indolizine compounds, their preparation process, pharmaceutical compositions, their uses and hydroch

专利摘要:
INDOLIZINE COMPOUNDS, A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. The present invention relates to compounds of formula (I): (I) where Ra, Rb, Rc, Rd, R1, R2, R3, R4, R5, X, Y and Het are as defined in the specification. Medicines.
公开号:BR112014018165B1
申请号:R112014018165-9
申请日:2013-01-23
公开日:2020-11-17
发明作者:Jérôme-Benoít Starck；Jean-Michel Henlin；Miklos Nyerges；Guillaume de Nanteuil；Thierry Le Diguarher；Patrick Casara；James Edward Paul Davidson；James Brooke Murray；Christopher John Graham；I-Jen Chen；Olivier Geneste；John Hickman；Stéphane Depil；Arnaud Le Tiran
申请人:Vernalis (R&D) Ltd；Les Laboratoires Servier；
IPC主号:

专利说明:

[001] The present invention relates to the new compounds of dolizine, a process for its preparation and the pharmaceutical compositions containing them.
[002] The compounds of the present invention are new and have very valuable pharmacological characteristics in the field of apoptosis and cancerology.
[003] Apoptosis, or programmed cell death, is a physiological process that is crucial for embryonic development and the maintenance of tissue homeostasis.
[004] The death of the apoptotic cell involves morphological changes, such as a hundred nucleus census, DNA fragmentation, and also biochemical phenomena, such as the activation of caspases that cause damage to the key structural components of the cell, as well inducing their separation 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 Re-view Cancer, 2002, 2, 647-656).
[005] The dysregulation of apoptosis is involved in certain pathologies. Increased apoptosis is associated with neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and ischemia. Conversely, deficiencies in the effect of apoptosis play a significant role in the development of cancers and their chemoresistance, in autoimmune diseases, inflammatory diseases and viral infections. Consequently, the absence of apoptosis is one of the phenotypic characteristics of cancer (Hanahan D. et al., Cell 2000, 100, 57-70).
[006] The anti-apoptotic proteins of the Bcl-2 family are associated with several pathologies. The involvement of proteins in the Bcl-2 family is described in many types of cancer, such as colon cancer, breast cancer, small cell lung cancer, non-small cell lung cancer, cancer of the bladder, ovarian cancer, prostate cancer, chronic lymphoid leukemia, follicular lymphoma, myeloma, prostate cancer, etc. The overexpression of anti-apoptotic proteins of the Bcl-2 family is involved in tumorigenesis, resistance to chemotherapy and the clinical prognosis of patients affected by cancer. There is, therefore, a therapeutic need for compounds that inhibit the anti-poptic activity of proteins in the Bcl-2 family.
[007] In addition to being new, the compounds of the present invention have pro-apoptotic properties, making it possible to use them in pathologies that involve a defect in apoptosis, such as, for example, in the treatment of cancer and immune and autoimmune diseases.
[008] The present invention relates more particularly to the compounds of formula (I):
where: ♦ X and Y represent a carbon atom or a nitrogen atom, it being understood that they cannot simultaneously represent two carbon atoms or two nitrogen atoms, H5 '1 ♦ the Het portion of the group
represents an optionally substituted ring, aromatic or non-aromatic, composed of 5, 6 or 7 members in the ring, which may contain, in addition to the nitrogen represented by X or Y, from one to 3 heteroatoms independently selected from oxygen, sulfur and nitrogen, being understood that the nitrogen in question can be substituted by a group representing a hydrogen atom, a linear or branched (Ci-Cβ) alkyl group or a -C (O) -O-Alk group, where Alk is a linear or branched (C-Ce) alkyl group, ♦ Ri and R2, independently of each other, represent a hydrogen atom or a linear or branched (C-Ce) alkyl group, or Ri and R2 form with the nitrogen atom that carries a heterocycloalkyl composed of 4 to 7 members in the ring, which may contain, in addition to the nitrogen atom, another hetero atom selected from oxygen, sulfur, SO2 and NR, where R represents a hydrogen atom, a group (Ci -Cθ) straight or branched alkyl, a group (Ci- Cejalkylsulfo nyl, a linear or branched (C1-C6) polyhaloalkyl group or a -C (O) -O-Alk group, where Alk is a linear or branched (C1-Cβ) alkyl group, 4 R3 represents a group ( C1-Cβ) straight or branched alkyl, an (C2-C6) alkenyl group, a (C2-C6) alkynyl group, a cycloalkyl group, a (C4-Cio) cycloalkyl- (Ci-C6) alkyl group, where the alkyl group can be linear or branched, an aryl group or a heteroaryl group, 4 R4 represents an aryl, heteroaryl, cycloalkyl or (C1-Cβ) linear or branched alkyl group, ♦ R5 represents a hydrogen atom or a ha- logene, ♦ Ra, Rb, Rc and Rd, independently of each other, represent a hydrogen atom, a halogen atom, a group (linear or branched Cejalkyl), a linear or branched (Ci-Ce) alkoxy group, a hydroxy group, a linear or branched (Ci-Ce) polyhaloalkyl group, or a trifluoromethoxy group, or the substituents of one of the pairs (Ra, Rb), (Rb, Rc) or (Rc, Rd) form with the atoms carbon that carries them m a ring composed of 5 to 7 members in the ring, which may contain from 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, it being understood that the nitrogen in question can be replaced by a group representing a hydrogen atom, a straight or branched (C1-Cβ) alkyl group or a -C (O) -O-Alk group, where Alk is a straight or branched (C1-Cβ) alkyl group, also being understood that one or more carbon atoms of ring defined above can be deuterated, it being understood that: - "aryl" means a phenyl, naphthyl, biphenyl or indenyl group, - "heteroaryl" means any mono- or bicyclic group composed of 5 to 10 members in the ring, having at least an aromatic portion and containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, - "cycloalkyl" means any non-aromatic mono- or bicyclic carbocyclic group, containing 4 to 10 members in the ring, being possible for the groups alkyl, aryl, heteroaryl, cy-cloalkyl ila and heterocycloalkyl thus defined are replaced by 1 to 3 groups selected from optionally substituted linear or branched (Ci-Ce) alkyl, (Cs-Cβjespiro, (Ci-Ce) linear or branched alkoxy, (Ci-Cβjalquila-S -, hydroxy, oxo (or / V-oxide, where appropriate), nitro, cyano, -COOR ', NR'R ", (linear or branched Ci-CeJpoli-haloalkyl, trifluoromethoxy, (Ci-C6) alkylsulfonyl or halogen , being understood that R 'and R ", independently of each other, represent a hydrogen atom or a linear or branched (Ci-Cβ) alkyl group, Hal) being possible for the Het portion of the group
defined above to be replaced by a group selected from (C-Ce) straight or branched alkyl, hydroxy, NRi'Ri "and halogen, it being understood that Ri 'and Ri" have the same definitions as the groups R' and R "mentioned above, their enantiomers and diastereoisomers, and their addition salts with a pharmaceutically acceptable acid or base.
[009] Among the pharmaceutically acceptable acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid can be mentioned, without implying any limitation. malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid etc.
[0010] Among the pharmaceutically acceptable bases, there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, ferc-butylamine etc.
[0011] The group:

[0012] advantageously represents one of the following groups: 5,6,7,8-tetrahydroindolizine optionally substituted by a hydroxy, indolizine, 1,2,3,4-tetrahydropyrrolo [1,2-a] pyrazine, 3 , Tert-butyl 4-dihydropyrrolo [1,2-a] pyrazine-2 (1H) -carboxylate, 3,4-dihydro-1 H-pyrrolo [2,1 -c] [1,4] oxazine, 2,3-dihydro-1H-pyrrolizine optionally substituted by a hydroxy, 6,7,8,9-tetrahydro-5H-pyrrolo [1,2-a] azepine or pyrrole [1,2-a ] pyrazine.
[0013] In the preferred compounds of the invention, Ri and R2 each represent an alkyl group optionally substituted by a methoxy, or Ri and R2 form with the nitrogen atom that carries them a heterocycloalkyl selected from the following groups: morpholine optionally substituted by one or more (Ci-Cβ) linear or branched alkyls, oxidomorpholine, thiomorpholine 1,1-dioxide, 1,4-oxazepan, 3-methoxypyrrolidine, 3,3-difluorpyrrolidine, 3-methoxyzetidine, 3-fluorazetidine, oxopiperazine or piperazine, the last two groups being replaced by a linear or branched (C1-Cβ) alkyl group, a linear or branched (C1-CJPoli-haloalkyl) group or a methylsulfonyl group.
[0014] Preferably, Ra and Rd each represent a hydrogen atom and (Rb.Rc) form with the carbon atoms that carry them a 1,3-dioxolane group, where one of the carbon atoms is optionally deuterated, a 1,4-dioxane group, a 1,4-dioxepan group, or Ra, Rc and Rd each represent a hydrogen atom and Rb represents a halogen, a methyl, a methoxy, an ethoxy, a trifluoromethyl or a trifluoromethoxy.
The preferred group R4 is a 4-hydroxyphenyl, 3-fluoro-4-hydroxyphenyl or 5-hydroxypyrimidine.
[0016] In preferred compounds, R3 represents a group selected from phenyl, indole, indoline, 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-benzoxazine, indane , 1H-indazole, 1H-pyrrolo [2,3- b] pyridine, pyrimidine, cyclobutylmethyl, cyclopropylmethyl, 1H-pyrazole, pyridine, pyridazine, groups optionally having one or more substituents selected from halogen, (Ci-Cβ) straight or branched alkyl, cyano and (C1-Ce) straight or branched alkoxy.
[0017] Preferred compounds of the invention are listed below: A / - (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 ( 1 / - /) - isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} - / V-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide, 3- {5-chloro -2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1/7) - isoquinolinyl) carbonyl] phenyl} - / V- (4-hydroxyphenyl) - / V - (1-methyl-1 / - / - indol-5-yl) - 5,6,7,8-tetrahydro-1-indolizine carboxamide, / V- (4-h id roxifenyl) - / V- (1-methyl-1 H-indazol-5-yl) -3- {2,2-dideuterium-6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 ( 1H) - isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide, / V- (4-h id roxifenyl) - / V - (1-methyl-1 H- ndazol-5-i) -3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1 / - /) - yl] carbonyl} -1,3-benzodioxol-5-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide, A / - (4-hydroxyphenyl) -3- {7 - [(((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -2,3-dihydro-1,4-benzodioxin-6-yl } - / V- feni 1-5,6,7,8-tetrahydro-1-indolizine carboxamide, A / - (4-hydroxyphenyl) - / V- (1-methyl-1H-indol-5-yl) -3- {6- [(((3S) -3 - [(4-methyl-1-piperazinyl) methyl] -3,4-dihydro-2 (1 H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -1 -indolizine carboxamide, / V- [4- (hydroxy) phenyl] - / V- (1-methyl-1H-indol-5-yl) -3- {6 - [((3S) -3- (4 - morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide, A / - (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3- benzodioxol-5-yl} -N-phenyl-1-indolizine carboxamide, 3- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H ) - isoquinolinyl) carbonyl] phenyl} - / V- (4-h id roxiphenyl) -N- (1-methyl-1 H-indol-5-yl) -1 - indolizine carboxamide, 6- {5-chloro- 2 - [(((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) - isoquinolinyl) carbonyl] phenyl} - / V- (3-fluor-4-methylphenyl) - / V- (4-hydroxyphenyl) -3,4-dihydro-1 H -pyrrolo [2,1 -c] [1,4] oxazine-8-carboxamide, 3- (5-chloro-2 - {[ (3S) -3- (morfolin-4-ylmet il) -3,4-dihydroisoquinolin-2 (1 / - /) - yl] carbonyl} phenyl) -A / - (4-hydroxyphenyl) -Δ / - (1-methyl-1 H-pyrazole-4- il) -5,6,7,8-tetrahydroindolizine-1-carboxamide, A / - (3-fluoro-4-methylphenyl) - / V- (4-hydroxyphenyl) -3- {6 - [((3S ) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -5,6,7,8-tetrahydro -1-indolizine carboxamide, / V- [4- (hydroxy) phenyl] -A / - (1-methyl-2,3-dihydro-1 / - / - indol-5-yl) -3- {6 - [(((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -5,6,7, 8-tetrahydro-1-indolizine carboxamide, 3- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) - isoquinolinyl) carbonyl ] phenyl} -A / - (4-hydroxyphenyl) -A / - (1-methyl-2,3-dihydro-1 H-indol-5-yl) -5,6,7,8-tetrahydro -1-indolizine carboxamide, / V- (4-hydroxyphenyl) - / V- (1-methyl-1H-indol-5-yl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1 H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -1-indolizine carboxamide, 3- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) - isoqu inolinyl) carbonyl] phenyl} - / V- (4-hydroxyphenyl) -A / - (1-methyl-2,3-dihydro-1 H- indol-5-i) -1 -indolizine carboxamide, 6- { 5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) - isoquinolinyl) carbonyl] phenyl} - / V- (4-hydroxyphenyl) - / V-phenyl-3,4-dihydro-1 H-pyrrolo [2,1 -c] [1,4] oxazine-8-carboxamide, A / - (3-fluorophenyl) -A / - (4-hydroxyphenyl ) -3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} -1,3-benzodioxol-5-yl ) - 5,6,7,8-tetrahydroindolizine-1-carboxamide, its enantiomers and diastereoisomers, and their addition salts with a pharmaceutically acceptable acid or base.
[0018] The invention also relates to a process for the preparation of the compounds of formula (I), a process which is characterized by the fact that the compound of formula (II) is used as starting material:

[0019] where Ra, Rb, Rc and Rd are as defined for the formula (D.
[0020] compound of the formula (II) which is subjected to a Heck reaction, in an aqueous or organic medium, in the presence of a palladium catalyst, a base, a phosphine and the compound of the formula (III):

[0021] in which groups X, Y and Het are as defined for formula (I),
[0022] to obtain the compound of the formula (IV):

[0023] where Ra, Rb, Rc, Rd, X, Y and Het are as defined for formula (I),
[0024] the aldehyde function of whose compound of the formula (IV) is oxidized to the carboxylic acid to form the compound of the formula (V):

[0025] where Ra, Rb, Rc, Rd, X, Y and Het are as defined for formula (I),
[0026] whose compound of formula (V) is then subjected to peptide coupling with a compound of formula (VI):

[0027] where Ri, R2 and Rs are as defined for formula (I),
[0028] to produce the compound of the formula (VII):

[0029] where Ra, Rb, Rc, Rd, KI. ^ 2, for formula (I),
[0030] the ester function of which the compound of formula (VII) is hydrolyzed to produce the hot corresponding carboxylic acid or carboxylate, which can be converted into an acid derivative, such as acyl chloride or the hot corresponding anhydride , before being coupled with an NHR3R4 amine, where R3 and R4 have the same meanings as for formula (I), to produce the compound of formula (I),
[0031] whose compound of formula (I) can be purified according to a conventional separation technique, which is converted, if desired, to its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers - rosters according to a conventional separation technique,
[0032] it being understood that at any time considered appropriate during the course of the process described above, some groups (hydroxy, amino ...) of the starting reagents or of the synthesis intermediates can be protected and subsequently unprotected, as required by the synthesis,
[0033] More particularly, when one of the groups R3 or R4 of the amine NHR3R4 is replaced by a hydroxy function, it can be subjected in advance to a protective reaction, before coupling with the carboxylic acid formed from the compound of the formula ( VII), or ∞m a correspondingly warm acid derivative thereof, the resulting protected compound of formula (I) subsequently undergoes a deprotection reaction and is then optionally converted to one of its addition salts with a pharmaceutically acceptable acid or base.
[0034] The compounds of formulas (II), (III), (VI) and the amine NHR3R4 are commercially available or can be obtained by the person skilled in the art using conventional chemical reactions, described in the literature.
[0035] The pharmacological study of the compounds of the invention showed that they have pro-apoptotic properties. The ability to reactivate the apoptotic process in cancer cells is of great therapeutic interest in the treatment of cancers and immune and autoimmune diseases.
[0036] More especially, the compounds according to the invention will be useful in the treatment of cancers resistant to chemo or radio, and in malignant hemopathies and small cell lung cancer.
[0037] Among the cancer treatments considered, can be mentioned, without implying any limitation, cancers of the bladder, brain, breast and uterus, chronic lymphoid leukemias, colon, esophagus and liver cancer, lymphoblastic leukemias, lymphomas follicular diseases, melanomas, malignant hemopathies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer.
[0038] The present invention also relates to pharmaceutical compositions that comprise at least one compound of formula (I) in combination with one or more pharmaceutically acceptable excipients.
[0039] Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or pills can be mentioned , sublingual tablets, sachets, packages, capsules, glossettes, lozenges, suppositories, creams, ointments, skin gels, and drinkable or injectable ampoules.
[0040] The dosage varies according to the patient's sex, age and weight, the route of administration, the nature of the therapeutic indication, or any associated treatments, and ranges from 0.01 mg to 1 g for 24 hours , in one or more administrations.
[0041] In addition, the present invention also relates to the association of a compound of the formula (I) with an anticancer agent selected from genotoxic agents, mitotic poisons, antimetabolites, proteasome inhibitors, inhibitors of kinase and antibodies, and also to the pharmaceutical compositions that comprise this type of association and its use in the manufacture of medicines for use in the treatment of cancer.
[0042] The compounds of the invention can also be used in combination with radiation therapy in the treatment of cancer.
[0043] The following Preparations and Examples illustrate the invention, but do not limit it in any way. PREPARATION 1: 6- [1- (METOXICARBONIL) -5,6,7,8-TETRA- HYDRO-3-INDOLIZINYL] -1,3-BENZODIOXOL-5-CARBOXYLIC ACID STEP A: 1-FORMYL-2-PIPERIDINACARBOXYLIC ACID
[0044] To a solution of 40 g of a racemic mixture of 2-piperidinecarboxylic acid (0.310 mmol) in 300 ml of formic acid, at 0 ° C, 200 ml (2.15 mmoles) of acetic anhydride. The whole is then stirred at room temperature overnight. The reaction mixture is then cooled to 0 ° C, hydrolyzed by adding 250 ml of water and stirred for half an hour at 0 ° C, before being concentrated to dryness. The oil thus obtained is absorbed in 200 ml of methanol and then concentrated to dryness. The title product is obtained in the form of an oil, with a yield of 98%. It is used directly, without further purification, for the next step. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 13.0 (m, 1H OH); 8.0-8.05 (2s, 1H aldehyde); 4.9-4.5 (2d, 1H α of N and COOH); 4.1-2.6 (m, 2H for N); 2.2-1.2 (m, 6H piperidine). IV: v: -OH: 2000-3000 cm-1 acid; v:> C = O 1703 cm-1 wide band. STEP B: 5,6,7,8-TETRA-HYDRO-1-INDOLIZINACARBOXYLATE
[0045] To a solution of 10 g of carboxylic acid obtained in Step A (63.6 mmoles) in 65 ml_ of dichloroethane, 13.4 g of tosyl chloride (70.4 mmoles) are added in sequence, 11 , 5 ml of methyl 2-chloroacrylate (113.5 mmoles) and then, dropwise, 17.8 ml of A /, A /, / V-triethylamine (127.2 mmoles). The reaction mixture is then refluxed for 1.5 hours. It is then brought to room temperature, then 5 ml of methyl 2-chloroacrylate (48.9 mmoles) and, dropwise, 9 ml of N, / V, N-triethylamine (64 mmoles) are added. The whole is heated to reflux overnight.
[0046] The reaction mixture is subsequently diluted with methylene chloride, washed in sequence with a 1 N HCI solution, a saturated solution of NaHCOs and then a saturated solution of NaCI until a neutral pH is obtained. The organic phase is then dried over MgSO4, filtered, concentrated to dryness, and purified by chromatography on silica gel (fr heptane / AcOEt gradient). The title product is obtained in the form of an oil. 1H NMR: δ (400 MHz; CDCh; 26.9 ° C): 6.55-6.40 (d, 2H, tetrahydroindolizine); 3.91 (t, 3H methyl ester); 3.78 (s, 3H tetrahydroindolizine); 3.08 (t, 2H, tetrahydroindolizine); 1.95-1.85 (m, 4H, tetrahydroindolizine) IV: v:> C = O 1692 cm-1ester STEP C: a-iβ-FORMIL-ta-BENZODIOXOL-S-ILJ-S.βJ.β -TETRA- METHYL HYDRO-1-INDOLIZINACARBOXYLATE
[0047] To a solution of 6.4 g of the ester obtained in Step B (35.7 mmol) in 12 mL of / V, / V-dimethylacetamide is added, in sequence, 12.3 g of 6-bromo-1 , 3-benzodioxol-5-carbaldehyde (53.6 mmoles) and 7 g of potassium acetate (71.4 mmoles), and the whole is then stirred, under argon, for 20 minutes. 1.3 g of palladium catalyst PdCl2 (PPh3) 2 (1.8 mmol) is then added. The reaction mixture is subsequently heated to 130 ° C for one hour, before 139 pL of H2O is added to it. The heating is kept at the same temperature, overnight. The mixture is allowed to return to room temperature and is then diluted with AcOEt. The charcoal is added (2 g per g of product) and the whole is stirred at room temperature for one hour and then filtered. The organic phase is then washed with water, dried over magnesium sulfate and concentrated to dryness. The crude product thus obtained is purified on silica gel (heptane / AcOEt gradient). The title product is obtained in the form of an oil. 1H NMR: δ: (400 MHz; dmso-d6; 79.9 ° C): 9.65 (s, 1H, H aldehyde); 7.3-7.15 (2s, 2H, aromatic H); 6.45 (s, 1H tetrahydroindolizine); 6.20 (s, 2H methylenedioxy); 3.70 (s, 3H methyl ester); 3.5-4.0 (m, 2H tetrahydroindolizine); 3.05 (m, 2H tetrahydroindolizine); 1.85 (m, 4H tetrahydroindolizine) IV: v:> C = O 1695 cm -1 ester; v:> C = O 1674 cm-1 STEP D: 6- [1- (METOXICARBONYL) -5,6,7,8-TETRA-HYDRO-3-INDOLIZINYL] -1,3-BENZODIOXOL-5-CARBOXYLIC ACID
[0048] Prepare a solution containing 3.37 g of the compound obtained in Step C (10.3 mmoles) in 9.3 ml_ of acetone and 8.8 ml_ (80.24 mmoles) of 2-methyl-2- butene, which solution is placed at 0 ° C. 9.3 ml of an aqueous solution containing a mixture of 3.3 g of NaCIO2 (36.05 mmol) and 3.6 g of Na2PO4 (25.75 mmol) are added dropwise. The whole is subsequently stirred at room temperature for 7 hours. The reaction mixture is then concentrated to remove the acetone. The solid then obtained is filtered, washed with water and then stirred in vacuo at 40 ° C, overnight. The title product is obtained in the form of a solid, which is used subsequently without being further purified. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 12.10 (m, 1H, H carboxylic acid); 7.40-6.88 (2s, 2H, aromatic H); 6.20 (s, 1H, H tehydroindolizine); 6.18 (s, 2H, H methylenedioxy); 3.70 (s, 3H, methyl ester); 3.55 (t, 2H tetrahydroindolizine); 3.00 (t, 2H tetrahydroindolizine); 1.80 (m, 4H, H tetrahydroindolizine) IV: v: -OH: 3000-2000 CΠT1 acid; v:> C = O 1686-1676 cm '1ester + acid; v:> C = C <1608 cm'1 PREPARATION 2: 4-BROMO-2- [1- (METOXICARBONYL ACID) - 5,6,7,8-TETRA-HYDRO-3-INDOLIZINYL] BENZOIC ACID
[0049] The procedure is the same as in Preparation 1, replacing 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with 2,4-dibromobenzaldehyde. A mixture of two regions is obtained, which are separated by chromatography. PREPARATION 3: 4-CHLORINE-2- [1- (METOXICARBONYL) - 5,6,7,8-TETRA-HYDRO-3-INDOLIZINYL] BENZOIC ACID
[0050] The procedure is the same as in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 2-bromo-4-chlorobenzaldehyde. PREPARATION 4: 4-FLUOR-2- [1- (METOXICARBONYL) - 5,6,7,8-TETRA-HYDRO-3-INDOLIZINYL] BENZOIC ACID
[0051] The procedure is the same as in Preparation 1, replacing 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with 2-bromo-4-fluorbenzaldehyde. PREPARATION 5: 8- [1- (METOXICARBONYL) -5,6,7,8-TETRA- HYDRO-3-INDOLIZINYL] -3,4-DI-HYDRO-2H-1,5-BENZODIOXEPINE-7- CARBOXYLIC ACID
[0052] The procedure is as in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 8-bromo-3,4-dihydro-2 / - / - 1,5-benzodioxepine-7-carbaldehyde. PREPARATION 6: 4-METOXY-2- [1- (METOXICARBONYL) - 5,6,7,8-TETRA-HYDRO-3-INDOLIZINYL] BENZOIC ACID
[0053] The procedure is the same as in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 2-bromo-4-methoxybenzaldehyde. PREPARATION 7: 7- [1- (METOXICARBONIL) -5,6,7,8-TETRA-HYDRO-3-INDOLIZINYL] -2,3-DI-HYDRO-1,4-BENZODIOXIN-6-CARBOXYLIC ACID
[0054] The procedure is the same as in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C by the 7-bromo-2,3-dihydro-1,4-benzodioxin -6-carbaldehyde. PREPARATION 8: 4-ETOXY-2- [1- (METOXICARBONYL) -5,6,7> - 8-TETRA-HYDRO-3-INDOLIZINYL] BENZOIC ACID
[0055] The procedure is the same as in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C by the 2-bromo-4-ethoxybenzaldehyde. PREPARATION 9: 2,2-DIDEUTERIC-6- [1- (METOXICARBO-NIL) -5,6,7,8-TETRA-HYDRO-3-INDOLIZINIL] -1,3-BENZODIOXOL-5- CARBOXYLIC ACID STEP A: 2.2-DIDEUTERY-1,3-BENZODIOXOL-5-CARBALDEHYDE
[0056] To a solution of 30 g of 3,4-dihydroxybenzaldehyde (217 mmoles) in 110 ml of anhydrous DMF, 114 g of cesium carbonate (347 mmoles) and 22 ml of methyl chloride are added in sequence. - dideuterated leno (347 mmoles). The reaction mixture is subsequently stirred at room temperature overnight. After filtering the insoluble part over Celite, the residual filtrate is subsequently hydrolyzed by adding 200 ml of water and then extracted with ethyl acetate. The organic phases are then combined, washed with a saturated LiCl solution and then dried over MgSCXi. After concentrating to dryness, the residue is purified by chromatography on silica gel (petroleum ether / AcOEt gradient). The title product is obtained as a solid. dehyde); 7.4-6.95 (m, 3H, aromatic H) IV: v: C = O aldehyde: 1670 cm'1 STEP B: 6-BROMO-2,2-DIDEUTERY-1,3-BENZODIOXOL-5-CAR - BALDEHYDE
[0057] To a solution of 10 g of the compound obtained in Step A (65.7 mmol), in 100 ml_ of methanol cooled to 0 ° C, 3.7 ml_ of a bromine solution ( 1.1 molar equivalent) in 10 mL of methanol. The whole is subsequently stirred at room temperature overnight. The reaction mixture is concentrated to dryness and then absorbed into water. After stirring, the resulting solid is subsequently filtered and then dried. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 10.2 (s, 1H, H aldehyde); 7.4 (s, 1H, aromatic H); 7.05 (s, 1H, aromatic H) IV: v: C = Aldehyde: 1670 cm2; C = aromatic C: 1611 cm-1 STEP C: 2,2-DIDEUTERIC ACID-6- [1- (METOXICARBONIL) - 5,6,7,8-TETRA-HYDRO-3-INDOLIZINIL] -1,3-BENZODIOXOL -5- CARBOXYLIC
[0058] The procedure is as in the protocol described in Steps C and D of Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 6-bromo-2,2-dideuterium-1 , 3-benzodioxol-5-carbaldehyde. PREPARATION 10: 2- [1- (METOXICARBONYL) -5,6,7,8-TE-TRA-HYDRO-3-INDOLIZINIL] -4- (TRIFLUORMETYL) BENZOIC ACID
[0059] The procedure is as in the protocol described in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 2-bromo-4- (trifluormethyl) benzaldehyde. PREPARATION 11: 2- [1- (METOXICARBONYL) -5,6,7,8-TE-TRA-HYDRO-3-INDOLIZINIL] -4- (TRIFLUORMETEXY) BENZOIC ACID
[0060] The procedure is as in the protocol described in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 2-bromo-4- (trifluoromethoxy) benzaldehyde. PREPARATION 12: 2- [1- (METOXICARBONYL) -5,6,7,8-TE-TRA-HYDRO-3-INDOLIZINYL] BENZOIC ACID
[0061] The procedure is as in the protocol described in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 2-bromobenzaldehyde. PREPARATION 13: 6- [1- (METOXICARBONYL) -3-INDOLIZI-NIL] -1,3-BENZODIOXOL-5-CARBOXYLIC ACID STEP A: 1- (CARBOXIMETHYL) -1,2-DI-HYDROPIRI-DYNIUM BROMIDE
[0062] To a solution of 16.2 ml of pyridine (200 mmoles) in 120 ml of ethyl acetate are added, in portions, 27.8 g (200 mmoles) of bromoacetic acid. The whole is subsequently stirred at room temperature overnight. The precipitate thus obtained is filtered and then washed with ice-cold ethyl acetate. After drying, the title product is obtained in the form of a powder, which is used directly for the next step. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 9.15 (d, 2H, H aromatic pyridine)); 8.7 (t, 1H, aromatic H); 8.25 (t, 2H, aromatic H); 5.65 (s, 2H, H CH2 COOH) IV: v: C = O: 1732 cm -1; -OH acid: 2800 cm1 STEP B: 1-METHYL INDOLIZINACARBOXYLATE
[0063] To a suspension of 6.55 g of the pyridinium salt obtained in Step A (30 mmoles), in 240 ml of toluene, are added, in sequence, 16.7 ml of methyl acrylate (150 mmoles), 4 , 2 mL of triethylamine (30 mmoles) and then, in portions, 20.9 g of MnÜ2 (240 mmoles). The whole is subsequently heated to 90 ° C for 3 hours. After cooling, the reaction mixture is filtered over a Celite cake and concentrated to dryness. The title product is then isolated by purification on silica gel (heptane / AcOEt gradient: 0-10%) as an oil, which crystallizes when frozen. 1H NMR: δ (300 MHz; dmso-d6; 26.9 ° C): 8.5 (d, 1H, H indolizine); 8.05 (d, 1H, H indolizine); 7.6 (s, 1H, H indolizine); 7.15 (m, 2H, H indolizine); 6.85 (m, 1H, H indolizine); 4.25 (q, 2H, -C (O) CH2 CH3); 1.35 (t, 3H, -C (O) CH2 CH3) IV: v: C = The ester: 1675 cm -1; C = aromatic C: 1634 cm-1 STEP C: 6- [1- (METOXICARBONYL) -3-INDOLIZINIL] -1,3- BENZODIOXOL-5-CARBOXYLIC ACID
[0064] The procedure is as in the protocol described in Steps C and D of Preparation 1. PREPARATION 14: 4-CHLORINE-2- [1- (METOXICARBONYL) -3- INDOLIZINYL] BENZOIC ACID
[0065] Methyl 1-indolizinecarboxylate is formed according to the process described in Steps A and B of Preparation 13. The title product is subsequently obtained according to the protocol described in Steps C and D of Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C by 2-bromo-4-chlorobenzaldehyde. PREPARATION 15: 7- [1- (METOXICARBONYL) -3-INDOLIZI-NIL] -2,3-DI-HYDRO-1,4-BENZODIOXIN-6-CARBOXYLIC ACID
[0066] Methyl 1-indolizinecarboxylate is formed according to the process described in Steps A and B of Preparation 13. The title product is subsequently obtained according to that described in Steps C and D of Preparation 1, replacing 6 -bromo-1,3-benzodioxol-5-carbaldehyde used in Step C by 7-bromo-2,3-dihydro-1,4-benzodioxin-6-carbaldehyde. PREPARATION 16: 4-METOXY-2- [1- (METOXICARBONYL) -3- INDOLIZINYL] BENZOIC ACID
[0067] Methyl 1-indolizinecarboxylate is formed according to the process described in Steps A and B of Preparation 13. The title product is subsequently obtained according to the protocol described in Steps C and D of Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 2-bromo-4-methoxybenzaldehyde. PREPARATION 17: 6- [2- (TERC-BUTOXICARBONIL) ACID -8- (METOXICARBONIL) -I, 2,3,4-TETRA-HYDROPIRROLEUM [1,2- A] PIRAZIN-6-IL] -1,3- BENZODIOXOL-5-CARBOXYLIC STEP A: 4-FORMIL-1,3-PIPERAZINADICARBOXYLATE 1-TERC-BUTYL 3-METHYL
[0068] To a solution of pentafluorfenol in 520 ml_ of anhydrous ether, at 0 ° C, 49 g of 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide (286 mmoles) are added in sequence , and 12 ml of formic acid (312 mmol). The whole is stirred at room temperature for 2 hours. Subsequently, a mixture of 32 g of 1-ferc-butyl 3-methyl 1,3-piperazinadicarboxylate (130 mmoles) and 18 ml of triethylamine (130 mmoles) in solution in 520 ml of CH2 Cl2 is added. The whole is stirred overnight at room temperature. The reaction mixture is hydrolyzed with a 1 N aqueous HCl solution and extracted with CH2 Cl2. The organic phases are subsequently combined and then washed with a saturated aqueous solution of NaHCOa and then with a saturated aqueous solution of NaCl until neutral. After drying over MgSO4, filtration and concentration to dryness, the product is isolated by chromatography on silica gel (petroleum ether / AcOEt gradient: 0-30%). The title product is obtained in the form of an oil. IV: v: C = O: 1674-1745 cm'1 m / z (C12H20N2O5): 272.1 (M +); 295.121 (M + Na) +; 567,253 (2M + Na) + STEP B: 4- (TERC-BUTOXICARBONIL) -1-FORMYL-2-LITHIUM PYPERAZINACARBOXYLATE
[0069] To a solution of 28 g of the compound obtained in Step A (103 mmoles) in 515 ml of dioxane is added 4.8 g of LiOH (113 mmoles), in solution, in 100 ml of H2O. The whole is stirred at room temperature for 4 hours. The reaction mixture is subsequently concentrated to dryness and then coevaporated several times with ethyl acetate. The title product is obtained as a solid and is used directly for the next cyclization step. 13C-NMR: δ (500 MHz; dmso-d6; 26.9 ° C): 46 (s, C piperazine); 42-38 (m, C piperazine); 58-53 (s, C piperazine); 28.5 (s, C3). IV: v: C = O: 1650 cm -1; 2800 cm'1
[0070] STEP C: 3,4-DI-HYDROPIRROLO [1,2-A] PIRAZINE- 2,8 (1 H)-2-TERC-BUTYL 8-METHYL DICARBOXYLATE
[0071] To a suspension of 29 g of the compound obtained in Step B (103 mmoles) in 800 ml of dichloroethane are added, in sequence, 24 g of tosyl chloride (124 mmoles), 12.6 ml of 2-chloroacrylate methyl (124 mmoles) and then 35 ml of triethylamine (247 mmoles). The whole is stirred at reflux for 2 hours. After cooling, the reaction mixture is diluted with ethyl acetate, and the organic phase is washed with a saturated solution of NaCl until neutral. After drying over MgSO4, filtration and concentration to dryness, the title product is isolated by chromatography on silica gel (petroleum ether / AcOEt gradient: 0-20%) as a solid. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 6.8-6.43 (m, 2H, H pyrrole); 4.75-3.75 (m, 6H, H piperazine)); 3.73 (s, 3H, H COOCH3); 1.48 (s, 9H, H fBu). IV: v: C = O (conjugated ester): 1712 cm-1; C = O (carbamate): 1677 cm'1 STEP D: 6- [2- (TERC-BUTOXICARBONYL) ACID -8- (METOXY-CARBONYL) -1,2,3,4-TETRA-HYDROPIRROLEY [1,2- A] PIRAZIN-6-IL] - 1,3-BENZODIOXOL-5-CARBOXYL
[0072] The procedure is as in the protocol described in Steps C and D of Preparation 1. PREPARATION 18: 6- [7- (METOXICARBONYL) -2,3-DI-HYDRO-1 H-PIRROLIZIN-5-IL] - ACID 1,3-BENZODIOXOL-5-CARBOXYL
[0073] The procedure is as in the protocol described in Preparation 1, replacing the 2-piperidinecarboxylic acid used in Step A with proline. PREPARATION 19: 4-CHLORINE-2- [7- (METOXICARBONYL) -2,3- DI-HYDRO-1H-PIRROLIZIN-5-IL] BENZOIC ACID
[0074] The procedure is as in the protocol described in Preparation 1, replacing the 2-piperidinecarboxylic acid used in Step A with proline, while the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C is replaced by 2 -bromo-4-chlorobenzaldehyde. PREPARATION 20: 4-CHLORINE-2- [8- (METOXICARBONIL) -3,4- DI-HYDRO-1 H-PIRROLEUM [2,1 -C] [1,4] OXAZIN-6-IL] BENZOIC ACID
[0075] The procedure is as in the protocol described in Preparation 1, replacing 2-piperidinecarboxylic acid with 3-morpholinecarboxylic acid, while 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C is replaced by 2- bromo-4-chlorobenzaldehyde. PREPARATION 21: 6- [8- (METOXICARBONIL) ACID -3,4-DI-HYDRO- 1 H-PIRROLEUM [2,1 -C] [1,4] OXAZIN-6-IL] -1,3-BENZODIOXOL- 5- CARBOXYLIC
[0076] The procedure is as in the protocol described in Preparation 1, replacing 2-piperidinecarboxylic acid with 3-morpholinecarboxylic acid. PREPARATION 22: 4-CHLORINE-2- [1- (METOXICARBONIL) ACID - 6,7,8,9-TETRA-HYDRO-5H-PYRROLEUM [1,2-A] AZEPIN-3-IL] BENZOIC
[0077] The procedure is as in the protocol described in Preparation 1, replacing 2-piperidinecarboxylic acid with 2-azepanocarboxylic acid, while 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C is replaced by 2- bromo-4-chlorobenzaldehyde. PREPARATION 23: 6- [1- (METOXICARBONIL) ACID -6,7,8,9- TETRA-HYDRO-5H-PIRROLEUM [1,2-A] AZEPIN-3-IL] -1,3- BENZODIOXOL-5- CARBOXYLIC
[0078] The procedure is as in the protocol described in Preparation 1, replacing 2-piperidinecarboxylic acid with 2-azepanocarboxylic acid. PREPARATION 24: 4-CHLORINE-2- [3- (METOXICARBONIL) - 5,6,7,8-TETRA-HYDRO-1-INDOLIZINIL] BENZOIC ACID STEP A: 1- (4-BROMOBUTYL) -1 H-PIRROL- 2-METHYL CARBOXYLATE
[0079] To a suspension of 6.7 g (241.7 mmoles) of NaH (60%) in 400 ml of anhydrous THF, at 0 ° C, 20 g (161.13 mmoles) of 1 H-pyrrole are added Methyl -2-carboxylate (see Tetrahedron2008, 64, 7745). The whole is subsequently stirred at room temperature for one hour. Then, 95 ml of 1,4-dibromobutane are added. After the addition, the reaction mixture is heated to reflux for 12 hours. The precipitate obtained is filtered and then washed with THF. The filtrate is subsequently concentrated to dryness. The compound is then isolated by chromatography on silica gel (cyclohexane / ethyl acetate gradient: 0 to 20%) as an oil. Elementary microanalysis:% of C% of H% of N% of Br Calculated 46.17 5.42 5.38 30.72 Found 46.76 5.56 5.29 30.77 IV: v: -C = O: 1700 cm1; v: C-O-C: 1238 cnr1 STEP B: 5,6,7,8-TETRA-HYDRO-3-METHYL INDOLIZINACARBOXYLATE
[0080] A solution of 8 g (30.8 mmoles) of the brominated derivative obtained in Step A in 700 ml of acetonitrile is taken to reflux. A solution of a mixture of 25 g of azobisisobutyronitrile (151 mmoles) and 30 g of BuaSnH (100 mmoles) in 500 ml of toluene is added. The whole is refluxed for 120 hours. The reaction mixture is subsequently concentrated to dryness. The compound is then isolated by chromatography on silica gel (5 to 10% cyclohexane / ethyl acetate gradient) as an oil. 1H NMR: δ (400 MHz; CDCh; 26.9 ° C): 6.90 (d, 1H, H pyrrole); 5.85 (d, 1H, H pyrrole); 4.30 (t, 2H, CH2 indolizine); 3.80 (s 3H, Me); 2.80 (t, 2H, CH2 indolizine); 1.95 (m, 2H, CH2 indolizine); 1.80 (m, 2H, CH2 indolizine) IV: v: -C = O: 1695 cm1 STEP C: 4-CHLORINE-2- [3- (METOXICARBONYL) -5,6,7,8- TETRAHYDRO -1-INDOLIZINIL] BENZOIC
[0081] The procedure is as in the protocol described in Steps C and D of Preparation 1. PREPARATION 25: 2- [1- (METOXICARBONYL) -5,6,7,8- TETRA-HYDROINDOLIZIN-3-IL] -4 -METHYLBENZOIC
[0082] The procedure is as in Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C with the 2-bromo-4-methylbenzaldehyde. PREPARATION 26: 4-FLUOR-2- [8- (METOXICARBONYL) -3,4- DI-HYDRO-1H-PYRROLEIC [2,1-C] [1,4] OXAZIN-6-IL] BENZOIC ACID
[0083] The procedure is as in the protocol described in Preparation 1, replacing 2-piperidinecarboxylic acid with 3-morpholinecarboxylic acid, while 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C is replaced by 2- bromo-4-fluorbenzaldehyde. PREPARATION 27: 4-FLUOR-2- [r- (METOXICARBONIL) ACID - 5 ■ J6, -DI-HYDRO-8, H-SPIRUS [1,3-DIOXOLAN-2,7, -INDOLIZIN] -3, - IL ] BENZOICO STEP A: 8-FORMIL-1,4-DIOXA-8-AZAESPIRO [4.5] DEAN-7- METHYL CARBOXYLATE
[0084] 24 g of 1,4-dioxa-8-azaespiro [4.5] decane-methyl 9-carboxylate (111 mmoles) are dissolved in 80 ml of ethyl acetate and 80 ml of dichloromethane. 26 g of (4-nitrophenyl) format (155 mmoles) are added, and the whole is stirred at room temperature for one hour. The reaction mixture is evaporated to dryness and absorbed in ethyl acetate. The organic phase is subsequently washed, in sequence, with a 1 N NaOH solution, water, and then with a saturated NH4 Cl solution until a neutral pH is reached. It is subsequently dried over magnesium sulfate, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (heptane / ethyl acetate gradient). The title product is obtained in the form of an oil.
[0085] 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 8.15 (s, 1H, CHO); 5.0-4.75 (m, 1H, tertiary H); 4.3-3.7 (m, 5H, 4H ethylenedioxy + 1H aliphatic pipe-ridine); 3.70 (s, 3H, Me); 3.4-2.9 (2m, 1H, H aliphatic piperidine); 2.3-1.75 (m, 2H, H aliphatic piperidine); 1.7-1.5 (m, 2H, H aliphatic piperidine) STEP B: 8-FORMYL-1,4-DIOXA-8-AZAESPIRO ACID [4.5] DE-CANO-7-CARBOXYLIC
[0086] 15.25 g of the compound obtained in Step A (62.7 mmoles) are dissolved in 160 ml of dioxane. A 125 mL solution of 1 M KOH is added dropwise and the whole is stirred at room temperature for one hour. 125 ml of 1 M HCI are subsequently added, and the compound is extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated to dryness. The title product is obtained in the form of a powder. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C) 13.5-12 (m, 1H, OH); 8.1 + 8.0 (2s, 1H, CHO); 4.9 + 4.6 (2m, 1H, H tertiary); 4.0-3.8 (m, 4H, ethylene-dioxide); 4.2 +3.7 (2ms, 1H, H aliphatic piperidine); 3.4 + 2.9 (2m, 1H, H aliphatic piperidine); 2.4-1.5 (m, 4H, H aliphatic piperidine) IV: v: OH: 3500-2000 cm -1; -C = O (acid + aldehyde): 1731 + 1655 cm'1 STEP C: S '^' - DI-HYDRO-S'H-ESPIROyl ^ -DIOXOLAN ^ J'-INDO-LIZINE] -1'-CARBOXYLATE METHYL
[0087] To a solution of 13.5 g (62.7 mmoles) of the acid obtained in Step B in 380 ml of dichloroethane are added, in sequence, 39.5 ml (238.4 mmoles) of triethylamine and then, by spatula, 12.5 g (65.6 mmoles) of para-toluenesulfonyl chloride and 23.7 mL (238.4 mmoles) of methyl chloroacrylate. The whole is stirred at 80 ° C for 18 hours. The reaction mixture is subsequently filtered over Celite. The filtrate is subsequently washed with a saturated solution of NaHCOa and then with a saturated solution of NH4 Cl. The organic phase is dried over MgSO4, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (heptane / ethyl acetate gradient). The product is obtained as a solid. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C) 6.70 (d, 1H, pyrrole); 6.40 (d, 1H, pyrrole); 4.05 (t, 2H, H aliphatic piperidine); 4.00 (m, 4H, ethylenedioxy); 3.70 (s, 3H, methyl); 3.15 (s, 2H, H aliphatic piperidine): 2.05 (t, 2H, H aliphatic piperidine) IV: v: -C = O (ester): 1689 cm'1 STEP D: 3 '- (5- FLUOR-2-FORMYLPHENYL) -5 ', 6, -DI-HYDRO-8'H-ESPI- RO [1,3-DIOXOLAN-2,7'-INDOLIZINE] -1' -METHYL CARBOXYLATE
[0088] The procedure is as in the process of Step C of Preparation 1, replacing 6-bromo-1,3-benzodioxol-5-carbaldehyde with 2-bromo-4-fluorbenzaldehyde. STEP E: 4-FLUOR-2- [r- (METOXICARBONYL) -5 ', 6'-DI-HI- DRO-8'H-SPIRAL ACID [1 jS-DIOXOLAN ^^' - INDOLIZIN ^ S'- ILJBENZOIC
[0089] The procedure is like in the process of Step D of Preparation 1. PREPARATION 28: 4-FLUOR-2 ACID - [(2R) -2-HYDROXY-7- (METHYCARBONYL) -2,3-DI-HYDRO -1 H-PIRROLIZIN-5-IL] BENZOIC STEP A: (4R) -4 - {[TERC-BUTYL (DIMETHYL) SILIL] OXY} -L-METHYL PROLINATE
[0090] The protection of the alcohol function of methyl (4R) -4-hydroxy-L-prolinate by a tert-butyldimethylsilyl group is carried out according to the protocol described in WO 2012040242. STEP B: (4R) -4- {[TERC-BUTIL (DIMETHIL) SILIL] OXY} -1-FORMIL-L- METHIL PROLINATE
[0091] 13.7 g (52.8 mmoles) of the compound from Step A are dissolved in 100 ml of acetonitrile. 13.2 g (79.3 mmoles) of (4-nitrophenyl) format and 39 mL (238 mmoles) of diisopropylethylamine are added to them. The whole is stirred at room temperature for 6 hours. The reaction mixture is evaporated to dryness and absorbed in ethyl acetate. The organic phase is subsequently washed, in sequence, with a 1 N NaOH solution, with water, and then with a saturated NH4 Cl solution until neutral. It is subsequently dried over magnesium sulfate, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (gradient: dichloromethane / ammoniacal methanol). The title product is obtained in the form of an oil. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 8.15 and 8.12 (s, 1H, formyl); 4.62 and 4.25 (t, 1H, H alpha ester); 4.40 (m, 1H, SiOCH); 3.65 and 3.6 (s, 3H, OMe); 3.5 and 3.3 (m, 2H, 2H proline); 2.12 and 1.95 (m, 2H, 2H proline); 0.8 (s, 9H, SifBu); 0.05 (s, 6H, SiMe2). IV: v: C = The ester: 1749 cm -1; C = Formyl: 1659 cm-1 STEP C: (2S, 4R) -4 - {[TERC-BUTYL (DIMETHYL) SILIL] OXY} -1- FORMYL PYRROLIDINE-2-LITHIUM CARBOXYLATE
[0092] The compound from Step B (26.2 g; 91.1 mmoles) is dissolved in 450 ml of dioxane. A solution of lithium hydroxide (4.2 g; 100 mmoles) in water (90 ml) is added. The whole is stirred at room temperature for 7 hours. The reaction mixture is evaporated to dryness and used as such for the next step. STEP D: (2R) -2 - {[TERC-BUTYL (DIMETHIL) SILIL] OXY} -2,3-DI-HYDRO- 1H-PIRROLIZIN A-7-C METHYL ARBOXYLATE
[0093] To a solution of 22.4 g (80.2 mmoles) of the lithium carboxylate obtained in Step D in 640 ml of dichloroethane is added, in sequence, 27 ml (192 mmoles) of triethylamine and then, in portions, 18 g (96 mmoles) of para-toluenesulfonic chloride and 9.7 mL (96.2 mmoles) of methyl chloroacrylate. The reaction mixture is heated to reflux for 18 hours and then cooled and diluted with ethyl acetate. The organic phase is washed with water and then with brine, before being dried over MgSO4. After filtration and concentration of the mixture, the oil obtained is purified by flash chromatography (gradient: heptaine / ethyl acetate). The title product is obtained in the form of an oil. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 6.7 (d, 1H, pyrol H); 6.4 (d, 1H, H pyrrole); 5.0 (m, 1H, SiOCH,); 4.2-3.75 (ABx, 2H, 2H dihydropyrrolizine); 3.3 + 2.8 (ABx, 2H, 2H dihydropyrrolizine); 3.70 (s, 3H, CO2CH3); 0.9 (s, 9H, ‘Bu); 0.10 (ABx, 6H, SiMe2) IV: v: -C = O (ester): 1701 cm -1; SiCH3: 1249 cm'1; Si-O: 1118-1090 cm -1; Si-C: 835-777 cm'1 STEP E: (2R) -2 - {[TERC-BUTIL (DIMETHYL) SILIL] OXI} -5- (5-FLUOR-2- FORMYLPHENYL) -2,3-DI- METHYL HYDRO-1 H-PYRROLIZINE-7-CARBOXYLATE
[0094] The procedure is as in the process of Step C of Preparation 1, replacing 6-bromo-1,3-benzodioxol-5-carbaldehyde with 2-bromo-4-fluorbenzaldehyde. STEP F: ACID 2 - [(2R) -2 - {[TERC-BUTYL (DIMETHYL) SILIL] OXI} -7- (METOXICARBONIL) -2,3-DI-HYDRO-1 H-PIRROLIZIN-5-IL] - 4- FLUORBENZOIC
[0095] The procedure is as in the process of Step D of Preparation 1. PREPARATION 29: ACID 4-FLUOR-2 - [(2S) -2-HYDROXY-7- (METOXICARBONIL) -2,3-DI-HYDRO-1 / 7-PIRROLIZIN-5- IL] BENZOIC
[0096] The procedure is as in Preparation 28, replacing the methyl (4 / ) - 4-hydroxy-L-prolinate used in Step A with the methyl (4S) -4-hydroxy-L-prolinate. PREPARATION 30: 4-FLUOR-2- [7-HYDROXY-1- (METOXICARBONYL) -5,6,7,8-TETRA-HYDROINDOLIZIN-3-IL] BENZOIC ACID
[0097] The procedure is as in the process of Preparation 27, replacing the 2-bromo-4-fluorbenzaldehyde used in Step D with the 6-bromo-1,3-benzodioxol-5-carbaldehyde. PREPARATION 31: 6- [8- (METOXICARBONIL) ACID PIRROLEUM [1,2- A] PIRAZIN-6-IL] -1,3-BENZODIOXOL-5-CARBOXYLIC STEP A: PIRROLEUM [1,2-A] PIRAZINE-8 -METHYL CARBOXYLATE
[0098] To a solution of 10 g (65.7 mmoles) of methyl pyrazin-2-ylacetate in 263 ml of anhydrous acetone (4 ml / mmol), 5.7 g of lithium bromide ( 65.7 mmoles), 22.1 g of sodium bicarbonate (263 mmoles) and then 9.4 ml of chloroacetaldehyde (50% solution in water) (72.6 mmoles). The whole is subsequently heated to reflux overnight. The reaction mixture is subsequently concentrated to dryness and then absorbed in ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness. An oil is obtained, which is purified by chromatography on silica gel (CF4 Ch / ethyl acetate gradient). After concentration, the title product is obtained as a solid. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 9.36 (m, 1H, H pyrazine); 8.50 (dd, 1H, H pyrazine)); 7.8 (m, 2H, 1H pyrazine, 1H pyrrole); 7.31 (m, 1H, H pyrrole), 3.88 (s, 3H, OCH3) IV: v: -C = O (conjugated ester): 1686 cm-1 STEP B: 6- [8- ACID (METOXICARBONIL ) PIRROLO [1,2-A] PIRA- ZIN-6-IL] -1,3-BENZODIOXOL-5-CARBOXYLIC
[0099] The procedure is as in the processes of Steps C and D of Preparation 1. PREPARATION 32: 4-FLUORIC-2- [1- (METOXICARBONYL) -3- INDOLIZINYLBENZOIC ACID
[00100] Methyl 1-indolizinecarboxylate is formed according to the process described in Steps A and B of Preparation 13. The title product is subsequently obtained according to the protocol described in Steps C and D of Preparation 1, replacing the 6-bromo-1,3-benzodioxol-5-carbaldehyde used in Step C by 2-bromo-4-fluorbenzaldehyde. PREPARATION V: (3S) -3- (4-MORPHOLINYLMETHIL) -1,2,3,4-TETRA-H- IDROISOQUINOLINE STEP A: (3S) -3- (4-MORPHOLINYL CARBONIL) -3,4-DI-HYDRO -2 (1 H) - BENZILA CARBOXYLATE ISOQUINOLINE
[00101] To a solution of 5 g of (3S) -2 - [(benzyloxy) carbonyl] - 1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid (16 mmoles) in 160 ml of dichloromethane 1.5 mL of morpholine (17.6 mmoles) and then 9 mL of / V, / V, / V-triethylamine (64 mmoles), 3.3 g of 1-ethyl-3- (3'-dimethylaminopropyl) - carbodiimide (EDC) (19.2 mmoles) and 2.6 g of hydroxybenzotriazole (HOBT) (19.2 mmoles). The reaction mixture is stirred at room temperature overnight and is then poured over an ammonium chloride solution and extracted with ethyl acetate. The organic phase is subsequently dried over magnesium sulfate and then filtered and evaporated to dryness. The crude product thus obtained is then purified by chromatography on silica gel (dichloromethane / methanol gradient). The product is obtained in the form of a foam. 1H NMR: δ (400 MHz; dmso-d6; 79.9 ° C): 7.30 (m, 5H benzyl); 7.15 (m, aromatic 4H); 5.2-5.0 (m, 3H, 2H benzyl, 1H dihydroisoquinoline); 4.75-4.5 (2d, 2H dihydroisoquinoline); 3.55-3.3 (m, 8H morpholine); 3.15-2.9 (2dd, 2H dihydroisoquinoline) IV: v:> C = O: 1694; 1650 cm'1 STEP B: (3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) -ISO- QUINOLINE CARBOXYLATE OF BENZILA
[00102] To a solution of 5.3 g of the product obtained in Step A (13.9 mmoles) in 278 ml of tetrahydrofuran is added 14 ml of BH3Mβ2S (27.8 mmoles), at room temperature. The whole is heated for 4 hours at 80 ° C. It is allowed to return to room temperature, and then 7 mL (14 mmoles) of BHsMe2S is added. The reaction mixture is again heated to 80 ° C for 2 hours. The tetrahydrofuran is subsequently evaporated, and then methanol and then 5.6 ml of 5 N hydrochloric acid (27.8 mmoles) are then added slowly. The mixture is stirred at room temperature overnight and then at 80 ° C for one hour. Subsequently, a saturated solution of NaHCOa is added to the reaction mixture, at 0 ° C, until a pH of 8 is reached, and then extraction with ethyl acetate is carried out. The organic phase is subsequently dried over magnesium sulfate and then filtered and evaporated to dryness. The title product is obtained in the form of an oil. 1H NMR: δ (400 MHz; dmso-d6; 79.9 ° C): 7.43-7.30 (unresolved peak, 5H benzyl); 7.19 (m, aromatic 4H); 5.16 (m, 2H, 2H benzyl); 4.79-4.29 (d, 2H dihydroisoquinoline); 4.58 (m, 1H dihydroisoquinoline); 3.50 (m, 4H morpholine); 3.02-2.80 (dd, 2H dihydroisoquinoline); 2.42-2.28 (unresolved peak, 5H, 4H morpholine, 1H morpholine); 2.15 (dd, 1H morpholine) IV: v:> CH: 2810 cm -1; v:> C = O: 1694 cm -1; v:> C-O-C <: 1114 cm-1; v:> CH-Ar: 751; 697 cm'1 STEP C: (3S) -3- (4-MORPHOLINYLMETHY) -1,2,3,4-TETRA-HYDROISO-QUINOLIN
[00103] To a solution of 4.9 g of the compound of Step B (13.4 mmoles) in 67 ml of ethanol is added 0.980 g of palladium dihydroxide (20% by mass), at room temperature. The reaction mixture is placed under 120 kPa (1.2 bar) of hydrogen, at room temperature, for 4 hours. It is subsequently passed over a Whatman filter, and then the palladium is rinsed several times with ethanol. The filtrate is evaporated to dryness. The title product is obtained in the form of an oil. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 7.12-7.0 (unresolved peak, aromatic 4H); 3.92 (s, 2H tetrahydroisoquinoline); 3.60 (t, 4H morpholine); 2.98 (m, 1H tetrahydroisoquinoline); 2.68 (dd, 1H tetrahydroisoquinoline); 2.5-2.3 (unresolved peak, 8H, 1H tetrahydroisoquinoline, 6H morpholine, 1H NH) IV: v:> NH: 3322 cnv1; v:> C-O-C <: 1115 cm-1: v:> CH-Ar: 742 cm'1 2 'PREPARATION: (3R) -3- (4-MORPHOLINYLMETH) -1,2,3,4-TETRA- HYDROISOQUINOLINE
[00104] The procedure is the same as in Preparation 1 ', replacing (3S) -2 - [(benzyloxy) carbonyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid used in Step A with (3 / ) - 2- [(benzyloxy) carbonyl] -1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid. 3 'PREPARATION: (3S) -3 - [(4-METHYL-1-PIPERAZINIL) METHYL] -1,2,3,4- TETRA-HYDROISOQUINOLINE
[00105] The procedure is as in the process of Preparation 1 ', replacing the morpholine used in Step A with 1-methyl-piperazine. 4 'PREPARATION: (3S) -3- (1,4-OXAZEPAN-4-ILMETHIL) -1,2,3,4-TE-TRA-HYDROISOQUINOLINE
[00106] The procedure is like in the process of Preparation 1 ', replacing the morpholine used in Step A with 1,4-oxazepan. 5 'PREPARATION: (3S) -3 - {[(3R) -3-METHYLMORPHOLINYL] METHIL} -1,2, - 3,4-TETRA-HYDROISOQUINOLINE
[00107] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with (3R) -3-methylmorpholine. 6 'PREPARATION: (3S) -3 - {[(3S) -3-METHYLMORPHOLINYL] METHIL} -1,2, - 3,4-TETRA-HYDROISOQUINOLINE
[00108] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with (3S) -3-methylmorpholine. PREPARATION 7a: (3S) -3 - {[(3S, 5S) -3,5-DIMETHYLMORPHOLINYL] METHYL} -1,2,3,4-TETRA-HYDROISOQUINOLIN
[00109] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with (3S, 5S) -3,5-dimethylmorpholine. PREPARATION 8a: N, N-DIMETHYL ((3S) -1,2,3,4-TETRA-HYDRO-3-ISO-QUINOLINYL) METHANAMINE
[00110] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with / V, / V-dimethylamine. PREPARATION 9a: (3S) -3 - {[4- (2-METOXYETHIL) PIPERAZIN-1-IL] METHYL} -1,2,3,4-TETRA-HYDROISOQUINOLINE
[00111] The procedure is as in Preparation 1 ', replacing the morpholine used in Step A with 1- (2-methoxyethyl) piperazine. PREPARATION 10a: 1-METHYL-4 - [(3S) -1,2,3,4-TETRA-HYDROISOQUI- NOLIN-3-ILMETIL] PIPERAZIN-2-ONA
[00112] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with 1-methylpiperazin-2-one. 1T PREPARATION: 2-METOXY-N-METHYL-N - [(3S) -1,2,3,4-TETRA-HI- DROISOQUINOLIN-3-ILMETILJETAN AMINE
[00113] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with 2-methoxy-A / - methyl ethylamine. 12 'PREPARATION: N-ETHYL-2-METHYXY-N - [(3S) -1,2,3,4-TETRA-HI- DROISOQUINOLIN-3-ILMETILJETAN AMINE
[00114] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with W-ethyl-2-methoxyethanamine. PREPARATION 13 ': (3S) -3 - {[4- (METHYLSULFONYL) PIPERAZIN-1-IL] - METHILJ-1,2,3,4-TETRA-HYDROISOQUINOLINE
[00115] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with 1- (methylsulfonyl) piperazine. PREPARATION 14 ': (3S) -3 - {[4- (2,2,2-TRIFLUORETYL) PIPERAZIN-1- IL] METHIL} -1,2,3,4-TETRA-HYDROISOQUINOLINE
[00116] The procedure is as in the process of Preparation 1 ', replacing the morpholine used in Step A with 1- (2,2,2-trifluorethyl) piperazine. 15 'PREPARATION: (3S) -3 - [(1,1-DIOXIDOTIOMORFOLIN-4-IL) ME-TIL] -1,2,3,4-TETRA-HYDROISOQUINOLIN
[00117] The procedure is like in the process of Preparation 1 ', replacing the morpholine used in Step A with thiomorpholine 1,1-dioxide. 16 'PREPARATION: (3S) -3 - [(3-METOXYPIRROLIDIN-1-IL) METHIL] -1, - 2,3,4-TETRA-HYDROISOQUINOLINE
[00118] The procedure is the same as in Preparation 1 ', replacing the morpholine used in Step A with 3-methoxypyrrolidine. PREPARATION 17 ’: (3S) -3 - [(3,3-DIFLUORPIRROLIDIN-1-IL) METHYL] - 1,2,3,4-TETRA-HYDROISOQUINOLINE
[00119] The procedure is like in the process of Preparation 1 ', replacing the morpholine used in Step A with 3,3-difluorpyrrolidine. PREPARATION 18 ’: (3S) -3 - [(3-METOXIAZETIDIN-1-IL) METHIL] -1,2, - 3,4-TETRA-HYDROISOQUINOLINE
[00120] The procedure is like in the process of Preparation 1 ', replacing the morpholine used in Step A with 3-methoxyazetidine. PREPARATION 19 ’: (3S) -3 - [(3-FLUORAZETIDIN-1-IL) METHIL] -1,2,3,4- TETRA-HYDROISOQUINOLINE
[00121] The procedure is like in the process of Preparation 1 ', replacing the morpholine used in Step A with 3-fluorazetidine. PREPARAÇÃ01 ": 4 - {[TERC-BUTIL (DIMETHIL) SILIL] ÓXI} -N- PHENYLANILINE
[00122] To a solution of 12 g of 4-anilinophenol (64.7 mmoles) in 200 ml of acetonitrile are added, at room temperature, 6.7 g of imidazole (97.05 mmoldx) and 11.7 g of tert -butyl (chlorine) dimethylsilane (77.64 mmoles). The whole is stirred at 70 ° C for 4 hours. Then the reaction mixture is poured into water and extracted with ether. The organic phase is subsequently dried over magnesium sulfate and then filtered and evaporated to dryness. The crude product thus obtained is then purified by chromatography on silica gel (petroleum ether / dichloromethane gradient). The title product is obtained in the form of a powder. 1H NMR: δ (400 MHz; dmso-d6; 26.9 ° C): 7.84 (s, 1H NH); 7.17 (t, 2H aniline); 6.98 (d, 2H phenoxy); 6.94 (d, 2H aniline); 6.76 (d, 2H phenoxy); 6.72 (t, 1H aniline); 0.95 (s, 9H tert-butyl); 0.15 (s, 6H dimethyl) IV: v:> NH: 3403 cm'1:> Air: 1597 cm'1
[00123] NHR3R4 amines, in which R3 θ R4, independently of one another, represent an aryl or heteroaryl group, are prepared according to known procedures, described in the literature (Surry DS et al., Chemical Science, 2011, 2, 27-50, Charles MD et al., Organic Letters, 2005, 7, 3965-3968). The hydroxy function protection reaction of 4-anilinophenol described in Preparation 1 "can be applied to the various secondary amines NHR3R4 (as defined above) having one or more hydroxy functions, when they are commercially available. Alternatively, the secondary amines having at least at least one hydroxy substituent can be synthesized directly in a protected form, ie, starting from reagents whose hydroxy function has been protected in advance Among the protecting groups, tert-butylsilyloxy and 0 benzyloxy are especially preferred.
[00124] Among the NHR3R4 amines having a hydroxy substituent that are used to synthesize the compounds of the invention, there may be mentioned: 4- (4-toluidine) phenol, 4- (4-chloroanilino) phenol, 4- (3-fluorine) 4- methylanilino) phenol, 4- [4- (trifluoromethoxy) anilino] phenol, 4- [4-hydroxyanilino] -phenol, {4 - [(1-methyl-1 H-indol-6-yl) amino] phenyl} methanol, 4- (2,3-dihydro-1 H-indol-6-ylamino) phenol, 4 - [(1-methyl-2,3-dihydro-1H-indol-6-yl) amino] phenol, 4 - [(1-methyl-1 f / -indol-6-yl) amino] phenol, 4 - [(1-methyl-1 H-indol-6-yl) amino] cyclohexanol, 4- [ (1-methyl-1,2,3,4-tetrahydro-6-quinolinyl) amino] phenol, 4 - [(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7 -yl) amino] phenol, 4- [4- (diethylamino) anilino] phenol, 4- (2,3-dihydro-1H-inden-5-ylamino) phenol, 4 - [(1-methyl- 1 H-indazol-5-yl) amino] phenol, 4 - [(1 '-methyl-1', 2'-dihydrospiro [cyclopropa-no-1,3'-indol] -5'-yl) amino ] phenol, 4 - [(1,3,3-trimethyl-2,3-dihydro-1 H-indol-5-yl) amino] phenol, 4- [4-methoxy-3- (trifluormethyl) anilino] phenol, 4- [4- (methylsulfanyl) -3- (trifluormethyl) anion] fe nol, 2-fluoro-4 - [(1-methyl-1 H-indol-5-yl) amino] - phenol, 4 - [(1-ethyl-1 H-indol-5-yl) amino] phenol, 4 - [(1-ethyl-2,3-dihydro-1H-indol-5-yl) amino] phenol, 4 - [(1-isopropyl-2,3-dihydro-1H-indol-5-yl ) amino] phenol, 4- (butylamino) phenol, 3 - [(1-methyl-1H-indol-5-yl) amino] -1-propanol, 4- [(1-methyl-1H-indol-5 -yl) amino] -1-butanol, 4 - [(3-fluor-4-methylphenyl) amino] - phenol, 4 - [(3-chloro-4-methylphenyl) amino] phenol, 4 - [(4-fluorophenyl ) amino] phenol, 4 - [(1-methyl-1 H-pyrrolo [2,3-b] pyridin-5-yl) amino] phenol, 4 - [(4-fluorophenyl) aminoyphenol, 4 - [( 2-fluorophenyl) amino] phenol, 4 - [(3-fluorophenyl) amino] phenol, 4- [(2,4-difluorphenyl) amino] phenol, 4 - [(3,4-difluorphenyl) amino] phenol, 3- [(4-hydroxyphenyl) amino] benzonitrile, 4 - [(3-methoxyphenyl) amino] phenol, 4 - [(3,5-difluorophenyl) amino] phenol, 4 - [(3-methylphenyl) amino] phenol, 4 - [(4-hydroxyphenyl) aminobenzonitrile, 4 - [(3-chlorophenyl) amino] phenol, 4- (pyrimidin-2-ylamino) phenol, 4 - [(cyclobutylmethyl) amino] phenol, 2 - [(4-hydroxyphenyl) amino] benzonitrile, 4 - {[(1-methyl-1 H-pyrazol-4-yl) methyl] amin o} phenol, 4 - [(cyclopropylmethyl) amino-] phenol, 4 - {[(1-methyl-1 H-pyrazol-3-yl) methyl] amino} phenol, 4- (but-2-in-1- ylamine) phenol, 4- (pyrazin-2-ylamino) phenol, 4- (pyridin-2-ylamino) phenol, 4- (pyridazin-3-ylamino) phenol, 4- (pyrimidin-5-ylamino) phenol, 4- (pyridin-3-ylamino) phenol, 4 - [(3,5-difluoro-4-methoxyphenyl) amino] phenol, 4- (pyridin-4-ylamino) phenol, 4 - [(3- fluoro-4-methoxyphenyl) amino] phenol, 2- (phenylamino) pyrimidin-5-ol, 5 - [(4-hydroxyphenyl) amino] -2-methoxy benzonitrile, 4 - {[3- (trifluoromethyl) phenyl] amino} phenol.
[00125] The hydroxy function (s) of the secondary amines listed above is (are) protected in advance by a suitable protecting group, prior to coupling to an acid derivative of the compound of formula (VII) as defined in the previous general process. EXAMPLE 1: N- (4-HYDROXYPHENYL) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONIL] - 1,3-BENZODIOXOL-5-IL} - / V-PHENYL- 5,6,7,8-TETRA-HYDRO-1-INDOLIZINE CARBOXAMIDE STEP A: 3- {6 - [((3S) -3- (4 -MORFOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -5,6,7,8- TETRA-HYDRO-1-INDOLIZINACARBOXYLATE METHYL
[00126] To a solution of 2 g of the compound of Preparation 1 in 20 ml of dichloromethane is added, at room temperature, 5.5 ml of A /, / V, / V-triethylamine (6.96 mmoles), 2, 12 g of the compound of Preparation 1 '(6.96 mmoles), and then 0.94 g of hydroxybenzotriazole (HOBT) and 1.34 g of 1-ethyl-3- (3'-dimethylaminopropyl) -carbodiimide (EDC) ( 6.96 mmoles). The reaction mixture is subsequently stirred at room temperature overnight, and is then poured over an ammonium chloride solution and extracted with ethyl acetate. The organic phase is subsequently dried over magnesium sulfate and then filtered and evaporated to dryness. The crude product thus obtained is then purified by chromatography on silica gel (hepatic / AcOEt gradient). The title product is obtained in the form of an oil. 1H NMR: δ (500 MHz; dmso-d6; 26.9 ° C): 7.2-6.9 (m, 4H, aromatic H); 7.04-7.03-7.00 (m, 1H, aromatic H); 6.85 (m, 1H, aromatic H); 6.35-6.26-6.06 (m, 1H, H tetrahydroindolizine); 6.15-6.12 (m, 2H, H methylenedioxy); 5.06-4.84 (m, 1H, H dihydroisoquinoline); 4.86 - 4.17 (m, 2H, H dihydroisoquinoline); 3.65-3.6-3.55 (m, 3H, H methyl ester); 3.43-4.26 (m, 2H, H tetrahydroindolizine); 3.58-3.5 (m, 4H, H morpholine); 2.37-3.05 (m, 4H, 2H dihydroisoquinoline, 2H tetrahydroindolizine); 1.68-2.56 (m, 4H, H morpholine); 1.4-2.0 (m, 4H, H tetrahydroindolizine) IV: v:> C = O 1695 cm -1 ester; v:> C = O 1625 cm-1 amide; v:> C-O-C <1214-1176-1115 cm’1; > CH-Ar 772-744 cm'1 STEP B: 3- [6 - [(3S) -3- (MORPHOLINOMETHIL) -3,4-DI-HYDRO-1H- ISOQUINOLIN-2-CARBONIL] -1,3- BENZODIOXOL-5-IL] -5,6,7,8- TETRA-HYDRO-1-INDOLIZINACARBOXYLATE
[00127] To a solution of 4.6 g of the compound of Step A (8.26 mmoles) in 24 ml of dioxane is added a solution of lithium hydroxide (675 mg, 16.1 mmoles). The whole is placed in a microwave oven at 140 W for a period of 2.5 hours. The reaction mixture is subsequently filtered and dried. The solid thus obtained is dried at 40 ° C in a hot box, in the presence of P2O5. 1H NMR: δ (400 MHz; dmso-d6; 79.9 ° C): 6.7-7.15 (unresolved peak, 6H, aromatic H); 6.21 (s, 1H, aromatic H); 6.03 (s, 2H, H methylenedioxy); 4.0-5.0 (unresolved peak, 3H dihydroisoquinoline); 3.4-3.6 (unresolved peak, 3H tetrahydroindolizine, 3H morpholine); 2.5-3.1 (unresolved peak, 4H, 2H tetrahydroindolizine, 2H morpholine); 1.5-2.4 (unresolved peak, 10H morpholine) IV: v:> C = O broad 1567 cm-1 acetate; v: 1236 cm-1 STEP C: N- (4 - {[TERC-BUTYL (DIMETHYL) SILIL] OXY} PHENYL) -3- {6- [((3S) -3- (4-MORFOLINILMETYL) -3, 4-DI-HYDRO-2 (1 H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -N-FENIL- 5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00128] To a solution of 2.6 g of the compound of Step B (4.73 mmol) in 47 ml of dichloromethane is added, dropwise, 1.2 ml of oxalyl chloride, at 0 ° C. The reaction mixture is stirred at room temperature for 11 hours, and then coevaporated several times with dichloromethane. The product thus obtained is suspended in 37 ml of dichloromethane and is then added to a solution of 2.1 g of the compound obtained in Preparation 1 "(7.1 mmoles), in 10 ml of dichloromethane, in the presence of 0.6 ml pyridine (7.1 mmoles). The whole is stirred at room temperature overnight. The reaction mixture is concentrated and purified by chromatography on silica gel (dichloromethane / methanol gradient). The title product is obtained in the form 1H NMR: δ (500 MHz; dmso-d6; 26.9 ° C): 6.9-7.3 (aromatic 9H); 6.88 (aromatic 2H); 6.72-6, 87 (aromatic 2H); 6.64 (aromatic 2H); 6.13 (2H methylenedioxy); 5.05-4.74 (1H dihydroisoquinoline); 4.25-4.13 (2H dihydroisoquinoline) ; 3.44-3.7 (4H morpholine); 3.62-3.52 (2H tetrahydroindolizine); 3.0-2.6 (4H, 2H tetrahydroindolizine, 2H dihydroisoquinoline); 2, 54-1.94 (6H morpholine); 1.91-1.53 (4H tetrahydroindolizine); 0.92 (9H ether-butyl); 0.17 (6H dimethyl) IV: v:> C = O: 1632 cm'1; v:> COC <: 1237 cπr1; v: -Si-OC-: 1035 cπr1: -Si-C- : 910 cm-1;> CH-Air: 806 cm'1 STEP D: N- (4-HYDROXYphenyl) CHLORIDRATE -3- {6 - [((3S) -3- (4-MORPHOLINYLMETH) -3.4 -DI-HYDRO-2 (1 H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -N-FENIL- 5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00129] To a solution of 1.9 g of the compound obtained in Step C (2.3 mmoles) in 4 ml of methanol is added 0.646 g (11.5 mmoles) of potassium hydroxide dissolved in 8 ml of methanol. The whole is stirred at room temperature for 30 minutes. The reaction mixture is subsequently diluted in dichloromethane and washed, in sequence, with a 1 N HCI solution, a saturated solution of NaHCOa and then a saturated solution of NaCI until a neutral pH is reached. The organic phase is subsequently dried over magnesium sulfate, filtered and evaporated. The crude product thus obtained is purified on silica gel (dichloromethane / methanol gradient). The solid is subsequently dissolved in dichloromethane, and 2 ml of 1 N ethereal hydrogen chloride are added. The whole is stirred for an hour and then evaporated to dryness. The hydrochloride thus obtained is dissolved in a water / acetonitrile mixture until completely dissolved and is then lyophilized. Elementary microanalysis:% of C% of H% of N% of Or Calculated 69.11 5.8 7.5 4.74 Found 68.95 5.46 7.51 4.48 Rotating capacity: (a) D20 = + 50.8 ° (c = 9 mg / mL, MeOH) EXAMPLE 2: N- (4-HYDROXYPHENYL) -N- (4-METHYLphenyl) -3- {6 - [((3S) -3- (4 -MORFOLINYLMETHIL) -3,4-DI-HYDRO- 2 (1H) -ISOQUINOLINYL) CARBONIL] -1,3-BENZODIOXOL-5-IL} - 5,6,7,8-TETRA-HYDRO-l -INDOLIZINE CARBOXAMIDE
[00130] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with 4 - {[ether-butyl (dimethyl) silyl] oxy} -A / - (4-methylphenyl) aniline. Elementary microanalysis:% of C% of H% of N% of Cl% of Cl- Calculated 69.42 5.96 7.36 4.66 4.66 Found 69.19 5.76 7.19 4.62 4.48 EXAMPLE 3: / V- (4-CHLOROPHENYL) - / V- (4-HYDROXYphenyl) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETHYL) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} - 5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00131] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (4-chlorophenyl) aniline. Elementary microanalysis:% C% H% N% Cl% Cl- Calculated 66.07 5.42 Found 65.74 5.14 7.17 9.07 4.54 7.08 9.02 4, 48 Rotating capacity: (a) D20 = + 80.9 ° (c = 2.5 mg / mL, MeOH) EXAMPLE 4: N- (3-FLUOR-4-METHYLPHYL) CHLORIDRATE - / V- (4-HYDROXYphenyl ) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINYL) CARBONYL] -1,3-BENZODIOXOL-5-IL} - 5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00132] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (3-fluorine-4- methylphenyl) aniline High resolution mass (ESI +): Empirical formula: C44H43FN4O6 [M + H] + calculated: 743.3245 [M + H] + measure: 743.3250 Rotating capacity: (α) D20 = + 40.7 ° (c = 2.5 mg / ml, MeOH) EXAMPLE 5: / V- (4-HYDROXYPHENYL) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETHYL) -3,4- DI-HYDRO-2 (1H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} - / V- [4- (TRIFLUORMETÓXI) FENIL] -5,6,7,8-TETRA-HIDRO-1 -INDOLIZINE CARBOXAMIDE
[00133] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (4-trifluormethoxyphenyl) aniline. Elementary microanalysis:% C% H% N% Cl- Calculated 63.57 5.09 6.74 4.26 Found 63.38 4.95 6.88 4.23 EXAMPLE 6: N, N- CHLORIDATE BIS (4-HYDROXYphenyl) -3- {6- [((3S) -3- (4-MORPHOLINYLMETHYL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] -1,3-BENZODIOXOL- 5-IL} -5,6,7,8- TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00134] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (4 - {[ tert-butyl (dimethyl) silyl] oxy} phenyl) aniline Elemental microanalysis:% of C 67.66 67.11 Calculated% of N 7.34 7.31% of Cl- 4.64 4.74 Found Rotating capacity: (o ) EXAMPLE 7: N- [4- (HYDROXIMETHYL) PHENYL] -N- (1- METHYL-1H-INDOL-5-IL) -3- {6 - [((3S) -3- (4-MORPHOLINILMETHYL ) -3,4-DI- HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE% deH 5.68 5.49 D20 = + 50.8 ° (c = 6 mg / mL, MeOH)
[00135] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with A / - [4- ({[tert-butyl (dimethyl) silyl] oxy} methyl) phenyl] -1 -methyl-1H-indole-5-amine Elemental microanalysis:% C% H% N% Cl- Calculated 69.32 5.94 8.6 4.35 Found 69.63 5.75 8.59 4.13 EXAMPLE 8: N- (2,3-DI-HYDRO-1H-INDOL-5-IL) -N- [4- (HYDROXY) PHENYL] -3- {6 - [(( 3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] -1,3-BENZODIOXOL-5-IL} -5,6,7,8- TETRA- HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00136] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with N- (4- {[tert-butyl (dimethyl) silyl] oxy} phenyl) -5-indolinamine. Microanalysis elementary:% of C% of H% ofN% of Cl Calculated 65.53 5.74 8.49 8.60 Found 65.47 5.69 8.43 7.82 Rotating capacity: (a) D20 = + 40.9 ° (c = 3.5 mg / ml, MeOH) EXAMPLE 9: N- [4- (HYDROXY) PHENYL] -N- (1-METHYL-2,3-DI-HYDRO-1H-INDOL-5- HYDROCHLORIDE IL) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETHIL) - 3,4-DI-HYDRO-2 (1H) -ISOQUINOLINYL) CARBONYL] -1,3- BENZODIOXOL-5-IL} -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CAR-BOXAMIDE
[00137] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with A / - (4- {[ferc-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl- 5-indolinamine High resolution mass (ESI +): Empirical formula: C46H47N5O6 [M + H] + calculated: 766.3605 [M + H] + measure: 766.3601 EXAMPLE 10: M- [4- (HYDROXY CHLORIDATE) ) PHENYL] -A / - (1-METHYL-1H-INDOL-5-IL) -3- {6 - [((3S) -3- (4-MORFOLINYLMETHIL) -3,4-DI-HYDRO-2 ( 1 H) -ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -5,6,7,8- TETRA-HYDRO-1-INDOLIZINE CARBOXAMIDE
[00138] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with / V- (4- {[ferc-butyl (dimethyl) silyl] oxy} phenyl) -1- methyl-1 H-indole-5-amine Elemental microanalysis: (theory for HC11.1)% of N% of C% of H% of Cl- Calculated 68.72 68.39 8.71 8.66 4.85 4.33 5.78 5.55 D20 = + 37.6 ° (c = 7 mg / mL, MeOH) Found Rotating capacity: (α) EXAMPLE 11: N- (4-HYDROXYphenyl) CHLORIDRATE -3- {6 - [( (3R) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] -1,3-BENZODIOXOL-5-IL} -N-PHENYL-5,6,7 , 8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00139] The procedure is as in the process of Example 1, replacing the compound from Preparation 1 'used in Step A with the compound from Preparation 2'. Elementary microanalysis:% of C% of H% of N% of Cl- Calculated 69.11 5.80 7.50 4.74 Found 68.89 5.23 7.41 4.62 Rotating capacity: (a) D20 = -45, 1 ° (c = 9 mg / ml, MeOH) EXAMPLE 12: / V- (4-HYDROXICICLOEXYL) - / V- (1- METHYL-1H-INDOL-5-IL) -3- {6 - [( (3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI- HYDRO-2 (1H) -ISOQUINOLINYL) CARBONYL] -1,3-BENZODIOXOL-5-IL} - 5,6,7,8-TETRA -HYDRO-1-INDOLIZINE CARBOXAMIDE
[00140] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with N- (4- {[tert-butyl (dimethyl) silyl] oxy} cyclohexyl) -1-methyl-1H -indole-5-amine High resolution mass (ESI +): Empirical formula: C46H51N5O6 [M + H] + calculated: 770.3918 [M + H] + measure: 770.3928 EXAMPLE 13: N BIS (CHLORIDATE) - (4-HYDROXYphenyl) -N- (1- METHYL-1 H-INDOL-5-IL) -3- {6 - [((3S) -3 - [(4-METHYL-1 - PIPERAZINIL) METHYL] - 3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] -1,3-BENZODIOXOL-5-IL} -5,6,7,8- TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00141] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation T used in Step A with the compound of Preparation 3 'and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indole-5-amine. Elemental microanalysis:%% C% H%% N% Cl% de Cl- Calculated 66.43 5.93 9.89 8.34 8.34 Found 66.36 5.79 9.83 8.11 7.67 Rotating capacity: (o) D20 = + 60.1 ° (c = 6 mg / mL, MeOH) EXAMPLE 14: N- (4-HYDROXYphenyl) -N- (1-METHYL-1 H-INDOL-5-IL) -3- {6 - [((3S) -3 - (1,4-OXAZEPAN-4-ILMETIL) -3,4-DI- HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONY] -1,3-BENZODIOXOL-5-IL} -5,6,7,8 -TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00142] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation T used in Step A with the compound of Preparation 4 'and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 H-indole-5-amine. Elemental microanalysis:% C% H% deN% Cl%% CL- Calculated 69.32 5.94 8.60 4.35 4.35 Found 69.24 5.56 8.52 4.47 4.44 EXAMPLE 15: N- (4-HYDROXYphenyl) -N- ( 1- METHYL-1H-INDOL-5-IL) -3- {6 - [((3S) -3 - {[(3R) -3- METHYLMORFOLINYL] METHIL} -3,4-DI-HYDRO-2 (1H ) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -5,6,7,8- TETRA-HYDRO-1 -IN FROM LIZIN TO CARBOXAMIDE
[00143] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation T used in Step A with the compound of Preparation 5 'and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 H-indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69.32 5.94 8.60 4.35 Found 69.10 5.68 8.52 4.29 EXAMPLE 16: N- (4-HYDROXYphenyl) -N- (1-METHYL-1 H-INDOL- HYDROCHLORIDE 5-IL) -3- {6 - [((3S) -3 - {[(3S) -3-METHYLMORPHOLINYL] METHIL} - 3,4-DI-HYDRO-2 (1H) -ISOQUINOLINYL) CARBONY] - 1,3- BENZODIOXOL-5-IL} -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CAR-BOXAMIDE
[00144] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation T used in Step A with the compound of Preparation 6 'and, on the other hand, the compound of Preparation 1 "used in Step C by N- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69.32 5.94 8.60 4.35 Found 68.97 5.55 8.44 3.73 EXAMPLE 17: CHLORIDRATE OF 3- {6 - [((3S) -3 - {[(3S, 5S ) -3,5- DIMETHYLMORFOLINIL] METHIL} -3,4-DI-HYDRO-2 (1H) - IS0QUIN0LINIL) CARB0NIL] -1,3-BENZODIOXOL-5-IL} -N- (4- HIDR0XIFENIL) -N- (1-METHYL-1 H-INDOL-S-ILJ-δ.βJ.δ-TETRA-HYDRO- 1-INDOLIZINE CARBOXAMIDE
[00145] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation T used in Step A with the compound of Preparation T and, on the other hand, the compound of Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69.59 6.08 8.45 4.28 Found 69.29 5.52 8.46 4.09 EXAMPLE 18: 3- {5-BROMO-2 - [((3S) -3- (4- MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONYL] FENIL} -N- (4-HYDROXYphenyl) -N- (1- METHYL-1 H-INDOL-5-IL) -5 , 6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00146] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 2 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indole-5-amine. High resolution mass (ESI +): Empirical formula: C45H4479BrNsO4 [M + H] + calculated: 798.2655 [M + H] + measure: 798.2626 EXAMPLE 19: 3- {5-BROMO-2 - [((3S) -3- (4-MOR- FOLINILMETIL) CHLORIDATE - 3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] PHENYL} -N- (4-HYDROXYphenyl) -N- (1-METHYL-2,3-DI-HYDRO-1H-INDOL-5-IL ) -5,6,7,8-TETRA-HYDRO-1- INDOLIZINE CARBOXAMIDE
[00147] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 2 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-5-indolinamine. High resolution mass (ESI +): Empirical formula: C45H4679BrNsO4 [M + H] + calculated: 800 , 2811 [M + H] + measure: 800.2791 EXAMPLE 20: 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETHYL) -3,4-DI-HYDRO CHLORIDATE -2 (1H) - ISOQUINOLINYL) CARBONY] FENIL} -N- (4-HYDROXYphenyl) -N-FENYL- 5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00148] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 used in Step A with the compound of Preparation 3. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 68.38 5.74 7 , 59 4.81 Found 67.89 5.71 7.72 4.68 Rotating capacity: (a) D20 = + 53.7 ° (c = 6 mg / mL, MeOH) DE 3- {5-CHLORINE-2 - [(((3S) -3- (4- EXAMPLE 21: BIS (CHLORIDRATE) MORPHOLINYLMETHYL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] PHENYL} -N- (2,3- DI-HYDRO-1H-INDOL-5-IL) -N- (4-HYDROXYphenyl) -5,6,7,8-TETRA-HYDRO-1-INDOLIZINE CARBOXAMIDE
[00149] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 5-indolinamine. High-resolution mass (ESI +): Empirical formula: C44H4435CIN5θ4 [M + H] + calculated: 742.3160 [M + H] + measure: 742,3120 EXAMPLE 22: 3- {5-CHLORINE-2 - [((3S) -3- (4-MORPHOLINYLMETHYL) -3,4-DI-HYDRO-2 (1 H) CHLORIDRATE - ISOQUINOLINIL) CARBONIL] PHENYL} -N- (4-HYDROXYphenyl) -N- (1- METHYL-1 H-INDOL-5-IL) -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00150] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1/7-indole-5-amine. Elemental microanalysis:% C% H% N% Cl% - Calculated 68.04 5.72 8.82 4.91 Found 67.84 5.46 8.64 5.21 Rotating capacity: (a) D20 = + 55.9 ° (c = 7 mg / mL, MeOH) EXAMPLE 23: 3- {5-CHLORINE-2 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINIL) CARBONY] BIS (CHLORIDATE) } -N- (4-HYDROXYphenyl) -N- (1- METHYL-2,3-DI-HYDRO-1 H-INDOL-5-IL) -5,6,7,8-TETRA-HYDRO-1 - INDOLIZINE CARBOXAMIDE
[00151] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-5-indolinamine Elemental microanalysis:% C% H% deN% Cl% Cl- Calculated 65.18 5 , 83 8.45 12.83 8.55 Found 65.75 5.45 8.39 11.71 7.54 Rotating capacity: (a) D20 = + 56.6 ° (c = 6 mg / mL, MeOH) EXAMPLE 24: 3- {5-FLUOR-2 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONIL] PHENYL} -N- (4-HYDROXYphenyl) -N- (1-METHYL-1 H-INDOL-5-IL) -5,6,7,8-TETRA-HYDRO-1-INDOLIZINE CARBOXAMIDE
[00152] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 4 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1/7-indole-5-amine. Elemental microanalysis:% C% H% N Cl- Calculated 69.80 5.86 Found 69.57 5.62 9.04 4.58 8.76 4.47 Rotating capacity: (a) D20 = + 55.0 ° (c = 5 mg / mL, MeOH) EXAMPLE 25: 3- {5-FLUOR-2 - [((3S) -3- (4-MOR- FOLINYLMETHYL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] PHENYL} -N - (4-HYDROXYphenyl) -N-PHENYL- 5,6,7,8-TETRA-HYDRO-1-INDOLIZINE CARBOXAMIDE
[00153] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 used in Step A with the compound of Preparation 4. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69.94 5.87 7 , 77 4.92 Found 69.70 5.32 7.72 4.80 EXAMPLE 26: 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETHYL) -3 HYDROCHLORIDE, 4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONY] PHENYL} -N- (4-HYDROXYphenyl) -N- (1-METHYL-1,2,3,4-TETRA-HYDRO-6-QUINOLINY) -5,6,7,8-TETRA- HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00154] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1,2,3,4-tetrahydro-6-quinolinamine. Elemental microanalysis: (theory for HC11,5 )% deC% deH% deN% Cl- Calculated 66.97 6.05 8.49 6.45 Found 66.80 5.55 8.32 6.23 EXAMPLE 27: 3- {5-CHLORINE-2 CHLORIDATE - [(((3S) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINIL) CARBONY] FENIL} -N- (4-HYDROXYphenyl) -N- (4- METHYL-3,4-DI-HYDRO-2H-1,4-BENZOXAZIN-7-IL) -5,6,7,8-TETRA- HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00155] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-amine. Elementary microanalysis: (theory for HCI 1.1)% C% H%% N% Cl ~ Calculated 66.53 5.84 8.62 4.80 Found 66.59 5.39 8.47 4.80 EXAMPLE 28: 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETHYL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] PHENYL) -N- [4- (DIETHYLAMINE ) PHENYL] -N- (4-HYDROXYphenyl) -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00156] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V1- (4 - {[tert-butyl (dimethyl) - silylJoxyJfeniO-A / t / Adietyl-1,4-benzenediamine. Elemental microanalysis: (theory for HC11,6)% of C% of H% of N% of Cl- Calculated 66.51 6.26 8.43 6.83 Found 66.71 5.58 8.39 7.08 EXAMPLE 29: 3- {5-CHLORINE-2 - [((3S) -3- (4- MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] FENIL} -N- (2,3-DI-HYDRO-1H-INDEN-5- IL) -N- (4- HYDROXYphenyl) -5,6,7,8-TETRA-HYDRO-1-INDOLIZINE CARBOXAMIDE
[00157] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 5-indanamine. Elementary microanalysis: Calculated Found% C 70% H%% N% CI- 69.49 69.47 5.96 7.20 4.56 5.43 7.21 4.21 EXAMPLE 30: 3- {5-CHLORINE-2 - [((3S) -3 - [(4- METHYL-1-PIPERAZINIL) BIS (CHLORIDATE) METHIL] -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONYL] PHENYL} -N- (4-HYDROXYphenyl) -N- (1- METHYL-1 H-INDOL-5-IL) -5 , 6,7,8-TETRA-HYDRO-1 -INDOLIZINE CAR BOXAMIDE
[00158] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the respective compounds of Preparations 3 and 3' and, on the other hand, the compound of Preparation 1 "used in Step C by N- (4- {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1H-indole-5-amine. High resolution mass (ESI +): Empirical formula: C46H4735CINβθ3 [M + H] + calculated: 767.3476 [M + H] + measure: 767.3476 EXAMPLE 31: N- (4-HYDROXYphenyl) CHLORIDATE -3- {8 - [((3S) -3- ( 4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONYL -3,4-DI-HYDRO-2H-1,5-BENZODIOXEPIN-7-IL} -N-PHENYL-5 , 6,7,8-TETRA-HYDRO-1- INDOLIZINE CARBOXAMIDE
[00159] The procedure is as in the process of Example 1, replacing the compound from Preparation 1 used in Step A with the compound from Preparation 5. High resolution mass (ESI +): Empirical formula: C45H46N4O6 [M + H] + calculated: 739 , 3496 [M + H] + measure: 739,3479 EXAMPLE 32: N- (4-HYDROXYPHENYL) -N- (1-METHYL-1H-INDOL-5-IL) -3- {8 - [(( 3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONY] -3,4-DI-HYDRO-2H-1,5- BENZODIOXEPIN-7-IL} -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CAR-BOXAMIDE
[00160] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 5 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69.59 6.08 8.45 4.78 Found 69.23 5.46 8.41 4.16 EXAMPLE 33: N- (4-HYDROXYphenyl) CHLORIDRATE -3- {5-ME- TOXY-2- [ ((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] PHENYL} -N- (1-METHYL-1H-INDOL-5-IL) - 5 , 6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00161] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 6 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 70.26 6.15 8.91 4.51 Found 69.78 5.36 8.90 4.29 Rotating capacity: (a) D20 = + 42.1 ° (c = 6 mg / mL, MeOH) EXAMPLE 34: N- (4-HYDROXYphenyl) -3- {7 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONYL] - 2,3-DI-HYDRO-1,4-BENZODIOXIN-6 IL} -N-PHENYL-5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00162] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 used in Step A with the compound of Preparation 7. Elemental microanalysis:% of C% of H% of N ° / o of Cl- Calculated 69.42 5 , 96 7.36 4.66 Found 69.39 5.56 7.30 4.49 Rotating capacity: (a) D20 = + 34.5 ° (c = 6 mg / mL, MeOH) EXAMPLE 35: N- ( 4-HYDROXYphenyl) -N- (1-METHYL-1H-INDOL-5-IL) -3- {7 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 ( 1 H) - ISOQUINOLINIL) CARBONIL] -2,3-DI-HYDRO-1,4-BENZODIOXIN-6-IL} -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00163] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 7 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 H-indole-5-amine, it being understood that the product thus obtained is not subjected to a step of formation of salt in the presence of ethereal hydrogen chloride Elemental microanalysis:% of C 7odeH 7odeN Calculated 72.57 6.09 9.00 Found 3.11 5.70 8.95 Rotating capacity: (a) D20 = + 88.2 ° ( c = 7 mg / mL, MeOH) EXAMPLE 36: 3- {5-ETOXY-2 - [((3S) -3- (4-MOR-FOLINYLMETHYL) -3,4-DI-HYDRO-2 (1H) CHLORIDRATE ) - ISOQUINOLINYL) CARBONYL] PHENYL) -N- (4-HYDROXYphenyl) -N- (1- METHYL-1 H-INDOL-5-IL) -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CAR -BOXAMIDE
[00164] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 8 and, on the other hand, the compound from Preparison 1 "used in Step C by / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indole-5-amine. Elemental microanalysis:% C% H% N% of Cl Calculated 70.53 6.30 8.75 4.43 Found 70.77 5.59 8.66 4.22 EXAMPLE 37: N- (4-HYDROXYphenyl) -N- (1-METHYL- 1H- HYDROCHLORIDE INDOL-5-IL) -3- {2,2-DIDEUTERY-6 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONIL] - 1,3-BENZODIOXOL-5-IL} -5,6,7,8- TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00165] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 9 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1/7-indole-5-amine. High resolution mass (ESI +): Empirical formula: C46H43N5O6D2 [M + H] + calculated: 766.3573 [M + H] + measure: 766.3533 Rotating capacity: (a) D20 = + 35.5 ° (c = 3.5 mg / mL, MeOH) EXAMPLE 38: N-CHLORIDATE - (4-HYDROXYphenyl) -3- {2,2- DIDEUTERY-6 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -N- PHENYL-5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE STEP A: N- (4-HYDROXYphenyl) -3- {2,2- DIDEUTÉRIO-6 - [((3S) -3- (4- MORPHOLINILMETIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -N-FENIL - 5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00166] The procedure is as in the process of Example 1, replacing the compound from Preparation 1 used in Step A with the compound from Preparation 9, it being understood that the salt formation step in the presence of ethereal hydrogen chloride is performed only in Step B below. STEP B: N- (4-HYDROXYPHENYL) -3- {2,2-DIDEU- THERIUM-6 - [((3S) -3- (4-MORPHOLINYLMETHYL) -3,4-DI-HYDRO-2 ( 1 H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -N-PHENYL- 5,6,7,8-TETRA-HYDRO-1-INDOLIZINE CARBOXAMIDE
[00167] The product obtained in Step A is dissolved in dichloromethane, and 2 mL of 1 N ethereal hydrogen chloride are added. The whole is stirred for an hour and then evaporated to dryness. The hydrochloride thus obtained is dissolved in a water / acetonitrile mixture until completely dissolved, and is then lyophilized. Elementary microanalysis:% of C% of H% of N% of Cl% of Cl- Calculated 68.93 5.80 7.48 4.73 4.73 Found 68.45 5.49 7.57 4.63 4.54 EXAMPLE 39 : N- (4-HYDROXYphenyl) -N- (1-METHYL-1H-INDAZOL-5-IL) -3- {7 - [((3S) -3- (4-MORPHOLINILMETHYL) -3,4- DI-HYDRO- 2 (1 H) -ISOQUINOLINIL) CARBONIL] -2,3-DI-HYDRO-1,4-BENZODIOXIN- 6-IL} -5,6,7,8-TETRA-HYDRO-1-INDOLIZINE CARBOXAMIDE
[00168] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 7 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indazol-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 67.76 5.81 10.31 4.35 Found 67.82 5.25 9.87 4.18 Rotating capacity: (α) D20 = + 42.6 ° (c = 5 mg / mL, MeOH) EXAMPLE 40 : N- (4-HYDROXIFENYL) -N- (1-METHYL- 1,2,3,4-TETRA-HYDRO-6-QUINOLINYL) -3- {7 - [((3S) -3- (4 -MORFOLINI- LMETIL) -3,4-DI-HYDRO-2 (1H) -ISOQUINOLINIL) CARBONIL] -2,3-DI- HYDRO-1,4-BENZODIOXIN-6-IL} -5,6,7,8 -TETRA-HYDRO-1 - INDOLIZINE CARBOXAMIDE
[00169] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 7 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1,2,3,4-tetrahydro-6-quinolinamine. Elementary microanalysis:% deC% deH% deN % Cl% Cl- Calculated 66.51 6.16 8.08 8.18 8.18 Found 66.85 5.88 8.04 6.47 6.25 EXAMPLE 41: N- (4-HYDROXYPHENYL CHLORIDATE) ) -N- (4-METIL- 3,4-DI-HYDRO-2H-1,4-BENZOXAZIN-7-IL) -3- {7 - [((3S) -3- (4-MORPHO-LINYLMETH)) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONIL] -2,3- DI-HYDRO-1,4-BENZODIOXIN-6-IL} -5,6,7,8-TETRA-HYDRO -1 -INDOLIZINE CARBOXAMIDE
[00170] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 7 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-amine. High resolution mass ( ESI +): Empirical formula: C47H49N5O7 [M + H] + calculated: 796.3710 [M + H] + measure: 796.3687 EXAMPLE 42: 3- {5-CHLORINE-2 - [((3S) -3 - (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] FENIL} -N- (4-HYDROXYphenyl) -N- (1- METHYL-1 H-INDAZOL-5 -IL) -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00171] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indazol-5-amine. Elemental microanalysis:% C% H% N%% Cl% of Cl- Calculated 66.75 5.60 10.61 Found 66.63 5.06 10.42 8.96 4.48 8.83 4.46 EXAMPLE 43: 1- {5-CHLORINE-2 CHLORIDATE - [(((3S) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] FENIL} -N- (4-HYDROXYphenyl) -N- (1- METHYL-2,3-DI-HYDRO-1H-INDOL-5-IL) -5,6,7,8-TETRA-HYDRO-3-INDOLIZINE CARBOXAMIDE
[00172] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 24 and, on the other hand, the compound from Preparation 1 "used in Step C with ti I) silyl] oxy} phen i I) -1-methyl-1 H-indole-5-amine Elemental microanalysis: N- (4 - {[tert-butyl (dime-% of C% of H% of N% deCI Calculated 68.35 5.74 8.86 Found 68.29 5.21 8.76 8.97 9.04 EXAMPLE 44: 3- {5-FLUOR-2 - [((3S) -3 HYDROCHLORIDE - (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONY] FENIL} -N- (4-HYDROXYphenyl) -N- (1- METHYL-1 H-INDAZOL- 5-IL) -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00173] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 4 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indazol-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 68.16 5.72 10.84 4.57 Found 67.93 5.01 10.89 4.24 EXAMPLE 45: 3- {5-CHLORINE-2 - [((3S) -3- (4-MORPHOLINYLMETH)) -3,4- DI-HYDRO-2 (1H) -ISOQUINOLINYL) CARBONY] FENIL} -N- (4-HYDROXYphenyl) -N- (1'-METHYL-1 a, 2'-DI-HYDROESPIRO [CYCLOPROPANE] -1,3'-INDOL] -5'-IL) -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00174] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[ether-butyl (dimethyl) silyl] oxy} phenyl) - (1-methyl-1 ', 2'-dihydrospiro [cyclopropane-1,3'-indole] -5'-yl ) ami na Elemental microanalysis:% C% H% N Calculated 72.15 6.18 8.95 Found 71.86 5.76 8.85 EXAMPLE 46: 3- {5-CHLORINE-2 - [( (3S) -3- (1,4-OXA- ZEPAN-4-ILMETYL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONYL] PHENYL} -N- (4-HYDROXYphenyl) -N - (1- METHYL-1 H-INDOL-5-IL) -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00175] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the respective compounds of Preparations 3 and 4' and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4- {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1H-indol-5-amine. Elemental microanalysis:% deC% deH% deN Calculated 68.65 5.89 8.70 Found 68.33 5.45 8.54 Rotating capacity: (a) D20 = + 13.6 ° (c = 4 mg / mL, MeOH) EXAMPLE 47: N- ( 4-HYDROXYphenyl) -N- (1-METHYL-1H-INDOL-5-IL) -3- [2 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 ( 1 H) -ISOQUINOLINIL) CARBONIL] -5- (TRIFLUORMETYL) PHENYL] - 5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00176] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 10 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) - silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 67.02 5.50 8.50 4.30 Found 67.01 5.11 8.47 4.21 EXAMPLE 48: N- (4-HYDROXYphenyl) -N- (1-METHYL-1H-INDOL-5 HYDROCHLORIDATE -IL) -3- [2 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO- 2 (1H) -ISOQUINOLINIL) CARBONY] -5- (TRIFLUORMETÓXI) FENIL] - 5 , 6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00177] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 11 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) - silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:% C% H%% N% Cl% of Cl- Calculated 65.75 5.40 8.33 4.22 4.22 Found 65.78 5.00 8.35 4.33 4.50 EXAMPLE 49: 3- {5-CHLORINE-2 - [(( 3S) -3- (4-MORFOLINYLMETHYL) -3,4- DI-HYDRO-2 (1 H) -ISOQUINOLINYL) CARBONYL] FENIL} -N- (4-HYDROXYphenyl) -N- (1,3,3-TRIMETYL -2,3-DI-HYDRO-1 H-INDOL-5-IL) - 5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00178] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1,3,3-trimethyl-5-indolinamine, it being understood that the product thus obtained is not subjected to a salt formation step in the presence of ethereal hydrogen chloride Elemental microanalysis:% deC% deH% deN Calculated 71.97 6.42 8.93 Found 71.87 6.22 8.94 EXAMPLE 50: N- (4-HYDROXYphenyl) CHLORIDATE - N- (1-METHYL-1 H-INDAZOL-5-IL) -3- {2,2-DIDEUTERY-6 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO- 2 (1 H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -5,6,7,8- TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00179] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 9 and, on the other hand, the compound from Preparison 1 "used in Step C by AJ- (4 - {[ferc-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indazol-5-amine. Elemental microanalysis:% C% H% N% Cl- Calculated 67.28 5.66 10.46 4.41 Found 66.77 5.07 10.25 3.92 EXAMPLE 51: N- (3-FLUOR-4-METHYLphenyl) -N- (4 - HYDROXYphenyl) -3- {2,2-DIDEUTERY-6 - [(((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONIL] -1,3 -BENZODIOXOL-5-IL} -5,6,7,8- TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00180] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 9 and, on the other hand, the compound from Preparation 1 "used in Step C with N- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-fluor-4-methylaniline. Elemental microanalysis:% C% H%% N% Cl- Calculated 67.64 5.69 7, 17 4.54 Found 67.08 5.18 7.04 4.28 EXAMPLE 52: TYLAMINE HYDROCHLORIDE) METHIL -3,4-DI-HYDRO-2 (1 H) - 3- {5-CHLORINE-2- [(((3S) <J - [(DIME- ISOQUINOLINYL) CARBONY] PHENYL} -N- (4-HYDROXYphenyl) -N- (1-METYL-1 H-INDOL-5-IL) -5,6,7, 8-TETRA-HYDRO-1-INDOLLZINE CARBOXAMIDE
[00181] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A by the respective compounds of Preparations 3 and 8' and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4- {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. High resolution mass (ESI +): Empirical formula: C43H4235CINsO3 [M + H] + calculated: 712.3054 [M + H] + measure: 712.3060 Rotating capacity: (a) D20 = + 35.8 ° (c = 6 mg / mL, MeOH) EXAMPLE 53: 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETHYL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL] CARBONYL] PHENYL} - N- (4-HYDROXYPHENYL) -N- [4- METHYXY-3- (TRIFLUORMETHYL) PHENY] -5,6,7,8-TETRA-HYDRO-1- INDOLIZINE CARBOXAMIDE
[00182] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 4-methoxy-3- (trifluormethyl) aniline. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 63.23 5 , 19 6.70 4.24 Found 63.08 4.68 6.79 3.92 EXAMPLE 54: 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETH) CHLORIDATE -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] FENIL} -N- (4-HYDROXYphenyl) -N- [4- (METHYLSULFANYL) -3- (TRIFLUORMETYL) FENY] -5.6, 7,8-TETRA- HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00183] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 4- (methylsulfanyl) -3- (trifluormethyl) aniline. Elemental microanalysis:% C% H% deN% deS% Cl- Calculated 62.04 5.09 6.58 3.76 4.16 Found 62.10 4.90 6.61 3.37 3.99 EXAMPLE 55: 3- {5-CHLORINE-2 - [((3S ) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] FENIL} -N- (3-FLUOR-4-HYDROXYphenyl) -N- (1 -METHYL -1 H-INDOL-5-IL) -5,6,7,8-TETRA-HYDRO- 1-INDOLIZINE CARBOXAMIDE
[00184] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} -3- fluorophenyl) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:% C% H% deN % Cl- Calculated 66.83 5.48 8.66 4.38 Found 66.84 4.92 8.68 3.63 EXAMPLE 56: N- (4-HYDROXYphenyl) -N- (1-METHYL- HYDROCHLORIDE) 1H- INDOL-5-IL) -342 - [((3S) -3- (4-MORFOLINILMETlL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINIL) CARBONIL] PHENYL} -1 -INDOLIZINE CARBOXAMIDE
[00185] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 12 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) - silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 71.84 5.63 9.31 4.71 Found 71.74 5.25 9.24 4.38 EXAMPLE 57: N- (4-HYDROXYphenyl) -N- (1- METHYL-1 H) BIS (CHLORIDRATE) -INDOL-5-IL) -3- {6 - [((3S) -3 - [(4-METHYL-1 - PIPERAZINIL) METHIL] -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -1 - INDOLIZINE CARBOXAMIDE
[00186] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the respective compounds of Preparations 13 and 3' and, on the other hand, the compound of Preparation 1 "used in Step C by N- (4- {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1H-indole-5-amine. Elemental microanalysis:% of C% of H Calculated% of N 9.94 9.80% Cl- 8.38 8.03 5.48 5.25 Rotating capacity: (α) D20 = + 113.2 ° (c = 6 mg / nriL, MeOH) EXAMPLE 58: CHLORIDATE OF N- (4-HYDROXYphenyl) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINIL) CARBONY] -1,3-BENZODIOXOL -5-IL} -N-FENIL-1 - INDOLIZINE CARBOXAMIDE Found 66.74 66.69
[00187] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 13. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69, 49 5.29 7.54 4.77 Found 69.41 5.00 7.61 4.45 Rotating capacity: (o) D20 = + 111.4 ° (c = 6 mg / mL, MeOH) EXAMPLE 59: CHLORIDATE DE N- (4-HYDROXYphenyl) -N- (1-METHYL-1H-INDOL-5-IL) -3- {6 - [((3S) -3- (4-MORFOLINYLMETHIL) -3,4-DI- HYDRO- 2 (1H) -ISOQUINOLINYL) CARBONYL -1,3-BENZODIOXOL-5-IL} -1- INDOLIZINE CARBOXAMIDE
[00188] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 13 and, on the other hand, the compound from Preparation 1 "used in Step C with N- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69.38 5.32 8.79 4.45 Found 68.95 5.12 8.57 3.92 Rotating capacity: (a) D20 = + 116.8 ° (c = 5 mg / mL, MeOH) EXAMPLE 60 : N- (1-ETHYL-1H-INDOL-5-IL) -N- (4-HYDROXYphenyl) -3- {6 - [((3S) -3- (4-MORPHOLINILMETHYL) -3,4- DI-HYDRO- 2 (1 H) -ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -1 - INDOLIZINE CARBOXAMIDE
[00189] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 13 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) - silyl] oxy} phenyl) -1-ethyl-1 H-indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69.66 5.47 8.64 4.38 Found 69.81 5.13 8.64 4.30 EXAMPLE 61: N- (4-HYDROXYphenyl) -N- (1-METHYL-2,3-DI HYDROCHLORIDE -HYDRO-1 H-INDOL-5-IL) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETH) - 3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINYL) CARBONIL] -1,3- BENZODIOXOL-5-ILJ-1 -INDOLIZINE CARBOXAMIDE
[00190] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 13 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[ferc-butyl (dimethyl) - silyl] oxy} phenyl) -1-methyl-5-indolinamine. High-resolution mass (ESI +): Empirical formula: C46H43N5O6 [M + H] + calculated: 762.3292 [M + H] + measure: 762.3284 EXAMPLE 62: N- (4-HYDROXYphenyl) -N- (1-ISSO- PROPIL-1 H-INDOL-5-IL) -3- {6 - [(((3S) -3- (4-MORPHOLINYLMETHYL) -3,4- DI-HYDRO-2 (1H) -ISOQUINOLINYL) CARBONIL] -1,3-BENZODIOXOL- 5-IL} -1-INDOLIZINE CARBOXAMIDE
[00191] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 13 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[ferc-butyl (dimethyl) - silyl] oxy} phenyl) -1 -isopropyl-1 H-indole-5-amine. Elemental microanalysis: (theory for HC11.3)% Cl- % deC% deH% deN Calculated 69.94 5.62 8.50 4.30 Found 69.66 5.50 8.42 4.28 EXAMPLE 63: N- (1-ETHYL-2,3-DI- HYDROCHLORIDE HYDRO-1H-IN- DOL-5-IL) -N- (4-HYDROXYphenyl) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 ( 1H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -1- INDOLIZINE CARBOXAMIDE
[00192] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 13 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) - silyl] oxy} phenyl) -1-ethyl-5-indolinamine. Elementary microanalysis: (theory for HCI 1.3)% C% H% N % Cl- Calculated 68.57 5.67 8.51 5.60 Found 68.11 5.23 8.36 5.65 EXAMPLE 64: N- (4-HYDROXYphenyl) -N- (1-THIS- PROPIL-2,3-DI-HYDRO-1H-INDOL-5-IL) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H ) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -1 - INDOLIZINE CARBOXAMIDE
[00193] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 13 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) - silyl] oxy} phenyl) -1 -isopropyl-5-indolinamine. Elemental microanalysis: (theory for HCI 1.3)% Cl-% deC% deH% of Calculated N 68.85 5.81 8.36 5.50 Found 68.58 5.68 8.49 5.10 EXAMPLE 65: 3- {5-CHLORINE-2 - [((3S) BIS (CHLORIDRATE) - -3 - [(4-METHYL-1-PYPERAZINYL) METHYL] -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] PHENYL} -N- (4-HYDROXYphenyl) -N- (1HYL -1 H-INDOL-5-IL) -1 -INDOLIZINE CARBOXAMIDE
[00194] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the respective compounds of Preparations 14 and 3' and, on the other hand, the compound of Preparation 1 "used in Step C by A / - (4- {[ether-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. Elemental microanalysis: (theory for HC11.9 )% C% H% N% Cl- Calculated 66.36 5.44 10.09 8.09 Found 66.35 5.38 9.86 7.70 EXAMPLE 66: 3- BIS (CHLORIDATE) 3- {5-CHLORINE-2 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONY] PHENYL} -N- (4-HYDROXYphenyl) - N- (1- METHYL-2,3-DI-HYDRO-1 H-INDOL-5-IL) -1 -INDOLIZINE CARBOXAMIDE
[00195] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 14 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) - silyl] oxy} phenyl) -1-methyl-5-indolinamine Elemental microanalysis:% C% H% N% Cl% 65.50 5 , 37 Found 66.02 4.91 8.49 12.89 8.50 12.11 Rotating capacity: (a) D20 = + 142.2 ° (c = 3.5 mg / mL, MeOH) EXAMPLE 67: CHLORIDATE DE 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINIL) CARBONY] FENIL} -N- (4 -HYDROXYphenyl) -N- (1-METHYL-1 H-INDOL-5-IL) -1 -INDOLIZINE CARBOXAMIDE
[00196] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 14 and, on the other hand, the compound of Preparation 1 "used in Step CI il ] oxy} phenyl) -1-methyl-1 H-indole-5-amine Elemental microanalysis: by A / - (4 - {[tert-butyl (dimethyl) si-% C% H% N% Cl- Calculated 68.70 5.25 Found 68.43 4.88 8.90 4.51 8.83 4.13 Rotating capacity: (a) D20 = + 133.3 ° (c = 3.5 mg / mL, MeOH) EXAMPLE 68: 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETHYL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINIL HYDROCHLORATE CARBONIL] FENIL} -N- (4-FLUORFENIL) -N- (1- METHYL-1 H-INDOL-5-IL) -1 -INDOLIZINE CARBOXAMIDE
[00197] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 14 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4-fluorophenyl) -1-methyl-1 H-indole-5-amine, it being understood that step D is then limited to a hydrochloride formation step Elemental microanalysis:% deC% deH% deN% de Cl- Calculated 68.53 5.11 8.88 4.49 Found 68.48 4.71 9.09 4.28 EXAMPLE 69: N- (4-HYDROXYphenyl) -N- (1-METHYL- 2,3,4-TETRA-HYDRO-6-QUINOLINYL) -3- {7 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONIL] -2,3-DI-HYDRO-1,4-BENZODIOXIN-6- ILJ-1-INDOLIZINE CARBOXAMIDE
[00198] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 15 and, on the other hand, the compound from Preparation 1 "used in Step C with N- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1,2,3,4-tetrahydro-6-quinolinamine. High resolution mass (ESI +): Empirical formula : C48H47N5O6 [M + H] + calculated: 790.3605 [M + H] + measure: 790.3591 EXAMPLE 70: N- (4-HYDROXYphenyl) -N- (1-METHYL-1 H-INDOL-5 HYDROCHLORIDE -IL) -3- {7 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONY] -2,3-DI-HYDRO- 1,4- BENZ0DI0XIN-6-IL} -1 -INDOLIZINE CARBOXAMIDE
[00199] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 15 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) si-yl] oxy} phen i I) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:% deC% deH% deN% de Cl% of Cl- Calculated 69.66 5.47 8.64 4.38 4.38 Found 69.45 4.68 8.56 4.64 4.21 EXAMPLE 71: N- (4-HYDROXYphenyl) HYDROCHLORATE - 3- {5- METOXY-2 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] PHENYL} -N- (1-METHYL- 1H-INDOL-5-IL) -1- INDOLIZINE CARBOXAMIDE
[00200] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 16 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (di methyl) si I il] oxy} phen i I) -1-methyl-1 F / -indol-5-amine. High resolution mass (ESI +): Empirical formula : C46H43N5O5 [M + H] + calculated: 746.3342 [M + H] + measure: 746.3348 EXAMPLE 72: 8 - {[4-HYDROXY (1-METHYL-1H-INDOL-5-IL) ANILINE] - CARBONIL} -6- {6 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONY] -1,3-BENZODIOXOL-5-IL } -3,4-DI- HYDROPIRROLEUM [1,2-A] PIRAZINE-2 (1 H) -CARBOXYLATE TERC- BUTYL
[00201] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 17 and, on the other hand, the compound from Preparation 1 "used in Step C by / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine, it being understood that the product thus obtained is not subjected to a step of salt formation in the presence of ethereal hydrogen chloride Elemental microanalysis:% deC% deH% deN Calculated 69.43 6.06 9.72 Found 69.41 5.84 9.68 EXAMPLE 73: 8 - {[4- HYDROXY (1-METHYL-2,3-DI-HYDRO-1H-INDOL-5-IL) ANILINE] CARBONYL} -6- {6 - [((3S) -3- (4-MORPHOLINYLMETH) -3,4- DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -3,4-DI-HYDROPYROROLE [1,2-A] PIRAZINE-2 (1 H) - CARBOXYLATE TERC-BUTILA
[00202] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 17 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-5-indolinamine, it being understood that the product thus obtained is not subjected to a salt formation step in the presence of ethereal hydrogen chloride Elemental microanalysis:% of C% of H% of N Calculated 69.27 Found 69.20 6.28 9.69 6.11 9.77 EXAMPLE 74: N- (4) CHLORIDATE -HYDROXYphenyl) -N- (1-METHYL-1 H-INDOL-5-IL) -6- {6 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI- HYDRO-2 ( 1 H) -ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5- IL} -1,2,3,4-TETRA-HYDROPIRROLEUM [1,2-A] PIRAZINE-8- CARBOXAMIDE
[00203] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 17 and, on the other hand, the compound from Preparation 1 "used in Step C with N- (4 - {[tert-butyl (dimethyl) Si-lil] oxy} phenyl) -1-methyl-1 H-indole-5-amine, it being understood that the product thus obtained is not subjected to a formation step of salt in the presence of ethereal hydrogen chloride, as described in Example 1, Step D. The compound thus obtained is deprotected in the presence of 10 equivalents of trifluoroacetic acid in dichloromethane (10 mL / mmol), at room temperature, overnight. Then, the product is subsequently isolated by concentrating the reaction mixture to dryness, it is finally subjected to a salt formation step in the presence of ethereal hydrogen chloride. Elemental microanalysis: (theory for HC11.9)% Cl- % deC% deH% of N Calculated 64.80 5.55 10.08 8.08 Found 64.48 5.41 9.85 7.84 EXAMPLE 75: TRIS (CLORID N- (4-HYDROXYphenyl) -N- (1- METHYL-2,3-DI-HYDRO-1H-INDOL-5-IL) -6- {6 - [((3S) -3- (4) - MORFOLINILMETIL) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CAR- BONIL] -1,3-BENZODIOXOL-5-IL} -1,2,3,4-TETRA- HYDROPIRROLE [1, 2-A] PIRAZINA-8-CARBOXAMIDA
[00204] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 17 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silis] oxy} phenyl) -1-methyl-5-indolinamine, it being understood that the product thus obtained is not subjected to a salt formation step in the presence of ethereal hydrogen chloride, as described in Example 1, Step D. The compound thus obtained is deprotected in the presence of 10 equivalents of trifluoroacetic acid in dichloromethane (10mL / mmol), at room temperature, overnight. subsequently isolated by concentrating the reaction mixture to dryness, it is finally subjected to a salt formation step in the presence of ethereal hydrogen chloride Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 61.68 5 , 64 9.59 12.14 Found 61.65 5.35 9.45 11.72 EXAMPLE 76: N- (4-HYDROXIFEN BIS (CHLORIDATE) IL) -N- (1-METHYL-1 H-INDOL-5-IL) -5- {6 - [((3S) -3 - [(4-METHYL-1-PIPERAZINIL) METHIL] -3,4- DI-HYDRO-2 (1 H) - ISOQUINOLINIL) CARBONIL] -1,3-BENZODIOXOL-5-IL} -2,3-DI- HYDRO-1 H-PIRROLIZINE-7-CARBOXAMlDA
[00205] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the respective compounds of Preparations 18 and 3' and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4- {[tert-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. High resolution mass (ESI +): Formula empirical: C46H46N6O5 [M + H] + calculated: 763.3608 [M + H] + measure: 763.3594 EXAMPLE 77: 5- {5-CHLORINE-2 - [((3S) -3- [(4- METHYL-1-PIPERAZINIL) METHIL] -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] FENIL} -N- (4-HYDROXYphenyl) -N- (1-METHYL-1 H -INDOL-5-IL) -2,3-DI-HYDRO-1 H-PIRROLIZINE-7- CARBOXAMIDE
[00206] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and T used in Step A with the respective compounds of Preparations 19 and 3 'and, on the other hand, the compound of Preparation 1 "used in Step C by / / - (4 - {[ether-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. Elementary microanalysis: (theory for HC11.9 )% deC% deH% deN% Cl- Calculated 65.70 5.75 10.22 8.19 Found 65.46 5.55 10.68 7.65 EXAMPLE 78: 6- {5-CHLORINE-2 CHLORIDATE - [(((3S) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINIL) CARBONY] FENIL} -N- (4-HYDROXYphenyl) -N- FENIL- 3,4-DI-HYDRO-1 H-PYRROLEUM [2,1 -C] [1,4] OXAZIN A-8- CARBOXAMIDE
[00207] The procedure is as in the process of Example 1, replacing the compound from Preparation 1 used in Step A with the compound from Preparation 20. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 66.57 5.45 7 , 57 4.79 Found 66.22 5.23 7.53 4.57 EXAMPLE 79: 6- {5-CHLORINE-2 - [((3S) -3- (4-MORPHOLINYLMETH) -3 BIS (CHLORIDRATE) -3 , 4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] PHENYL} -N- (2,3-DI-HYDRO-1H-INDOL-5-IL) -N- (4-HYDROXYphenyl) -3.4 -DI-HYDRO-1H-PYRROLEUM [2,1- C] [1,4] OXAZINE-8-CARBOXAMIDE
[00208] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 20 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[fer-butyl (dimethyl) silyl] oxy} phenyl) -5-indolinamine. Elemental microanalysis:% C% H% N% Cl- Calculated 63.20 5.43 8, 57 8.68 Found 62.64 5.19 8.39 8.03 EXAMPLE 80: N- (4-HYDROXYphenyl) -N- (1-METHYL-1H-INDOL-5-IL) -6- {6- [ ((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINIL) CARBONYL] -1,3-BENZODIOXOL-5-IL} -3,4-DI- HYDRO -1 H-PIRROLEUM [2,1 -C] [1,4] OXAZINE-8-CARBOXAMIDE
[00209] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 21 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) sylyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine, it being understood that the product thus obtained is not subjected to a salt formation in the presence of ethereal hydrogen chloride Elemental microanalysis:% deC% deH% deN Calculated 70.57 5.66 9.14 Found 69.99 5.53 9.04 EXAMPLE 81: N- (4- HYDROXYphenyl) -N- (1-METHYL-2,3-DI-HYDRO-1H-INDOL-5-IL) -6- {6 - [((3S) -3- (4-MORPHOLINYLMETHY) - 3,4- DI-HYDRO-2 (1H) -ISOQUINOLINYL) CARBONIL] -1,3-BENZO- DIOXOL-5-IL} -3,4-DI-HYDRO-1 H-PYRROLEUM [2,1 -C] [1,4 ] OXAZINA-8- CARBOXAMIDA
[00210] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 21 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silic] oxy} phenyl) -1-methyl-5-indolinamine. Elementary microanalysis:% C% H% N% Cl- Calculated 67.20 5.76 8.71 4.41 Found 66.67 5.60 8.66 5.10 EXAMPLE 82: 6- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETH HYDROCHLORIDE ) -3,4-DI-HYDRO-2 (1 H) - ISOQUINOLINYL) CARBONY] PHENYL} -N- (3-FLUOR-4-METHYLPHYL) -N- (4-HYDROXYphenyl) -3,4-DI-HYDRO -1 H-PIRROLEUM [2,1 - C] [1,4] OXAZIN A-8-CARB0XAMIDA
[00211] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 20 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) -3-fluoro-4-methylaniline. Elemental microanalysis:% C% H%% N% Cl% Cl- Calculated 65 , 37 5.35 7.26 9.19 4.59 Found 65.49 4.67 7.45 9.18 4.40 Rotating capacity: (a) D20 = + 35.0 ° (c = 6 mg / mL , MeOH) EXAMPLE 83: 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR-FOLINYLMETH) -3,4-DI-HYDRO-2 (1H) -ISOQUINOLINYL) CARBONYL] - FENIL} -N- (4-HYDROXYphenyl) -N- (1 -METHYL-1 H-INDOL-6-IL) -6,7,8,9- TETRA-HYDRO-5H-PYRROLEUM [1,2-A ] AZEPIN A-1 -CARBOXAMIDA
[00212] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 22 and, on the other hand, the compound of Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) si-II] oxy} phen i I) -1-methyl-1 F / -indol-5-amine. High resolution mass (ESI +): Empirical formula : C46H4635CINsO4 [M + H] + calculated: 768.3317 [M + H] + measure: 768.3254 EXAMPLE 84: N- (4-HYDROXYphenyl) CHLORIDRATE -N- (1-METHYL-1 H-INDOL-6 -IL) -3- {6 - [((3S) -3- (4-MORPHOLINYLMETHIL) -3,4-DI-HYDRO- 2 (1 H) -ISOQUINOLINIL) CARBONY] -1,3-BENZODIOXOL-5- IL} - 6,7,8,9-TETRA-HYDRO-5H-PYRROLEUM [1,2-A] AZEPINE-1 - CARBOXAMIDE
[00213] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 23 and, Preparation 1 "used in Step C il] oxy} fen i I ) -1-methyl-1 / - / - indole-5-amine Elemental microanalysis:% C% H Calculated 69.32 5.94 Found 69.42 5.52 Rotating capacity: (a) D20 = + 86 , 6 'on the other hand, the compound of by A / - (4 - {[ferc-butyl (dimethyl) sil-% N% Cl- 8.60 4.35 8.74 4.05 (c = 8 mg / mL, MeOH) EXAMPLE 85: 3- {5-CHLORINE-2 - [((3S) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINIL HYDROCHLORIDE ) CARBONIL] PHENYL} -N- (4-HYDROXYphenyl) -N- (3-THYLENYL) -5,6,7,8-TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00214] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-thiophenamine. Elemental microanalysis:% C% H% N%% S% Cl- Calculated 64.60 5.42 7 , 53 4.31 4.77 Found 64.67 5.05 7.37 3.90 4.19 EXAMPLE 86: 6- {5-CHLORINE-2 - [((3S) -3- (4-MOR - FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONYL] FENIL} -N- (4-HYDROXYphenyl) -N- (1- METHYL-1 H-INDOL-5-IL) -3 , 4-DI-HYDRO-1 H-PYRROLEUM [2,1 - C] [1,4] OXAZIN A-8-CARBOXAMIDE
[00215] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 20 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) si-II] oxy} phen i I) -1-methyl-1 H-indole-5-amine. High resolution mass (ESI +): Empirical formula: C44H4235CINsO5 [M + H] + calculated: 756.2953 [M + H] + measure: 756.2936 EXAMPLE 87: N-BUTYL-N- (4-HYDROXYphenyl) CHLORIDRATE -3- {6 - [((3S) -3- (4-MORPHOLINYLMETHY) -3,4-DI-HYDRO-2 (1H) - ISOQUINOLINYL) CARBONY] -1,3-BENZODIOXOL-5-IL} -5,6,7,8- TETRA-HYDRO- 1 -INDOLIZINE CARBOXAMIDE
[00216] The procedure is as in the process of Example 1, replacing the compound from Preparation 1 "used in Step C with / V-butyl-4- {[tert-butyl (dimethyl) silyl] oxy} aniline. Elementary microanalysis:% deC% deH% deN% Cl- Calculated 67.71 6.51 7.70 4.87 Found 67.48 6.30 7.74 5.01 EXAMPLE 88: N-BUTYL-N CHLORIDATE - [(3- {6 - [((3S) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1 H) -ISOQUINOLINIL) CARBONIL] - 1,3-BENZODIOXOL-5-IL} -5 , 6,7,8-TETRA-HYDRO-1 -INDOLIZINYL) - METHIL] -1 -BUTANAMINE
[00217] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C by N, 1 d-dibutylamine, it being understood that Step D is then limited to a stage of formation of the high resolution mass (ESI +): Empirical formula: C39H50N4O5 [M + H] + calculated: 655.3859 [M + H] + measure: 655.3826 EXAMPLE 89: 3- {5-CHLORINE-2- CHLORIDATE [(((3S) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) -ISOQUINOLINYL) CARBONY] - FENIL} -N- (3-H IDROXYPROPI L) -N- ( 1-METI L-1H-INDOL-5-IL) -5,6,7,8- TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00218] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (3 - {[tert-butyl (dimethyl) silyl] oxy} propyl) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:%% C% H%% N% Cl%% Cl- Calculated 66.66 6.26 9.25 9.37 4.68 Found 66.51 5.87 9.25 9.12 4.21 EXAMPLE 90: 3- {5-CHLORINE-2 - [( (3S) -3- (4-MOR- FOLINYLMETHIL) -3,4-DI-HYDRO-2 (1H) -ISOQUINOLINIL) CARBONIL] - FENIL} -N- (4-HYDROXYBUTYL) -N- (1 -METHIL- 1 H-INDOL-5-IL) -5,6,7,8- TETRA-HYDRO-1 -INDOLIZINE CARBOXAMIDE
[00219] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 3 and, on the other hand, the compound of Preparation 1 "used in Step C with / V- (3 - {[tert-butyl (dimethyl) silyl] oxy} butyl) - 1-methyl-1 / - / - indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 67.01 6.41 9.09 4.60 Found 66.93 5.88 9.23 4.30 EXAMPLE 91: N- (3-FLUOR-4-METHYLphenyl) CHLORIDRATE -3- (5- FLUOR-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINO- LIN-2 (1 H) -IL] CARBONIL} PHENYL) -N- (4-HYDROXYphenyl) -5, 6,7,8-TETR- A-HYDROINDOLIZIN-1-CARBOXAMIDE
[00220] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 4 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-fluor-4-methylaniline. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 68.56 5.75 7 , 44 4.71 Found 68.57 5.23 7.53 4.74 EXAMPLE 92: N- (3-FLUOR-4-METHYLPHYL) -N- (4-HYDROXYphenyl) -6- (6 - {[ (3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HID- ROISOQUINOLIN-2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) - 3.4-DI- HYDRO-1 H-PIRROLE [2,1 -C] [1,4] OXAZIN A-8-CARBOXAMIDE
[00221] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 21 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[ferc-butyl (dimethyl) silyl] oxy} phenyl) -3-fluorine-4-methylaniline. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 66.11 5, 42 7.17 4.54 Found 66.02 4.92 7.13 4.26 EXAMPLE 93: 3- (5-CHLORINE-2 - {[(3R) -3- (MOR- FOLIN-4-ILMETIL) CHLORIDRATE ) -3,4-DI-HYDROISOQUINOLIN-2 (1H) - IL] CARBONYL} PHENYL) -N- (4-HYDROXYphenyl) -N- (1 -METHIL-1 H-INDOL- 5-IL) -5.6 , 7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00222] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the compounds of Preparations 3 and 2' and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4 - {[tert-butyl (di methyl) si I il] oxy} phen i I) -1-methyl I-1 H-indole-5-amine. Elementary microanalysis:% deC% deH% deN% Cl% Cl- Calculated 68.35 5.74 8.86 8.97 4.48 Found 68.27 5.14 8.92 8.70 4.08 EXAMPLE 94: N CHLORIDATE - (4-HYDROXYphenyl) -N- (1-METHYL-1H-INDAZOL-5-IL) -3- (6 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -5,6,7,8-TETRA-HYDROINDOLIZINE-1-CARBOXAMIDE
[00223] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with / V- (4- {[ferc-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl- 1H-indazol-5-amine Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 67.45 5.66 10.49 4.42 Found 67.40 5.19 10.40 4.11 EXAMPLE 95: N- (4-HYDROXYphenyl) -N- (1-METHYL-1 H-INDOL-S-ILJ-S-ÍS-METHIL-3-HYDROXYphenyl) -N-HYDROYOXINOLIN ^ IH Hydrochloride ^ IH ) -IL] CARBONIL} FENIL) -5,6,7,8- TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with compound of Preparation 25 and, on the other hand, the compound of Preparation 1 "used in Step C by A / - (4 - {[ferc-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 H-indole -5-amine. Elementary microanalysis: Calculated Found% of C 71.72 71.17% of H 6.28 5.66% of N 9.09 8.85% of Cl- 4.60 4.47 EXAMPLE 96: N- (4-HYDROXYPHYL CHLORIDATE) ) -N- (1- METHYL-1 H-INDOL-5-IL) -5- (6 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4- DI-HYDROISOQUINOLIN-2 ( 1 H) -IL] CARBONIL} -1,3- BENZODIOXOL-5-IL) -2,3-DI-HYDRO-1 H-PIRROLIZINE-7- CARBOXAMIDE
[00224] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 18 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[ferc-butyl (dimethyl) silyl] oxy} phen i I) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:% of C% of H% of N% of Cl - Calculated 68.74 5.64 8.91 4.51 Found 68.41 4.96 8.84 4.31 EXAMPLE 97: N- (3-CHLORINE-4-METHYLPHYL) CHLORIDRATE - 3- (5-CHLORINE -2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1H) -IL] CARBONY} PHENYL) -N- (4-HYDROXYphenyl) -5.6 , 7,8-TETRA-HYDROINDOLIZIN A-1 - CARBOXAMIDE
[00225] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-chloro-4-methylaniline. Elemental microanalysis:% C% H% N% Cl- Calculated 65.69 5, 51 7.13 4.51 Found 65.58 5.03 7.05 4.25 EXAMPLE 98: N- (3-FLUOR-4-METHYLphenyl) CHLORIDRATE -6- (5- FLUOR-2 - {[(3S ) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINO- LIN-2 (1H) -IL] CARBONY} PHENYL) -N- (4-HYDROXYphenyl) -3,4-DI-HIDR- O-1H-PIRROLO [2,1-C] [1,4] OXAZINE-8-CARBOXAMIDE
[00226] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 26 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silis] oxy} phenyl) -3-fluorine-4-methylaniline. High resolution mass (ESI +): Empirical formula: C42H40F2N4O5 [M + H] + calculated : 719,3045 [M + H] + measure: 719,3030 EXAMPLE 99: 6- (5-FLUOR-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3.4 -DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONI- L} PHENYL) -N- (4-FLUORPHENYL) -N- (4-HYDROXYphenyl) -3,4-DI-HYDRO- 1 H-PYRROLO [2 , 1 -C] [1,4] OXAZINE-8-CARBOXAMIDE
[00227] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 26 and, on the other hand, the compound from Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (4-fluorophenyl) aniline. High resolution mass (ESI +): Empirical formula: C41H38F2N4O5 [M + H] + calculated: 705.2889 [M + H] + measure: 705,2882 EXAMPLE 100: 3- (5-FLUOR-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 HYDROCHLORIDE (1H) -IL] CARBONI- L} PHENYL) -7-HYDROXY-N- (4-HYDROXYphenyl) -N-FENYL-5,6,7,8-TETRA-HYDROINDOLIZIN-1 -CARBOXAMIDE STEP A: 3'- (5-FLUOR-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1H) -IL] CARBONIL} PHENYL) -5 ', 6'-DI -HYDRO- 8'H-SPIRUS [1,3-DIOXOLAN-2,7'-INDOLIZINE] -1 '-METHYL CARBOXYLATE
[00228] The procedure is as in the process of Step A of Example 1, replacing the compound of Preparation 1 with the compound of Preparation 27. STEP B: 3- (5-FLUOR-2 - {[(3S) -3- (MORFOLIN -4-ILMETIL) -3,4-DI- Hl DROISOQUI NOLI N -2 (1 H) -IL] CARBONI LJFENI L) -7- (PROP-2-EN-1-ILOXY) -5,6,7, 8-METHYL TETRA-HYDROINDOLIZINE-1-CARBOXYLATE
[00229] The procedure is as in the process of Steps B, C and D of Example 113. STEP C: N- (4 - ([TERC-BUTIL (DIMETHIL) SILIL] ÓXI} FENIL) -3- (5- FLUOR- 2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1H) -IL] CARBONIL} PHENYL) -N-PHENYL-7- (PROP-2-EN -1 -ILOXY) -5,6,7,8-TETRA-HYDROINDOLIZIN A-1 - CARBOXAMIDE
[00230] The procedure is as in the processes of Steps B and C of Example 1. STEP D: N- (4 - ([TERC-BUTIL (DIMETHIL) SILIL] OXY} FENIL) -3- (5- FLUOR-2- {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1H) -IL] CARBONIL} PHENYL) -N-PHENYL-7- HYDROXY-5,6,7, 8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00231] A deprotection reaction of the allyl group is subsequently carried out in the presence of 1,3-dimethylpyrimidine-2,4,6 (1H, 3H, 5H) - trione (also called dimethyl barbiturate) and tetra-wanted (triphenylphosphine) palladium, in a mixture of methanol and dichloromethane. STEP E: 3- (5-FLUOR-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} PHENYL CHLORIDATE - 7-HIDR0XI-N- (4-HYDROXYphenyl) -N-PHENYL-5,6,7,8-TETRA-HYDROI- NDOLIZINE-1 -CARBOXAMIDE
[00232] Deprotection of the tert-butylsilyloxy group is carried out according to the process of Step D of Example 1. Elemental microanalysis:% of C% of H% of N Calculated 71.98 5.90 7.99 Found 71.18 5.98 7.18 High resolution mass (ESI +): Empirical formula: C42H42FN4O5 [M + H] + calculated: 701.3139 [M + H] + measure: 701.3134 EXAMPLE 101: 6- (5-CHLORINE-2 CHLORIDATE) - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBONI- L} PHENYL) -N- (4-HYDROXYphenyl) -N - (1-METHYL-1H-INDAZOL-5-IL) -3,4- DI-HYDRO-1 H-PYRROLEUM [2,1 -C] [1,4] OXAZIN A-8-CARBOXAMIDE
[00233] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 20 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phen i I) -1-methyl-1 H-indazol-5-amine. Elemental microanalysis:% of C% of H% of N Calculated 65 , 07 5.33 10.59 Found 65.54 4.86 10.57 EXAMPLE 102: (2R) -5- (5-FLUOR-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL HYDROCHLORIDE ) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} PHENYL) -2-HYDROXY-N- (4-HYDROXYphenyl) -N-PHENYL- 2,3-DI-HYDRO-1 H- PIRROLIZINE-7-CARBOXAMIDE STEP A: (2R) -2 - {[TERC-BUTYL (DIMETHYL) SILYL] OXY} -5- (5-FLUOR- 2 - {[(3S) -3- (MORFOLIN-4-ILMETIL ) -3,4-DI-HYDROISOQUINOLIN- 2 (1 H) -IL] CARBONY} PHENYL) -2,3-DI-HYDRO-1 H-PYRROLIZINE-7- METHYL CARBOXYLATE
[00234] The procedure is as in the process of Step A of Example 1, replacing the compound of Preparation 1 with the compound of Preparation 28. STEP B: (2R) -5- (5-FLUOR-2 - {[(3S) - 3- (MORFOLIN-4-ILMETIL) -3,4- DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} PHENYL) -2-HYDROXY-2,3-DI-HYDRO-1 H-PIRROLIZINE-7- METHYL CARBOXYLATE
[00235] To a solution of the compound from Step A (1 g; 1.54 mmol) in THF (8 mL) is added a 1 M solution of tetrabutylammonium fluoride (1.7 mL; 1.7 mmol ). The reaction mixture is stirred for 3 hours at room temperature, and then the THF is evaporated and replaced with ethyl acetate. The organic phase is washed with water and then with brine, before being dried over MgSCU, filtered and concentrated to dryness. The obtained crude product (830 mg) is used as such in the next step. 1H NMR: δ (500 MHz; dmso-d6; 26.9 ° C) 7.55-6.9 (m, 7H, aromatic H); 6.55-6.35 (m, 1H, aromatic dihydropyrrolizine H); 5.5-5.3 (m, 1H, alcohol); 5.25-4.6 (m, 1H, tertiary Tetrahydroisoquinoline H); 5.0-4.2 (m, 2H, H aliphatic tetrahydroisoquinoline); 4.95-4.62 (m, 1H, HCOH); 3.7-3.6 (si, 3H, OMe); 3.6-3.2, (m, 2H, 2H, H aliphatic dihydropyrrolizine); 3.7-3.5 (m, 4H, H morpholine); 3.0-2.4 (m, 2H, H aliphatic tetrahydroisoquinoline); 2.6-1.96 (m, 4H, H morpholine); 2.6-1.96 (m, 2H, H aliphatic dihydropyrrolizine) STEP C: (2R) -5- (5-FLUOR-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) - 3,4- DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBONIL} PHENYL) -2- (PROP-2- EN-1 -ILOXY) -2,3-DI-HYDRO-1 H-PIRROLIZINE-7-CARBOXYLATE METHYL
[00236] To a suspension of 62 mg (1.54 mmol) of sodium hydride in 8 mL of anhydrous THF, cooled to 0 ° C, is added a solution of the compound from Step B (820 mg; 1.54 mmol ) in THF (6 ml). The suspension is stirred for 15 minutes at 0 ° C. Subsequently, 0.15 ml (1.69 mmol) of allyl bromide is added dropwise. The reaction mixture is stirred for 5 hours at room temperature, and then hydrolyzed with a saturated aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic phase is dried over MgSO4, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (gradient: dichloromethane / ammoniacal methanol) to produce the title product in solid form. 1H NMR: δ (500 MHz; dmso-d6; 26.9 ° C): 7.5-6.8 (m, 7H, aromatic H); 6.55-6.3 (m, 1H, H aromatic dihydropyrrolizine); 5.9 (s, 1H, H-ally); 5.3-5.2 (m, 2H, H-ally); 5.2-5.0 (m, 1H, tertiary H tetrahydroisoquinoline); 5.0-4.2 (m, 2H, aliphatic tetrahydroindolizine H); 4.7-4.42 (m, 1H, HCOalyl); 4.6-3.85 (m, 2H, H aliphatic dihydropyrrolizine); 4.6-3.85 (m, 2H, CH2 allyl); 3.7-3.5 (m, 3H, OMe); 3.65-3.5 (m, 4H, morpholine); 3.3-2.4 (m, 4H, morpholine and H aliphatic dihydropyrrolidine); 2.4-1.7 (m, 6H, morpholine and CH2N) STEP D: (2R) -N- (4 - {[TERC-BUTYL (DIMETHIL) SILIL] OXY} PHENYL) -5- (5- FLUOR- 2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINO- LIN-2 (1H) -IL] CARBONIL} PHENYL) -N-FENYL 2- (PROP-2 -EN-1-ILOXY) - 2,3-DI-HYDRO-1 H-PIRROLIZINE-7-CARBOXAMIDE
[00237] The procedure is as in the processes of Steps B and C of Example 1. STEP E: (2R) -N- (4 - {[TERC-BUTIL (DIMETHIL) SILIL] ÓXI} FENIL) -5- (5- FLUOR-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUI- NOLIN-2 (1H) -IL] CARBONIL} FENIL) -2-HYDROXY-N-PHENYL- 2,3-DI- HYDRO-1H-PIRROLIZINE-7-CARBOXAMIDE
[00238] A deprotection reaction of the allyl group is then carried out in the presence of 1,3-dimethylpyrimidine-2,4,6 (1H, 3H, 5H) -trione (also called dimethyl barbiturate) and tetrakis (triphenylphosphine) palladium (Synlett, 2007, 21, p. 3136). STEP F: (2R) -5- (5-FLUOR-2 - {[(3S) -3- (MORFO- LIN-4-ILMETYL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - CHLORIDATE IL] CARBONIL} - PHENYL) -2-HYDROXY-N- (4-HYDROXYphenyl) -N-PHENYL-2,3-DI-HYDRO-1H- PYRROLIZINE-7-CARBOXAMIDE
[00239] The deprotection of the tert-butylsilyloxy group is carried out according to the process of Step D of Example 1. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 68.09 5.57 7.75 4.90 Found 67.73 5.10 7.54 4.84 High resolution mass (ESI +): Empirical formula: C41FH39N4O5 [M + H] + calculated: 687.2983 [M + H] + measure: 687.2958 EXAMPLE 103: 3- (5-CHLORINE-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4- DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBONIL} PHENYL) -N- (4- HYDRO- XYPHENYL) -N- (1-METHYL-1H-PYRROLEUM [2,3-B] PYRIDIN-5-IL) -5,6,7,8-TE-TRA-HYDROINDOLIZINE-1-CARBOXAMIDE
[00240] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1/7-pyrrolo [2,3-b] pyridin-5-amine. High resolution mass (ESI +) : Empirical formula: C44CIH44N6O4 [M + H] + calculated: 755.3113 [M + H] + measure: 755.3088 EXAMPLE 104: N- (4-HYDROXYphenyl) -3- (5- METHYXY-2- {{ [(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} PHENYL) -N- (1-METHYL-1 H- INDAZOL-5- IL) -5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00241] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 6 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - indazol-5-amine. Elemental microanalysis:% C% H% N% N% Cl- Calculated 68.65 6.02 Found 67.91 5.52 10.67 4.50 10.53 4.08 EXAMPLE 105: N- (4-HYDROXYPHENYL) -3- (6- { [(3S) -3 - {[4- (2-METOXYETHIL) PIPERAZIN-1-IL] METHIL} -3,4-DI- Hl DROISOQUI NOLI N-2 (1 H) -IL] CARBONI L} -1, 3-BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00242] The procedure is as in the process of Example 1, replacing the compound of Preparation T used in Step A with the compound of Preparation 9 '. Elementary microanalysis:% C% H% deN Calculated 65.71 6.11 Found 66.57 6.16 8.33 8.44 EXAMPLE 106: (2S) -5- (5-FLUOR-2- { [(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} PHENYL) -2-HYDROXY-N- (4-HYDROXYphenyl) -N- FENIL- 2,3-DI-HYDRO-1 H-PYRROLIZINE-7-CARBOXAMIDE
[00243] The procedure is as in the process of Example 102 replacing the compound of Preparation 28 used in Step A with the compound of Preparation 29. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 68.09 5.57 7, 75 4.90 Found 68.16 5.13 7.74 4.97 EXAMPLE 107: CHLORIDRATE OF 3- (5-CHLORINE-2 - {[(3S) -3 - [(4- METHYL-3-OXOPIPERAZIN-1 -IL) METHIL] -3,4-DI-HYDROISOQUINOLIN- 2 (1 H) -IL] CARBONIL} PHENYL) -N- (4-HYDROXYphenyl) -N- (1 -METHIL-1 H- INDOL-5-IL ) -5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00244] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the respective compounds of Preparations 3 and 10' and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4- {[ether-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1 H-indole-5-amine. Elemental microanalysis:% deC% deH% deN % Cl% Cl- Calculated 67.56 5.67 10.28 8.67 4.34 Found 67.31 5.14 10.18 8.27 3.76 EXAMPLE 108: 3- (5-CHLORINE CHLORIDATE) -2 - {[(3S) -3 - {[(2- METOXYETHIL) (METHIL) AMINO] METHIL} -3,4-DI-HYDROISOQUINOLIN- 2 (1 H) -IL] CARBONY} PHENYL) -N- ( 4-HYDROXYphenyl) -N- (1-METHYL-1 H- INDOL-5-IL) -5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00245] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the respective compounds of Preparations 3 and 11' and, on the other hand, the compound of Preparation 1 "used in Step C by N- (4- {[ferc-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1H-indole-5-amine. Elementary microanalysis:% deC% deH% deN% de Cl- Calculated 68.18 5.98 8.83 4.47 Found 68.30 5.61 8.78 4.46 EXAMPLE 109: N- (4-HYDROXYphenyl) -3- (6 - {[(3S) - 3 - [(4-OXIDOMOR- FOLIN-4-IL) METHIL] -3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBO- NIL} -1,3-BENZODIOXOL-5-IL) -N- FENIL-5,6,7,8-TETRA-HIDROIN- DOLIZIN A-1 -CARBOXAMIDA
[00246] To a solution of the compound of Example 1, obtained as the free base, in 10 ml of CH2 Cl2, is added, in portions, mefa-chloroperbenzoic acid (0.242 mg, 1.4 mmol). The whole is subsequently stirred at room temperature overnight. The reaction mixture is subsequently concentrated to dryness, and then the residue is purified by reversed-phase flash chromatography (gradient: acetonitrile / water / trifluoroacetic acid). After concentration, the title product is obtained as a solid. Elementary microanalysis:% C% H% deN Calculated 71.06 5.82 7.71 Found 70.59 5.36 7.69 High resolution mass (ESI +): Empirical formula: C43H42N4O7 [M + H] + calculated: 727.3132 [M + H] + measure: 727.3110 EXAMPLE 110: 3- (5-CHLORINE-2 - {[(3S) -3 - {[ETHYL (2-METOXYETHYL) AMINO] METHIL} -3) , 4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONY} PHENYL) -N- (4-HYDROXYphenyl) -N- (1 -METHYL-1H-INDOL- 5-IL) -5,6,7, 8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00247] The procedure is as in the process of Example 1, replacing, on the one hand, the compounds of Preparations 1 and 1 'used in Step A with the respective compounds of Preparations 3 and 12' and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4- {[ferc-butyl (dimethyl) silyl] oxy} phenyl) -1-methyl-1H-indol-5-amine. Elemental microanalysis:% deC% deH% deN% of Cl- Calculated 68.48 6.12 8.68 4.39 Found 68.40 5.78 8.61 4.23 EXAMPLE 111: 3- (5-CHLORINE-2 - {[(3S) -3 CHLORIDATE - (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} FENIL) -N- (4-FLUORPHENYL) -N- (4-HYDROXYphenyl) - 5, 6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00248] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (4-fluorophenyl) aniline. High-resolution mass (ESI +): Empirical formula: C42H40CIN4O4 [M + H] + calculated: 719.2722 [M + H] + measure: 719.2806 EXAMPLE 112: N- (4-HYDROXYPHENYL) -3- (5- METÒXI-2 - {[(3S) -3- (MORFOLIN-4-ILMETYL) -3.4 -DI- HYDROISOQUINOLIN-2 (1H) -IL] CARBONIL} PHENYL) -N-PHENYL-5,6,7,8- TETRA-HYDROINDOLIZINE-1-CARBOXAMIDE
[00249] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 used in Step A with the compound of Preparation 6. Elemental microanalysis: Calculated% of C% of H% of N% of Cl- 70.43 6.19 7 , 64 4.83 Found 70.17 5.79 7.60 4.69 EXAMPLE 113: 7-HIDR0XI-N- (4-HYDROXYphenyl) HYDROCHLORIDE - 3- (6 - {[(3S) -3- (MORFOLIN -4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN- 2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8- TETRA- HYDROINDOLIZIN-1-CARBOXAMIDE STEP A: 3 '- (6 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} -1 , 3-BENZODIOXOL-5-IL) -5 ', 6, -DI-HYDRO-8, H-SPIRUS [1,3-DIOXOLAN-2,7'-INDOLIZINE] - 1'-METHYL CARBOXYLATE
[00250] The procedure is as in the process of Step A of Example 1, replacing the compound of Preparation 1 with the compound of Preparation 30. STEP B: 3- (6 ~ {[(3S) -3- (MORFOLIN-4-ILMETIL ) -3,4-DI- Hl DROISOQUI NOLI N -2 (1 H) -IL] CARBONI L} -1,3-BENZODIOXOL-5-IL) -7-OXO-5,6,7,8-TETRA- HYDROINDOLIZIN-1 -METHYL CARBOXYLATE
[00251] 2.75 g of the compound from Step A (4.47 mmoles), in solution, in 75 ml of THF, are stirred in the presence of 37 ml of 1 M HCI at reflux, for 15 hours. 100 ml of water and 100 ml of ethyl acetate are added to the reaction mixture. Subsequently, 4 g of NaHCOs (4.7 mmoles) in powder form are added until a basic pH is reached. The compound is extracted with ethyl acetate, and the organic phase is dried over MgSO4, filtered and concentrated to dryness. The title product is obtained in the form of an oil. 1H NMR: δ (500 MHz; dmso-d6; 26.9 ° C): 7.9-7.2 (m, 4H, aromatic H); 7.02 (m, 1H, aromatic H); 6.88 (m, 1H, aromatic H); 6.44-5.87 (m, 1H, aromatic tetrahydroindolizine H); 6.17 (d, 2H, methylenedioxy CH2); 5.07 / 4.85 / 3.79 (m, 1H, tertiary Tetrahydroisoquinoline H); 4.88 / 4.27 / 4.24 (m, 2H, H aliphatic tetrahydroisoquinoline); 4.22 - 3.43 (m, 4H, aliphatic tetrahydroindolizine H); 3.59-3.49 (m, 4H, H aliphatic morpholine); 3.75-3.52 (s, 3H, Me); 2.93-2.49 (m, 2H, aliphatic tetrahydroindolizine H); 2.75-2.28 (m, 2H, aliphatic H tetrahydroindolizine); 2.68-1.68 (m, 6H, H aliphatic morpholine + CH2) STEP C: 7-HYDROXY-3- (6 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4- DI- HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -5,6,7,8-TETRA-HYDROINDOLIZINE-1-CARBOXYLATE
[00252] To a solution of 2.55 g of the compound obtained in Step B (4.47 mmoles) in 30 ml of methanol is added, in portions, 558 mg (14.75 mmoles) of sodium boron hydride. The reaction mixture is stirred for one hour at room temperature. 50 ml of 1 M HCI are subsequently added, and the methanol is evaporated. The aqueous phase is subsequently neutralized with NaHCOs and then extracted with dichloromethane. The organic phase is washed, in sequence, with H2O, dried over MgSO4, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (dichloromethane / ethanol-ammonia gradient). The title product is obtained as a solid. 1H NMR: δ (500 MHz; dmso-d6; 26.9 ° C): 7.22-6.97 (m, 4H, aromatic tetrahydroisoquinoline H); 7.05 (s, 1H, aromatic H); 6.89 (s, 1H, aromatic H); 6.37 / 6.3 / 6.07 (m, 1H, aromatic tetrahydroindolizine H); 6.16 (d, 2H, methylenedioxy CH2); 5.09 (m, 1H, tertiary Tetrahydroisoquinoline H); 4.87-4.21 (m, 2H, aliphatic tetrahydroindolizine H); 4.20-3.67 (m, 2H, aliphatic tetrahydroindolizine H); 4.10-3.86 (m, 1H, tertiary H tetrahydroindolizine); 3.69-3.58 (s, 3H, Me); 3.69 - 3.52 (m, 4H, H aliphatic morpholine); 2.96 + 2.43 (m, 2H, H aliphatic tetrahydroisoquinoline); 2.55-2.0 (m, 6H, H aliphatic morpholine + CH2); 2.4-1.5 (m, 4H, H aliphatic tetrahydroindolizine) IV: OH: 3239 cm -1; -C = 0 (ester): 1696 cm -1; -C = O (amide): 1624 cm-1; CC-OH (secondary alcohol): 1034 cm'1 STEP D: 3- (6 - {[(3S) -3- (MORFOLIN-4-ILIVIETIL) -3> 4-DI- HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} -1.3-BENZODIOXOL-5- IL) -7- (PROP-2-EN-1-IL0XI) -5,6,7,8-TETRA-HYDROINDOLIZINE-1- METHYL CARBOXYLATE
[00253] To a suspension of 331 mg (8.26 mmoles) of sodium hydride in 15 ml of anhydrous THF, cooled to 0 ° C, 2.37 g (4.13 mmoles) of the compound obtained in Step C are added The suspension is stirred for 15 minutes at 0 ° C, and then a solution of 790 pL (9.1 mmol) of allyl bromide in 10 mL of THF is added slowly (over a period of 15 minutes). The reaction mixture is stirred for one hour, at 0 ° C, and then for 15 hours at room temperature. The solution is hydrolyzed with a saturated aqueous solution of NH4 Cl. The compound is extracted with ethyl acetate; the organic phase is dried over MgSO4, filtered and concentrated to dryness. The oil thus obtained is purified by flash chromatography (cyclohexane / ethyl acetate gradient). The title product is obtained as a solid. 1H NMR: δ (500 MHz; dmso-d6; 26.9 ° C): 7.2-6.9 (m, 4H, aromatic tetrahydroisoquinoline H); 7.2-6.8 (m, 2H, aromatic H); 6.4 - 6.0 (m, 1H, aromatic tetrahydroindolizine H); 6.10 (d, 2H, methylenedioxy CH2); 5.9 (m, 1H, ally); 5.35-5.10 (m, 2H, ally); 5.1 + 4.75 (m, 1H, tertiary Tetrahydroisoquinoline H); 4.15-3.9 (m, 2H, CH2 allyl); 3.9-3.6 (m, 1H, tertiary H tetrahydroindolizine); 4.1-3.4 (m, 4H, H aliphatic morpholine); 4.9-3.4 (m, 4H, 2H aliphatic tetrahydroindolizine + 2H aliphatic tetrahydroisoquinoline); 3.8-3.6 (s, 3H, Me); 2.55-1.6 (m, 6H, H aliphatic morpholine + CH2); 3.3-1.5 (m, 6H, 4H aliphatic tetrahydroindolizine + 2H aliphatic tetrahydroisoquinoline) STEP E: N- (4 - {[TERC-BUTIL (DIMETHIL) SILIL] OXY} PHENY) -3- ( 6- {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N- FENIL-7- (PROP-2-EN-1 - IL0XI) -5,6,7,8-TETRA-HIDR0IND0LIZINA-1-CARBOXAMIDA
[00254] The procedure is as in the processes of Steps B and C of Example 1. STEP F: N- (4 - ([TERC-BUTIL (DIMETHIL) SILIL] OXI} FENIL) -7- HYDROXY-3- (6- {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5- IL) -N-FENIL- 5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00255] A deprotection reaction of the allyl group is then carried out in the presence of 1,3-dimethylpyrimidine-2,4,6 (1 H, 3H, 5H) -trione (also called dimethyl barbiturate) and tetrakis ( triphenylphosphine) palladium, in a mixture of methanol and dichloromethane. STEP G: 7-HYDROXY-N- (4-HYDROXYPHENYL) -3- (6- {[(3S) -3- (MORFOLIN-4-ILMETYL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) CHLORIDATE ) - IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8-TETRA- HYDROINDOLIZIN-1-CARBOXAMIDE
[00256] Deprotection of the silyloxy group is carried out according to the process of Step D of Example 1. Elemental microanalysis:% C% H% N% Cl- Calculated 67.66 5.68 7.34 4.64 Found 67.02 5.27 7.36 4.61 High resolution mass (ESI +): Empirical formula: C43H43N4O7 [M + H] + calculated: 727.3132 [M + H] + measure: 727.3121 EXAMPLE 114: CHLORIDATE DE N- (3-FLUOR-4-METHYLphenyl) -N- (4-HYDROXYphenyl) -3- (5-METHYXY-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) - 3,4- DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} PHENYL) -5,6,7,8- TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00257] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 6 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-fluor-4-methylaniline. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 69.05 6.06 7 , 32 4.63 Found 68.90 5.56 7.33 4.41 EXAMPLE 115: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) - HYDROCHLORIDE - 3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBONI- L} PHENYL) -N- (2-FLUORPHENYL) -N- (4-HYDROXYphenyl) -5,6,7,8-TETRA- HYDROINDOLIZINE- 1 -CARBOXAMIDE
[00258] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (2-fluorophenyl) aniline. High-resolution mass (ESI +): Empirical formula: C42H40CIN4O4 [M + H] + calculated: 719.2722 [M + H] + measure: 719.2802 EXAMPLE 116: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 HYDROCHLORIDE (1 H) -IL] CARBONI- L} PHENYL) -N- (3-FLUORPHENYL) -N- (4-HYDROXYphenyl) -5,6,7,8-TETRA- HYDROINDOLIZIN-1 -CARBOXAMIDE
[00259] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C by 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (3-fluorophenyl) aniline. High resolution mass (ESI +): Empirical formula: C42H40CIN4O4 [M + H] + calculated: 719.2722 [M + H] + measure: 719.2819 EXAMPLE 117: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN CHLORIDATE -2 (1 H) - IL] CARBONIL} PHENYL) -N- (2,4-DIFLUORPHENYL) -N- (4-HYDROXYphenyl) - 5,6,7,8-TETRA-HYDROINDOLIZINE-1-CARBOXAMIDE
[00260] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) -2,4-difluoraniline. High resolution mass (ESI +): Empirical formula: C42H39CIF2N4O4 [M + H] + calculated: 737 , 2628 [M + H] + measure: 737.2660 EXAMPLE 118: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI -HYDROISOQUINOLIN-2 (1 H) -IL] CARBONI- L} PHENYL) -N- (3,4-DIFLUORPHENYL) -N- (4-HYDROXYphenyl) -5,6,7,8-TE- TRA-HYDROINDOLIZINE- 1 -CARBOXAMIDE
[00261] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3,4-difluoraniline. Elemental microanalysis:% C% H% N% Cl- Calculated 65.20 65.26 EXAMPLE 119: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL CHLORIDATE} PHENYL) -N- (3-Cyanophenyl) -N- (4-HYDROXYphenyl) - 5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00262] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 3 and, on the other hand, the compound of Preparation 1 "used in Step C il] oxy} phenyl) amino] benzonitrile Elemental microanalysis: Found 5.21 5.01 7.24 6.90 4.58 4.57 by 3 - [(4 - {[íe / "c-butyl (dimethyl) sil- Calculated% of C% of H% of N% of Cl- 5.42 5.20 EXAMPLE 120: HYDROCHLORIDE Found 67.71 67.00 4.65 4.54 9.18 8.89 N- (4 -HIDROXIFENIL) -6- (6 - {[(3S) - 3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} -1,3-BENZODIOXOL- 5-IL) -N-FENILPIRROLO [1,2-A] - PIRAZINA-8-CARBOXAMIDA
[00263] The procedure is as in the process of Example 1, replacing the compound from Preparation 1 used in Step A with the compound from Preparation 31. High resolution mass (ESI +): Empirical formula: C42H37N5O6 [M + H] + calculated: 708 , 2822 [M + H] + measure: 708.2788 EXAMPLE 121: N- (3-FLUORPHENYL) -N- (4-HYDROXYphenyl) -6- (6 - {[((3S) -3- (MORFOLIN- 4-ILMETIL) -3,4-DI- Hl DROISOQUI NOLI N-2 (1 H) -IL] CARBONI L} -1,3-BENZODIOXOL-5- IL) PIRROLO [1,2-A] PIRAZINA-8- CARBOXAMIDE
[00264] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 31 and, on the other hand, the compound from Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (3-fluorophenyl) aniline. High resolution mass (ESI +): Empirical formula: C42H36FN5O6 [M + H] + calculated: 726.2728 [M + H] + measure: 726.2723 EXAMPLE 122: N- (3-FLUORPHENYL) -N- (4-HI- DROXIFENlL) -3- (6 - {[((3S) -3- (MORFOLIN-4-) ILMETIL) -3,4-DI-HYDROI- SOQUINOLIN-2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -5,6-, 7,8-TETRA-HYDROINDOLIZINE-1- CARBOXAMIDE
[00265] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 "used in Step C with 4 - {[ferc-butyl (dimethyl) silyl] oxy} -A / - (3-fluorphenyl) aniline. High resolution mass (ESI +): Empirical formula: C43H41FN4O6 [M + H] + calculated: 729.3088 [M + H] + measure: 729.3068 EXAMPLE 123: N- (4-HYDROXYphenyl) CHLORIDATE -3- ( 6 - {[(3S) - 3 - {[4- (METHYLSULFONIL) PIPERAZIN-1-IL] METHIL} -3,4-DI-HYDROISO- QUINOLIN-2 (1 H) -IL] CARBONIL} -1,3 -BENZODIOXOL-5-IL) -N-PHENYL- 5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00266] The procedure is as in the process of Example 1, replacing the compound from Preparation 1 'used in Step A with the compound from Preparation 13'. Elementary microanalysis:% C% H% N% S% Cl- Calculated 64.11 5.62 8.50 3.89 4.30 Found 64.19 5.07 8.52 3.87 4, 02 EXAMPLE 124: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONI CHLORIDATE - L} PHENYL) -N- (4-HYDROXYphenyl) -N- (3-METOXYphenyl) -5,6,7,8-TETRA- HYDROINDOLIZINE-1 -CARBOXAMIDE
[00267] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-methoxyaniline. Elemental microanalysis:% C% H% N% Cl- Calculated 67.27 5.78 7.30 4 , 62 Found 67.54 5.35 7.32 4.62 EXAMPLE 125: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3.4 -DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBO- NIL} PHENYL) -N- (3,5-DIFLUORPHENYL) -N- (4-HYDROXYphenyl) -5,6,7,8- TETRA-HYDROINDOLIZINE-1 -CARBOXAMIDA
[00268] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3,5-difluoraniline. Elemental microanalysis:% of C 7 of H% of N% of Cl- Calculated 65.20 5.21 7.24 4 , 58 Found 65.85 4.93 7.04 4.76 EXAMPLE 126: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3.4 -DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBO- NIL} PHENYL) -N- (4-HYDROXYphenyl) -N- (3-METHYLphenyl) -5,6,7,8-TETRA- HYDROINDOLIZINE-1 -CARBOXAMIDE
[00269] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-methylaniline. Elemental microanalysis:% C% H% N% Cl- Calculated 68.70 5.90 7, 45 4.72 Found 68.94 5.72 7.21 4.84 EXAMPLE 127: N- (4-HYDROXYPHENYL) -N-PHENYL-3- (6 - {[(3S) -3 - {[4 - (2,2,2-TRIFLUORETYL) PIPERAZIN-1-IL] METHIL} -3,4- DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -5 , 6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00270] The procedure is as in the process of Example 1, replacing the compound from Preparation T used in Step A with the compound from Preparation 14 '. Elemental microanalysis:% deC% deH% deN% of Cl- Calculated 65.25 5.48 8.45 4.28 Found 64.91 5.23 8.37 4.96 EXAMPLE 128: N- (4-HYDROXYPHENIL CHLORIDATE) ) -3- (6 - {[(3S) - 3 - [(4-METIL-3-OXOPIPERAZIN-1-IL) METHIL] -3,4-DI-HYDROISOQUI- NOLIN-2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00271] The procedure is as in the process of Example 1, replacing the compound from Preparation T used in Step A with the compound from Preparation 10 '. Elementary microanalysis:% C% H% N% Cl- Calculated 68.25 5.73 9.04 4.58 Found 68.04 5.09 8.82 4.64 EXAMPLE 129: 3- ( 5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONI- L} PHENYL) -N- ( 4-Cyanophenyl) -N- (4-HYDROXYphenyl) -5,6,7,8-TETRA- HYDROINDOLIZIN-1 -CARBOXAMIDE
[00272] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C lil] oxy} phenyl) amino] benzonitrile Elemental microanalysis: at 4 - [(4 - {[tert-butyl (dimethyl) si-% C% H% deN Calculated 67.71 5.42 Found 68.17 5.15 9.18 8.71 EXAMPLE 130: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 HYDROCHLORIDE (1H) -IL] CARBONI- L} PHENYL) -N, N-DIPHENYL-5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00273] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V-phenylaniline High resolution mass (ESI +): Empirical formula: C42H40CI2N4O4 [M + H] + calculated: 735.2427 [M + H] + measure: 735.2524 EXAMPLE 131: 3- (5-CHLORINE CHLORIDATE) -2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBON- IL} PHENYL) -N- (3-CHLOROPHENIL ) -N- (4-HYDROXYphenyl) -5,6,7,8-TETRA- HYDROINDOLIZIN-1 -CARBOXAMIDE
[00274] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 3 and, on the other hand, the compound of Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-chloroaniline. Elemental microanalysis:% of C% of H% of N% of Cl- Calculated 65.33 5.35 7.26 4, 59 Found 64.08 5.29 6.92 4.59 EXAMPLE 132: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4- DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBON- IL} PHENYL) -N- (4-HYDROXYphenyl) -N- (PYRIMIDIN-2-IL) -5,6,7,8-TETRA- HYDROINDOLIZINE-1 - CARBOXAMIDE
[00275] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 3 and, on the other hand, the compound of Preparation 1 "used in Step C lil] oxy} phenyl) pyrimidin-2-amine. By / V- (4 - {[tert-butyl (dimethyl) si-
[00276] Elementary microanalysis:% C% H% deN Calculated 64.95 5.45 Found 64.62 5.07 11.36 10.92 EXAMPLE 133: 3- (5-CHLORINE-2 - {[ (3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBON- IL} PHENYL) -N- (CYCLEBUTYLMETHIL) -N- (4-HYDROXYphenyl) ) -5,6,7,8- TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00277] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C by 4 - {[tert-butyl (dimethyl) silyl] oxy} - / / - (cyclobutylmethyl) aniline Elemental microanalysis:% C% H% N% Cl- Calculated 68.16 6.39 7, 76 3.93 Found 68.69 5.93 7.45 3.81 EXAMPLE 134: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3 HYDROCHLORIDE -3 , 4-DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONI- L} PHENYL) -N- (2-Cyanophenyl) -N- (4-HYDROXYphenyl) -5,6,7,8-TETRA- HYDROINDOLIZIN A -1 -CARBOXAMIDE
[00278] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C by 2 - [(4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) amino] benzonitrile Elemental microanalysis:% C% H% deN Calculated 67.71 5.42 9.18 Found 67.34 4.95 8.73 EXAMPLE 135: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 CHLORIDATE (1H) -IL] CARBONI- L} PHENYL) -N- (4-HYDROXYphenyl) -N- (1-METHYL-1H-PIRAZOL-4-IL) -5.6, - 7.8-TETRA-HYDROINDOLIZINE -l-CARBOXAMIDE
[00279] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - pyrazol-4-amine. Elemental microanalysis:% C% H% N%% Cl- Calculated 64.77 5.71 11.33 4.78 Found 64.62 5.33 10.71 4.10 EXAMPLE 136: 3- (5-CHLORINE-2 - {[((3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBO- NIL} PHENYL) -N- (CYCLOPROPYLMETHEL) -N- (4-HYDROXYphenyl) -5,6 , 7.8- TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00280] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 3 and, on the other hand, the compound of Preparation 1 "used in Step C by (cyclopropylmethyl) aniline Elemental microanalysis: 4 - {[tert-butyl (dimethyl) silyl] oxy} -N-% deC% H 7odeN 7o Cl- Calculated 67.13 6.20 7.83 4, 95 Found 67.58 5.79 7.36 4.16 EXAMPLE 137: FOLIN-4-ILMETHYL CHLORIDRATE -3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBONI- L} PHENYL) -N- (4-HYDROXYphenyl) -N- (1-METHYL-1H-PIRAZOL-3-IL) -5,6, - 7,8-TETRA-HYDROINDOLIZINE-1-CARBOXAMIDE
[00281] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 3 and, on the other hand, the compound of Preparation 1 "used in Step C by / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 1-methyl-1 / - / - pyrazol-3-amine. Elemental microanalysis: 3- (5-CHLORINE- 2 - {[(3S) -3- (MOR- Calculated%% C% H% Cl- 4.78 5.27% N 11.33 10.78 64.77 64.20 EXAMPLE 138: N- ( BUT-2-IN-1-IL) -3- (5-CHLORINE-2- {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1H) - Found 5.71 5.47 IL] CARBONIL} PHENYL) -N- (4-HYDROXYphenyl) -5,6,7,8-TETRA-HYDRO- INDOLIZIN A-1 -CARBOXAMIDE
[00282] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with 4 - {[tert-butyl (dimethyl) silyl] oxy} - / V- (but- 2-in-1-yl) aniline Elemental microanalysis:% C% H% deN% Cl- Calculated 64.95 5, 45 11.36 4.79 Found 65.53 5.19 10.88 5.38 EXAMPLE 139: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) CHLORIDRATE ) -3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBO- NIL} PHENYL) -N- (4-HYDROXYphenyl) -N- (PIRIDIN-2-IL) -5,6,7,8- TETRA- HYDROINDOLIZIN-1-CARBOXAMIDE
[00283] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 3 and, on the other hand, the compound of Preparation 1 "used in il] oxy} phenyl) pyridin-2-amine Elemental microanalysis: Step C by A / - (4 - {[tert-butyl (dimethyl) sil-% deC% deH% deN Calculated 66.66 5.59 9.48 Found 67.12 5.37 9.11 EXAMPLE 140: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN- 2 (1H) -IL] CARBON- IL} PHENYL) -N- (4-HYDROXYphenyl) -N- (PYRIDAZIN-3-IL) -5,6,7,8-TETRA- HYDROINDOLIZINE-1 -CARBOXAMIDE
[00284] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silic] oxy} phenyl) pyridazin-3-amine. High resolution mass (ESI +): Empirical formula: C42H39CIN6O4 [M + H] + calculated: 703, 2721 [M + H] + measure: 703.2783 EXAMPLE 141: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1 H) -IL] CARBO- NIL} PHENYL) -N- (4-HYDROXYphenyl) -N- (PYRIMIDIN-5-IL) -5,6,7,8-TETRA- HYDROINDOLIZINE-1 -CARBOXAMIDE
[00285] The procedure is as in the process of Example 1, replacing, on the one hand, the compound of Preparation 1 used in Step A with the compound of Preparation 3 and, on the other hand, the compound of Preparation 1 "used in Step C il] oxy} phenyl) pyrimidin-5-amine Elemental microanalysis: by A / - (4 - {[tert-butyl (dimethyl) sil-% deC% deH% deN% Cl- Calculated 68.32 68 , 05 5.59 5.52 11.95 11.83 Found EXAMPLE 142: BIS (CHLORIDRATE) OF 5.04 5.50 3- (5-CHLORINE-2 - {[(3S) -3- (MORFOLIN-4 -ILMETHIL) -3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CAR- BONY} PHENYL) -A / - (4-HYDROXYphenyl) -A / - (PIRIDIN-3-IL) -5,6, 7,8-TE- TRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00286] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) pyridin-3-amine. High resolution mass (ESI +): Empirical formula: C41H40CIN5O4 [M + H] + calculated: 702, 2769 [M + H] + measure: 702.2858 EXAMPLE 143: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI- HIDROISOQUINOLIN-2 (1 H) -IL] CARBO- NIL} FENIL) -N- (3,5-DIFLÚOR-4-METOXIFENIL) -N- (4-HIDROXI- FENIL) -5,6,7,8-TETRA -HYDROINDOLIZIN-1-CARBOXAMIDE
[00287] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3,5-difluoro-4-methoxyaniline. High resolution mass (ESI +): Empirical formula: C43H41CIF2N4O5 [M + H] + calculated : 767.2734 [M + H] + measure: 767.2804 EXAMPLE 144: 3- (5-CHLORINE-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3 BIS (CHLORIDATE) -3, 4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONYL} PHENYL) -N- (4-HYDROXYphenyl) -N- (PYRIDIN-4-IL) - 5,6,7,8-TETRA-HYDROINDOLIZINE-l -CARBOXAMIDA
[00288] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[ether-butyl (dimethyl) sylyl] oxy} phenyl) pyridin-4-amine. High resolution mass (ESI +): Empirical formula: C41H40CIN5O4 [M + H] + calculated: 702, 2842 [M + H] + measure: 702.2842 EXAMPLE 145: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1H) -IL] CARBON- IL} PHENYL) -N- (3-FLUOR-4-METOXYphenyl) -N- (4-HYDROXYphenyl) -5,6, - 7,8-TETRA-HYDROINDOLIZINE-l -CARBOXAMIDA
[00289] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) - 3-fluor-4-methoxyaniline. High resolution mass (ESI +): Empirical formula: C43H42CIFN4O5 [M + H] + calculated: 749 , 2828 [M + H] + measure: 749.2878 EXAMPLE 146: N- (4-HYDROXYPHENYL) -3- (6 - {[(3S) - 3 - {[(2-METOXYETHIL) (METHYL) AMINO CHLORIDATE) ] METHIL} -3,4-DI- HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8-TETRA-HYDROINDOLIZINE- 1-CARBOXAMIDE
[00290] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 'used in Step A with the compound of Preparation 11'. Elementary microanalysis:% of C% of H% of N% of Cl- Calculated 68.93 6.05 7.48 4.73 Found 68.84 5.85 7.56 4.60 EXAMPLE 147: 3- (6- { [(3S) -3 - [(1,1-DIOXIDO- TIOMORFOLIN-4-IL) METHIL] -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} -1,3-BENZODIOXOL-5 -IL) -N- (4-HYDROXYphenyl) -N- PHENYL-5,6,7,8-TETRA-HYDROINDOLIZINE-1-CARBOXAMIDE
[00291] The procedure is as in the process of Example 1, replacing the compound from Preparation 1 'used in Step A with the compound from Preparation 15'. Elementary microanalysis:% ofC% ofH% of N% ofS% of Cl- Calculated 64.94 5.45 7.04 4.03 4.46 Found 65.27 5.13 7.14 3.90 4.30 EXAMPLE 148 : N- (5-HYDROXYPIRIMIDIN- 2-IL) -3- (6 - {[(3S) -3- (MORFOLIN-4-ILMETYL) -3,4-DI-HYDROISOQUINO- Ll N-2 (1 - TRIFLUORACETATE) H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8- TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE STEP A: N- [5- (BENZILOXI) PIRIMIDIN -2-IL] -3- (6 - {[(3S) -3- (MORFO- LIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBONIL} - 1,3 -BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8-TETRA- HYDROINDOLIZIN-1-CARBOXAMIDE The procedure is as in Steps A, B and C of the process of Example 1, replacing the compound of Preparation 1 "used in Step C by 5- (benzyloxy) -N-phenylpyrimidin-2-amine. STEP B: N- (5-HYDROXYPIRIMIDIN-2-IL) TRIFLUORACETATE - 3- (6 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN- 2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8- TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00292] The compound from Step A (150 mg; 0.2 mmol) is dissolved in 8 ml of methanol, and 30 mg of Pd / C (10 wt% palladium) are added. The reaction mixture is stirred under an atmosphere of hydrogen [120 kPa (1.2 bar)] for 15 hours, and is then filtered over a Whatman filter, concentrated in vacuo and purified by reverse phase chromatography (gradient: acetonitrile / water in the presence of trifluoroacetic acid). The desired product is obtained in the form of a trifluoracetate salt. High resolution mass (ESI +): Empirical formula: C41H40N6O6 [M + H] + calculated: 713.3082 [M + H] + measure: 713.3080 EXAMPLE 149: N- (4-HYDROXYphenyl) CHLORIDATE -3- ( 6 - {[(3S) - 3 - [(3-METOXIPIRROLIDIN-1-IL) METHIL] -3,4-DI-HYDROISOQUINOLIN- 2 (1 H) -IL] CARBONIL} -1,3-BENZODIOXOL-5- IL) -N-PHENYL-5,6,7,8- TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00293] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 'used in Step A with the compound of Preparation 16'. Elementary microanalysis:% deC% deH% deN% de Cl- Calculated 69.42 5.96 7.36 4.66 Found 70.19 5.48 7.22 4.53 EXAMPLE 150: 3- (5-CHLORINE CHLORIDATE) -2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBO- NIL} FENIL) -N- (3-CYAN- 4-METOXYphenyl) -N- (4-HYDROXYphenyl) - 5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00294] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 ”used in Step C with 5 - [(4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) amino] -2-methoxybenzonitrile. High resolution mass (ESI +): Empirical formula: C44H42CIN5O5 [M + H] + calculated: 756.2874 [M + H] + measure: 756.2917 EXAMPLE 151: N- (4-HYDROXYPHENYL) -3- ( 5- METOXY-2 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4-DI- HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} PHENYL) -N- (1 -METHIL- 1 H- PIRAZOL-4-IL) -5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00295] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 6 and, on the other hand, the compound from Preparation 1 ”used in Step C by / V- (4 - {[tert-butyl (dimethyl) si-yl] oxy} phen i I) -1-methyl-1 H-pyrazol-4-amine. High resolution mass (ESI +): Empirical formula: C41H44N6O5 [M + H] + calculated: 701.3446 [M + H] + measure: 701.3446 EXAMPLE 152: 3- (5-CHLORINE-2 - {[ (3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} PHENYL) -N- (4-HYDROXYphenyl) -N- [3- (TRIFLUORMETIL) FENIL] -5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00296] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 3 and, on the other hand, the compound from Preparation 1 "used in Step C with A / - (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) -3- (trifluormethyl) aniline. High resolution mass (ESI +): Empirical formula: C43H40CIF3N4O4 [M + H] + calculated: 769.2690 [M + H] + measure: 769.2718 EXAMPLE 153: 3- (6 - {[(3S) - HYDROCHLORATE 3 - [(3,3-DIFLUOR- PIRROLIDIN-1-IL) METHIL] -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N - (4-HYDROXYphenyl) -N- PHENYL-5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00297] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 'used in Step A with the compound of Preparation 17'. Elementary microanalysis:% deC% deH% deN Calculated 67.31 5.39 7.30 Found 68.07 5.60 7.23 EXAMPLE 154: N- (4-HYDROXYphenyl) -N- (1- METHYL-1 HYDROCHLORIDE) H-PIRAZOL-4-IL) -3- (7 - {[(3S) -3- (MORFOLIN-4-ILMETIL) -3,4- DI-HYDROISOQUINOLIN-2 (1 H) -IL] CARBONIL} -2 , 3-DI-HYDRO-1,4-BENZODIOXIN-6-IL) -5,6,7,8-TETRA-HYDROINDOLIZIN-1-CARBOXAMIDE
[00298] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 7 and, on the other hand, the compound from Preparation 1 ”used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phen i I) -1-methyl-1 H-pyrazol-4-amine. EXAMPLE 155: N- (4-HYDROXYPHENYL) -3- (7 - {[(3S) - 3- (MORFOLIN-4-ILMETYL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) -IL] CHLORIDATE CA- RBONIL} -2,3-DI-HYDRO-1,4-BENZODIOXIN-6-IL) -N- (PIRIMIDIN-5-IL) - 5,6,7,8-TETRA-HYDROINDOLIZINE-1-CARBOXAMIDE
[00299] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 7 and, on the other hand, the compound from Preparation 1 ”used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phenyl) pyrimidin-5-amine. EXAMPLE 156: N- (4-HYDROXYphenyl) -3- (6 - {[(3S) -3 - [(3-METOXIA- ZETIDIN-1-IL) METHIL] -3,4-DI-HYDROISOQUINOLIN-2 (1H ) - IL] CARBONIL} -1,3-BENZODIOXOL-5-IL) -N-PHENYL-5,6,7,8-TETRA- HYDROINDOLIZIN-1-CARBOXAMIDE
[00300] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 'used in Step A with the compound of Preparation 18'. Elementary microanalysis:% deC% deH% deN Calculated 72.66 5.96 7.88 Found 72.32 5.51 7.96 High resolution mass (ESI +): Empirical formula: C43H42N4O6 [M + H] + calculated: 711 , 3177 [M + H] + measure: 711.3178 EXAMPLE 157: CHLORIDRATE OF 3- (6 - {[(3S) -3 - [(3-FLUORAZE- TIDIN-1-IL) METHIL] -3,4- DI-HYDROISOQUINOLIN-2 (1H) -IL] CARBONI- L} -1,3-BENZODIOXOL-5-IL) -N- (4-HYDROXYphenyl) -N-PHENYL-5,6,7,8- TETRA-HYDROINDOLIZINE -1-CARBOXAMIDE
[00301] The procedure is as in the process of Example 1, replacing the compound of Preparation 1 'used in Step A with the compound of Preparation 19'. EXAMPLE 158: 3- (5-FLUOR-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1H) - IL] CARBONIL} PHENYL CHLORIDATE ) -N- (4-HYDROXYphenyl) -N- (1 -METHYL-1 H-PIRAZOL-4-IL) -5,6,7,8-TETRA-HYDROINDOLIZINE-1-CARBOXAMIDE
[00302] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 4 and, on the other hand, the compound from Preparation 1 ”used in Step C with / V- (4 - {[tert-butyl (dimethyl) silyl] oxy} phen i I) -1-methyl-1 H-pyrazol-4-amine. EXAMPLE 159: 3- (5-FLUOR-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1H) - IL] CARBONIL} PHENYL CHLORIDATE ) -N- (4-HYDROXYphenyl) -N- (1 -METHYL-1 H-PIRAZOL-4-IL) INDOLIZINE-1-CARBOXAMIDE
[00303] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 32 and, on the other hand, the compound from Preparation 1 ”used in Step C with / / - (4 - {[ether-butyl (dimethyl) silyl] oxy} phen i I) -1-methyl-1 H-pyrazol-4-amine. EXAMPLE 160: 3- (5-CHLORINE-2 - {[(3S) -3- (MOR- FOLIN-4-ILMETIL) -3,4-DI-HYDROISOQUINOLIN-2 (1 H) - IL] CARBONYL CHLORIDATE} PHENYL) -N- (4-HYDROXYphenyl) -N- (1 -METHYL-1 H-PIRAZOL-4-IL) INDOLIZINE-1-CARBOXAMIDE
[00304] The procedure is as in the process of Example 1, replacing, on the one hand, the compound from Preparation 1 used in Step A with the compound from Preparation 14 and, on the other hand, the compound from Preparation 1 ”used in Step C with A / - (4 - {[ether-butyl (dimethyl) si-yl] oxy} phen i I) -1-methyl-1 H-pyrazol-4-amine. PHARMACOLOGICAL STUDY EXAMPLE A: BCL-2 INHIBITION BY FLUORESCENCE POLARIZATION TECHNIQUE
[00305] Fluorescence polarization tests were performed on microplates (384 wells). The Bcl-2 protein, in a final concentration of 2.50 x 10'8 M, is mixed with a fluorescent peptide (Fluorescein-REIGAQLRRMADDLNAQY), in a final concentration of 1.00 x 10'8 M, in a solution of buffer (10 mM Hepes, 150 mM NaCI, 0.05% Tween20, pH 7.4), in the presence or absence of increasing concentrations of test compounds. After incubation for 2 hours, fluorescence polarization is measured.
[00306] The results are expressed as IC50 (the concentration of compound that inhibits fluorescence polarization by 50%) and are shown in Table 1 below.
[00307] The results show that the compounds of the invention inhibit the interaction between the Bcl-2 protein and the fluorescent peptide described above. EXAMPLE B: IN VITRO CYTOTOXICITY
[00308] Cytotoxicity studies were performed on the leukemia tumor lineage RS4; 11. The cells are distributed on the microplates and exposed to the test compounds for 48 hours. The cell's viability is then quantified by a colorimetric assay, the Tetrazolium Assay in Microculture (Cancer Res., 1987, 47, 939-942).
[00309] Results are expressed as IC 50 (the concentration of compound that inhibits cell viability by 50%) and are shown in Table 1 below.
[00310] The results show that the compounds of the invention are cytotoxic. TABLE 1: IC50 OF BCL-2 INHIBITION (FLUORESCENCE POLARIZATION TEST) AND CYTOTOXICITY FOR RS4 CELLS; 11




EXAMPLE C: INDUCTION OF CASPASE IN VIVO ACTIVITY
[00311] The ability of the compounds of the invention to activate caspase 3 is evaluated in an RS4 leukemia cell xenograft model; 11.
[00312] 1 x 107 RS4 cells; 11 are grafted subcutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after grafting, the animals are treated orally with the various compounds. Sixteen hours after treatment, the tumor masses are recovered and lysed, and caspase 3 activity is measured in the tumor patients.
[00313] The enzymatic measurement is carried out by testing the appearance of a fluorogenic cleavage product (DEVDase activity, Promotion). It is expressed in the form of an activation factor corresponding to the ratio between the two activities of the caspase: the activity for the treated mice divided by the activity for the control mice.
The results obtained are shown in Table 2 and show that the compounds of the invention are capable of inducing apoptosis in RS4; 11 tumor cells in vivo. TABLE 2: CASPASE ACTIVATION FACTORS (DEVDASE ACTIVITY IN TUMORS OF TREATED MICE VERSUS CONTROL MICE) IN VIVO, AFTER ORAL TREATMENT (EXACT DOSES BETWEEN BRACKETS)
EXAMPLE D: QUANTIFICATION OF THE CLIVED FORM OF CAS-PASE 3 IN VIVO
[00315] The ability of the compounds of the invention to activate caspase 3 is evaluated in a leukemic cell xenograft model RS4; 11.
[00316] 1 x 107 RS4 cells; 11 are grafted subcutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after grafting, the animals are treated orally with the various compounds. After treatment, the tumor masses are recovered and lysed, and the cleaved (activated) form of caspase 3 is quantified in the tumor lysates.
[00317] Quantification is performed using the "Meso Scale Discovery (MSD) ELISA platform" test, which specifically tests the cleaved form of caspase 3. It is expressed in the form of an activation factor corresponding to the ratio between the quantity of caspase 3 cleaved in the treated mice divided by the amount of caspase 3 cleaved in the control mice.
[00318] The results obtained are shown in Table 3 and show that the compounds of the invention are capable of inducing apoptosis in RS4; 11 tumor cells in vivo. TABLE 3: CASPASE ACTIVATION FACTORS (MSD CASPASE 3 TEST CLIVED IN TUMORS OF TREATED MICE VERSUS CONTROL MICE) IN VIVO, AFTER ORAL TREATMENT (EXACT DOSES BETWEEN BRACKETS)
EXAMPLE E: IN VIVO ANTI-TUMOR ACTIVITY
[00319] The antitumor activity of the compounds of the invention is evaluated in an RS4 leukemia cell xenograft model; 11.
[00320] 1 x 107 RS4 cells; 11 are grafted subcutaneously into immunosuppressed mice (SCID strain). 25 to 30 days after the graft, when the tumor mass has reached about 150 mm3, the mice are treated orally with the various compounds in two different regimens (daily treatment for five days a week, for two weeks, or two weekly treatments) for two weeks). The tumor mass is measured twice weekly from the start of treatment.
[00321] The compounds of the invention have antitumor activities, by the oral route, in the leukemia model of RS4; 11 (acute lymphoblastic leukemia), with ΔT / C (parameter of qualification of the activity of a product, which is defined as the ratio of tumor volume in the treated group / tumor volume in the untreated control group) ranging from -15 to -56% in relation to tumor regression. The results obtained therefore show that the compounds of the invention are capable of inducing significant tumor regression during the treatment period. EXAMPLE F: PHARMACEUTICAL COMPOSITION: TABLETS 1000 tablets containing a dose of 5 mg of a compound selected from Examples 1 to 160 5 g Wheat starch 20 g Corn starch 20 g Lactose 30 g Magnesium stearate 2 g Silica 1 g Hydroxypropylcellulose 2 g

权利要求:
Claims (20)
[0001]
1. Compound, characterized by the fact that it presents the formula (I):
[0002]
2. A compound of formula (I) according to claim 1, characterized by the fact that the group
[0003]
3. A compound of the formula (I) according to claim 1, characterized by the fact that Ri and R2 each represent an alkyl group optionally substituted by a methoxy, or Ri and R2 form with the nitrogen atom that carries them a heterocycloalkyl selected from the following groups: morpholine optionally substituted by one or more (Ci-Ce) straight or branched alkyls, oxidomorpholine, thiomorpholine 1,1-dioxide, 1,4-oxazepan, 3-methoxypyrrolidine, 3, 3-difluorpyrrolidine, 3-methoxyzetidine, 3-fluorazetidine, oxopiperazine or piperazine, the latter two groups being replaced by a linear or branched (Ci-Cβ) alkyl group, linear or branched (Ci-C6) -polyhaloalkyl group or group methylsulfonyl.
[0004]
4. A compound of formula (I) according to claim 1, characterized by the fact that Ra and Rd, each, represent a hydrogen atom, and (Rt>, Rc) form with the carbon atoms that carry them a 1,3-dioxolane group, in which one of the carbon atoms is optionally deuterated, a 1,4-dioxane group, a 1,4-dioxepan group, or Ra, Rc and Rd each represent a hydrogen atom and Rb represents a halogen, a methyl, a methoxy, an ethoxy, a trifluoromethyl or a trifluoromethoxy.
[0005]
Compound of formula (I) according to claim 1, characterized in that R4 represents a 4-hydroxyphenyl group, a 3-fluoro-4-hydroxyphenyl group or a 5-hydroxypyrimidine group.
[0006]
6. The compound of formula (I) according to claim 1, characterized by the fact that R3 represents a group selected from phenyl, indole, indoline, 1,2,3,4-tetrahydroquinoline, 3,4- dihydro-2H-1,4-benzoxazine, indane, 1H-indazole, 1H-pyrrolo [2,3-b] pyridine, pyrimidine, cyclobutylmethyl, cyclopropylmethyl, 1H-pyrazole, pyridine, pyridazine, these groups optionally having one or more substituents selected from halogen, (C1-C6) straight or branched alkyl, cyano and (C1-Cθ) straight or branched alkoxy.
[0007]
7. A compound of formula (I) according to claim 1, characterized in that it is selected from the following group: A / - (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4- morpholinylmethyl) -3,4-dihydro-2 (1 H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} - / V-phenyl-5,6,7,8- tetrahydro- 1 -indolizine carboxamide, 3- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) - isoquinolinyl) carbonyl] phenyl} - / V - (4-hydroxyphenyl) - / V- (1-methyl-1 / - / - indol-5-yl) - 5,6,7,8-tetrahydro-1-indolizine carboxamide, A / - (4- hydroxyphenyl) - / V- (1-methyl-1 / - / - indazol-5-yl) -3- {2,2- dideuterium-6 - [((3S) -3- (4-morpholinylmethyl) -3, 4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide, N- (4-hydroxyphenyl ) -A / - (1-methyl-1 H-indazol-5-yl) -3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1A7) -yl] carbonyl} -1,3-benzodioxol-5-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide, N- (4-hydroxyphenyl) -3- {7- [ ((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -2 , 3-dihydro-1,4-benzodioxin-6-yl} - / V-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide, A / - (4-hydoxyphenyl) - N- (1-methyl-1 H-indol-5-yl) -3- {6 - [((3S) -3 - [(4-methyl-1-pi perazinyl) methyl] -3,4-d i-hyd ro-2 (1 H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -1-indolizine carboxamide, A / - [4- (hydroxy) phenyl] - / V- (1- methyl-1H-indol-5-yl) -3- {6 - [((3S) -3- (4-morpholinyl methyl) -3,4-dihydro-2 (1/7) -isoquinolinyl) carbonyl] -1,3- benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide, N- (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -A / -phenyl-1-indolizine carboxamide, 3- {5- chloro-2 - [(((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) - isoquinolinyl) carbonyl] phenyl} - / V- (4-hid roxiphenyl) - / V- (1-methyl-1 H-indol-5-yl) -1 - indolizine carboxamide, 6- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4- dihydro-2 (1H) - isoquinolinyl) carbonyl] phenyl} - / V- (3-fluor-4-methylphenyl) -A / - (4-hydroxyphenyl) -3,4-dihydro-1 H-pyrrole [2,1-c] [1,4] oxazine-8- carboxamide, 3- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1 H) -yl] carbonyl} phenyl) -A / - (4-hydroxyphenyl) - / V- (1-methyl-1 H-pyrazol-4-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide, A / - (3-fluorine-4 -methylphenyl) - / V- (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] - 1,3-benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide, / V- [4- (hydroxy) phenyl] - / V- (1-methyl-2, 3-dihydro-1H-indol-5-yl) -3- {6- [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl ] -1,3- benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide, 3- {5-chloro-2 - [((3S) -3- (4- morpholinylmethyl) -3,4-dihydro-2 (1H) - isoquinolinyl) carbonyl] phenyl} -A / - (4-hydroxyphenyl) - / V- (1-methyl-2,3-dihydro-1 / - / - indole-5-iI) -5,6,7,8-tetrahydro-1-indolizine carboxamide, / V- (4-hydroxyphenyl) - / V- (1-methyl-1H-indole-5- il) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -1 -indolizine carboxamide, 3- {5-chloro-2 - [( (3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] phenyl} - / V- (4-hydroxyphenyl) - / V- (1-methyl-2 , 3-dihydro-1 / - / - indole-5-iI) -1 -indolizine carboxamide, 6- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4 -dihydro-2 (1 / - /) - isoquinolinyl) carbonyl] phenyl} - / V- (4-hydroxyphenyl) - / V-phenyl-3,4-dihydro-1 H-pyrrole [2,1 -c] [1,4] oxazine-8-carboxamide, / V- (3-fluorophenyl) - / V- (4-hydroxyphenyl) -3- (6 - {[(3S) -3- (morfolin-4- ylmethyl) -3,4-dihydroisoquinolin-2 (1 H) -yl] carbonyl} -1,3-benzodioxol-5-yl) - 5,6,7,8-tetrahydroindolizine-1-carboxamide, their enantiomers and diastereoisomers, and their addition salts with a pharmaceutically acceptable acid or base.
[0008]
8. Compound of formula (I) according to claim 1, characterized in that it is selected from the following group: A / - (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4- morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -A / -phenyl-5,6,7,8-tetrahydro-1 -indolizine carboxamide, 3- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) - isoquinolinyl) carbonyl] phenyl} - / V- (4-hydroxyphenyl) - / V- (1-methyl-1 H-indol-5-yl) - 5,6,7,8-tetrahydro-1-indolizine carboxamide, / V- (4-hydroxyphenyl) - / V- (1-methyl-1 H-indazol-5-yl) -3- {2,2- dideuterium-6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro -2 (1H) - isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide, / V- (4-h id roxifenyl) - / V- (1-methyl-1 H-indazol-5-yl) -3- (6 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 ( 1H) -yl] carbonyl} -1,3-benzodioxol-5-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide, / V- (4-hydroxyphenyl) -3- {7- [ ((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -2,3-dihydro-1,4-benzodioxin-6-yl} - / V-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide, / V- (4-hydroxyphenyl) - / V- (1-methyl-1 H-indol-5-yl) -3- {6 - [((3S) -3 - [(4-methyl-1-pi perazinyl) methyl] -3,4- d ih id ro-2 (1 H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -1 -indolizine carboxamide, / V- [4- (hydroxy) phenyl] - / V- (1- methyl-1H-indol-5-yl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1, 3-benzodioxol-5-yl} -5,6,7,8-tetrahydro-1-indolizine carboxamide, A / - (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4 -morpholinylmethyl) -3,4-dihydro-2 (1A /) - isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} - / V-phenyl-1-indolizine carboxamide, 3- {5-chlorine -2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro-2 (1H) - isoquinolinyl) carbonyl] phenyl} - / V- (4-hydroxyphenyl) - / V- ( 1-methyl-1 H-indol-5-yl) -1 - indolizine carboxamide, 6- {5-chloro-2 - [((3S) -3- (4-morpholinylmethyl) -3,4-dihydro- 2 (1 / - /) - isoquinolinyl) carbonyl] phenyl} - / V- (3-fluor-4-methylphenyl) -A / - (4-hydroxyphenyl) -3,4-dihydro-1 H-pyrrole [2,1 -c] [1,4] oxazine-8- carboxamide, 3- (5-chloro-2 - {[(3S) -3- (morpholin-4-ylmethyl) -3,4-dihydroisoquinolin-2 (1H) -yl] carbonyl} phenyl) -A / - (4-hydroxyphenyl) - / V- (1-methyl-1 H-pyrazol-4-yl) -5,6,7,8-tetrahydroindolizine-1-carboxamide, its enantiomers and diastereoisomers, and their addition salts with a pharmaceutically acceptable acid or base.
[0009]
Compound of formula (I) according to claim 1, characterized by the fact that it is N- (4-hydroxyphenyl) -3- {6 - [((3S) -3- (4-morpholinylmethyl) -3, 4-dihydro-2 (1H) -isoquinolinyl) carbonyl] -1,3-benzodioxol-5-yl} -N-phenyl-5,6,7,8-tetrahydro-1-indolizine carboxamide.
[0010]
10. Hydrochloride salt, characterized in that it is a compound of the formula (I) as defined in any one of claims 7 to 9.
[0011]
11. Process for the preparation of a compound of formula (I) as defined in claim 1, characterized by the fact that the compound of formula (II) is used as starting material:
[0012]
Process according to claim 11, for the preparation of a compound of formula (I), in which one of the groups R3 and R4 is replaced by a hydroxy function, characterized by the fact that the amine NHR3R4 is subjected in advance to a protective reaction of the hydroxy function before coupling with the carboxylic acid formed from the compound of the formula (VII), or with a hot-corresponding acid derivative thereof, the resulting protected compound of the formula (I) subsequently undergoes a deprotection reaction and is then optionally converted to one of its addition salts with a pharmaceutically acceptable acid or base.
[0013]
Pharmaceutical composition, characterized in that it comprises a compound of the formula (I) as defined in any one of claims 1 to 9 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically excipients acceptable.
[0014]
14. Pharmaceutical composition according to claim 13, characterized in that it is for use as pro-apoptotic agents.
[0015]
15. Pharmaceutical composition according to claim 13, characterized by the fact that it is for use in the treatment of cancers and immune and autoimmune diseases.
[0016]
16. Pharmaceutical composition according to claim 13, characterized in that it is for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukemias, cancer of the colon, esophagus and liver, lymphoblastic leukemias, follicular lymphomas, melanomas, malignant hemopathies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer.
[0017]
17. Use of a pharmaceutical composition as defined in claim 13, characterized by the fact that it is in the manufacture of medicaments for use as pro-apoptotic agents.
[0018]
18. Use of a pharmaceutical composition as defined in claim 13, characterized by the fact that it is in the manufacture of medicaments for use in the treatment of cancers and immune and autoimmune diseases.
[0019]
19. Use of a pharmaceutical composition as defined in claim 13, characterized by the fact that it is used in the manufacture of medicaments for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukemias, cancer of the colon, esophagus and liver , lymphoblastic leukemias, follicular lymphomas, melanomas, malignant hemopathies, myelomas, ovarian cancer, non-small cell lung cancer, prostate cancer and small cell lung cancer.
[0020]
20. Use of a compound of the formula (I) as defined in any one of claims 1 to 8, or of its addition salt with a pharmaceutically acceptable acid or base, characterized in that it is in the manufacture of medicines for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukemias, colon, esophagus and liver cancer, lymphoblastic leukemias, follicular lymphomas, melanomas, malignant hemopathies, myelomas, ovarian cancer, non-small cell lung cancer, cancer of the prostate and small cell lung cancer.

类似技术:

---

公开号 | 公开日 | 专利标题

---

BR112014018165B1|2020-11-17|indolizine compounds, their preparation process, pharmaceutical compositions, their uses and hydrochloride salt

---

JP5121716B2|2013-01-16|Pyridine derivatives and their use in the treatment of mental disorders

---

ES2834462T3|2021-06-17|Bicyclic heterocyclic compounds and their uses in therapy

---

DK2829545T3|2016-09-19|Novel phosphate derivatives, process for their preparation, and to pharmaceutical compositions containing them

---

ES2371053T3|2011-12-27|BENZAZEPINE COMPOUNDS THAT HAVE AFFINITY FOR THE D3 DOPAMINE RECEIVER AND USES OF THE SAME.

---

JP2009507801A5|2012-10-25|

---

CZ20031707A3|2003-11-12|Substituted pyridoquinolines and pyridoquinolines functioning as serotonin agonists and antagonists

---

BR102014017950A2|2015-11-17|pyrrol compounds, a process for their preparation and pharmaceutical compositions containing the same

---

US10414754B2|2019-09-17|Indolizine compounds, a process for their preparation and pharmaceutical compositions containing them

---

KR20160033224A|2016-03-25|New isoindoline or isoquinoline compounds, a process for their preparation and pharmaceutical compositions containing them

---

OA16963A|2016-01-25|New indolizine derivatives, their preparation process and pharmaceutical compositions containing them.

同族专利:

---

公开号 | 公开日

---

ZA201405101B|2015-12-23|

---

CN104144930B|2017-02-22|

---

IL233663D0|2014-08-31|

---

WO2013110890A1|2013-08-01|

---

TN2014000283A1|2015-09-30|

---

HUE031895T2|2017-08-28|

---

LT2807159T|2017-01-10|

---

CY1118547T1|2017-07-12|

---

PL2807159T3|2017-04-28|

---

KR101946911B1|2019-02-12|

---

PE20141405A1|2014-10-20|

---

IL233663A|2018-04-30|

---

FR2986002A1|2013-07-26|

---

CA2861160A1|2013-08-01|

---

MY172811A|2019-12-12|

---

GT201400142A|2015-11-24|

---

EP2807159A1|2014-12-03|

---

AU2013213474A1|2014-07-24|

---

US20150051189A1|2015-02-19|

---

HRP20170153T1|2017-03-24|

---

FR2986002B1|2014-02-21|

---

SI2807159T1|2017-03-31|

---

DOP2014000156A|2014-10-15|

---

PH12014501488A1|2014-09-22|

---

US9603854B2|2017-03-28|

---

ECSP14008606A|2015-07-31|

---

US20170151251A1|2017-06-01|

---

MD4490B1|2017-06-30|

---

PH12014501488B1|2014-09-22|

---

SA113340219B1|2015-10-14|

---

ME02601B|2017-06-20|

---

CR20140311A|2014-10-07|

---

EA026641B1|2017-04-28|

---

MD20140084A2|2014-12-31|

---

JO3195B1|2018-03-08|

---

GEP201606540B|2016-09-12|

---

EP2807159B1|2016-11-23|

---

EA201400833A1|2014-12-30|

---

HK1203507A1|2015-10-30|

---

TW201335157A|2013-09-01|

---

CU20140089A7|2014-11-27|

---

AP2014007882A0|2014-08-31|

---

CA2861160C|2016-08-09|

---

AU2013213474B2|2017-06-08|

---

ES2616679T3|2017-06-14|

---

SG11201403748RA|2014-10-30|

---

CL2014001829A1|2015-01-02|

---

AR089774A1|2014-09-17|

---

PT2807159T|2017-01-05|

---

RU2014134388A|2016-03-27|

---

MX351206B|2017-10-05|

---

NI201400081A|2014-10-24|

---

UY34578A|2013-09-02|

---

HK1201527A1|2015-09-04|

---

KR20140129052A|2014-11-06|

---

DK2807159T3|2017-02-27|

---

MA35903B1|2014-12-01|

---

TWI476198B|2015-03-11|

---

AP4028A|2017-02-04|

---

RU2646223C2|2018-03-02|

---

US9120791B2|2015-09-01|

---

MX2014008913A|2015-01-19|

---

MD4490C1|2018-01-31|

---

JP5978317B2|2016-08-24|

---

RS55739B1|2017-07-31|

---

UA112215C2|2016-08-10|

---

US20150313911A1|2015-11-05|

---

CN104144930A|2014-11-12|

---

NZ626942A|2016-07-29|

---

JP2015506368A|2015-03-02|

---

US10258626B2|2019-04-16|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

---

US5932590A|1996-12-05|1999-08-03|Merck & Co., Inc.|Inhibitors of farnesyl-protein transferase|

---

AT420879T|2001-09-19|2009-01-15|Aventis Pharma Sa|INDOLICINE AS KINASEPROTEINHEMMER|

---

JP4901102B2|2002-05-03|2012-03-21|エクセリクシス，インク．|Protein kinase modulator and method of use thereof|

---

US20050070570A1|2003-06-18|2005-03-31|4Sc Ag|Novel potassium channels modulators|

---

WO2006023778A2|2004-08-20|2006-03-02|The Regents Of The University Of Michigan|Small molecule inhibitors of anti-apoptotic bcl-2 family members and the uses thereof|

---

JP5496877B2|2007-04-16|2014-05-21|アッヴィ・インコーポレイテッド|7-substituted indole Mcl-1 inhibitors|

---

EP2225207A2|2007-11-30|2010-09-08|Biota Scientific Management Pty. Ltd.|Tetrahydro-isoquinoline ppat inhibitors as antibacterial agents|

---

US20090297897A1|2007-12-07|2009-12-03|Robert Walter Boyd|Methods for monitoring hydrogen fueling systems|

---

EP2252617A1|2008-02-13|2010-11-24|CGI Pharmaceuticals, Inc.|6-aryl-imidaz0[l, 2-a]pyrazine derivatives, method of making, and method of use thereof|

---

WO2012040242A1|2010-09-22|2012-03-29|Intermune, Inc.|Substituted proline inhibitors of hepatitis c virus replication|

---

WO2012162365A1|2011-05-25|2012-11-29|Bristol-Myers Squibb Company|Substituted sulfonamides useful as antiapoptotic bcl inhibitors|

---

FR2986002B1|2012-01-24|2014-02-21|Servier Lab|NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

FR3008976A1|2013-07-23|2015-01-30|Servier Lab|"NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"|FR2986002B1|2012-01-24|2014-02-21|Servier Lab|NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

FR3008979B1|2013-07-23|2015-07-24|Servier Lab|NOVEL PHOSPHATE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

FR3008977A1|2013-07-23|2015-01-30|Servier Lab|NOVEL ISOINDOLINE OR ISOQUINOLINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|

---

FR3008975A1|2013-07-23|2015-01-30|Servier Lab|NOVEL PYRROLE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

FR3008978A1|2013-07-23|2015-01-30|Servier Lab|"NOVEL INDOLE AND PYRROLE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"|

---

FR3008976A1|2013-07-23|2015-01-30|Servier Lab|"NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"|

---

FR3015483B1|2013-12-23|2016-01-01|Servier Lab|NOVEL THIENOPYRIMIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|

---

WO2015160975A2|2014-04-16|2015-10-22|Infinity Pharmaceuticals, Inc.|Combination therapies|

---

WO2016190847A1|2015-05-26|2016-12-01|Calitor Sciences, Llc|Substituted heteroaryl compounds and methods of use|

---

FR3037956B1|2015-06-23|2017-08-04|Servier Lab|NOVEL AMINO ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|

---

FR3037959B1|2015-06-23|2017-08-04|Servier Lab|NOVEL BICYCLIC DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME|

---

FR3037958B1|2015-06-23|2019-01-25|Les Laboratoires Servier|NOVEL HYDROXY ACID DERIVATIVES, PROCESS FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

WO2017013271A1|2015-07-23|2017-01-26|Les Laboratoires Servier|Combination of an inhibitor of phosphatidylinositol 3-kinase delta and a bcl-2 inhibitor, uses and pharmaceutical compositions thereof|

---

UY37316A|2016-07-07|2018-01-31|Servier Lab|SOLID PHARMACEUTICAL DISPERSION OF A BCL-2 INHIBITOR, PHARMACEUTICAL COMPOSITIONS OF THIS, AND USES FOR CANCER TREATMENT|

---

TW201806600A|2016-07-22|2018-03-01|法商施維雅藥廠|Combination of a BCL-2 inhibitor and a MCL1 inhibitor, uses and pharmaceutical compositions thereof|

---

WO2018158225A1|2017-02-28|2018-09-07|Les Laboratoires Servier|Combination of a bcl-2 inhibitor and a mdm2 inhibitor, uses and pharmaceutical compositions thereof|

---

TWI672302B|2017-07-06|2019-09-21|法商施維雅藥廠|New crystalline form of a bcl-2 inhibitor, a process for its preparation and pharmaceutical compositions containing it|

---

RU2745431C1|2017-07-27|2021-03-25|Цзянсу Хэнжуй Медицин Ко., Лтд.|Heteroaryl piperazine derivative, method for its preparation and application in medicine|

---

WO2019134970A1|2018-01-05|2019-07-11|Les Laboratoires Servier|Novel salts of a bcl-2 inhibitor,related crystalline forms,method for preparing the same and pharmaceutical compositions containing the same|

---

AU2019221672A1|2018-02-16|2020-09-03|Abbvie Inc.|Selective BCL-2 inhibitors in combination with an anti-PD- 1 or an anti-PD-L1 antibody for the treatment of cancers|

---

CA3139009A1|2019-05-14|2020-11-19|Les Laboratoires Servier|Bcl-2 inhibitors for use in the treatment of a bcl-2 mediated cancer carrying the gly101val mutation|

---

AU2020279979A1|2019-05-20|2021-11-25|Les Laboratoires Servier|Mcl-1 inhibitor antibody-drug conjugates and methods of use|

法律状态:
2018-01-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|

---

2018-03-27| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

---

2019-04-24| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|Free format text: NOTIFICACAO DE ANUENCIA RELACIONADA COM O ART 229 DA LPI |

---

2019-06-04| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

---

2020-02-18| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

---

2020-06-23| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

---

2020-11-17| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 23/01/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

---

申请号 | 申请日 | 专利标题

---

FR1200193A|FR2986002B1|2012-01-24|2012-01-24|NOVEL INDOLIZINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|

---

FR1200193|2012-01-24|

---

PCT/FR2013/050136|WO2013110890A1|2012-01-24|2013-01-23|New indolizine derivatives, method for preparing same and pharmaceutical compositions containing same|

---