WO2011070298A1 - DERIVES 9H-PYRIDINO[3,4-b]INDOLE DISUBSTITUES, LEUR PREPARATION ET LEUR UTILISATION THERAPEUTIQUE - Google Patents

DERIVES 9H-PYRIDINO[3,4-b]INDOLE DISUBSTITUES, LEUR PREPARATION ET LEUR UTILISATION THERAPEUTIQUE Download PDF

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WO2011070298A1
WO2011070298A1 PCT/FR2010/052652 FR2010052652W WO2011070298A1 WO 2011070298 A1 WO2011070298 A1 WO 2011070298A1 FR 2010052652 W FR2010052652 W FR 2010052652W WO 2011070298 A1 WO2011070298 A1 WO 2011070298A1
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substituted
alkyl
optionally mono
branched
linear
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French (fr)
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Didier Babin
Olivier Bedel
Thierry Gouyon
Alexandre Gross
Serge Mignani
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Sanofi-Aventis
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to 9H-pyridino [3,4-b] indole derivatives, their preparation and their therapeutic application.
  • the present invention relates to compounds acting on protein kinases, these kinases being involved in the development of cancers. More particularly, the present invention relates to compounds acting on a target called Pim involved in the development of cancers.
  • Pim kinases encompassing Pim-1, Pim-2 and Pim-3, form a distinct family of serine / threonine kinases, and play a functional role in cell growth, differentiation and apoptosis.
  • One of the mechanisms by which Pim kinases can increase cancer cell survival and promote cancer progression is through the modulation of ADB activity, a key regulator of apoptosis.
  • Pim kinases are highly homologous to each other and display similar oncogenic behavior.
  • Pim kinases particularly Pim-1 and Pim-2, have been found to be abnormally expressed in a large number of hematological malignancies.
  • Amson et al. report the overexpression of Pim-1 in acute myeloid leukemia and acute lymphoid leukemia, and that overexpression of Pim-1 appears to result from inappropriate activation in various leukemias (Proc Natl Acad Sci, Vol 86. , 8857-8861 (1989)).
  • Studies have demonstrated overexpression of Pim-1 in primary and metastatic CNS lymphoma, an aggressive form of non-Hodgkin lymphoma (Rubenstein et al., Blood, Vol 107, 9, 3716-3723 (2006)).
  • Pim-2 in B cell chronic lymphocytic leukemia and suggest that upregulation of Pim-2 may be associated with more aggressive disease progression (Leukemia, 20, 1774-1782). 2006).
  • Abnormal expression of Pim-1 and Pim-2 has been linked to multiple myeloma (Claudio et al., Blood, v. 100, No. 6, 2175-2186 (2002)).
  • Hypermutations of Pim-1 have been identified in diffuse large cell lymphomas (Pasqualucci et al., Nature, Vol 412, 2001, pp. 341-346 (2001)) and in nodular and predominantly nodular Hodgkin's lymphoma predominantly (Liso et al., Blood, Vol 108, No.
  • Pim-1 and Pim-2 have been implicated in prostate cancer (Chen et al., Mol Cancer Res, 3 (8) 443-451 (2005)).
  • Valdman et al. have demonstrated upregulation of Pim-1 in patients with prostate carcinoma and in high-grade prostatic intraepithelial neoplasia (precancerous lesions) ⁇ The Prostate, (60) 367-371 (2004) ), while Dai et al.
  • Pim-2 is linked to the perineural invasion (PNI), during which cancer cells curl around the nerves, which are often found in certain cancers such as cancers of the prostate, pancreas, ducts biliary and head and neck (Ayala et al., Cancer Research, 64, 6082 - 6090 (2004)).
  • PNI perineural invasion
  • Pim-3 is aberrantly expressed in human and mouse hepatocarcinomas and human pancreatic cancer tissues (Cancer Res. 66 (13), 6741-6747 (2006)).
  • Aberrant expression of Pim-3 has also been observed in gastric adenoma and metastatic sites of gastric carcinoma (Zheng et al., J Cancer Res Clin Oncol, 134: 481-488 (2008)).
  • Pim kinase inhibitors are useful for the treatment of cancer, including leukemias, lymphomas, myelomas, and various solid tumors, including head and neck cancers, colon cancer, prostate cancer, pancreatic cancer, liver cancer and oral cancer, for example. Since cancer remains a disease for which existing therapies are inadequate, it is clearly necessary to identify new inhibitors of Pim kinases that are effective in the treatment of cancer.
  • the present invention relates to products of the following general formula (I):
  • Z 3 being a 5- or 6-membered heteroaryl with 1 to 4 heteroatoms chosen from N, S or O) linked to the carboline unit, either by a C or by an N belonging to Z 3, Z 3 being optionally mono or poly substituted;
  • Z6 is chosen from:
  • -X-heteroaryl O, S, SO, SO2, 5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to X, either C or N) optionally mono, di or substituted tripping ⁇
  • heteroaryl whose heteroaryl part (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom by a C or an N) is optionally mono, di or substituted tri;
  • alkyl (aryl) whose alkyl (linear, branched or cyclic) and aryl portions are optionally mono, di or tri substituted;
  • -N alkyl (heteroaryl) whose alkyl (linear, branched or cyclic) and heteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom with either C or N) are optionally mono, di or tri substituted;
  • Oheteroaryl heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to oxygen by a C atom
  • -CON (alkyl) (heteroaryl), linear, branched or cyclic alkyl and heteroaryl of 5- or 6-membered with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or by an N) of which the alkyl and the hetroaryl parts are optionally mono, di or tri substituted;
  • heteroaryl (5- or 6-membered with 1 to 4 heteroatoms selected from N, S or O) linked to the carboline moiety either by a C or by an N belonging to Z6, Z6 being optionally mono or poly substituted;
  • the present invention relates in particular to compounds of general formula (I) as defined above in which Z3 has the meaning indicated above and Z6 represents in particular:
  • alkoxy whose alkyl part is optionally mono, di or tri substituted
  • alkyl -NH (alkyl), -N (alkyl) 2 linear (s), branched (s) or cyclic (s) of which the alkyl part is optionally mono, di or tri substituted;
  • heteroaryl whose heteroaryl part (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom is a C or an N) is optionally mono , di or substituted tri;
  • alkyl (heteroaryl) of which the alkyl (linear, branched or cyclic) and heteroaryl (heteroaryl) parts of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or an N) are optionally mono, di or tri substituted;
  • Oheteroaryl heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to oxygen by a C atom
  • -CON (alkyl) (heteroaryl), linear, branched or cyclic alkyl and heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or by an N) of which the alkyl and the hetroaryl parts are optionally mono, di or tri substituted;
  • aryl optionally mono, di or tri substituted
  • heteroaryl (5 or 6-membered with 1 to 4 heteroatoms selected from N, S or O) linked to the carboline unit either by a C or by an N belonging to Z6, Z6 being optionally mono or poly substituted;
  • the present invention relates to products of general formula (I) as defined above in which the possible substituents of Z3 is the groups R2a, R2b, R2c, R2d or R2e are chosen independently of one another among:
  • R3a, R3b, R3c identical or different
  • aryl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;
  • heteroaryl consisting of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded either by a C or by N) optionally mono or poly substituted with R3a, R3b, R3c, the same or different;
  • heterocycloalkyl optionally mono or poly substituted with R3a,
  • -C2-C6 alkynyl optionally substituted with R3a; the groups R3a, R3b, R3c, or the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from:
  • aryl optionally mono or poly substituted with R4a, R4b, R4c;
  • heteroaryl optionally mono or poly substituted with R4a, R4b, R4c;
  • heterocycloalkyl optionally mono or poly substituted with R4a, R4b, R4c;
  • the present invention relates to products of general formula (I) as defined above in which the possible substituents of Z6 is the groups R2a, R2b, R2c, R2d or R2e are chosen independently of one another among: 2. Cl;
  • R3c identical or different
  • aryl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;
  • heteroaryl consisting of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded either by a C or by N) optionally mono or poly substituted with R3a, R3b, R3c, the same or different;
  • heterocycloalkyl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;
  • -C2-C6 alkynyl optionally substituted with R3a; the groups R3a, R3b, R3c, or the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from:
  • aryl optionally mono or poly substituted with R4a, R4b, R4c;
  • heteroaryl optionally mono or poly substituted with R4a, R4b, R4c;
  • heterocycloalkyl optionally mono or poly substituted with R4a, R4b, R4c;
  • the present invention relates to products of general formula (I) as defined above in which
  • Z 3 represents a 5- or 6-membered heteroaryl radical with 1 to 4 heteroatoms chosen from N, S or O bonded to the carboline unit, either by a C or by an N belonging to Z 3, Z 3 being optionally mono or poly substituted with R 2a, R 2b R2c, R2d, R2e, the same or different;
  • Z6 is chosen from:
  • -X-aryl O, S, SO, SO2) optionally mono, di or tri substituted by R2a, R2b, R2c, the same or different;
  • -X-heteroaryl O, S, SO, SO2, 5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to X, either C or N) optionally mono, di or tri substituted by R2a, R2b, R2c, the same or different;
  • heteroaryl whose heteroaryl part (heteroaryl of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom by a C or an N) is optionally mono, di or tri substituted by R2a, R2b, R2c, the same or different;
  • Oheteroaryl (5- or 6-membered heteroaryl with 1 to 4 heteroatoms selected from N, S or O bonded to oxygen by a C atom) optionally mono, di or tri substituted by R2a, R2b, R2c, identical or different;
  • -CON (alkyl) (heteroaryl), linear, branched or cyclic alkyl and heteroaryl of 5- or 6-membered with 1 to 4 heteroatoms selected from N, S or O bonded to the nitrogen atom either by a C or by an N) of which the alkyl and the hetroaryl parts are optionally mono, di or tri substituted by R2a, R2b, R2c, which are identical or different;
  • aryl optionally mono, di or tri substituted by R2a, R2b, R2c, the same or different;
  • heteroaryl (5- or 6-membered with 1 to 4 heteroatoms selected from N, S or O) linked to the carboline moiety either by C or N belonging to Z6, Z6 being optionally mono or poly substituted with R2a, R2b, R2c, R2d, R2e identical or different;
  • heterocycloalkyl optionally mono or poly substituted with R2a, R2b, R2c, the same or different;
  • aryl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;
  • heteroaryl consisting of 5 or 6 members with 1 to 4 heteroatoms selected from N, S or O bonded either by a C or by N) optionally mono or poly substituted with R3a, R3b, R3c, the same or different; 14. heterocycloalkyl optionally mono or poly substituted with R3a, R3b, R3c, the same or different;
  • R3b identical or different
  • the groups R3a, R3b, R3c, or the substituents of the groups R2a, R2b, R2c, R2d or R2e, are chosen independently of one another from:
  • aryl optionally mono or poly substituted with R4a, R4b, R4c;
  • heteroaryl optionally mono or poly substituted with R4a, R4b, R4c; 14. heterocycloalkyl optionally mono or poly substituted with R4a, R4b,
  • C1-C10 linear or branched alkyl or O-alkyl (C1-C10) is optionally mono or poly substituted by Hal
  • the substituent formed can be CF3, CHF2 or OCF3, -OCHF2.
  • Z3 may especially represent a pyridine, pyrazole, pyrimidine, imidazole, triazole or tetrazole radical, all optionally substituted by one or more radicals R2a, R2b, R2c, R2d and R2e as indicated. above.
  • Z3 can thus be substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, alkoxy, alkylthio, NH 2, NHalk or N (alk) 2 radicals.
  • Z6 represents a heteroaryl radical
  • Z6 represents in particular a pyrazolyl, isoxazolyl, oxazolyl, thiazolyl or thienyl radical, all optionally substituted by one or more radicals chosen from Ra, Rb, Rc, Rd and Re as indicated above for Z6.
  • Z6 can thus be in particular substituted by one or more identical or different radicals chosen from halogen atoms and alkyl, alkoxy, alkylthio, NH 2, NHalk or N (alk) 2 and especially alkyl radicals.
  • the present invention relates in particular to products of general formula (I) as defined above in which Z3 represents a heteroaryl radical consisting of 5- or 6-membered with 1 to 4 N heteroatoms, linked to the carboline moiety either by a C or by a N belonging to Z3, Z3 being optionally mono or poly substituted as indicated above, and Z6 having the meanings indicated above,
  • Alkyl, (C 1 -C 10 ) alkyl or C 1 -C 10 alkyl means all carbon chains of 1 to 10 carbons, saturated, linear or branched.
  • - C 2 -C 6 alkenyl means all carbon chains of 1 to 6 carbons, linear or branched, having at least one carbon-carbon double bond.
  • - C 2 -C 6 alkynyl means all carbon chains of 1 to 6 carbons, linear or branched, having at least one carbon-carbon triple bond.
  • Aryl means phenyl or naphthyl.
  • Heteroaryl means all aromatic 5- or 6-membered aromatic monocycles having at least one heteroatom (N, O, S) in particular: pyridine, pyrimidine, imidazole, pyrazole, triazole, thiophene, furan, thiazole, oxazole, isoxazole, etc. that aromatic bicyclic systems possessing at least one heteroatom (N, O, S) in particular indole, benzimidazole, azaindole, benzofuran, benzothiophene, quinoloin, tetrazole
  • Heterocycloalkyl means all unicyclic monocycles and bicycles (spiro or non-aromatic) having at least one heteroatom (N, O, S at the different possible oxidation states) with or without unsaturation, in particular: morpholine, piperazine, piperidine, pyrrolidine, oxetane, epoxide, dioxane, imidazolone, imidazolinedione, 7-oxa-bicyclo [2.2.1] heptane, azetidine, azepine, hexahydropyrrolo [3,4-b] pyrrole, hexahydropyrrolo [2,3-b] pyrrole, hexahydropyrrolo [3,4- c] pyrrole, hexahydropyrrolo [2,3-c] pyrrole, 2,7-diazaspiro [4,4] nonane, 2,6-diazaspiro [4,
  • Cycloalkyl (C 3 -C 7 ) means all non-aromatic rings consisting solely of carbon atoms, especially cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane; but may also carry unsaturation, for example cyclopentene, cyclohexene, cycloheptene, bicyclo [2.2.1] heptane.
  • - C-I-C-10 alkylhydroxy means all carbon chains of 1 to 10 carbons, saturated, linear or branched carrying at least one hydroxyl (OH) group.
  • - C1-C10 alkoxy means all carbon chains of 1 to 10 carbons, saturated, linear or branched in which is at least one ether function (C-O-C).
  • - C1-C10 alkylamino means all carbon chains of 1 to 10 carbons, saturated, linear or branched in which there is at least one amine function (primary, secondary or tertiary).
  • the present invention also relates to the following products of formula (I):
  • the compounds of formula (I) can comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures, form part of the invention.
  • the compounds of formula (I) may comprise one or more E / Z type stereochemies on double bonds or cis / trans bonds on nonaromatic rings. These different stereoisomers and their mixtures are part of the invention.
  • the compounds of formula (I) may exist in the form of bases or addition salts with acids. Such addition salts are part of the invention.
  • salts can be prepared with pharmaceutically acceptable acids (P.Stahl, C.Wermuth, Handbook of Pharmaceutical Salts, Wiley Ed.), But salts of other acids useful, for example, for purification or isolation of compounds of formula (I) are also part of the invention.
  • the compounds of formula (I) may comprise one or more isotopes of the atoms described above, in particular deuterium D, tritium T, 11 C, 13 C, 14 C, 15 O, 15 N, 18 F , 123 l, 124 l and 135 l. These compounds, whatever their isotopic compositions, are part of the invention.
  • the present invention also relates to any synthesis method known to those skilled in the art for preparing the products of formula (I) as defined above.
  • the subject of the present invention is in particular a process for the synthesis of the products of formula (I) as defined above, described in scheme 1.
  • the preparation of the compound of structure (III) is obtained from compound (II) by the action of formaldehyde in the presence of a strong acid such as sulfuric acid, hydrochloric acid or phosphoric acid at a concentration of about 1 M in the presence of an alcohol such as methanol or isopropanol at ordinary temperature.
  • the compound of structure (IV) may be prepared from (III) by the action of an alcohol such as methanol, ethanol or ispropanol in the presence of a strong acid such as hydrochloric acid or sulfuric acid under reflux of the reaction medium.
  • the compound (V) can be obtained from the compound (IV) in an inert solvent such as xylene, p-cymene or decalin by the action of Pd / C (for example at 10%) at reflux of the reaction medium by application or adaptation of the methods described in J. Am. Chem. Soc., 82, 5233, 1960; J. Org. Chem., 17, 1295, 1952 and Organic Synthesis, IV page 536.
  • the compound of structure (VI) can be prepared by hydrolysis of (V) using, for example, LiOH, NaOH or KOH in water at a temperature of temperature ranging from ordinary temperature to reflux of the reaction medium.
  • the compound (VII) can be prepared from (VI) by the action for example of diphenyl phosphorazidoate in the presence of tert-butanol in an inert solvent such as DMF at a temperature ranging from ordinary temperature to the reflux of the reaction medium or by example by application or adaptation described in Journal of Medicinal Chemistry, 52 (10), 3205, 2009 which consists of reacting the starting acid in question in the presence of ter-butanol, 4-dimethylaminopyridine (4-DMAP) and 1 3-dicyclohexylcarbodiimine (DCC) at room temperature.
  • the amine of structure (VIII) may be prepared from (VII) by the action of an acid such as trifluoroacetic acid for example (see Protective group in organic synthesis, 3rd edition p520).
  • the compound of structure (IX) can be obtained from (VIII) for example by the action of bromidic acid, copper bromide in a solvent mixture such as dichloromethane and polyethylene glycol (PEG 200) in the presence of nitrite of 3-methylbutyl at a temperature of -10 ° C to room temperature or by application or adaptation of the method described in Tetrahedron Asymetry, (1 1), 1673, 2004 which comprises reacting the starting amine with presence of copper bromide and sodium nitrite (NaNO 2) in the presence of HBr.
  • a solvent mixture such as dichloromethane and polyethylene glycol (PEG 200)
  • nitrite of 3-methylbutyl at a temperature of -10 ° C to room temperature
  • Tetrahedron Asymetry (1 1), 1673, 2004 which comprises reacting the starting amine with presence of copper bromide and sodium nitrite (NaNO 2) in the presence of HBr.
  • Compound (Ia) can be obtained from (IX) by a so-called “Suzuki coupling" reaction by the action of either a cyclic dioxaborolane such as (4,4,5,5-tetramethyl [1, 3,2] dioxaborolane) aryl or boronic acid derivative such as an aryl-boronic acid in the presence of Pd (0) such as Pd (Ph3P) 4, in a solvent such as a cyclic ether such as dioxane or THF, whether or not micro-irradiation is wave at a temperature ranging from 100 ° C to 150 ° C in sealed tube or not.
  • a cyclic dioxaborolane such as (4,4,5,5-tetramethyl [1, 3,2] dioxaborolane)
  • aryl or boronic acid derivative such as an aryl-boronic acid
  • Pd (0) such as Pd (Ph3P) 4
  • a solvent such as a cyclic ether such
  • the compound of structure (Ia) can be prepared from (I), when Z6 represents a hydrogen atom, for example by the action of N-bromosuccinimide in a solvent such as dichloromethane or chloroform at a temperature ranging from the temperature common to the reflux of the reaction medium or by application or adaptation of the methods described in Organic Synthesis, III, 138.
  • the compound of structure (I) can be prepared from (la) by the same methods as for the preparation of (I) from (IX).
  • the products of formulas (Ia) are products of formulas (I) in which Z6 represents a bromine atom.
  • the compounds of structure (I) may also be prepared according to the following general scheme 2:
  • the present invention thus relates in particular to a process for the synthesis of the products of formula (I) as defined above, described below in general scheme 2.
  • General scheme 2 :
  • the compound of general structure (X) may be prepared by application or adaptation of the described methodology as for example (non-exclusive list) in the Indian Pat patent. appl. 2004DEO2465, Nov 17, 2006; Journal of Heterocycle Chemistry, 44 (6), 1485, 2007, Journal of Combinatorial Chemistry, 7 (6), 879, 2005; US Patent 5502194, March 26, 1996; Eur. Pat. Appl., 591624, April 13, 1994 and in Chemical & Pharmaceutical Bulletin, 36 (6), 2244, 1988 and cited references.
  • the compound of general structure (XI) can be prepared from (X) by a so-called “Suzuki coupling" reaction by the action of either a cyclic dioxaborolane such as (4,4,5,5-tetramethyl [1,3] , 2] dioxaborolane) of aryl or boronic acid derivative such as an aryl-boronic acid in the presence of Pd (0) such as Pd (Ph3P) 4, in a solvent such as a cyclic ether such as dioxane or THF, in the presence or absence of microwave irradiation at a temperature ranging from 100 ° C to 150 ° C in sealed tube or not.
  • a cyclic dioxaborolane such as (4,4,5,5-tetramethyl [1,3] , 2] dioxaborolane
  • aryl or boronic acid derivative such as an aryl-boronic acid
  • Pd (0) such as Pd (Ph3P) 4
  • a solvent such
  • the compound of structure (XII) can be prepared from (XI) by action of a base such as LDA (lithium salt of diisopropylamine) or n-butyl lithium and a chlorinated derivative of tin , such as trimethyltin chloride or tributyltin chloride, in a solvent such as an ether such as for example THF or dioxane at a temperature ranging from -70 ° C to the reflux of the reaction mixture.
  • a base such as LDA (lithium salt of diisopropylamine) or n-butyl lithium and a chlorinated derivative of tin , such as trimethyltin chloride or tributyltin chloride
  • a solvent such as an ether such as for example THF or dioxane
  • the compound of structure (XIV) can be obtained from (XII) by a so-called "Stille coupling" reaction which consists in reacting, for example, the compound (XII) and the compound (XIII) in the presence or absence of iodide copper (Cul), Pd (O) such as Pd (Ph 3 P) 4 in a solvent such as a cyclic ether, THF or dioxane for example, under microwave irradiation or not at a temperature ranging from ordinary temperature to reflux of the reaction mixture.
  • a so-called "Stille coupling" reaction which consists in reacting, for example, the compound (XII) and the compound (XIII) in the presence or absence of iodide copper (Cul), Pd (O) such as Pd (Ph 3 P) 4 in a solvent such as a cyclic ether, THF or dioxane for example, under microwave irradiation or not at a temperature ranging from ordinary temperature to
  • the compound (I) can be obtained from (XIV) by the action of a copper derivative at any of its oxidation levels in a solvent such as DMSO or by the action of a palladium complex (0 ) such tris (dibenzylideneacetone) dipalladium (0) in the presence of a ligand such as 2-dicyclohexylphosphino-2 '- (N, N-dimethylamino) biphenyl and potassium tert-butoxide as a strong base in a cyclic ether such as THF or dioxane at a temperature ranging from ordinary temperature to reflux of the reaction mixture, or by application or adaptation of the methods described in Bioorganic & Medicinal Chemistry Letters, 17 (4), 1043, 2007 which consists in using Pd (Ph3P) 4 as palladium complex in the presence of a salt such as sodium carbonate.
  • a palladium complex such tris (dibenzylideneacetone) dipalladium (0) in
  • the compound of structure (XIII) is commercially available or can be obtained by application or adaptation of the method described in Syniett, 6, 450, 1994; Bulletin of the Chemical Society of France, 1, 93, 1990 or Tetrahedron Letters, 30 (45), 6209, 1989.
  • the subject of the present invention is also, as medicaments, the products of formula (I) as defined above. and their prodrugs, said products of formula (I) being in all isomeric forms possible racemic, enantiomers and diastereoisomers, as well as the addition salts with acids inorganic and organic or with the pharmaceutically acceptable inorganic and organic bases of said products of formula (I).
  • the subject of the present invention is, in particular, as medicaments the products of formula (I) as defined above, whose names follow:
  • the subject of the present invention is also, as medicaments, the products of formula (I) as defined above whose names follow:
  • the present invention also relates to pharmaceutical compositions containing as active ingredient, a compound according to any one of the preceding claims and at least one pharmaceutically compatible excipient.
  • the present invention also relates to the pharmaceutical compositions according to the preceding claim used for the treatment of cancer.
  • the present invention relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
  • These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt, of said compound, as well as at least one pharmaceutically acceptable excipient.
  • excipients are chosen according to the pharmaceutical form and the desired mode of administration from the usual excipients which are known to those skilled in the art.
  • compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous administration may be administered in unit dosage form. administration, in admixture with conventional pharmaceutical excipients, to animals and humans for the treatment of the above disorders or diseases.
  • Suitable unit dosage forms include oral forms such as tablets, soft or hard capsules, powders, granules and oral solutions or suspensions, sublingual, oral, subcutaneous, intramuscular or intravenous administration forms.
  • Pim kinase inhibitors of the present invention are useful for the treatment of cancer. Since cancer remains a disease for which existing therapies are inadequate, it is clearly necessary to identify new inhibitors of Pim kinases that are effective in the treatment of cancer.
  • the present invention also relates to a method of treatment of the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention, or one of pharmaceutically acceptable salts thereof.
  • DAD wavelength scanning detector
  • HATU O-Azabenzotriazol-1-y NN-N-tetra-methyluronium
  • LiTMP lithium amide of 2,2,6,6-tetramethylpiperidine
  • the dilution solvents are dimethylsulfoxide, methanol, acetonitrile, dichloromethane.
  • aqueous phase is extracted twice with 150 ml of ethyl acetate and the combined organic phases are dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure.
  • the residue is purified by chromatography on a silica column [eluent dichloromethane / methanol gradient from 99/1 to 93/7 with 1% triethylamine] and 803 mg of (6-methoxy-9H-beta-carbolin-3-yl are obtained. ) 2-methylpropan-2-yl carbamate whose characteristics are as follows:
  • the aqueous phase is extracted twice with 100 ml of ethyl acetate and the combined organic phases are dried over anhydrous sodium sulphate, filtered and concentrated to dryness under reduced pressure.
  • the residue is purified by chromatography on a silica column [eluent dichloromethane / methanol gradient from 99/1 to 95/5 with 1% triethylamine] and 232 mg of 3-bromo-6-methoxy-9H-beta-carboline are obtained.
  • the characteristics are as follows:
  • aqueous phase is extracted with twice 15 ml of ethyl acetate and the combined organic phases are dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure.
  • the residue is purified by preparative HPLC in basic medium (method 1). 15 mg of 6-methoxy-3- (pyridin-3-yl) -9H-beta-carboline are obtained, the characteristics of which are as follows:
  • 2-Methylpropan-2-yl 9H-beta-carbolin-3-ylcarbamate can be prepared as described for the preparation of 2-methylpropan-2- (6-methoxy-9H-beta-carbolin-3-yl) carbamate but from 4.4 g of 9H-beta-carbolin-3-carboxylic acid, in 167 ml of dimethylformamide, 31 ml of terbutanol of 6.2 ml of triethylamine and 6.7 ml of diphenylphosphorazidoate. After four hours at a temperature of 80 ° C.
  • 9H-beta-carbolin-3-amine can be prepared as described for the preparation of 6-methoxy-9H-beta-carbolin-3-amine at but from 3.8 g of 9H-beta- carbolin-3-ylcarbamate. 2-methylpropan-2-yl in 100 ml of dichloromethane and 20 ml of trifluoroacetic acid. After stirring overnight at a temperature in the region of 20 ° C. and purification by chromatography on a silica column (eluent dichloromethane / methanol gradient from 99/1 to 94/6 with 1% triethylamine), 1.25 g of 9H-beta are obtained.
  • -carbolin-3-amine whose characteristics are as follows:
  • 3-Bromo-9H-beta-carboline can be prepared as described for the preparation of 3-bromo-6-methoxy-9H-beta-carboline but from 820 mg of 9H-beta-carbolin-3-amine in 41 ml of dibromomethane, 13 ml of polyethylene glycol (PEG 200), 1.224 ml of 48% hydrobromic acid and 1.1 g of copper bromide and 0.663 ml of 3-methylbutyl nitrite.
  • 3- (Pyridin-3-yl) -9H-beta-carboline can be prepared as described for the preparation of Example 1 but starting from 220 mg of 3-bromo-9H-beta-carboline in a mixture of 4.7 ml of dioxane and 0.5 ml of water, 255 mg of 3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, 725 mg of cesium carbonate and 103 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 140 ° C. and purification by preparative HPLC in a basic medium (method 1), 75 mg of 3- (pyridin-3-yl) -9H-beta-carboline are obtained. whose characteristics are as follows:
  • the medium is poured into 50 ml of a 10% aqueous solution of sodium hydrogencarbonate and 5 ml of water.
  • the aqueous phase is extracted twice with 50 ml of ethyl acetate.
  • the combined organic phases are dried over anhydrous sodium sulphate and filtered and concentrated to dryness under reduced pressure.
  • the residue is purified by preparative HPLC in basic medium (method 2) and 75 mg of methyl 3- (pyridin-3-yl) -9H-beta- carboline-6-carboxylate are obtained, the characteristics of which are as follows:
  • the compound can be prepared as described for the preparation of the product of Example 1 but starting from 60 mg of 3-bromo-6-methoxy-9H-beta-carboline in a mixture of 0.825 ml of dioxane and 0.12 ml of water, 71 mg of 3-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine, 176 mg of cesium carbonate and 25 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 125 ° C., the residue is purified by preparative HPLC in basic medium (method 1). 18 mg of 6-methoxy-3- (5-methoxypyridin-3-yl) -9H-beta-carboline are obtained, the characteristics of which are as follows:
  • the compound can be prepared as described for the preparation of the product of Example 1 but from 75 mg of 3-bromo-6-methoxy-9H-beta-carboline in a mixture of 1 ml of dioxane and 0.15 ml of water, 77 mg of 5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridin-2-amine, 220 mg of cesium carbonate and 31 mg of tetrakistriphenylphosphine palladium. After 1 hour of microwave irradiation at a temperature of 125 ° C., the residue is purified by preparative HPLC in basic medium (method 1). 42 mg of 5- (6-methoxy-9H-beta-carbolin-3-yl) pyridin-2-amine are obtained, the characteristics of which are as follows:
  • 6-Methoxy-3- [6- (methylsulfanyl) pyridin-3-yl-9H-beta-carboline can be prepared as described for the preparation of the product of Example 1 but from 75 mg of 3-bromine. 6-methoxy-9H-beta-carboline in a mixture of 1 ml of dioxane and 0.15 ml of water, 59.5 mg of (2-methylthio-5-pyridinyl) boronic acid, 220 mg of cesium and 31 mg of tetrakistriphenylphosphine palladium.
  • 6-Methoxy-3- (6-methoxypyridin-3-yl) -9H-beta-carboline can be prepared as described for the preparation of the product of Example 1 but from 60 mg of 3-bromo-6- methoxy-9H-beta-carboline in a mixture of 0.8 ml of dioxane and 0.12 ml of water, 57.5 mg of the hydrochloric acid salt of (2-methoxy-5-pyridinyl) boronic acid, 247 mg of cesium carbonate and 25 mg of tetrakistriphenylphosphine palladium.
  • 3- (Pyrimidin-5-yl) -9H-beta-carboline can be prepared as described for the preparation of the product of Example 1 but from 220 mg of 3-bromo-9H-beta-carboline in a mixture 4.6 ml of dioxane and 0.5 ml of water, 256 mg of pinacolic ester of 5-pyrimidyl boronic acid, 725 mg of cesium carbonate and 103 mg of tetrakistriphenylphosphine palladium.
  • After 1 hour of microwave irradiation at a temperature of 140 ° C. and purification by preparative HPLC in a basic medium (method 1) we obtain 19 mg of 3- (pyrimidin-5-yl) -9H-beta-carboline, the characteristics of which are as follows:
  • Tr (min) 2.75; [M + H] +: m / z 247;
  • Step 1
  • a mixture of 15 ml of diisopropylamine and 40 ml of tetrahydrofuran is cooled to -74 ° C and then 64 ml of 1.6 N n-butyllithium in hexane are added over 20 minutes keeping the temperature below -70 ° C.
  • To the reaction mixture are added 16.2 g of 2- (3'-pyridyl) -5-chloropyridine prepared according to the reference Journal of the Chemical Society, Perkin Transactions 1, 2002, 16, 1847-1849 in solution in 170 ml of tetrahydrofuran, always keeping the temperature below -70 ° C.
  • the mixture is stirred at -74 ° C.
  • step 1 A mixture of 188 mg of 2-bromo-4-trifluoromethoxyaniline, 0.26 g of 5-chloro-4- (trimethylstannanyl) -2,3'-bipyridine (step 1), 29.5 mg of Cul and 59.5 mg of tetrakistriphenylphosphine palladium in 2 ml of dioxane is heated at 125 ° C. under microwave irradiation for one hour.
  • Tr (min) 3.86 [M + H] +: m / z 366 (1 CI)
  • step 2 In a 5 ml microwave tube, 130 mg of 4-trifluoromethoxy-2- ⁇ 4- [5-chloro-2- (3-pyridinyl)] pyridinyl ⁇ -aniline (step 2), 16.2 mg of tris ( dibenzylideneacetone) dipalladium (0), 15.3 mg of 2-dicyclohexylphosphino-2 '- (n, n-dimethylamino) biphenyl, 55.8 mg of potassium tert-butoxide and 2 ml of dioxane.
  • step 2 In a 5 ml microwave tube, 130 mg of 4-trifluoromethoxy-2- ⁇ 4- [5-chloro-2- (3-pyridinyl)] pyridinyl ⁇ -aniline (step 2), 16.2 mg of tris ( dibenzylideneacetone) dipalladium (0), 15.3 mg of 2-dicyclohexylphosphino-2 '- (n,
  • reaction medium After heating under microwave for 1 hour at 130 ° C., the reaction medium is hydrolysed with 50 ml of 10% NaHCO 3 and 10 ml of water and then extracted with AcOEt (2 ⁇ 50 ml). The combined organic phases are dried over Na 2 SO 4, filtered and concentrated to obtain 195 mg of crude which is purified by chromatography (30 g SiO 2, eluent: pure AcOEt and then AcOEt / MeOH mixture, 95/5.
  • Step 1
  • a solution of 10.45 ml (74.32 mmol) of diisopropylamine in 1000 ml of tetrahydrofuran is stirred under an argon atmosphere at -78 ° C.
  • 28.6 ml (74.32 mmol) of a solution of butyllithium (2.5 M) in hexane are added slowly keeping the temperature below -70 ° C.
  • a solution of 10 g (67.57 mmol) of 2,5-dichloropyridine in 200 ml of tetrahydrofuran is added over 25 minutes.
  • reaction medium After the reaction medium has been cooled to room temperature, 90 mg of tetrakistriphenylphosphine palladium is added and heated again under microwave irradiation at 140 ° C. for 1.5 h. The reaction medium cooled at room temperature is then poured into 30 ml of water and extracted with 3 ⁇ 30 ml AcOEt. The organic solution is dried over magnesium sulfate, filtered and concentrated. This gives 520 mg of a rust oil.
  • aqueous phase is extracted with 25 ml AcOEt
  • the combined organic phases are washed with 2 times 25 ml of water, dried over magnesium sulphate, filtered and concentrated Biotage SNAP Silica cartridge purification KP-SIL 10 g of silica 40 -63 ⁇ using as eluent CH 2 Cl 2 (5 column volumes) then a gradient CH 2 Cl 2 / MeOH, 100/0 to 95/5 (5 column volumes), CH 2 Cl 2 / MeOH, 95 / 5 (5 column volumes) then a gradient CH 2 Cl 2 / MeOH, 95/5 to 90/10 (5 volumes of co). lonne), 15 ml / min, gives 35 mg of 6 (difluoromethoxy) -3- (pyridin-3-yl) -9H-beta-carboline as an off-white solid.
  • reaction medium cooled at room temperature is poured into 20 ml of saturated aqueous ammonium chloride solution and 20 ml AcOEt. The mixture is filtered on celite. After decantation, the aqueous phase is extracted with 20 ml AcOEt. The combined organic phases are washed with twice 30 ml of water, dried over magnesium sulfate, filtered and concentrated. 72 mg of an ocher yellow solid are obtained.
  • the chlorocarboline of step 2 54 mg of 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) is placed.
  • dichloropyridine (3.23 g, 21.8 mmol)
  • 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) - 1 H-pyrazole (5 g, 24 mmol)
  • cesium carbonate 14.17 g, 43.6 mmol
  • DME 60 ml
  • water 6 ml
  • tetrakistriphenylphosphine palladium 126 mg, 0.1 mmol.
  • the reaction medium is heated at 100 ° C. overnight.
  • the reaction medium is diluted with ethyl acetate (50 ml).
  • a saturated aqueous solution of ammonium chloride (50 ml) is then added.
  • the aqueous phase is then separated and extracted twice with ethyl acetate (20 ml).
  • the organic phases are then combined and dried over magnesium sulfate.
  • the solvent is then evaporated to give 5 g of residue which is purified by chromatography eluting with pure ethyl acetate to obtain 3.6 g of desired product.
  • the lithium diisopropylamide solution is freshly prepared: to a solution of diisopropylamine (0.95 ml, 6.7 mmol) in THF (10 ml), cooled to -40 ° C., a solution of nBuLi (4.2 ml, 6.7 mmol). The solution is stirred for 30 minutes at -40 ° C.
  • step 1 In another flask, the product of step 1 (1 g, 5.18 mmol) in THF (20 ml) is diluted. The solution of trimethylsilyl chloride (5.18 ml, 5.18 mmol) in THF is then added under nitrogen. The reaction medium is cooled to -70 ° C. At this temperature is added the solution of lithium diisopropyl amide previously prepared. The mixture is stirred at -70 ° C for 30 to 45 minutes. After 45 minutes at -70 ° C., 1.3 additional equivalents of lithium diisopropylamide are then added, again at -70 ° C.
  • the reaction is stirred at -70 ° C for 30 minutes and then the 1 M trimethyltinane chloride solution in THF (6.7 ml, 6.7 mmol) is added.
  • the reaction medium is then stirred for 30 minutes at -70 ° C.
  • the reaction medium is treated with the addition of water and then allowed to rise to room temperature.
  • the mixture is then extracted with AcOEt.
  • the organic phase is dried over magnesium sulphate, and the final product is purified by flash chromatography using as eluent heptane / AcOEt 95/5 for 20 minutes then passage with heptane / AcOEt 80/20 over 10 minutes then heptane / AcOEt 80/20 for 30 minutes to give 650 mg of desired product.
  • step 2 In a sealed tube are mixed the product of step 2 (200 mg, 0.47 mmol), 4-bromo-2-iodo-phenylamine (139 mg, 0.47 mmol), tetrakistriphenylphosphine palladium (27 mg, 0.023 mmol), cesium fluoride (143 mg, 0.94 mmol), copper iodide (18 mg, 0.094 mmol) and DMF (5 ml). The whole is heated at 120 ° C in the microwave oven for 1 hour. The reaction medium is filtered on celite then the solvent is evaporated. The residue obtained is purified directly by flash chromatography using AcOEt 100% for 20 minutes then AcOEt / iPrOH / NH 4 OH, 95/5/1 for 20 minutes to give 170 mg of the desired product.
  • step 3 In a sealed tube is placed the product of step 3 (138 mg, 0.38 mmol), followed by potassium carbonate (158 mg, 1.10 mmol), copper iodide (15 mg, 0.08 mmol) and DMSO (5 ml). The reaction mixture is heated at 170 ° C for two hours using the microwave oven. The reaction mixture is filtered through celite and the filtrate is purified directly by flash chromatography using 100% DCM for 10 minutes then DCM / MeOH / NH 4 OH-85/15/1 for 30 minutes to give 63 mg of desired product. .
  • step 4 In a sealed tube are placed the product of step 4 (63 mg, 0.19 mmol), the boronic ester prepared in step 5 (57 mg, 0.19 mmol), tetrakistriphenylphosphine palladium (11 mg, 0.009 mmol) , cesium carbonate (126 mg, 0.39 mmol), DME (5 ml) followed by water (0.5 ml).
  • the reaction mixture is heated at 100 ° C using the microwave oven for two hours.
  • Boronic ester 45 mg, 0.15 mmol
  • the reaction medium is filtered on celite, diluted in a mixture of ethyl acetate and methanol, and then washed with water.
  • the organic phase is then dried over magnesium sulfate and the solvent is evaporated.
  • the final product is purified by flash chromatography using DCM / MeOH / NH 4 OH, 95/5/1 for 10 minutes and then DCM / MeOH / NH 4 OH, 90/10/1 for 20 minutes. 17 mg of final product are obtained.
  • the reaction medium is filtered on celite, diluted in a mixture of ethyl acetate and methanol, and then washed with water. The organic phase is then dried over magnesium sulfate and the solvent is evaporated.
  • the final product is purified by flash chromatography using DCM / iPrOH / NH 4 OH, 90/10/1 for 10 minutes and then DCM / iPrOH / NH 4 OH, 80/20/1 for 20 minutes to obtain 10 mg of final product.
  • step 1 In a sealed tube is placed the product of step 1 (1.70 g, 4.75 mmol), followed by potassium carbonate (1.97 g, 14.25 mmol), copper iodide (181 mg, 0.95 mmol) and DMSO (20 ml). The reaction mixture is then heated at 170 ° C for two hours using the microwave oven. The reaction mixture is filtered through Celite and the filtrate is purified directly by flash chromatography using 100% ethyl acetate for 10 minutes then AcOEt / iPrOH 95/5 for 30 minutes to obtain 540 mg of desired product.
  • step 2 In a sealed tube are placed the product of step 2 (100 mg, 0.31 mmol), the boronic ester prepared in step 5 of Example 16 (91 mg, 0.31 mmol), tetrakistriphenylphosphine palladium. (18 mg, 0.015 mmol), cesium carbonate (200 mg, 0.61 mmol), DME (5 mL) followed by water (0.5 mL).
  • the reaction mixture is heated at 100 ° C using the microwave oven for two hours.
  • Boronic ester 45 mg, 0.15 mmol
  • the reaction medium is heated to 100 ° C. for an extra hour.
  • the reaction medium is filtered on celite, diluted with a mixture of ethyl acetate and methanol, and then washed with water.
  • the organic phase is then dried over magnesium sulfate and the solvent is evaporated.
  • the final product is purified by flash chromatography using AcOEt / iPrOH / NH 4 OH, 95/5/1 for 10 minutes and then AcO Et / i PrO H / NH 4 0 H, 90/10/1 for 20 minutes then AcOEt / iPrOH. / NH 4 OH, 70/30/1 for 20 minutes.
  • the organic phase is then dried over magnesium sulfate and the solvent is evaporated.
  • the final product is purified by flash chromatography using DCM / iPrOH / NH 4 OH- 90/10/1 for 10 minutes and then DCM / iPrOH / NH 4 OH-50/50/1 for 20 minutes to obtain 20 mg of final product.
  • compositions as defined above could be carried out with any of the products of formula (I) according to the present invention: such pharmaceutical compositions form part of the present invention.
  • the pharmacological properties of the compounds of the invention can be confirmed by a number of pharmacological assays.
  • the following examples of pharmacological assays were carried out with compounds according to the invention.
  • the compounds of the invention are tested according to a TR-FRET assay ("Time Resolved-Fluorescence Resonance Energy Transfer", fluorescence energy transfer by resonance in time. resolved) in vitro used routinely.
  • TR-FRET assay is based on the detection of phosphorylation of the Ser1 12 specific residue in the Bad protein, which has been shown to be a natural substrate of Pim kinases in cells.
  • the following reagents are used:
  • Pim-kinase Pim-1 protein, Pim-2 or Hisim-tagged recombinant full-length human pim-3 prepared according to J. Mol Biol (2005) 348, 183-193); Bad - His6-tagged recombinant full-length human Bad Protein (prepared according to J. Mol Biol (2005) 348, 183-193);
  • the assay is based on PerkinElmer's LANCE TM technology: the Eu-labeled antibody binds to phospho-SerI 12 and generates a TR-FRET signal by interaction with PCA-labeled His6 antibody bound to His6 tag of Bad.
  • the fluorescence signal ratio at 665 nm on fluorescence signal at 615 nm is used as the signal reading for Cl 50 (calculations based on the 4-parameter logistic model).
  • the assay is implemented in a 384-well format; the handling of liquids are carried out using a station of
  • Test compounds are tested at 10 concentration points in duplicate; the highest compound concentration is typically 30 ⁇ .
  • concentration of ATP is equal to 40 ⁇ .
  • Class A IC50 less than 1000 nM (or 1 ⁇ )
  • Class B IC50 between 1 ⁇ and 5 ⁇
  • Class C IC50 greater than 5 ⁇

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US9126999B2 (en) 2012-05-31 2015-09-08 Eisai R&D Management Co., Ltd. Tetrahydropyrazolopyrimidine compounds
CN106588918A (zh) * 2016-12-08 2017-04-26 广东省测试分析研究所（中国广州分析测试中心） 一种3‑氨基‑β‑咔啉的制备方法及其应用
US11485734B2 (en) 2018-10-02 2022-11-01 Northwestern University Beta-carbolines as positive allosteric modulators of the human serotonin receptor 2C (5-HT2C)

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