 6.72 (d, 1 H), 6.03 (m, 1 H), 5.38 / 5.24 (m, 2 H), 4.49 (dt, 2 H), 4.45 (br., 2 H), 4.24 (t, 2 H), 3.98 (t, 2 H), 3.53 (t, 2 H), 2.61 (t, 2 H), 1.78 (m, 2 H), 1.78 (m, 2 H), 1.56 (m, 2 H), 1.41 (s, 3 H). Preparation 25b": 5-{4-[(5-{[4-(prop-2-én-1-yloxy)phényl]amino}pyrimidin-2 yl)oxy]butoxy}-3,4-dihydroisoquinoléine-2(1H)-carboxylate de tert-butyle

[0454] The compound of the titer is obtained according to the process of Preparation 22b" by replacing 2-(2-chloroethoxy)-ethanol with 6-chlorobutanol at Stage A.

[0455] 1H NMR (500 MHz, dmso-d6) δ ppm 8.29 (s, 2 H), 7.8 (s, 1 H), 7.12 (t, 1 H), 6.93 (d, 2 H), 6.86 (d, 2 H), 6.8 (d, 1 H), 6.72 (d, 1 H), 6.07-5.98 (m, 1 H), 5.4-5.21 (m, 2 H), 4.48 (dt, 2 H), 4.45 (br, 2 H), 4.28 (t, 2 H), 4.02 (t, 2 H), 3.53 (t, 2 H), 2.62 (t, 2 H), 1.87 (br, 4 H), 1.4 (s, 9 H). Preparation 26b": 3-[(2-{2-[(5-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethoxy}ethoxy)methyl]piperidine-1-carboxylate of tert-butyl Stage A: 3-({2-[2-(benzyloxy)ethoxy]ethoxy}methyl)piperidine-1-carboxylate of tert-butyl

[0456] A solution of 3-(hydroxymethyl)piperidine-1-carboxylate tert -butyl (7.54 g; 35 mmol) in N,N -dimethylformamide at 0 °C, 60% sodium hydride in oil (1.6 g; 40.2 mmol) is added. The mixture is then stirred for 60 minutes. After returning to room temperature, a solution of 2-(2-benzyloxyethoxy)ethyl-4-methylbenzenesulfonate (12.26 g, 35 mmol) in N,N-Dimethylformamide (20 mL) is added. The mixture is then stirred for 60 minutes and subsequently hydrolyzed slowly. After extraction with dichloromethane, the organic phases are evaporated, and the residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titer.

[0457] 1H NMR (500 MHz, dmso-d6) δ ppm 7.36-7.29 (m, 4 H), 7.27 (m, 1 H), 4.48 (s, 2 H), 4-3.77 / 2.7-2.36 (br, 2 H), 3.75 / 2.74 (br+td, 2 H), 3.59-3.44 (m, 8 H), 3.27 / 3.21 (dd, 2 H), 1.66 / 1.11 (br, 2H), 1.62 (br, 1 H), 1.55 / 1.29 (m, 2 H), 1.37 (s, 9 H). Stage B: 3-{[2-(2-hydroxyethoxy)ethoxy]methyl}piperidine-1-carboxylate of tert-butyl

[0458] A solution of the compound obtained in Stage A (11.0 g; 27.95 mmol) in ethanol (85 mL) is to which palladium on carbon (10 wt%) is added. The mixture is hydrogenated for 10 hours at room temperature under 4 bar pressure. The reaction mixture is filtered and then concentrated to dryness to obtain the product of the titer.

[0459] 1H NMR (500 MHz, dmso-d6) δ ppm 4.45 (t, 1 H), 3.87 / 2.57 (brm+brs, 2 H), 3.74 / 2.78 (m+m, 2 H), 3.56-3.46 (m, 4 H), 3.49 (m, 2 H), 3.43 (t, 2 H), 3.28 / 3.23 (dd+dd, 2 H), 1.68 / 1.15 (m+m, 2 H), 1.64 (m, 1 H), 1.58 / 1.32 (m+m, 2 H), 1.39 (s, 9 H). Stage C: 3-[(2-{2-[(5-bromopyrimidin-2-yl)oxy]ethoxy}ethoxy)methyl]piperidine-1-carboxylate of tert-butyl

[0460] A solution of the compound obtained in Stage B (8.34 g, 27.5 mmol) and 5-bromo-2-chloropyrimidine (5.31 g, 27 mmol) in acetonitrile (160 mL) is supplemented with cesium carbonate (17.9 g, 55 mmol), and the mixture is stirred for 7 hours at 85 °C. After cooling, the reaction mixture is filtered, and the filtrate is concentrated. The residue is purified by silica gel chromatography using heptane and ethyl acetate as eluents to obtain the product of the titration.

[0461] 1H NMR(500 MHz, dmso-d6) δ ppm 8.75 (s, 2 H), 4.4 (m, 2 H), 4.04-2.27 (brm, 4 H), 3.75 (m, 2 H), 3.57 (t, 2 H), 3.49 / 3.47 (m+m, 2 H), 3.25 / 3.2 (dd+dd, 2 H), 1.64 / 1.1 (m+m, 2 H), 1.6 (m, 1 H), 1.55 / 1.29 (m+m, 2 H), 1.37 (s, 9 H). Stage D: 3-[(2-{2-[(5-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethoxy}ethoxy)methyl]piperidine-1-carboxylate of tert-butyl

[0462] The compound of the titer is obtained according to the process described in Stage B of Preparation 2b" using the compound from the previous stage and the compound obtained in Stage B of Preparation 15b".

[0463] 1H NMR (500 MHz, dmso-d6) δ ppm 8.29 (s, 2 H), 7.81 (s, 1 H), 6.94 (m, 2 H), 6.86 (m, 2 H), 4.33 (m, 2 H), 4-3.73 / 2.71-2.34 (br+br., 2 H), 3.73 / 2.74 (br+m, 2 H), 3.73 (m, 2 H), 3.58 (t, 2 H), 3.49 (m, 2 H), 3.27 / 3.21 (dd+dd, 2 H), 1.66 / 1.1 (brd+br., 2 H), 1.62 (br., 1 H), 1.55 / 1.29 (m+m, 2 H), 1.37 (s, 9H). Preparation 27b": 4-[(2-{2-[(5-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethoxy}ethoxy)methyl]piperidine-1-carboxylate of tert-butyl

[0464] The compound of the titer is obtained according to the process of Preparation 26b" by replacing in Stage A the 3-(hydroxymethyl)piperidine-1-carboxylate of tert -butyl by 4-(hydroxymethyl)piperidine-1-carboxylate of tert -butyl.

[0465] 1H NMR (500 MHz, dmso-d6) δ ppm 8.29 (s, 2 H), 7.82 (s, 1 H), 6.94 (m, 2 H), 6.86 (m, 2 H), 6.03 (m, 1 H), 5.38 / 5.24 (m+m, 2 H), 4.49 (m, 2 H), 4.32 (m, 2 H), 3.91 / 2.67 (br+br., 4 H), 3.73 (m, 2 H), 3.57 (m, 2 H), 3.49 (m, 2 H), 3.23 (d, 2 H), 1.67 (m, 1 H), 1.61 / 0.98 (brd+qd, 4H), 1.37 (s, 9 H). Preparation 28b": 5-[2-(methyl{2-[(5-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethyl}amino)ethoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate Stage A: 2-{[2-(benzyloxy)ethyl](methyl)amino}ethanol

[0466] A solution of 2-chloroethoxymethylbenzene (4.6 mL; 30 mmol) and 2-(methylamino)ethanol (3.1 mL; 39 mmol) in the N , N-dimethylacetamide (40 mL) is mixed with potassium iodide (1.0 g, 6 mmol), followed by triethylamine (5.4 mL; 39 mmol). The mixture is stirred at 120 °C overnight. After filtering the precipitate, the filtrate is concentrated to dryness and then purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the titer product.

[0467] 1H NMR (500 MHz, dmso-d6) δ ppm 7.38-7.24 (m, 5 H), 4.46 (s, 2 H), 4.34 (brt, 1 H), 3.51 (t, 2 H), 3.45 (brt, 2 H), 2.58 (t, 2 H), 2.45 (t, 2 H), 2.21 (s, 3 H). Stage B: 5-(2-{[2-(benzyloxy)ethyl](methyl)amino}lethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0468] To a solution of the compound obtained in Stage A (6.28 g, 30 mmol) and the compound obtained in Preparation 3b' (4.99 g, 20 mmol) in tetrahydrofuran (150 mL), triphenylphosphine (7.87 g, 30 mmol) is added under a nitrogen atmosphere at 0 °C, followed by dropwise addition of a 40% diethyl azodicarboxylate solution in toluene (14 mL, 30 mmol). After returning to room temperature, the mixture is stirred for 1 hour. After evaporation of the solvents, the residue is resuspended twice in diisopropyl ether, and then purified by RP-18 chromatography using acetonitrile, water, and ammonium carbonate as eluents to obtain the titration product.

[0469] 1H NMR (500 MHz, dmso-d6) δ ppm 7.35-7.24 (m, 5 H), 7.11 (t, 1 H), 6.79 (dd, 1 H), 6.72 (dd, 1 H), 4.46 (s, 2 H), 4.45 (s, 2 H), 4.02 (t, 2 H), 3.53 (t, 2 H), 3.51 (t, 2 H), 2.7 (t, 2 H), 2.65 (t, 2 H), 2.6 (t, 2 H), 2.3 (s, 3 H), 1.41 (s, 9 H). Stage C: 5-{2-[(2-hydroxyethyl)(methyl)amino]ethoxy}-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0470] To a solution of the compound obtained in Stage B (3.88 g; 8.8 mmol) in tetrahydrofuran (50 mL) and ethanol (80 mL), 4 M hydrochloric acid in dioxane (2.4 mL) and then palladium on carbon (570 mg) are added. The mixture is hydrogenated at room temperature under 4 bar for 15 hours. After filtration and evaporation, the residue is dissolved in water, and then a 2 M aqueous sodium hydroxide solution is added until a pH of 12 is reached. After extraction with ethyl acetate and evaporation of the solvents, the product of the titration is obtained.

[0471] 1H NMR (400 MHz, dmso-d6) δ ppm 7.12 (t, 1 H), 6.8 (dd, 1 H), 6.73 (dd, 1 H), 4.45 (s, 2 H), 4.34 (t, 1 H), 4.03 (t, 2 H), 3.53 (t, 2 H), 3.47 (t, 2 H), 2.77 (t, 2 H), 2.62 (t, 2 H), 2.51 (t, 2 H), 2.28 (s, 3 H), 1.41 (s, 3 H) Stage D: 5-{2-[{2-[(5-bromopyrimidin-2-yl)oxy]ethyl}(methyl)amino]ethoxy}-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0472] The titer compound is obtained according to the process described in Stage B of Preparation 28b" using the compound from the previous stage and 5-bromopyrimidin-2-ol.

[0473] 1H NMR (500 MHz, dmso-d6) δ ppm 8.72 (s, 1 H), 7.11 (t, 1 H), 6.78 (d, 1 H), 6.72 (d, 1 H), 4.45 (s, 2 H), 4.38 (t, 2 H), 4.03 (t, 2 H), 3.49 (t, 2 H), 2.84 (t, 2 H), 2.83 (t, 2 H), 2.57 (t, 2 H), 2.35 (s, 3 H), 1.41 (s, 9 H) Stage E: 5-[2-(methyl{2-[(5-{[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethyl}amino)ethoxy]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0474] The compound of the titer is obtained according to the process described in Stage D of Preparation 26b" using the compound from the previous stage.

[0475] 1H NMR (500 MHz, dmso-d6) δ ppm 8.28 (s, 2 H), 7.8 (s, 1 H), 7.11 (t, 1 H), 6.93 (m, 2 H), 6.85 (m, 2 H), 6.8 (dd, 1 H), 6.72 (dd, 1 H), 6.03 (m, 1 H), 5.38 / 5.24 (dq, 2 H), 4.49 (dt, 2 H), 4.44 (brs, 2 H), 4.32 (t, 2 H), 4.04 (t, 2 H), 3.5 (t, 2 H), 2.84 (t, 2 H), 2.83 (t, 2 H), 2.59 (t, 2 H), 2.35 (s, 3 H), 1.4 (s, 9 AM). Example 1: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-20,23-dioxa-1,10,14-triazahexacyclo [26.3.1.1∼9,12∼.1∼15,19∼.0∼3,8∼.0∼24,29∼]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-2,13-dione

[0476] Stage A: 5-(5-chloro-2-{[5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-ethyl carboxylate

[0477] To a solution of the compound from Preparation 1a (9.5 g; 29.5 mmol) in dichloromethane (110 mL), the compound obtained from Preparation 1a' (7.32 g; 32.4 mmol), 1-hydroxybenzotriazole (4.78 g; 35.4 mmol), 1,(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6.1 g; 35.4 mmol), and triethylamine (20.6 mL; 147.5 mmol) are successively added. The mixture is then stirred overnight at room temperature. The reaction mixture is diluted with a mixture of dichloromethane and water. After settling, the organic phase is washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0478] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm : 7.54 / 7.45 (2m, 3 H), 7.12 / 7 (2t, 1 H), 6.75 / 6.45 (2d, 1 H), 6.75 / 6.65 (2d, 1 H), 6.35 / 6.25 (2s, 1 H), 6.05 (m, 1 H), 5.4 (m, 1 H), 5.25 (m, 1 H), 4.55-3.95 / 2.95 (m, 8 H), 3.45 / 3.21 (2s, 3 H), 2.6-2.2 (m, 2 H), 2.49 / 2.05 (2s, 3 H), 1.22 (t, 3 H).

[0479] IR: v : >C=O : 1695 cm -1< . Stage B: 5-(5-chloro-2-{[5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-yl]carbonylphenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0480] To a solution of the compound obtained in Stage A (10.8 g; 21.9 mmol) in methanol (100 mL), lithium (1.8 g; 43.8 mmol) in solution in 50 mL of water is added. The mixture is then stirred at 90 °C for 48 hours. The reaction mixture is concentrated to remove the methanol, then acidified to pH 4 by adding a 1 N aqueous hydrochloric acid solution, and finally extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The titration product is obtained as a powder and is used in the next stage without purification.

[0481] NMR 1< H (400 MHz, dmso-d6, 300 K) δ ppm: 11.55 (br. s, 1 H), 7.52 / 7.45 (m, 3 H), 7.12 / 7 (2t, 1 H), 6.78 / 6.7 / 6.48 (3d, 2 H), 6.32 / 6.25 (2s, 1 H), 6.05 (m, 1 H), 5.4 (m, 1 H), 5.25 (m, 1 H), 4.8-3 (m, 6 H), 3.45 / 3.2 (2s, 3 H), 2.5 (m, 2 H), 2.5 / 2.05 (2s, 3 H). Stage C: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-N-[3-(2-chloroethoxy)phenyl]-5- ( 5-chloro-2-{[5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxamide

[0482] To a solution of the compound obtained in Stage B (1 g; 2.15 mmol) in dichloroethane (20 mL), 1-chloro- is added N , N 2-trimethylprop-1-en-1-amine (0.31 mL; 2.4 mmol). The reaction mixture is stirred at room temperature for 2 hours, and then the compound from Preparation 1 (1.6 g; 4.3 mmol) is added. The mixture is stirred at 80 °C for 24 hours. The reaction mixture is diluted in a mixture of dichloromethane and a saturated aqueous solution of sodium bicarbonate. After extraction of the aqueous phase with dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titer.

[0483] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm : 7.5-7.25 (m, 3 H), 7.2 (m, 2 H), 6.95 / 6.65 (m, 4 H), 6.85-6.6 (m, 5 H), 6.05 (m, 1 H), 5.4 / 5.25 (m, 2 H), 5.35-5.2 (m, 1 H), 4.8-3.9 (m, 2 H), 4.5 (m, 2 H), 4.15 (m, 2 H), 3.85 (m, 2 H), 3.3-2.9 (m, 2 H), 3.3-3.2 (m, 3 H), 2.8-2.5 (m, 2 H), 2.35-2.2 (m, 3 H), 0.85 (m, 9 H), 0.1 (m, 6 H). Stage D: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-N-[3-(2-chloroethoxy)phenyl]-5-{5-chloro-2-[(5-hydroxy-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]phenyl}-1,2-dimethyl-1H-pyrrole-3-carboxamide

[0484] To a solution of the compound obtained in Stage C (1.3 g; 1.57 mmol) in a mixture of dichloromethane (6 mL) and methanol (3 mL), 1,3-Dimethylbarbituric acid (0.49 g; 3.15 mmol) is added. The reaction mixture is degassed by bubbling with argon for 10 minutes, and tetrakis-(triphenylphosphine)palladium(0) (0.09 g; 0.07 mmol) is added. The mixture is heated at 40 °C for 19 hours. After concentration of the methanol, the reaction mixture is diluted in a mixture of ethyl acetate and water. After settling, the organic phase is washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titer.

[0485] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm : 9.45 (m, 1 H), 7.5-7.25 (m, 3 H), 7.2 (m, 1 H), 7-6.95 (m, 1 H), 6.8-6.6 (m, 2 H), 6.8-6.6 (m, 3 H), 6.75-6.6 (m, 4 H), 5.4-5.2 (m, 1 H), 4.8-4.1 (m, 2 H), 4.15 (m, 2 H), 3.9 (m, 2 H), 3.85 (m, 2 H), 3.3-3.2 (m, 3 H), 2.9-2.5 (m, 2 H), 2.35-2.2 (m, 3 H), 0.85 (m, 9 H), 0.1 (m, 6 H).

[0486] IR: v : -OH : 3260 cm -1< ; >C=O : 1624 cm -1< . Stage E: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-[5-chloro-2-[(5-hydroxy-3,4-dihydroisoquinoline-2(1H)-yl)carbonyl]phenyl}-N-[3-(2-iodoethoxy)phenyl]-1,2-dimethyl-1H-pyrrole-3-carboxamide

[0487] Sodium iodide (0.35 g; 2.34 mmol) is added to a solution of the compound obtained in Stage D (0.88 g; 1.17 mmol) in acetone (15 mL). The reaction mixture is stirred at 80 °C for 24 hours. After filtration, the filtrate is concentrated. The resulting residue is reconstituted in a mixture of ethyl acetate and water. After extraction of the aqueous phase with ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The resulting residue is used directly in the next step without purification. Stage F: 14-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-6-chloro-10,11-dimethyl-20,23-dioxa-1,10,14-triazahexacyclo[26.3.1.1∼9,12∼.1∼15,19∼.0-3,8∼.0∼24,29∼]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-2,13-dione

[0488] Cesium carbonate (0.36 g; 1.12 mmol) is added in three portions at one-hour intervals at room temperature to a solution of the compound obtained in Stage E (0.98 g; 1.12 mmol) in acetonitrile (112 mL). The reaction mixture is then heated to 50 °C for 4 hours and concentrated. The resulting residue is resuspended in a mixture of dichloromethane and water. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated. The residue is then used directly in the next step without purification. Stage G : 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-20,23-dioxa-1,10,14-triazahexacyclo[26.3.1.1∼9,12∼.1∼15,19~.0~3,8∼.0∼24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-2,13-dione

[0489] A solution of the compound obtained in Stage F (0.5 g; 0.67 mmol) in tetrahydrofuran (10 mL) is added to a solution of tetrabutylammonium fluoride in 1 N tetrahydrofuran (1 mL; 1.01 mmol). The mixture is stirred at room temperature for 1 hour. The reaction mixture is then diluted in a mixture of dichloromethane and water. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated. The resulting residue is purified by silica gel chromatography using dichloromethane and ammoniacal methanol as eluents, followed by IC3 chiral column chromatography using acetonitrile, isopropanol, and diethylamine. The resulting solid is dissolved in a water / acetonitrile mixture, filtered, and then lyophilized. High-resolution mass (ESI+):

[0490] Chemical formula: C37H32ClN3O5 [M+H]+ calculated 634.2103, [M+H]+ measured 634.2102. Example 2: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-20,24-dioxa-1,10,14-triazahexacyclo[27.3.1.1-9,12-.1-15,19-.0-3,8-.0-25,30-]pentatriaconta-3,5,7,9(35),11,15(34),16,18,25,27,29-undecaene-2,13-dione

[0491]

[0492] The compound of the titration is obtained according to the process of Example 1 using the acid of Preparation 1a and the compound of Preparation 1a' in Stage A, and the compound of Preparation 2a" in Stage C. Elemental microanalysis: (theoretical %: measured %)

[0493] %C = 70.42: 69.92; %H = 5.29: 5.00; %N = 6.48: 6.48. High-resolution mass (ESI+):

[0494] Chemical formula: C38H34ClN3O5 [M+H]+ calculated 648.2259, [M+H]+ measured 648.2260. Example 3: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-20,25-dioxa-1,10,14-triazahexacyclo [28.3.1.1∼9,12∼.1~15,19∼.0~3,8~.0~26,31~]hexatriaconta-3,5,7,9(36),11,15(35),16,18,26,28,30-undecaene-2,13-dione

[0495]

[0496] The compound of the titration is obtained according to the process of Example 1 using the acid of Preparation 1a and the compound of Preparation 1a' in Stage A, and the compound of Preparation 3a" in Stage C. Elemental microanalysis: (theoretical %: measured %)

[0497] %C = 70.74: 70.22; %H = 5.48: 5.37; %N = 6.35: 6.27. High-resolution mass (ESI+):

[0498] Chemical formula: C 39 H 36 ClN 3 O 5 [M+H]+ calculated 662.2416, [M+H]+ measured 662.2422. Example 4: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-20,23-dioxa-1,10,14-triazahexacyclo [26.3.1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-17-carbonitrile

[0499]

[0500] The compound of the titration is obtained according to the process of Example 1 using the acid of Preparation 1a and the compound of Preparation 1a' in Stage A, and the compound of Preparation 4a" in Stage C. Elemental microanalysis: (theoretical %: measured %)

[0501] %C = 69.24: 68.29; %H = 4.74: 4.68; %N = 8.50: 8.70; %Cl = 5.38: 5.33. High-resolution mass (ESI+):

[0502] Chemical formula: C38H31ClN4O5 [M+H]+ calculated 659.2057, [M+H]+ measured 659.2056. Example 5: 6-chloro-14-(4-hydroxyphényl)-10,11-diméthyl-2,13-dioxo-20,24-dioxa-1,10,14-triazahexacyclo[27.3.1.1~9,12~.1~15,19~.0~3,8~.0~25,30~]pentatriaconta-3,5,7,9(35),11,15(34),16,18,25,27,29-undécaène-17-carbonitrile

[0503]

[0504] The compound of the titration is obtained according to the process of Example 1 using the acid of Preparation 1a and the compound of Preparation 1a' in Stage A, and the compound of Preparation 5a" in Stage C. High-resolution mass (ESI+):

[0505] Chemical formula: C 39 H 33 ClN 4 O 5 [M+H]+ calculated 673.2212, [M+H]+ measured 673.2211. Example 6: 11-chloro-4-(4-hydroxyphényl)-1,7,8-triméthyl-4,16,17,23,24,25-hexahydro-1H,14H-15,18-méthano-6,9-(méthéno)dibenzo[b,h] pyrazolo[4,3-p][1,6,11,15]oxatriazacycloicosine-5,14(8H)-dione

[0506] Stage A: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-(5-chloro-2-{[5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-[5-(3-chloropropyl)-1-methyl-1H-pyrazol-4-yl)-1,2-dimethyl-1H-pyrrole-3-carboxamide]

[0507] Oxalyl chloride (0.28 mL; 3.2 mmol) is added to a solution of the compound obtained in Stage B of Example 1 (0.75 g; 1.6 mmol) in dichloroethane (40 mL). The reaction mixture is stirred at room temperature for 1 hour and then concentrated. The residue is reconstituted in dichloroethane and concentrated again, this operation being carried out twice. The final residue is resuspended in dichloroethane (20 mL) and then added to a solution of the compound from Preparation 6a (0.61 g; 1.6 mmol) and pyridine (0.4 mL; 4.8 mmol) in dichloroethane (10 mL). The mixture is stirred at 110 °C for 16 hours. The reaction mixture is concentrated, and the residue is then resuspended in a mixture of dichloromethane and a saturated aqueous solution of sodium bicarbonate. After extraction of the aqueous phase with dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated to dryness.The residue is purified by silica gel chromatography using dichloromethane and ethyl acetate as eluents to obtain the product of the titer.

[0508] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.5-7.25 (m, 3 H), 7.2-7.1 (m, 1 H), 7.15 (m, 1 H), 7.15-6.93 (m, 2 H), 6.82-6.7 (m, 2 H), 6.8 (m, 1 H), 6.62-6.5 (m, 1 H), 6.08 (m, 1 H), 5.5-5.2 (m, 2 H), 5.38-5.2 (m, 1 H), 4.75-2.9 (m, 2 H), 4.55 (m, 2 H), 4.25-3.9 (m, 2 H), 3.73 (m, 3 H), 3.55 (m, 2 H), 3.3-3.15 (m, 3 H), 2.7-2.3 (m, 2 H), 2.6 (m, 2 H), 2.3-2.15 (m, 3 H), 16 (m, 2 H), 0.8 (m, 9 H), 0.1 (m, 6 H). Stage B: 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-4,16,17,23,24,25-hexahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrazolo[4,3-p][1,6,11,15]oxatriazacycloicosine-5,14(8H)-dione

[0509] The compound of the title is obtained according to the processes described in Stages D, E, F and G of Example 1, using the compound from the previous stage as the starting product. Elemental microanalysis: (theoretical % : measure)

[0510] %C = 67.97: 68.05; %H = 5.39: 5.25; %N = 11.01: 10.77. High-resolution mass (ESI+):

[0511] Chemical formula: C36H34ClN5O4 [M+H]+ calculated 636.2372, [M+H]+ measured 636.2369. Example 7: 6-chloro-14-(4-hydroxyphenyl)-10,11,33-trimethyl-2,13-dioxo-23-oxa-1,10,14,18-tetraazahexacyclo[26.3.1.1~9,12~.1~15,18~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,24,26,28-decaene-17-carbonitrile

[0512]

[0513] The compound of the titration is obtained according to the process of Example 6 using the acid obtained in Stage B of Example 1 and the amine of Preparation 7a". Elemental microanalysis: (theoretical %: measured %)

[0514] %C = 69.48: 69.01; %H = 5.38: 5.34; %N = 10.39: 10.19. High-resolution mass (ESI+) :

[0515] Chemical formula: C 39 H 36 ClN 5 O 4 [M+H]+ calculated 674.2529, [M+H]+ measured 674.2515. Example 8: 6-chloro-14-(4-hydroxyphenyl)-10,11,32-trimethyl-2,13-dioxo-22-oxa-1,10,14,18-tetraazahexacyclo[25.3.1.1~9,12~.1~15,18~.0~3,8~.0~23,28~]tritriaconta-3,5,7,9(33),11,15(32),16,23,25,27-decaene-17-carbonitrile

[0516]

[0517] The compound of the titration is obtained according to the process of Example 6 using the acid obtained in Stage B of Example and the amine of Preparation 8a". High-resolution mass (ESI+):

[0518] Chemical formula: C38H34ClN5O4 [M+H]+ calculated 660.2372, [M+H]+ measured 660.2377. Example 9: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-23-oxa-1,10,14-triazahexacyclo[26.3.1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-17-carbonitrile

[0519]

[0520] The compound of the titration is obtained according to the process of Example 6 using the acid obtained in Stage B of Example 1 and the amine of Preparation 9a". High-resolution mass (ESI+) :

[0521] Chemical formula: C 39 H 33 ClN 4 O 4 [M+H]+ calculated 657.2263, [M+H]+ measured 657.2267. Example 10: 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,16,17,23,24-hexahydro-14H-15,18-methano-6,9-(metheno)dibenzo[l,r]pyrazolo[3,4-d][1,6,10,15]oxatriazacyclononadecin-5(8H)-one hydrochloride

[0522] Stage A: 5-(5-chloro-2-{[5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-ylmethyllphenyl)-1,2-dimethyl-1H-pyrrole-3-ethyl carboxylate

[0523] To a solution of the compound from Stage B of Preparation 1a (2 g; 6.54 mmol) in dichloromethane (25 mL), the compound obtained from Preparation 1a' (1.5 g; 6.54 mmol) and sodium triacetoxyborohydride (2.2 g; 10 mmol) are successively added. The mixture is then stirred overnight at room temperature. The reaction mixture is poured onto a mixture of water and ammonium chloride. After settling, the organic phase is dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using heptane and ammoniacal ethanol as eluents to obtain the titration product.

[0524] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.6 (d, 1 H), 7.47 (dd, 1 H), 7.3 (d, 1 H), 7.03 (t, 1 H), 6.74 (d, 1 H), 6.57 (d, 1 H), 6.43 (s, 1 H), 6.03 (m, 1 H), 5.38 (m, 1 H), 5.23 (m, 1 H), 4.54 (m, 2 H), 4.16 (quad, 2 H), 3.42 (s, 2 H), 3.4 (s, 2 H), 3.22 (s, 3 H), 2.64 (m, 2 H), 2.56 (m, 2 H), 2.49 (s, 3 H), 1.25 (t, 3 H).

[0525] IR: v: >C=O: 1692 cm -1< ; >COC<: 1063 cm -1< Stage B: 5-(5-chloro-2-{[5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-yl]methyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0526] A solution of the compound obtained in Stage A (2.1 g; 4.4 mmol) in dioxane (12 mL) is added to an aqueous solution of 1 N lithium (13 mL; 13.1 mmol). The mixture is stirred under microwave (300 W) at 120 °C for 4.5 hours. The reaction mixture is poured onto a mixture of 1 N hydrochloric acid and ice. The product is extracted with dichloromethane. The organic phases are combined, dried over sodium sulfate, filtered, and concentrated to yield the product of the titer without further purification.

[0527] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.61 (d, 1 H), 7.45 (dd, 1 H), 7.27 (br. s, 1 H), 7.03 (t, 1 H), 6.73 (d, 1 H), 6.57 (d, 1 H), 6.33 (s, 1 H), 6.04 (m, 1 H), 5.39 (d, 1 H), 5.23 (d, 1 H), 4.53 (m, 2 H), 3.45 (s, 2 H), 3.39 (s, 2 H), 3.2 (s, 3 H), 2.63 (m, 2 H), 2.55 (m, 2 H), 2.5 (s, 3 H).

[0528] IR: v: -OH: 3300-2200 cm -1<; >C=W: 1661 cm -1< ; >COC<: 1258 cm -1<. Stage C: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-(5-chloro-2-{[5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-yl]methyl}phenyl)-1,2-dimethyl-N-{1-methyl-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-pyrazol-4-yl}-1H-pyrrole-3-carboxamide

[0529] To a solution of the compound obtained in Stage B (2 g; 4.43 mmol) in dichloroethane (50 mL), 1-chloro- is added N,N2-trimethylprop-1-en-1-amine (0.59 mL; 4.87 mmol). The reaction mixture is stirred at room temperature for 2 hours, then the compound from Preparation 10a (3.2 g; 7.4 mmol) and pyridine (1.8 mL; 22.1 mmol) are added. The mixture is stirred at 80 °C for 24 hours. The reaction mixture is poured onto a mixture of a saturated aqueous solution of sodium bicarbonate and ice. After extraction of the aqueous phase with dichloromethane, the organic phases are combined, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and isopropanol as eluents to obtain the product of the titer.

[0530] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm: 7.45 (d, 1 H), 7.3 (dd, 1 H), 7.15 (s, 1 H), 7.05 (d, 1 H), 7.02 (d, 1 H), 6.97 (t, 1 H), 6.9 / 6.6 (ab, 4 H), 6.5 (d, 1 H), 5.95 (m, 1 H), 5.3 (s, 1 H), 5.3 / 5.15 (m, 2 H), 4.48 (m, 2 H), 4.3 (m, 1 H), 3.65 (s, 3 H), 3.5-3.25 (m, 6 H), 3.2-3.1 (m, 4 H), 3.08 (s, 3 H), 2.8-2.5 (m, 2 H), 2.5 (m, 2 H), 2.3 (s, 3 H), 1.6-1.2 (m, 6 H), 0.87-0.8 (s, 9 H), 0.1-0 (s, 6 H). Stage D: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-{5-chloro-2-[(5-hydroxy-3,4-dihydroisoquinoline-2(1H)-yl)methyl]phenyl}-N-[5-(2-hydroxyethyl)-1-methyl-1H-pyrazol-4-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide

[0531] The compound of the titration is obtained in two steps. The compound of Stage C is first subjected to a deprotection reaction according to the process described in Stage D of Example 1 and is engaged in the next step.

[0532] To a solution of the product thus obtained (430 mg; 0.52 mmol) in methanol (15 mL), the following is added para-pyridine toluenesulfonate (140 mg; 0.52 mmol). The reaction mixture is stirred at 80°C overnight and then concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the titration product.

[0533] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 9.2 (s, 1 H), 4.62 (s, 1 H), 7.44 (d, 1 H), 7.3 (d, 1 H), 7.15 (s, 1 H), 7.02 (s, 1 H), 6.94-6.6 (m, 4 H), 6.8 (t, 1 H), 6.5 (d, 1 H), 6.35 (d, 1 H), 5.7-5.3 (s, 1 H), 3.65 (s, 3 H), 3.3 (m, 2 H), 3.2 (m, 2 H), 3.1 (m, 2 H), 3.05 (s, 3 H), 2.6 (m, 2 H), 2.5 (m, 2 H), 2.48 (m, 2 H), 2.3 (s, 3 H), 0.8 (s, 9 H), 0.15 (s, 6 H). Stage E : 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,16,17,23,24-hexahydro-14H-15,18-methano-6,9-(metheno)dibenzo[l,r]pyrazolo[3,4-d][1,6,10,15]oxatriazacyclononadecin-5(8H)-one hydrochloride

[0534] A solution of the compound obtained in Stage D (250 mg; 0.34 mmol) in a mixture of tetrahydrofuran (80 mL) and toluene (80 mL) is degassed with argon for 10 minutes. Tri-cyanomethylene is added. n-butylphosphorane (0.18 mL; 0.75 mmol), then the mixture is sealed and shaken at 110 °C for 48 hours. The reaction mixture is concentrated and then diluted in a mixture of ethyl acetate and water. After settling, the organic phase is washed with water and a saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using ammonium dichloromethane as the eluent and then proceeded to the next step.

[0535] A 5 mL solution of the product obtained in methanol is combined with a 0.34 mL (0.34 mmol) solution of potassium hydroxide in 1 M methanol. The reaction mixture is stirred at room temperature for 2 hours and then poured over a mixture of saturated aqueous sodium bicarbonate and ice. After extraction of the aqueous phase with dichloromethane, the organic phases are combined, dried over sodium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ammoniacal ethanol as eluents. The resulting solid is dissolved in a mixture of 1 N hydrochloric acid and acetonitrile, filtered, and then lyophilized to obtain the titration product. High-resolution mass (ESI+):

[0536] Chemical formula: C35H34ClN5O3.HCl [M+H]+ calculated 608.2423, [M+H]+ measured 608.2425. Example 11: 11-chloro-4-(4-hydroxyphényl)-1,7,8-triméthyl-4,16,17,23,24,25-hexahydro-1H,14H-15,18-méthano-6,9-(méthéno)dibenzo[b,h]pyrazolo[4,3-p] [1,6,11,15]oxatriazacycloicosin-5(8H)-one

[0537] Stage A: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-(5-chloro-2-{[5-(prop-2-en-1-yloxy)-3,4-dihydroisoquinoline-2(1H)-yl]methyl}phenyl)-N-[5-(3-chloropropyl)-1-methyl-1H-pyrazol-4-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide

[0538] The compound of the titration is obtained according to the process described in Stage A of Example 6, using the acid from Stage B of Example 10 and the amine from Preparation 6a".

[0539] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.53 (d, 1 H), 7.41 (dd, 1 H), 7.28 (s, 1 H), 7.1 (d, 1 H), 7.05 (t, 1 H), 6.99 (d, 2 H), 6.75 (d, 1 H), 6.69 (d, 2 H), 6.59 (d, 1 H), 6.04 (m, 1 H), 5.4 / 5.24 (m+m, 1+1 H), 5.4 (s, 1 H), 4.55 (d, 2 H), 3.7 (s, 3 H), 3.59 (t, 2 H), 3.34 (s, 2 H), 3.22 (br. s, 2 H), 3.15 (s, 3 H), 2.63 (m, 2 H), 2.62 (m, 2 H), 2.5 (m, 2 H), 2.38 (s, 3 H), 1.73 (m, 2 H), 0.87 (s, 9 H), 0.08 (s, 6 H). Stage B : N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-{5-chloro-2-[(5-hydroxy-3,4-dihydroisoquinoline-2(1H)-yl)methyl]phenyl}-N-[5-(3-chloropropyl)-1-methyl-1H-pyrazol-4-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide

[0540] The compound of the title is obtained according to the process described in Stage D of Example 1 from the compound obtained in the previous stage.

[0541] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm 7.55 (d, 1 H), 7.4 (dd, 1 H), 7.3 (s, 1 H), 7.1 (d, 1 H), 7 (d, 2 H), 6.9 (t, 1 H), 6.7 (d, 2 H), 6.6 (d, 1 H), 6.4 (d, 1 H), 5.4 (s, 1 H), 3.7 (s, 3 H), 3.6 (t, 2 H), 3.3 (s, 2 H), 3.2 (br. s, 2 H), 3.15 (s, 3 H), 2.6 (m, 2 H), 2.55 (m, 2 H), 2.5 (m, 2 H), 2.35 (s, 3 H), 1.7 (quint, 2H), 0.85 (s, 9H), 0.1 (s, 6H).

[0542] IR: v: -OH: 3500-2500 cm-1< ; >C=O: 1635 and 1622 cm-1< . Stage C: N-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)-5-{5-chloro-2-[(5-hydroxy-3,4-dihydroisoquinoline-2(1H)-yl)methyl]phenyl}-N-[5-(3-iodopropyl)-1-methyl-1H-pyrazol-4-yl]-1,2-dimethyl-1H-pyrrole-3-carboxamide

[0543] The compound of the titration is obtained according to the process described in Stage E of Example 1 from the compound obtained in the previous stage. The residue obtained is directly used in the next step without purification. Stage D: 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-4,16,17,23,24,25-hexahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrazolo[4,3-p][1,6,11,15]oxatriazacycloicosin-5(8H)-one

[0544] The compound of the title is obtained according to the processes described in Stages F and G of Example 1 from the compound obtained in the previous stage. High-resolution mass (ESI+) :

[0545] Chemical formula: C 36 H 36 ClN 5 O 3 [M+H]+ calculated 622.2579, [M+H]+ measured 622.2573. Example 12: Disodium phosphate of 4-[6-chloro-17-cyano-10,11-dimethyl-2,13-dioxo-20,23-dioxa-1,10,14-triazahexacyclo[26.3.1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaen-14-yl]phenyl

[0546]

[0547] To a solution of the compound from Example 4 (75 mg; 0.113 mmol) in dichloromethane (1.5 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (34 µL; 0.227 mmol) and then bis(dimethylamino)phosphoryl chloride (16.5 µL; 0.113 mmol) are added. The reaction mixture is stirred at room temperature for 16 hours and then diluted in a mixture of ethyl acetate and a saturated aqueous solution of sodium bicarbonate. After extraction with dichloromethane, the organic phases are combined and dried over magnesium sulfate, filtered, and concentrated to dryness.

[0548] A solution of the product obtained in acetonitrile (2 mL) is combined with a solution of trifluoroacetic acid (1 mL) in water (0.5 mL). The reaction mixture is stirred at room temperature for 24 hours and then concentrated to dryness. The resulting residue is resuspended in acetonitrile, and then a saturated aqueous solution of sodium bicarbonate is added dropwise until pH 7 is reached. The mixture is concentrated to dryness, then resuspended in ethanol and filtered. The filtrate is concentrated, and the resulting residue is purified by Oasis® phase chromatography using acetonitrile and water as eluents before being lyophilized to obtain the titer product. High-resolution mass (ESI+) :

[0549] Chemical formula: C38H3OClN4O8P2Na [M+H]+ calculated 783.1358, [M+H]+ measured 783.1361. Example 13: 12-chloro-5-(4-hydroxyphenyl)-8,9-dimethyl-6,15-dioxo-6,9,22,23-tetrahydro-5H,15H,17H-16,22-methano-7,10-(metheno)tribenzo[b,j,o] [1,4,8,13]oxatriazacyclooctadecine-3-carbonitrile

[0550] Stage A: 5-(2-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-chlorophenyl)-1,2-dimethyl-1H-pyrrole-3-ethyl carboxylate

[0551] To a solution of Preparation 2a' (2.95 g; 18.1 mmol) in dichloromethane (30 mL), imidazole (3.08 g; 45.25 mmol), 4-(dimethyl)-aminopyridine (0.11 g; 0.9 mmol) and chloro- tert -butyl-dimethylsilane (3.28 g; 21.72 mmol). The mixture is stirred at room temperature for 2 hours. After hydrolysis, the organic phase is washed with water and dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents and then proceeds to the next step without purification.

[0552] The titration compound is obtained according to the process described in Stage A of Example 1, using the intermediate residue above and the acid from Preparation 1a.

[0553] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm: 7.6-7.35 (m, 3 H), 7.2-6.85 (m, 4 H), 6.45-5.9 (4s, 1 H), 5.05-2.7 (m, 4 H), 4.1 / 3.95 (2m, 2 H), 3.85-3.2 (m, 2 H), 3.45 / 3.3 (2s, 3 H), 2.9 / 2.6 (2m, 1 H), 2.45 / 2.35 / 2.2 (3s, 3 H), 1.2 / 1.05 (2m, 3 H), 0.85 / 0.7 (2 sets, 9 H), 0.05-0 (3 sets, 6 H) IR: v : >C=O : 1697 and 1634 cm -1< . Stage B: 5-(5-chloro-2-{[4-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0554] The compound of the title is obtained according to the process described in Stage B of Example 1 using the ester obtained in the previous stage.

[0555] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 7.6-7.4 (m, 3 H), 7.2-7 (m, 4 H), 6.5-6.2 (4br. s, 1 H), 5.05 / 4.3-3.95 (5m, 2 H), 4.3-2.8 (6m, 2 H), 3.75-2.8 (m, 2 H), 3.47 / 3.3 (2s, 3 H), 2.85 / 2.6 (3m, 1 H), 2.5 / 2.35 / 2.25 (3s, 3 H).

[0556] IR: v : >C=O : 1662 and 1613 cm -1< . Stage C: 5-(2-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-chlorophenyl)-1,2-dimethyl-1H-pyrrole-3-carboxylic acid

[0557] Chloro- is added to a solution of the compound obtained in Stage B (3.65 g; 8.32 mmol) in acetonitrile (10 mL). tert -butyl-dimethylsilane (3 g; 20 mmol) and 4-(dimethyl)-aminopyridine (0.11 g; 0.9 mmol), then the mixture is stirred at room temperature for 15 minutes. The 2,3,4,6,7,8,9,10-octahydropyrimido[1,2- aAzepine (1.65 mL; 10.8 mmol) is then added dropwise at 0°C. The reaction mixture is stirred at 70°C for 24 hours. After adding 10 mL of 0.1 N aqueous hydrochloric acid solution, the reaction mixture is stirred for 3 hours. The reaction mixture is diluted in a mixture of water and ethyl acetate. After extraction with ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane, methanol, and acetic acid as eluents to obtain the product of the titer.

[0558] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.5-7.1 (m, 7 H), 6.3 (m, 1 H), 3.6-3.4 (m, 2 H), 3.5 (m, 4 H), 3.4 (m, 3 H), 3 (s, 1 H), 2.5-2.3 (m, 3 H), 0.9 (s, 9 H), 0.1 (s, 6 H). S step D: 5-(2-{[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}-5-chlorophenyl)-N-(5-cyano-2-fluorophenyl)-1,2-dimethyl-N-[4-(prop-2-en-1-yloxy)phenyl]-1H-pyrrole-3-carboxamide

[0559] The compound is obtained according to the process described in Stage A of Example 6 using the acid obtained in the previous stage and the amine from Preparation 1 1a". The residue obtained is directly used in the next step without purification. Stage E: 5-(5-chloro-2-{[4-(hydroxymethyl)-3,4-dihydroisoquinoline-2(1H)-yl]carbonyl}phenyl)-N-(5-cyano-2-fluorophenyl)-1,2-dimethyl-N-[4-(prop-2-en-1-yloxy)phenyl]-1H-pyrrole-3-carboxamide

[0560] The compound for the titration is obtained according to the process described in Stage G of Example 1, using the compound from the previous stage. The residue obtained is directly used in the next step without purification. Stage F: 12-chloro-5-(4-hydroxyphenyl)-8,9-dimethyl-6,15-dioxo-6,9,22,23-tetrahydro-5H,15H,17H-16,22-methano-7,10-(metheno)tribenzo[b,j , o][1,4,8,13]oxatriazacyclooctadecin-3-carbonitrile

[0561] To a solution of the compound obtained in Stage E (40 mg; 0.058 mmol) in tetrahydrofuran (20 mL), sodium hydride (4.64 mg; 0.012 mmol) is added at 0 °C, and the mixture is stirred at 40 °C for 16 hours. On two further occasions, an identical amount of sodium hydride is added, and the reaction mixture is stirred at 40 °C for 16 hours before being diluted in saturated aqueous ammonium chloride solution. After extraction with ethyl acetate, the organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated to dryness. The compound of titer is obtained according to the process described in Stage D of Example 1 using the residue above. High-resolution mass (ESI+) :

[0562] Chemical formula: C37H29ClN4O4 [M+H]+ calculated 629.195, [M+H]+ measured 629.194. Example 14 : 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-20-oxa-1,10,14-triazahexacyclo[26.3.1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-17-carbonitrile

[0563] Stage A: 5-[3-(3-cyano-5-{[4-(prop-2-en-1-yloxy)phenyl)aminolphenoxy)propyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0564] A solution of the compound from Preparation 1b (1 g; 1.63 mmol) in tetrahydrofuran (10 mL) at 0 °C is mixed with a solution of tetrabutylammonium fluoride in 1 N tetrahydrofuran (2.45 mL; 2.45 mmol). The mixture is stirred at room temperature for 30 minutes. The reaction mixture is concentrated and then diluted in a mixture of ethyl acetate and water. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated.

[0565] Allyl bromide (142 µL; 1.63 mmol) and then cesium carbonate (0.53 g; 1.63 mmol) are added to a solution of the residue obtained in acetonitrile. The mixture is stirred at room temperature for 16 hours, then for 2 hours at 60 °C after the addition of 0.2 equivalents of allyl bromide. The reaction mixture is concentrated and then diluted in a mixture of ethyl acetate and water. After settling, the organic phase is washed with water and with a saturated aqueous solution of sodium chloride, then dried over magnesium sulfate, filtered, and concentrated. The residue thus obtained is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0566] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm: 8.24 (s, 1 H), 7.1 (dd, 1 H), 7.06 (dd, 2 H), 7 (d, 2 H), 6.94 (d, 2 H), 6.77-6.6 (3dd, 3 H), 6.04 (m, 1 H), 5.4 / 5.26 (2 ∗< d, 2 H), 4.54 (d, 2 H), 4.47 (s, 2 H), 3.96 (t, 2 H), 3.52 (t, 2 H), 2.76-2.64 (m, 4 H), 1.92 (m, 2 H), 1.42 (s, 9 H). IR: v: >NH: 3340 cm -1< ; -CN: 2225 cm -1< ; >C=W: 1624 cm -1<. Stage B: 5-[3-(3-{({5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1,2-dimethyl-1H-pyrrol-3-yl}carbonyl)[4-(prop-2-en-1-yloxy)phenyllaminol-5-cyanophenoxy)propyl]-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0567] A solution of the compound from Preparation 1b (0.7 g; 2 mmol) in dichloromethane (20 mL) and the N , N -dimethylformamide (5 drops), is added to 1-chloro- N,N-2-Trimethyl-prop-1-en-1-amine (0.53 mL; 4 mmol). The reaction mixture is stirred at room temperature for 1 hour and then concentrated. The residue is resuspended in dichloroethane and concentrated again, this operation being performed twice. The final residue is resuspended in dichloroethane (10 mL) and then added to a solution of the compound obtained in Stage A (1.08 g; 2 mmol) and pyridine (0.48 mL; 6 mmol) in dichloroethane (10 mL). The mixture is heated at 80 °C for 16 hours. The reaction mixture is diluted in a mixture of dichloromethane and a saturated aqueous sodium chloride solution. After extraction of the aqueous phase with dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using petroleum ether and ethyl acetate as eluents to obtain the product of the titer.

[0568] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm: 7.8 (d, 1 H), 7.55 (d, 1 H), 7.25 (s, 1 H), 7.15 (d, 2 H), 7.15 / 7.05 / 7 (3s, 3 H), 7.1-6.95 (m, 3 H), 6.9 (d, 2 H), 6 (m, 1 H), 5.35 / 5.2 (d+d, 1+1 H), 5.25 (s, 1 H), 4.55 (d, 2 H), 4.45 (br. s, 2 H), 4 (t, 2 H), 3.5 (t, 2 H), 3.15 (s, 3 H), 2.7 (m, 4 H), 2.45 (s, 3 H), 1.9 (quint, 2 H), 1.4 (s, 9 H), 1.3 (s, 9 H).

[0569] IR: v: -CN: 2230 cm -1< ; >C=W: 1695 cm -1< ; >C=W: 1645 cm -1<. Stage C: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-20-oxa-1,10,14-triazahexacyclo[26.3.1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene-17-carbonitrile

[0570] To a solution of the compound obtained in Stage B (0.58 g; 0.67 mmol) in dioxane (15 mL), triethylamine (1.38 mL; 10 mmol) and trimethylsilyl trifluoromethanesulfonate (1.8 mL; 10 mmol) are added. The reaction mixture is refluxed for 2 hours and then poured into ice-cold water. After extraction with ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated.

[0571] To a solution of the residue thus obtained in dichloromethane (200 mL), 1-hydroxybenzotriazole (0.108 g; 0.67 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.153 g; 0.8 mmol), and diisopropylethylamine (0.57 mL; 3.33 mmol) are successively added. The mixture is then stirred for 24 hours at room temperature. The reaction mixture is diluted with a mixture of dichloromethane and water. After settling, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ethyl acetate as eluents.

[0572] 1,3-Dimethylbarbituric acid (0.036 g; 0.23 mmol) is added to a solution of the residue thus obtained in a mixture of dichloromethane (10 mL) and methanol (5 mL). The reaction mixture is degassed with argon for 10 minutes, and tetrakis-(triphenylphosphine)palladium(0) (0.013 g; 0.01 mmol) is added. The reaction mixture is heated at 40 °C for 45 minutes. After concentration of the methanol, the reaction mixture is diluted in a mixture of ethyl acetate and water. After settling, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by Oasis® phase chromatography using acetonitrile and water as eluents. The solid thus obtained is dissolved in a mixture of water and acetonitrile, filtered and then lyophilized to obtain the product of the titration. Elemental Microanalysis : (theoretical %) : measure)

[0573] %C = 71.28: 70.81; %H = 5.06: 4.94; %N = 8.53: 8.51. High-resolution mass (ESI+) :

[0574] Chemical formula: C 39 H 33 ClN 4 O 5 [M+H]+ calculated 673.2212, [M+H]+ measured 673.2211. Example 15: 6-chloro-14-(4-hydroxyphenyl)-1C,11-dimethyl-23-oxa-1,10,14,17,18-pentaazahexacyclo[26.3.1.1~9,12~.1~15,18~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,24,26,28-decaene-2,13-dione

[0575] Stage A: 5-(4-{4-[({5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1,2-dimethyl-1H-pyrrol-3-yl}carbonyl)(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amino]-1H-pyrazol-1-yl}butoxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate tert-butyl

[0576] The compound of the titration is obtained according to the process described in Stage B of Example 14, using the compound from Preparation 1b (acid) and the compound from Preparation 2b" (amine).

[0577] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.83 (s, 1 H), 7.73 (d, 1 H), 7.51 (dd, 1 H), 7.15 (s, 1 H), 7.14-7.06 (m, 3 H), 7.1 (s, 1 H), 6.82 (d, 2 H), 6.73 (dd, 2 H), 4.97 (s, 1 H), 4.46 (s, 2 H), 4.1 (t, 2 H), 3.91 (t, 2 H), 3.53 (t, 2 H), 3.15 (s, 3 H), 2.59 (t, 2 H), 2.47 (s, 3 H), 1.9 (m, 2 H), 1.64 (m, 2 H), 1.41 (s, 9 H), 1.27 (s, 9 H), 0.86 (s, 9 H), 0.07 (s, 6 H).

[0578] IR: v: >C=O: 1695 cm -1< ; >C=W: 1633 cm -1<. Stage B: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-23-oxa-1,10,14,17,18-pentaazahexacyclo[26.3.1.1~9,12~.1~15,18~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,24,26,28-decaene-2,13-dione

[0579] To a solution of the compound obtained in Stage A (0.13 g; 0.14 mmol) in dioxane (5 mL), triethylamine (0.1 mL; 0.71 mmol) and trimethylsilyl trifluoromethanesulfonate (0.13 mL; 0.71 mmol) are added. The reaction mixture is refluxed for 1 hour and then poured into ice-cold water. After extraction with ethyl acetate, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated.

[0580] To a solution of the residue obtained in dichloromethane (85 mL), 1-hydroxybenzotriazole (0.046 g; 0.34 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.065 g; 0.34 mmol), and diisopropylethylamine (0.243 mL; 1.42 mmol) are successively added. The mixture is then stirred for 20 hours at room temperature. The reaction mixture is diluted with a mixture of dichloromethane and water. After settling, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents.

[0581] A solution of 1 N potassium hydroxide in methanol (0.11 mL; 0.11 mmol) is added to a 3 mL solution of the residue obtained. The mixture is then stirred for 18 hours at room temperature. After concentration of the methanol, the reaction mixture is diluted in a mixture of dichloromethane and water. After settling, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by Oasis® phase chromatography using acetonitrile and water as eluents. The resulting solid is dissolved in a mixture of water and acetonitrile and then lyophilized to obtain the titration product. High-resolution mass (ESI+) :

[0582] Chemical formula: C36H34ClN5O4 [M+H]+ calculated 636.2372, [M+H]+ measured 636.2375. Example 16 : 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,16,17,23,24-hexahydro-14H-15,18-methano-6,9-(metheno)dibenzo[l,r]pyrazolo[3,4-d][1,6,10,15]oxatriazacyclononadecine-5,14(8H)-dione

[0583]

[0584] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 3b". Elemental Microanalysis : (Theoretical %: measured)

[0585] %C = 67.57: 67.70; %H = 5.18: 4.89; %N = 11.26: 11.16. High-resolution mass (ESI+) :

[0586] Chemical formula: C 35 H 32 ClN 5 O 4 [M+H]+ calculated 622.2209, [M+H]+ measured 622.2216. Example 17 : 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-16-(morpholin-4-ylmethyl)-4,16,17,23,24,25-hexahydro-1H,1 4H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrazolo[4,3-p][1,6,11,15]oxatriazacycloicosine-5,14(8H)-dione

[0587] Stage A: 2-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl){1-methyl-5-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-1H-pyrazol-4-yl}carbamoyl]-1,5-dimethyl-1H-pyrrol-2-yl}-4-tert-butyl chlorobenzoate

[0588] The compound of the titration is obtained according to the process described in Stage B of Example 14, using the acid from Preparation 1b and the amine from Preparation 4b".

[0589] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 7.75 (d, 1 H), 7.52 (dd, 1 H), 7.21 (s, 1 H), 7.1 (d, 1 H), 7.02 (d, 2 H), 6.71 (d, 2 H), 6.19 (s, 1 H), 4.5 (t, 1 H), 3.71 (s, 3 H), 3.7-3.2 (4m, 4 H), 3.15 (s, 3 H), 2.55 (m, 2 H), 2.41 (s, 3 H), 1.7-1.2 (m, 8 H), 1.3 (s, 9 H), 0.85 (s, 9 H), 0.1 (s, 6 H).

[0590] IR: v: >C=O: 1706 cm -1< ; >C=O: 1640 cm -1<. Stage B: 2-(4-{(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)[5-(3-hydroxypropyl)-1-methyl-1H-pyrazol-4-yl]carbamoyl}-1,5-dimethyl-1H-pyrrol-2-yl)-4-tert-butyl chlorobenzoate

[0591] To a solution of the compound obtained in Stage A (3.28 g; 4.21 mmol) in methanol (30 mL), is added the paraPyridinium toluenesulfonate (1.5 g; 0.42 mmol) is added, and the mixture is stirred for 4 hours at 80 °C. After returning to room temperature, the reaction mixture is diluted with dichloromethane and a saturated aqueous solution of ammonium chloride. After settling, the organic phase is washed with water, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titer.

[0592] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.75 (d, 1 H), 7.59 (dd, 1 H), 7.22 (s, 1 H), 7.12 (d, 1 H), 7.05 (d, 2 H), 6.75 (d, 2 H), 5.15 (s, 1 H), 4.5 (m, 1 H), 3.71 (s, 3 H), 3.3 (t, 2 H), 3.2 (s, 3 H), 2.5 (t, 2 H), 2.45 (s, 3 H), 1.5 (m, 2 H), 1.31 (s, 9 H), 0.9 (s, 9 H), 0.1 (s, 6 H).

[0593] IR: v: -OH: 3421 cm -1< ; >C=W: 1708 cm -1< ; >C=W: 1634 cm -1<. Stage C: 5-(3-{4-[({5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1,2-dimethyl-1H-pyrrol-3-yl}carbonyl)(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)amtno]-1-methyl-1H-pyrazol-5-yl}propoxy)-3-(morpholin-4-ylmethyl)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0594] A solution of the compound obtained in Stage B (1.67 g; 2.9 mmol), triphenylphosphine (1.26 g; 3.5 mmol), and the compound from Preparation 4' (0.84 g; 2.9 mmol) in tetrahydrofuran (20 mL) is added dropwise to a solution of diisopropyl azodicarboxylate (1 mL; 3.5 mmol) in tetrahydrofuran (20 mL). The reaction mixture is stirred at room temperature for 2 hours and then diluted in a mixture of ethyl acetate and water. After extraction of the aqueous phase with ethyl acetate, the organic phases are combined, washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by RP-18 phase chromatography using acetonitrile and water as eluents to obtain the titer product.

[0595] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm : 7.74 (d, 1 H), 7.54 (d, 1 H), 7.26 (s, 1 H), 7.26 (s, 1 H), 7.1 (t, 1 H), 7.03 (d, 2 H), 6.74 (d, 1 H), 6.73 (d, 1 H), 6.69 (d, 2 H), 5.15 (s, 1 H), 4.64 / 4.08 (d+m, 1+1 H), 4.59 / 4.46 (m+m, 1 H), 3.9 (m, 2 H), 3.74 (s, 3 H), 3.49 (m, 4 H), 3.16 (s, 3 H), 2.73 / 2.58 (m+m, 1+1 H), 2.69 (m, 2 H), 2.5-2.2 (m, 4 H), 2.42 (s, 3 H), 2.24 / 1.98 (m+m, 1+1 H), 1.79 (m, 2 H), 1.42 (s, 9 H), 1.25 (s, 9 H), 0.85 (s, 9 H), 0.07 (s, 6 H).

[0596] IR: v : >C=O : 1693 cm -1< ; >C=O : 1641 cm -1< . Stage D: 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-16-(morpholin-4-ylmethyl)-4,16,17,23,24,25-hexahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrazolo[4,3-p][1,6,11,15]oxatriazacycloicosine-5,14(8H)-dione

[0597] To a solution of the compound obtained in Stage C (0.315 g; 0.31 mmol) in dichloroethane (12.5 mL), triethylamine (0.13 mL; 0.92 mmol) and zinc bromide (0.34 g; 1.53 mmol) are added. The reaction mixture is stirred at 120°C for 2 hours under microwave conditions (150 W) three times, then poured into a mixture of dichloromethane and ice water. After extraction with dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated.

[0598] To a solution of the residue thus obtained in dichloromethane (15 mL), 1-hydroxybenzotriazole (0.052 g; 0.23 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.072 g; 0.23 mmol), and diisopropylethylamine (0.2 mL; 0.6 mmol) are successively added. The mixture is then stirred for 16 hours at room temperature. The reaction mixture is diluted with a mixture of dichloromethane and water. After settling, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness.

[0599] A 1 M tetrabutylammonium fluoride solution in tetrahydrofuran (14 mL) is added to a solution of the residue thus obtained. The mixture is then stirred for 30 minutes at room temperature. After concentration, the residue is resuspended in a mixture of ethyl acetate and a saturated aqueous sodium chloride solution. After settling, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and ammoniacal methanol as eluents. The resulting solid is dissolved in a mixture of water and acetonitrile, then lyophilized to obtain the titration product. High-resolution mass (ESI+) :

[0600] Chemical formula: C 41 H 43 ClN 6 O 5 [M+H]+ calculated 735.3056, [M+H]+ measured 735.3061. Example 18: 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-5,14-dioxo-4,5,8,16,17,23,24,25-octahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrrolo[3,2-p][1,6,11,15]oxatriazacycloicosine-2-carbonitrile

[0601]

[0602] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 5b". Elemental Microanalysis : (theoretical %) : measure)

[0603] %C = 69.14: 68.70; %H = 5.19:5.16; %N = 10.61: 9.97. High-resolution mass (ESI+) :

[0604] Chemical formula: C38H34ClN5O4 [M+H]+ calculated 660.2372, [M+H]+ measured 660.2374. Example 19 : 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-5,14-dioxo-1,4,5,8,16,17,23,24-octahydro-14H-15,18-methano-6,9-(metheno)dibenzo[l,r]pyrrolo[2,3-d][1,6,10,15]oxatriazacyclononadecine-2-carbonitrile

[0605]

[0606] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 6b". Elemental Microanalysis : (theoretical %) : measure)

[0607] %C = 68.78: 68.64; %H = 4.99:5.01; %N = 10.84: 10.66. High-resolution mass (ESI+) :

[0608] Chemical formula: C 37 H 32 ClN 5 O 4 [M+H]+ calculated 646.2217, [M+H]+ measured 646.2216. Example 20 : 11-fluoro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,16,17,23,24-hexahydro-14H-15,18-methano-6,9-(metheno)dibenzo[l,r]pyrazolo[3,4-d][1,6,10,15]oxatriazacyclononadecine-5,14(8H)-dione

[0609]

[0610] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 2b and the amine of Preparation 3b". High-resolution mass (ESI+) :

[0611] Chemical formula: C 35 H 33 FN 5 O 4 [M+H]+ calculated 606.2511, [M+H]+ measured 606.2517. Example 21 : 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,16,17,23,24-hexahydro-14H-15,18-methano-6,9-(metheno)dibenzo[m,s]pyrazolo[3,4-e][1,4,7,11,16]dioxatriazacycloicosine-5,14(8H)-dione

[0612]

[0613] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 7b". Elemental microanalysis: (theoretical %: measured %)

[0614] %C = 65.88: 65.61; %H = 5.05: 4.98; %N = 10.60: 10.94. High-resolution mass (ESI+):

[0615] Chemical formula: C35H32ClN5O5 [M+H]+ calculated 638.2165, [M+H]+ measured 638.2166. Example 22 : 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,16,21,22,23-hexahydro-14H-15,21-methano-6,9-(metheno)dibenzo[j,o]pyrazolo[3,4-b][1,4,8,13]oxatriazacyclononadecine-5,14(8H)-dione

[0616]

[0617] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 8b". High-resolution mass (ESI+):

[0618] Chemical formula: C 35 H 32 ClN 5 O 4 [M+H]+ calculated 622.2216, [M+H]+ measured 622.2208. Example 23: 11-chloro-4-(4-hydroxyphenyl)-7,8-dimethyl-1-(tetrahydrofuran-3-yl)-1,4,16,17,23,24-hexahydro-14H-15,18-methano-6,9-(metheno)dibenzo[l,r]pyrazolo[3,4-d][1,6,10,15]oxatriazacyclononadecine-5,14(8H)-dione

[0619]

[0620] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 9b". Elemental Microanalysis : (theoretical %) : measure)

[0621] %C = 67.30: 67.12; %H = 5.35: 5.08; %N= 10.33: 10.31. High-resolution mass (ESI+) :

[0622] Chemical formula: C 38 H 36 ClN 5 O 5 [M+H]+ calculated 678.2478, [M+H]+ measured 678.2481. Example 24: 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4,22,23-tetrahydro-14H,16H-15,17-methano-6,9-(metheno)dibenzo[b,g]pyrazolo[4,3-o][1,5,10,14]oxatriazacyclooctadecine-5,14(8H)-dione

[0623]

[0624] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 10b". Elemental Microanalysis : (theoretical %) : measure)

[0625] %C = 67.16: 67.31; %H = 4.97: 4.91; %N = 11.52: 11.30. High-resolution mass (ESI+) :

[0626] Chemical formula: C34H3OClN5O4 [M+H]+ calculated 608.2059, [M+H]+ measured 608.2074. Example 25: (16R or S)-11-chloro-4-(4-hydroxyphenyl)-1,7,8,16-tetramethyl-5,14-dioxo-4,5,8,16,17,23,24,25-octahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrrolo[3,2-p][1,6,11,15]oxatriazacycloicosine-2-carbonitrile

[0627]

[0628] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 11b". Elemental Microanalysis : (theoretical %) : measure)

[0629] %C = 69.48: 69.13; %H = 5.38: 5.37; %N = 10.39: 10.05. High-resolution mass (ESI+) :

[0630] Chemical formula: C 39 H 36 ClN 5 O 4 [M+H]+ calculated 674.2529, [M+H]+ measured 674.253. Example 26: (16S or R)-11-chloro-4-(4-hydroxyphenyl)-1,7,8,16-tetramethyl-5,14-dioxo-4,5,8,16,17,23,24,25-octahydro-1H,14H-15,18-methano-6,9-(metheno)dibenzo[b,hjpyrrolo[3,2-p][1,6,11,15]oxatriazacycloicosine-2-carbonitrile

[0631]

[0632] The compound of the titration is obtained according to the process of Example 15 using the acid of Preparation 1b and the amine of Preparation 12b". Elemental Microanalysis : (theoretical %) : measure)

[0633] %C = 69.48: 68.73; %H = 5.38: 5.47; %N = 10.39: 10.13. High-resolution mass (ESI+) :

[0634] Chemical formula: C 39 H 36 ClN 5 O 4 [M+H]+ calculated 674.2529, [M+H]+ measured 674.2532. Example 27: 4-[15-chloro-3-hydroxy-18,19-dimethyl-12,21-dioxo-7,8,9,10,18,21-hexahydro-6H,12H,22H-8,11-ethano-20,17-(metheno)dibenzo[b,j][1,4,8,13]oxatriazacyclooctadecin-22-yl]-1,5-dimethyl-1H-pyrrole-2-carbonitrile

[0635] Stage A : 4-(2-{5-(benzyloxy)-2-[({5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1,2-dimethyl-1H-pyrrol-3-yl}carbonyl)(5-cyano-1,2-dimethyl-1H-pyrrol-3-yl)amino]phenoxy}ethyl)piperidine-1-carboxylate of tert-butyl

[0636] The compound of the titration is obtained according to the process described in Stage B of Example 14 using the acid of Preparation 1b and the amine of Preparation 13b".

[0637] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm : 7.8 (d, 1 H), 7.55 (dd, 1 H), 7.45-7.25 (m, 5 H), 7.05 (d, 1 H), 7.05 (s, 1 H), 6.65 (br. s, 1 H), 6.65 (s, 1 H), 6.5 (d, 1 H), 5.35 (br. s, 1 H), 5.05 (s, 2 H), 3.95 (br. s, 2 H), 3.85 / 2.55 (2br. s, 4H), 3.55 (s, 3 H), 3.15 (s, 3 H), 2.35 (s, 3 H), 2.1 (br. s, 3 H), 1.6 / 0.95 (m+m, 2+2 H), 1.55 (m, 1 H), 1.55 (m, 2 H), 1.35 (s, 9 H), 1.25 (s, 9 H).

[0638] IR: v : -CN : 2209 cm -1< ; >C=O : 1715, 1688 et 1640 cm -1< . Stage B: 4-[15-chloro-3-hydroxy-18,19-dimethyl-12,21-dioxo-7,8,9,10,18,21-hexahydro-6H,12H,22H-8,11-ethano-20,17-(metheno)dibenzo[bj][1,4,8,13]oxatriazacyclooctadecin-22-yl]-1,5-dimethyl-1H-pyrrole-2-carbonitrile

[0639] Zinc bromide (1.45 g; 6.44 mmol) is added to a solution of the compound obtained in Stage A (1.3 g; 1.29 mmol) in dichloromethane (12 mL). The reaction mixture is refluxed for 17 hours and then transferred to water. The reaction mixture is then stirred for 2 hours and extracted with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered, and concentrated. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents.

[0640] To a solution of the residue obtained in dichloromethane (470 mL), 1-hydroxybenzotriazole (0.252 g; 1.86 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.320 g; 1.86 mmol), and diisopropylethylamine (1.28 mL; 7.77 mmol) are successively added. The mixture is then stirred for 20 hours at room temperature. The reaction mixture is diluted with a mixture of dichloromethane and water. After settling, the organic phase is dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents.

[0641] A solution of the residue thus obtained in a mixture of methanol (25 mL) and ethyl acetate (25 mL) is to which palladium on carbon (15 wt%) is added, and the mixture is then hydrogenated for 4 hours at room temperature under 0.6 bar. The reaction mixture is filtered and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents, and then by supercritical RP-18 chromatography using ethanol with 0.1% diethylamine as the eluent. The resulting solid is dissolved in a mixture of water and acetonitrile, and then lyophilized to obtain the titration product. Elemental Microanalysis : (theoretical %) : measure)

[0642] %C = 66.71: 66.25; %H = 5.60: 5.52; %N = 11.44: 11.37. High-resolution mass (ESI+) :

[0643] Chemical formula: C 34 H 34 ClN 5 O 4 [M+H]+ calculated 612.2367, [M+H]+ measured 612.2372. Example 28: 4-[3-hydroxy-18,19-dimethyl-12,21-dioxo-7,8,9,10,18,21-hexahydro-6H,12H,22H-8,11-ethano-20,17-(metheno)dibenzo[b,j][1,4,8,13]oxatriazacyclooctadecin-22-yl]-1,5-dimethyl-1H-pyrrole-2-carbonitrile

[0644]

[0645] The title compound is obtained as a by-product during Stage B of Example 27. Elemental Microanalysis : (theoretical %) : measure)

[0646] %C = 70.69: 70.15; %H = 6.11:6.13; %N = 12.12: 12.86. High-resolution mass (ESI+) :

[0647] Chemical formula: C 34 H 35 N 5 O 4 [M+H]+ calculated 578.2773, [M+H]+ measured 578.2762. Example 29: 4-[16-chloro-3-hydroxy-19,20-ditnethyl-13,22-dioxo-6,7,8,9,10,11,19,22-octahydro-13H,23H- 8,12-methano-21,18-(metheno)dibenzo[b,j][1,4,8,13]oxatriazacyclononadecin-23-yl]-1,5-dimethyl-1H-pyrrole-2-carbonitrile

[0648]

[0649] The compound of the titration is obtained according to the process of Example 27 using the acid of Preparation 1b and the amine of Preparation 14b". High-resolution mass (ESI+) :

[0650] Chemical formula: C 34 H 34 ClN 5 O 4 [M+H]+ calculated 612.2372, [M+H]+ measured 612.2367. Example 30 : 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-23-oxa-1,10,14-triaza-19-azoniahexacyclo[26.3.1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene trifluoromethylsulfonate

[0651] Stage A: 3-[([5-[2-(tert-butoxycarbonyl)-5-chlorophenyll-1,2-dimethyl-1H-pyrrol-3-yl}carbonyl)[4-(prop-2-en-1-yloxy)phenyl]amino}-1-(3-{[2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-5-yl]oxy}propyl)pyridinium

[0652] To a solution of the compound obtained in Preparation 1b (0.47 g; 1.36 mmol) in dichloromethane (34 mL), 1-chloro- N , N -2-Trimethyl-prop-1-en-1-amine (0.183 mL; 1.49 mmol). The reaction mixture is stirred at room temperature for 1 hour and then concentrated. The residue is reconstituted in tetrahydrofuran (14 mL).

[0653] In parallel, a solution of sodium hydride (65 mg; 1.63 mmol) in tetrahydrofuran (5 mL) and of the compound from Preparation 15b (960 mg; 1.49 mmol) in tetrahydrofuran (15 mL) is prepared and stirred at room temperature for 30 minutes. The previously obtained residue is added, and the mixture is stirred for 3 hours. The reaction mixture is diluted in dichloromethane and water. After extraction of the aqueous phase with dichloromethane, the organic phases are combined, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titration.

[0654] 1H NMR(400 MHz, dmso-d6, 300 K) δ ppm: 9.14 (br. s, 1 H), 8.87 (d, 1 H), 8.18 (d, 1 H), 8.06 (dd, 1 H), 7.81 (d, 1 H), 7.58 (d, 1 H), 7.17 (d, 2 H), 7.13 (t, 1 H), 7.01 (s, 1 H), 6.95 (d, 2 H), 6.77 (d, 1 H), 6.77 (d, 1 H), 6.01 (m, 1 H), 5.34 (d, 1 H), 5.21 (d, 1 H), 5.2 (s, 1 H), 4.8 (t, 2 H), 4.57 (d, 2 H), 4.45 (br. s, 2 H), 4.05 (t, 2 H), 3.48 (m, 2 H), 3.16 (s, 3 H), 2.46 (m, 2 H), 2.46 (s, 3 H), 2.4 (m, 2 H), 1.41 / 1.3 (2s, 18 H). Stage B: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-23-oxa-1,10,14-triaza-19-azoniahexacyclo[26.3.1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11,15(33),16,18,24,26,28-undecaene trifluoromethylsulfonate

[0655] The compound of the title is obtained according to the process described in Stage C of Example 14 using the compound obtained in the previous stage. Elemental Microanalysis : (theoretical %) : measure)

[0656] %C = 58.27: 58.74; %H = 4.38: 4.35; %N = 7.15: 7.71. High-resolution mass (ESI+) :

[0657] Chemical formula: C38H34ClF3N4O7S [M-CF3SO3]+ calculated 633.2249, [M-CF3SO3]+ measured 633.2263. Example 31 : 6-chloro-14-(4-hydroxyphenyl)-10,11,18-trimethyl-22-oxa-1,10,14,17,19-pentaazahexacyclo[25.3.1.1 -9,12-.1-15,19-.0-3,8-.0-23,28-]tritriaconta-3,5,7,9(33),11,15,17,23,25,27-decaene-2,13,32-trione

[0658] Stage A : 4-chloro-2-[1,5-dimethyl-4-({2-methyl-4-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyrimidin-5-yl}[4-(prop-2-en-1-yloxy)phenyl]carbamoyl)-1H-pyrrol-2-yl]tert-butylbenzoate

[0659] The compound of the titer is obtained according to the process described in Stage A of Example 30 using the compound of Preparation 1b and that of Preparation 16b".

[0660] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 8.36 (s, 1 H), 7.79 (d, 1 H), 7.56 (dd, 1 H), 7.21 (d, 2 H), 7.05 (d, 1 H), 6.87 (d, 2 H), 5.99 (m, 1 H), 5.33 (d, 1 H), 5.29 (s, 1 H), 5.2 (d, 1 H), 4.56 (m, 1 H), 4.53 (d, 2 H), 4.45 (m, 2 H), 3.83 / 3.61 (2m, 2 H), 3.69 / 3.35 (2m, 2 H), 3.15 (s, 3 H), 2.5 (s, 3 H), 2.39 (s, 3 H), 1.63 / 1.37 (2m, 2 H), 1.51 / 1.38 (2m, 2 H), 1.42 / 1.32 (2m, 2 H), 1.29 (s, 9 H).

[0661] IR: v: >C=O: 1703 cm -1< ; >C=W: 1644 cm -1<. Stage B: 5-{2-[5-{({5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1,2-dimethyl-1H-pyrrol-3-yl}carbonyl)[4-(prop-2-en-1-yloxy)phenyllaminol-2-methyl-6-oxopyrimidin-1(6H)-yl]ethoxy}-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0662] To a solution of the compound obtained in Stage A (0.97 g; 1.35 mmol) in methanol (7 mL), is added the para-pyridinium toluenesulfonate (0.34 g; 1.35 mmol), then the mixture is stirred for 4 hours at 80 °C. After returning to room temperature, the reaction mixture is concentrated and then diluted with ethyl acetate and water. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness.

[0663] To a solution of the residue obtained (0.579 g; 0.915 mmol) in dichloromethane (5 mL), tosyl chloride (0.349 g; 1.83 mmol) and triethylamine (514 µL; 3.66 mmol) are added, and the mixture is stirred for 16 hours at room temperature. The reaction mixture is diluted with dichloromethane and water. After settling, the organic phase is washed with water and a saturated aqueous sodium chloride solution, then dried over magnesium sulfate, filtered, and concentrated to dryness.

[0664] A solution of the residue obtained (0.7 g; 0.752 mmol) in the N,N -dimethylformamide (5 mL), the compound from Preparation 3b' (0.225 g; 0.903 mmol) and potassium carbonate (0.313 g; 2.26 mmol) are added, and the mixture is stirred for 2 hours at 125 °C. The reaction mixture is diluted with ethyl acetate and water. After settling, the organic phase is washed with water and a saturated aqueous solution of lithium chloride, then dried over magnesium sulfate, filtered, and concentrated to dryness. The residue is purified by silica gel chromatography using dichloromethane and methanol as eluents to obtain the product of the titer.

[0665] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm: 7.88 (s, 1 H), 7.72 (d, 1 H), 7.5 (dd, 1 H), 7.15 (d, 2 H), 7.08 (t, 1 H), 7.07 (d, 1 H), 6.84 (d, 2 H), 6.74 (d, 1 H), 6.74 (d, 1 H), 5.99 (m, 1 H), 5.36 (s, 1 H), 5.33 (d, 1 H), 5.2 (d, 1 H), 4.52 (d, 2 H), 4.43 (br. s, 2 H), 4.39 (t, 2 H), 4.2 (t, 2 H), 3.48 (t, 2 H), 3.11 (s, 3 H), 2.62 (s, 3 H), 2.47 (t, 2 H), 2.36 (s, 3 H), 1.41 / 1.28 (2s, 18 H).

[0666] IR: v: >C=O: 1682 cm -1< ; >C=W: 1639 cm -1<. Stage C: 6-chloro-14-(4-hydroxyphenyl)-10,11,18-trimethyl-22-oxa-1,10,14,17,19-pentaazahexacyclo[25.3.1.1~9,12~.1~15,19~.0~3,8~.0~23,28~]tritriaconta-3,5,7,9(33),11,15,17,23,25,27-decaene-2,13,32-trione

[0667] The compound of the title is obtained according to the process described in Stage C of Example 14 using the compound from the previous stage. Elemental Microanalysis : (theoretical %) : measure)

[0668] %C = 66.51: 66.29; %H = 4.96: 4.95; %N = 10.77: 10.38. High-resolution mass (ESI+) :

[0669] Chemical formula: C36H32ClN5O5 [M+H]+ calculated 650.2169, [M+H]+ measured 650.2165. Example 32 : 18-chloro-11-(4-hydroxyphenyl)-2,14,15-trimethyl-1,12-dioxo-1,2,3,4,12,15-hexahydro-11H-6,10:13,16-di(metheno)-5,2,11,15-benzoxatriazacyclooctadecine-8-carbonitrile

[0670] Stage A: 2-(4-{(3-[2-[(tert-butoxycarbonyl)(methyl)aminolethoxyl-5-cyanophenyl)[4-(prop-2-en-1-yloxy)phenyl]carbamoyl}-1,5-dimethyl-1H-pyrrol-2-yl)-4-tert-butylchlorobenzoate

[0671] The compound of the titer is obtained according to the process described in Stage B of Example 14 using the compound of Preparation 1b and that of Preparation 17b".

[0672] 1H NMR (400 MHz, dmso-d6, 300 K) δ ppm: 7.78 (d, 1 H), 7.56 (dd, 1 H), 7.28 (br. s, 1 H), 7.19 (br. s, 1 H), 7.14 (d, 2 H), 7.07 (d, 1 H), 6.99 (massive, 1 H), 6.92 (d, 2 H), 6 (m, 1 H), 5.34 / 5.21 (2dquad, 2 H), 5.26 (s, 1 H), 4.55 (m, 2 H), 4.11 (m, 2 H), 3.48 (t, 2 H), 3.16 (s, 3 H), 2.8 (s, 3 H), 2.43 (s, 3 H), 1.3 (m, 18 H).

[0673] IR: v: >CN: 2230 cm -1< ; >C=W: 1697 and 1645 cm -1<. Stage B: 18-chloro-11-(4-hydroxyphenyl)-2,14,15-trimethyl-1,12-dioxo-1,2,3,4,12,15-hexahydro-11H6,10:13,16-di(metheno)-5,2,11,15-benzoxatriazacyclooctadecine-8-carbonitrile

[0674] The compound of the title is obtained according to the process described in Stage C of Example 14 using the compound from the previous stage. Elemental Microanalysis : (theoretical %) : measure)

[0675] %C = 66.60: 65.92; %H = 4.66: 4.62; %N = 10.36: 10.08. High-resolution mass (ESI+) :

[0676] Chemical formula: C30H25ClN4O4 [M+H]+ calculated 541.1642, [M+H]+ measured 541.1637. Example 33: 21-chloro-6-(4-hydroxyphenyl)-2,3,1 7-trimethyl-5,18-dioxo-5,6,13,14,15,16,17,18-octahydro-2H-4,1:11,7-di(metheno)-1 2,2,6,1 7-benzoxatriazacycloicosine-9-carbonitrile

[0677]

[0678] The compound of the titration is obtained according to the process of Example 32 using the acid of Preparation 1b and the amine of Preparation 18b". Elemental Microanalysis : (theoretical %) : measure)

[0679] %C = 67.54: 67.16; %H = 5.14:5.05; %N = 9.85: 9.27. High-resolution mass (ESI+) :

[0680] Chemical formula: C32H29ClN4O4 [M+H]+ calculated 569.1955, [M+H]+ measured 569.1950. Example 34: 18-chloro-11-(4-hydroxyphenyl)-14,15-dimethyl-6,7,10,11,23,24-hexahydro-9H,21H-1,22-methano-13,16-(metheno)dibenzo[m,s][1,4,7,11,16]dioxatriazacycloicosine-12,21(15H)-dione

[0681] Stage A: 5-(2-{2-[({5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1,2-dimethyl-1H-pyrrol-3-yl}carbonyl)(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)anùno]ethoxy}ethoxy)-3,4-dihydroisoquinoline-2(1H)-tert-butyl carboxylate

[0682] The compound of the titration is obtained according to the process described in Stage B of Example 14 using the acid from Preparation 1b and the amine from Preparation 19b".

[0683] 1H NMR(500 MHz, dmso-d6, 300 K) δ ppm: 7.7 (d, 1 H), 7.5 (dd, 1 H), 7.11 (d, 1 H), 7.05 (m, 2 H), 6.8 (t, 1 H), 6.7 (d, 2 H), 6.65 (m, 2 H), 4.85 (s, 1 H), 4.42 (s, 2 H), 4.05 (m, 2 H), 3.87 (m, 2 H), 3.7 (m, 2 H), 3.65 (m, 2 H), 3.45 (m, 2 H), 3.15 (s, 3 H), 2.6 (m, 2 H), 2.4 (s, 3 H), 1.4-0.8 (s, 27 H), 0.1 (s, 6 H). Stage B: 18-chloro-11-(4-hydroxyphenyl)-14,15-dimethyl-6,7,10,11,23,24-hexahydro-9H,21H-1,22-methano-13,16-(metheno)dibenzo[m,s][1,4,7,11,16]dioxatriazacycloicosine-12,21(15H)-dione

[0684] The compound of the title is obtained according to the process described in Stage D of Example 17 using the compound from the previous stage. High-resolution mass (ESI+) :

[0685] Chemical formula: C 33 H 32 ClN 3 O 5 [M+H]+ calculated 586.2103, [M+H]+ measured 586.2124. Example 35: 21-chloro-29-(4-hydroxyphenyl)-25,26-dimethyl-17,28-dioxo-2,3,4,16,25,29-hexaazaheptacyclo[28.3.1.1~2,5~.1~12,16~.1~24,27~.0~8,13~.0~18,23~]heptatriaconta-1(34),3,5(37),8,10,12,18,20,22,24(35),26,30,32-tridecaene-32-carbonitrile

[0686]

[0687] The compound of the titration is obtained according to the process of Example 34 using the acid of Preparation 1b and the amine of Preparation 20b". High-resolution mass (ESI+) :

[0688] Chemical formula: C 40 H 32 ClN 7 O 3 [M+H]+ calculated 694.2328, [M+H]+ measured 694.233. Example 36: 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-23,26,29-trioxa-2,6,15,31,34-pentaazahexacyclo[28.2.2.1~4,7~.1~15,18~.0~8,13~.0~17,22~]hexatriaconta-1(32),4,7(36),8,10,12,17,19,21,30,33-undecaene-3,14-dione

[0689] Stage A: 4-(2-{2-[(5-{({5-[2-(tert-butoxycarbonyl)-5-chlorophenyl]-1,2-dimethyl-1H-pyrrol-3-yl}carbonyl)[4-(prop-2-en-1-yloxy)phenyl]amino}pyrimidin-2-yl)oxy]ethoxy}ethoxy)-1,3-dihydro-2H-isoindole-2-carboxylate of tert-butyl

[0690] The compound of the titration is obtained according to the process described in Stage B of Example 14 using the acid from Preparation 1b and the amine from Preparation 21b".

[0691] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 8.46 / 8.45 (s, 2 H), 7.77 (d, 1 H), 7.54 (dd, 1 H), 7.26-6.83 (m, 3 H), 7.21 (m, 2 H), 7.08 (d, 1 H), 6.92 (m, 2 H), 5.99 (m, 1 H), 5.33 / 5.2 (m+m, 2 H), 5.23 / 5.22 (s, 1 H), 4.6-4.41 (m, 4 H), 4.54 (m, 2 H), 4.45-3.75 (m, 8 H), 3.15 (s, 3 H), 2.43 (s, 3 H), 1.46-1.25 (s, 18 H). Stage B : 4-chloro-2-(4-{(2-{2-[2-(2,3-dihydro-1H-isoindol-4-yloxy)ethoxy]ethoxy}pyrimidin-5-yl)[4-(prop-2-en-1-yloxy)phenyl]carbamoyl}-1,5-dimethyl-1H-pyrrol-2-yl)benzoic acid

[0692] To a solution of the compound obtained in Stage A (1.2 g; 1.36 mmol) in dioxane (18 mL), triethylamine (1.9 mL; 13.6 mmol) and trimethylsilyl trifluoromethanesulfonate (2.46 mL; 13.6 mmol) are added. The reaction mixture is stirred at room temperature for 20 minutes and then poured into ice-cold water. The resulting precipitate is filtered and then purified by RP-18 phase chromatography using acetonitrile, water, and ammonium acetate as eluents to obtain the titration product.

[0693] 1H NMR (500 MHz, dmso-d6, 300 K) δ ppm: 10.98 (brs, 2 H), 8.36 (s, 2 H), 7.58 (d, 1 H), 7.3 (dd, 1 H), 7.28 (t, 1 H), 7.16 (m, 2 H), 6.97 (d, 1 H), 6.95 (m, 2 H), 6.95 (d, 1 H), 6.92 (d, 1 H), 6.03 (m, 1 H), 5.41 (s, 1 H), 5.38 / 5.25 (m+m, 2 H), 4.57 (m, 2 H), 4.41 (brs, 2 H), 4.4-3.72 (m, 8 H), 4.33 (brs, 2 H), 3.15 (s, 3 H), 2.31 (s, 3 H). Stage C: 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-23,26,29-trioxa-2,6,15,31,34-pentaazahexacyclo[28.2.2.1~4,7~.1~15,18~.0~8,13~.0~17,22~]hexatriaconta-1(32),4,7(36),8,10,12,17,19,21,30,33-undecaene-3,14-dione

[0694] To a solution of the compound obtained in Stage B (370 mg; 0.61 mmol) in dichloromethane (50 mL), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholin-4-ium tetrafluoroborate (237 mg; 0.7 mmol) is added. The reaction mixture is stirred at room temperature for 1 hour. After washing with water, the organic phase is dried over magnesium sulfate, filtered, and concentrated.

[0695] To a solution of the residue thus obtained in a mixture of dichloromethane (10 mL) and methanol (5 mL), 1,3-Dimethylbarbituric acid (0.159 g; 1 mmol) is added. The reaction mixture is degassed with argon for 10 minutes, and tetrakis-(triphenylphosphine)palladium(0) (0.030 g; 0.02 mmol) is added. The mixture is then stirred for 16 hours at room temperature. After solvent concentration, the residue is purified by RP-18 phase chromatography using acetonitrile, water, and ammonium acetate as eluents to obtain the titer product. High-resolution mass (ESI+) :

[0696] Chemical formula: C 36 H 32 ClN 5 O 6 [M+H]+ calculated 666.2198, [M+H]+ measured 666.2108. Example 37: 10-fluoro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,27,30-trioxa-2,6,15,32,35-pentaazahexacyclo[29.2.2.1~4,7~.1~15,19~.0~8,13~.0~18,23~]heptatriaconta-1(33),4,7(37),8,10,12,18,20,22,31,34-undecaene-3,14-dione

[0697]

[0698] The compound of the titration is obtained according to the process of Example 36 using the acid of Preparation 2b and the amine of Preparation 22b". High-resolution mass (ESI+) :

[0699] Chemical formula: C 37 H 34 FN 5 O 6 [M+H]+ calculated 664.2559, [M+H]+ measured 664.2571. Example 38: 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,27,30-trioxa-2,6,15,32,35-pentaazahexacyclo[29.2.2.1~4,7~.1~15,19~. 0~8,13~. 0~18,23~]heptatriaconta-1(33),4, 7(37),8,10,12,18,20,22,31,34-undecaene-3,14-dione

[0700]

[0701] The compound of the titration is obtained according to the process of Example 36 using the acid of Preparation 1b and the amine of Preparation 22b". High-resolution mass (ESI+) :

[0702] Chemical formula: C37H34ClN5O6 [M+H]+ calculated 680.2276, [M+H]+ measured 680.2280. Example 39: 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,31-dioxa-2,6,15,33,36-pentaazahexacyclo[30,2,2,1~4,7~.1~15,1~.0~8,13~.0~18,23~]octatriaconta-1(34),4,7(38),8,10,12,18,20,22,32,35-undecaene-3,14-dione

[0703]

[0704] The compound of the titration is obtained according to the process of Example 38 using the amine of Preparation 23b". High-resolution mass (ESI+) :

[0705] Chemical formula: C 39 H 38 ClN 5 O 5 [M+H]+ calculated 692.2640, [M+H]+ measured 692.2646. Example 40: 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,30-dioxa-2,6,15,32,35-pentaazahexacyclo[29.2.2.1~4,7~.1~15,19~.0~8,13~.0~18,23~]heptatriaconta-1(33),4,7(37),8,10,12,18,20,22,31,34-undecaene-3,14-dione

[0706]

[0707] The compound of the titration is obtained according to the process of Example 38 using the amine of Preparation 24b". High-resolution mass (ESI+):

[0708] Chemical formula: C38H36ClN5O5 [M+H]+ calculated 678.2484, [M+H]+ measured: 678.2488. Example 41 : 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,29-dioxa-2,6,15,31,34-pentaazahexacyclo[28.2.2.1~4,7~.1~15,19~.0~8,13~.0~18,23~]hexatriaconta-1(32),4,7(36),8,10,12,18,20,22,30,33-undecaene-3,14-dione

[0709]

[0710] The compound of the titration is obtained according to the process of Example 38 using the amine of Preparation 25b". High-resolution mass (ESI+):

[0711] Chemical formula: C37H34ClN5O5 Calculated [M+H]+: 664.2328 Measured [M+H]+: 664.2331 Example 42: 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-21,24,27-trioxa-2,6,15,29,32-pentaazapentacyclo[26.2.2.1~4,7~.1 ~15,19~.0~8,13~]tetratriaconta-1 (30),4, 7(34), 8,1 0,12,28,31-octaene-3,14-dione

[0712]

[0713] The compound of the titration is obtained according to the process of Example 38 using the amine of Preparation 26b". High-resolution mass (ESI+):

[0714] Chemical formula: C 34 H 36 ClN 5 O 6 [M+H]+ calculated: 646.2433 [M+H]+ measured: 646.2427. Example 43: 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-19,22,25-trioxa-1,10,14,17,32-pentaazapentacyclo[25.2.2.2~15,18~.1~9,12~.0~3,8~]tetratriaconta-3,5,7,9(34),11,15,17,32-octaene-2,13-dione

[0715]

[0716] The compound of the titration is obtained according to the process of Example 38 using the amine of Preparation 27b". High-resolution mass (ESI+):

[0717] Chemical formula: C 34 H 36 ClN 5 O 6 [M+H]+ calculated: 646.2433 [M+H]+ measured: 646.2426. Example 44: 10-chloro-2-(4-hydroxyphenyl)-5,6,27-trimethyl-24,30-dioxa-2,6,15,27,32,35-hexaazahexacyclo[29.2.2.1~4,7~.1~15,19~.0~8,13~.0~18,23~] heptatriaconta-1 (33), 4, 7(3 7),8,10,12,18,20,22,31,34-undecaene-3,14-dione

[0718]

[0719] The compound of the titration is obtained according to the process of Example 38 using the amine of Preparation 28b". High-resolution mass (ESI+):

[0720] Chemical formula: C 38 H 37 ClN 6 O 5 [M+H]+ calculated: 693.2593 [M+H]+ measured: 693.2583. PHARMACOLOGICAL STUDY EXAMPLE A: Inbibition of Bcl-2 by the fluorescence polarization technique

[0721] Fluorescence polarization assays were performed in microplates (384 wells). The labeled Bcl-2 protein (histag-Bcl-2, where Bcl-2 corresponds to the UniProtKB® primary serial number: P10415), at a final concentration of 5 × 10⁻⁹ M, was mixed with a fluorescent peptide (Fluorescein-REIGAQLRRMADDLNAQY), at a final concentration of 1.00 × 10⁻⁹ M, in a buffer solution (Hepes 10 mM, NaCl 150 mM, Tween20 0.05%, pH 7.4), in the presence or absence of increasing concentrations of the test compounds. After 2 hours of incubation, the fluorescence polarization was measured.

[0722] The results are expressed as IC50 (concentration of compound that inhibits fluorescence polarization by 50%) and are presented in Table 1 below.

[0723] 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 : Cytotoxicity in vitro.

[0724] Cytotoxicity studies were performed on the RS4;11 leukemia tumor cell line. Cells were distributed into microplates and exposed to the compounds to be tested for 48 hours. Cell viability was then quantified by a colorimetric assay, the Microculture Tetrazolium Assay (Cancer Res., 1987, 47, 939-942).

[0725] The results are expressed as IC50 (concentration of compound that inhibits cell viability by 50%) and are presented in Table 1 below.

[0726] The results show that the compounds of the invention are cytotoxic. Table 1: IC 50 of Bcl-2 inhibition (fluorescence polarization test) and cytotoxicity for RS4 cells;11 IC 50 (µM) Bcl-2 FP IC 50 (M) MTT RS4;11 IC 50 (µM) Bcl-2 FP IC 50 (M) MTT RS4;11 Example 1 0,0067 1,07E-07 Example 22 0,0153 1,18E-08 Example 2 0,0044 1,79E-07 Example 23 0,0143 7,33E-08 Example 3 0,0655 7,49E-07 Example 24 0,0149 1,06E-07 Example 4 0,0023 7,73E-09 Example 25 0,268 8,09E-07 Example 5 0,00205 2,14E-08 Example 26 0,0041 1,66E-09 Example 6 0,0052 2,66E-08 Example 27 0,0098 1,04E-07 Example 7 0,003 4,94E-09 Example 28 0,0288 4,01E-07 Example 8 0,00615 4,93E-08 Example 29 not tested 7,05E-08 Example 9 0,0023 5,24E-09 Example 30 0,0314 >1,88E-06 Example 10 0,299 >3E-07 Example 31 74,55% @1,1 µM 1,33E-06 Example 11 0,157 4,48E-07 Example 34 0,0693 1,24E-06 Example 12 not tested not tested Example 36 41,5% @ 10 µM >6E-07 Example 13 0,0332 2,39E-07 Example 37 0,0102 4,96E-08 Example 14 0,0147 1,46E-08 Example 38 0,00385 2,31E-08 Example 15 0,0037 1,16E-08 Example 39 0,0768 1,49E-07 Example 16 0,00555 5,33E-08 Example 40 0,0064 2,99E-08 Example 17 0,0123 6,28E-08 Example 41 0,0467 1,97E-07 Example 18 0,00365 8,36E-09 Example 42 39,2% @ 10 µM >6E-07 Example 19 0,0055 1,03E-08 Example 43 34,8% @ 10 µM >1,88E-06 Example 20 0,0123 8,12E-08 Example 44 0,00497 3,54E-08 Example 21 0,0148 1,31E-07 EXAMPLE C : Quantification of the cleaved form of caspase 3 in vivo.

[0727] The ability of the compounds of the invention to activate caspase 3 is evaluated in an RS4 leukemic cell xenograft model;11.

[0728] 1.10< 7< RS4 cells; 11 are subcutaneously grafted into immunodeficient mice (SCID strain). 25 to 30 days post-grafting, the animals are orally treated with the different compounds. After 2 hours of treatment, tumor masses are recovered, lysed, and the cleaved (activated) form of caspase 3 is quantified in the tumor lysates.

[0729] This quantification is performed using the "Meso Scale Discovery (MSD) ELISA platform" assay, which specifically measures the cleaved form of caspase 3. It is expressed as an activation factor corresponding to the ratio of the amount of caspase 3 cleaved in treated mice divided by the amount of caspase 3 cleaved in control mice.

[0730] The results show that the compounds of the invention are capable of inducing apoptosis in RS4 tumor cells; 11 in vivo. Table 2: Caspase activation factors (caspase 3 cleaved MSD assay in tumors of treated mice versus control mice) in vivo after oral treatment (doses specified in parentheses) Tested compound Formulation Dose (mg / kg) Activation factor ± SEM (versus control) Example 6 PEG / EtOH / Water 12,5 6,8 ± 4,2 Example 6 PEG / EtOH / Water 25 32,3 ± 9,1 Example 16 PEG / EtOH / Water 25 31,7 ± 2,9 Example 16 PEG / EtOH / Water 50 75,1 ± 13,2 Example 18 PEG / EtOH / Phosal 6,25 7,8 ± 2,5 Example 18 PEG / EtOH / Phosal 12,5 31,7 ± 6,0 Example 29 PEG / EtOH / Phosal 25 13,3 ± 6,3 Example 29 PEG / EtOH / Phosal 50 54,4 ± 9,7 EXAMPLE D: Pharmaceutical composition: Tablets

[0731] 1000 tablets containing 5 mg of a compound chosen from examples 1 to 44 5 g Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g

Claims

1. Compound of a formula (I): wherein: ▪ A2 and A2 each represent a methyl group, ▪ G represents a -NR7- group, a 1,2,3,4-tetrahydroisoquinolinylene group optionally substituted by a T group, a 2,3-dihydro-1H-isoindolylene group optionally substituted by a T group, or a piperidinylene group, ▪ T represents a hydrogen atom, a linear or branched (C1-C6) alkyl optionally substituted by one to three halogen atoms, a (C1-C4)-alkyl-NR1R2 group, or a (C1-C4)-OR6 alkyl group, ▪ X represents a (C2-C8) alkylene group, 1 to 3 chain members of which may be replaced by a heteroatom selected from oxygen, sulphur and N-R5, or by an arylene or heteroarylene group, ▪ Y represents a -CH2- or -CO- group, ▪ R1 and R2 independently of each another represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, or R2 and R2, together with the nitrogen atom carrying them, form a heterocycloalkyl, ▪ R3 and R4 are such that: - one of them represents a phenyl group with the following formula: wherein W represents a hydroxy group or a phosphate group selected from - OPO (OM) (OM') -OPO (OM) (O-M1+) , -OPO (O-M1+) (O-M2+) , -OPO (O-) (O-) M32+, -OPO (OM) (O[CH2CH2O]nCH3), and -OPO(O-M1+) (O[CH2CH2O]nCH3), wherein M and M' represent, independently of each other, a hydrogen atom, a linear or branched (C1-C6) alkyl group, a linear or branched (C2-C6) alkenyl group, a linear or branched (C2-C6) alkynyl group, a cycloalkyl or a heterocycloalkyl, both composed of 5 or 6 ring members, whereas M1+ and M2+ independently of one another represent a pharmaceutically acceptable monovalent cation, M32+ represents a pharmaceutically acceptable divalent cation and n is an integer of between 1 and 5, - while the other represents an aryl, heteroaryl, heterocycloalkyl, cycloalkyl or linear or branched (C1-C6) alkyl group, it being understood that one or more carbon atoms of the foregoing groups, or of any substituents thereof, may be deuterated, ▪ R5 represents a hydrogen atom or a linear or branched (C1-C6) alkyl group, ▪ R6 and R7 independently of each another represent a hydrogen atom or a linear or branched (C1-C6) alkyl group, ▪ Ra, Rc and Rd each represent a hydrogen atom and Rb represents a hydrogen or halogen atom it being understood that: - the term "aryl" refers to a phenyl, naphthyl, biphenyl or indenyl group, - the term "heteroaryl" refers to any mono- or bi-cyclic group composed of 5 to 10 ring members, having at least one aromatic part, and containing from 1 to 4 heteroatoms chosen from oxygen, sulphur, nitrogen and quaternary nitrogen, - the term "cycloalkyl" refers to any non-aromatic, mono- or bi-cyclic carbocyclic group containing 3 to 10 ring members, - the term "heterocycloalkyl" refers to any non-aromatic mono- or bi-cyclic, fused or spiro, composed of 3 to 10 ring members and containing 1 to 3 heteroatoms chosen from oxygen, sulphur, SO, SO2 or nitrogen, - the terms arylene, heteroarylene, 1,2,3,4-tetrahydroisoquinolinylene, 2,3-dihydro-1H-isoindolylene or piperidinylene refer to a divalent aryl, heteroaryl, 1,2,3,4-tetrahydroisoquinoline or piperidine group, the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups thus defined and the alkyl, alkenyl, alkynyl and alkoxy groups, which may be substituted by 1 to 3 groups selected from: a linear or branched (C1-C6) alkyl optionally substituted by a hydroxy, morpholinyl, 3-3-difluoropiperidinyl or 3-3-difluoropyrrolidinyl group; spiro (C3-C6); linear or branched (C1-C6) alkoxy optionally substituted by a morpholinyl group; (C1-C6) alkyl-S-; hydroxy; oxo; N-oxide; nitro; cyano; -COOR'; - OCOR'; NR'R"; linear or branched (C1-C6) polyhaloalkyl; trifluoromethoxy; (C1-C6) alkylsulfonyl; halogen; aryl optionally substituted by one or more halogen atoms; heteroaryl; aryloxy; arylthio; cycloalkyl; heterocycloalkyl optionally substituted by one or more halogen atoms or linear or branched (C1-C6) alkyl groups; it being understood that R' and R" represent, independently of each other, a hydrogen atom or a linear or branched (C1-C6) alkyl group optionally substituted by a methoxy group, its enantiomers, diastereoisomers or its addition salts with a pharmaceutically acceptable acid or base.

2. Compound of the formula (I) according to claim 1 wherein Y represents a -CO- group.

3. Compound of the formula (I) according to claim 1 or 2 wherein G represents a group chosen among the following groups: where T represents a methyl group or a (4-morpholinyl)methyl group.

4. Compound of the formula (I) according to any of claims 1 to 3 wherein X represents a group chosen among the following groups:

5. Compound of the formula (I) according to any of claims 1 to 4 wherein one of the groups R3 or R4 represent a 4-hydroxyphenyl group while the other represents a group chosen from the following list: - a phenyl group optionally substituted by a cyano group, - a pyrazolyl group - an 1-methyl-1N-pyrazolyl group, - a 1-(tetrahydrofuran-3-yl)-1H-pyrazolyl group, - a 5-methyl-2-cyano-1H-pyrrolyl group, - a 1-methyl-2-cyano-1H-pyrrolyl group, - a 1,2-dimethyl-1H-pyrrolyl group, - a 1,5-dimethyl-2-cyano-1H-pyrrolyl group, - a pyrimidinyl group, - an ethyl group, - a pyridinium group.

6. Compound of the formula (I) according to claim 5 wherein R4 represents a 4-hydroxyphenyl group.

7. Compound of the formula (I) according to claim 5 wherein R3 represents a 4-hydroxyphenyl group.

8. Compound of the formula (I) according to claim 7 wherein R3 represents a 4-hydroxyphenyl group and G represents a piperidinylene.

9. Compound of the formula (I) according to claim 1 chosen among the following group: - 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-20,23-dioxa-1,10,14-triazahexacyclo[26.

3. 1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetratriaconta-3,5,7,9(34),11, 15(33),16,18,24,26,28-undecaene-17-carbonitrile, - 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-4,16,17,23,24,25-hexahydro-1H,14H-15,18-methano-6,9-(metheno) dibenzo [b, h] pyrazolo [4, 3-p] [1,6,11,15]oxatriazacycloicosine-5,14(8H)-dione, - 6-chloro-14-(4-hydroxyphenyl)-10,11-dimethyl-2,13-dioxo-23-oxa-1,10,14-triazahexacyclo[26.3.1.1~9,12~.1~15,19~.0~3,8~.0~24,29~]tetr atriaconta-3,5,7,9(34),11, 15(33),16,18,24,26,28-undecaene-17-carbonitrile, - 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-5, 14-dioxo-4,5,8, 16,17,23,24,25- octahydro- 1H, 14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrrolo[3,2-p] [1,6,11,15]oxatriazacycloicosine-2-carbonitrile, - 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-5, 14-dioxo-1,4,5,8,16, 17,23,24- octahydro-14H-15, 18-methano-6,9-(metheno)dibenzo[1,r]pyrrolo[2,3-d] [1,6,10,15]oxatriazacyclononadecine-2-carbonitrile, - 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4, 16,21,22,23-hexahydro-14H- 15,21-methano-6,9-(metheno)dibenzo[j,o]pyrazolo[3,4-b] [1,4,8,13]oxatriazacyclononadecine-5,14(8H)-dione, - (16S or R)-11-chloro-4-(4-hydroxyphenyl)-1,7,8,16-tetramethyl-5, 14-dioxo-4,5,8,16, 17,23,24,25-octahydro-1H, 14H-15,18-methano-6,9-(metheno)dibenzo[b,h]pyrrolo[3,2-p][1,6, 11,15]oxatriazacycloicosine-2-carbonitrile, - 4-[16-chloro-3-hydroxy-19,20-dimethyl-13,22-dioxo-6,7,8,9,10, 11,19,22-octahydro-13H,23H-8,12-methano-21,18-(metheno)dibenzo[b,j] [1,4,8,13]oxatriazacyclononadecin-23-yl]-1,5-dimethyl-1H-pyrrole-2-carbonitrile, - 10-fluoro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,27,30-trioxa-2, 6, 15, 32, 35-pentaazahexacyclo[29.2.2.1~4,7~.1~15,19~.0~8,13~.0~18,23~]he ptatriaconta-1(33),4,7(37),8, 10,12,18,20,22,31,34-undecaene-3,14-dione, - 10-chloro-2-(4-hydroxyphenyl)-5,6-dimethyl-24,30-dioxa-2,6,15,32,35-pentaazahexacyclo[29.2.2.1-4,7-.1-15,19-.0-8, 13~.0~18,23~]heptatriaconta-1(33),4,7(37),8,10,12,18,20,22,31,34-undecaene-3,14-dione, - 10-chloro-2-(4-hydroxyphenyl)-5,6,27-trimethyl-24,30-dioxa-2,6,15,27,32,35-hexaazahexacyclo[29.2.2.1~4,7~.1~15,19~.0~8,13~.0~18,23~]hep tatriaconta-1(33),4,7(37),8,10, 12,18,20,22,31,34-undecaene-3,14-dione, - 11-chloro-4-(4-hydroxyphenyl)-1,7,8-trimethyl-1,4, 16,17,23,24-hexahydro-14H-15,18-methano-6,9-(metheno)dibenzo[1,r]pyrazolo[3,4-d] [1,6,10,15]oxatriazacyclononadecine-5,14(8H)-dione.

10. A method for preparing a compound of a formula (I) according to claim 1 characterised in that the source material is the compound of a formula (II): wherein A1, A2, Ra, Rb, Rc, Rd, Y and G have the same meaning as in formula (I) defined in claim 1, and Alk represents a linear or branched (C1-C6) alkyl group, the compound of the formula (II) wherein which the ester function -OAlk is hydrolysed to give the carboxylic acid or the corresponding carboxylate, which may be converted into the corresponding acyl chloride or anhydride, before being coupled with an amine NHR3AR4, wherein R4 has the same meaning as in formula (I), and R3A represents: - a R3 group as defined in the formula (I) - or a R3-O-Alk'-Z, R3-Alk'-Z or R3-Z group in which Alk' represents a linear or branched (C1-C6) alkyl group, and Z represents a halogen atom or an -OH group, to form the compound of a formula (III): wherein A1, A2, Ra, Rb, Rc, Rd, R4, Y and G have the same meaning as in formula (I), which is subjected to a deprotection reaction of the alcohol function, followed either by an intramolecular nucleophilic substitution, or by a Mitsunobu reaction, or else by an aromatic nucleophilic substitution, to give the compound of the formula (I), which compound of the formula (I) can be purified by a conventional separation technique, which can be converted into its addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated by a conventional separation technique, it being understood that, at any time deemed appropriate during the process previously described, the hydroxy and amino groups of the synthesis reagents or intermediates can be protected and then deprotected for the purposes of the synthesis.

11. The method for preparing a compound of a formula (I) according to claim 1 characterised in that the source material is the compound of a formula (IV): wherein R3, R4 and X have the same meaning as in the formula (I) and GA represents a group chosen from the following list: the compound of the formula (IV) that is then coupled to a compound of a formula (V) wherein A1, A2, Ra, Rb, Rc and Rd, have the same meaning as in the formula (I), to give the compound of the formula (VI), wherein A1, A2, Ra, Rb, Rc, Rd, R3, R4 and X have the same meaning as in the formula (I), which is subjected to a deprotection reaction followed by intramolecular coupling to yield the compound of the formula (I), the compound of the formula (I) which can be purified using a conventional separation technique, which can be converted into its addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated using a conventional separation technique, it being understood that, at any time deemed appropriate during the process described above, the hydroxy and amino groups of the synthesis reagents or intermediates can be protected and then deprotected for the purposes of the synthesis.

12. Pharmaceutical composition containing a compound of formula (I) according to any one of claims 1 to 9, or one of its addition salts with a pharmaceutically acceptable acid or base, in combination with one or more pharmaceutically acceptable excipients.

13. The pharmaceutical composition according to claim 12 for use as a pro-apoptotic agent.

14. The pharmaceutical composition according to claim 12 for use in the treatment of cancers, autoimmune diseases and diseases of the immune system.

15. The pharmaceutical composition according to claim 14 wherein the cancer is selected from the following list: bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukaemia, colorectal cancer, oesophageal cancer, liver cancer, lymphoblastic leukaemia, non-Hodgkin's lymphoma, melanoma, haematological malignancy, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small-cell lung cancer.

16. Use of a compound of the formula (I) according to any of claims 1 to 9 for the manufacture a medicament useful as a pro-apoptotic agent.

17. Use of a compound of the formula (I) according to any of claims 1 to 9 for the manufacture a medicament for the treatment of cancers, immune and autoimmune diseases.

18. Use of a compound of the formula (I) according to claim 17 wherein the cancer is selected from the following list: bladder cancer, brain cancer, breast cancer, uterine cancer, chronic lymphocytic leukaemia, colorectal cancer, oesophageal cancer, liver cancer, lymphoblastic leukaemia, non-Hodgkin's lymphoma, melanoma, haematological malignancy, myeloma, ovarian cancer, non-small cell lung cancer, prostate cancer and small-cell lung cancer.

19. Combination of a compound of the formula (I) according to any of claims 1 to 9 with an anticancer agent chosen from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, kinase inhibitors or antibodies.

20. Pharmaceutical composition containing a combination according to claim 19 in combination with one or more pharmaceutically acceptable excipients.

21. A combination according to claim 19 for use in the treatment of cancer.

22. Use of a combination according to claim 19 for the manufacture a medicament useful in the treatment of cancer.

23. A compound of the formula (I) according to any of claims 1 to 9 for use in combination with radiotherapy in the treatment of cancer.