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EP2170865A2 - Indazoles substitues, leur preparation et leur utilisation en therapeutique - Google Patents

Indazoles substitues, leur preparation et leur utilisation en therapeutique

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Publication number
EP2170865A2
EP2170865A2 EP08826411A EP08826411A EP2170865A2 EP 2170865 A2 EP2170865 A2 EP 2170865A2 EP 08826411 A EP08826411 A EP 08826411A EP 08826411 A EP08826411 A EP 08826411A EP 2170865 A2 EP2170865 A2 EP 2170865A2
Authority
EP
European Patent Office
Prior art keywords
methyl
indazol
phenyl
group
piperidin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08826411A
Other languages
German (de)
English (en)
French (fr)
Inventor
Michel Aletru
Dominique Damour
Catherine Monseau
Patrick Mougenot
Claudie Namane
Frederico Nardi
Patrick Nemecek
Christophe Philippo
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi SA
Original Assignee
Sanofi Aventis France
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Filing date
Publication date
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Application filed by Sanofi Aventis France filed Critical Sanofi Aventis France
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new chemical compounds of the substituted indazole type, to compositions containing them and to their use as medicaments, especially as anticancer agents.
  • the invention also relates to the process for preparing these compounds and to certain of the reaction intermediates.
  • Protein kinases are a family of enzymes that catalyze the phosphorylation of hydroxyl groups of protein-specific residues such as tyrosine, serine or threonine residues. Such phosphorylations can largely modulate the function of proteins; thus, protein kinases play an important role in the regulation of a wide variety of cellular processes, including metabolism, cell proliferation, cell differentiation, cell migration, and cell survival. Among the various cellular functions in which the activity of a protein kinase is involved, some processes represent attractive targets for treating cancerous diseases as well as other diseases.
  • AGC refers to the group of cAMP-dependent protein kinases / G protein kinases / protein kinases C.
  • the AGC subfamily of kinases phosphorylates its substrates at the serine and threonine residues and participates in many well-known signaling pathways, such as cyclic AMP 1 (cAMP) signaling pathway, diacylglycerol signaling, insulin and other growth factor response, apoptosis and protein translation control (Peterson et al., Curr Biol., 1999, 9, R521).
  • This AGC subfamily includes the ROCK, PKA, PKB, PKC, PRK, P70S6K, SGK, RSK, GRK, MSK, PDK1 and PKG proteins.
  • the ribosomal protein kinases p70S6K (1 and 2) belong to the subfamily AGC.
  • the p70S6K kinases catalyze the phosphorylation of different substrates, and in particular the phosphorylation and activation of the S6 ribosomal protein that is involved in the upregulation of TOP mRNA translation.
  • These mRNAs contain an 5 'end oligopyrymidine extension, called 5TOP, and encode essential elements of the protein translation (Volarevic et al., Prog Nucleic Acid Res, Mol Biol 2001, 65, 101-186). Phosphorylation of ribosomal protein S6 is directly associated with regulation of cell size.
  • p70S6K is activated in response to numerous extracellular signals including the nutrient pathway and the PI3K / mTOR growth factor receptor signal transduction pathway (Hay and Sonenberg Genes Dev. 2004, 18, 1926-1945).
  • the p70S6K protein is found to be activated and / or amplified in various types of cancers, including in particular breast cancer, thyroid cancers and cancers exhibiting mutations inactivating TSC1 and / or TSC2 tumor suppressors (Miyakawa et al., Endocrin. J. 2003, 50, 77-83, Van der Hage et al, Br J.
  • AKT protein kinase also known as PKB or Rac-PK ⁇
  • PKB protein kinase
  • AGC serine / threonine kinase subfamily
  • AKT-1, -2 and -3 Three isoforms of human AKT, having a very strong homology between them, have been reported, AKT-1, -2 and -3, also called PKB ⁇ , PKB ⁇ and PKB ⁇ (Cheng et al., Proct Natl Acad Sci. USA 1992, 89, 9267-9271).
  • the PI3K / AKT pathway is activated by many factors, such as growth factors such as, for example, platelet-derived growth factor (PDGF) and IGF-1 growth factor (insulin- like Growth Factor).
  • growth factors such as, for example, platelet-derived growth factor (PDGF) and IGF-1 growth factor (insulin- like Growth Factor).
  • PDGF platelet-derived growth factor
  • IGF-1 growth factor insulin-like Growth Factor
  • PIP3 phosphatidylinositol
  • AKT plays a key role in the transduction of extracellular signals, notably from tyrosine kinase-enhanced growth factor receptors, via PI3K.
  • AKT by phosphorylating a wide variety of substrates, is involved in many cellular functions including cell survival and proliferation, protein translation, angiogenesis, chemoresistance, and radioresistance (Alessi et al., Curr., Opin. Dev 1998, 8, 55-62).
  • Genetic abnormalities in the PI3K / AKT pathway are common in human cancers and play an important role in cell transformation. In particular, the frequent disability in PTEN, a negative regulator of the pathway, in a very large number of human cancers, induces the constitutive activation of AKT.
  • AKT-2 was found to be genetically amplified in human carcinomas of the ovary, breast and pancreas (Testa JR and Bellacosa A. Proct Natl Acad Sci USA 2001, 98, 10983-10955, Cheng et al. Proct Natl Acad Sci USA 1992, 89, 9267-9271, Bellacosa et al., Int J Cancer 1995, 64, 280-285, Cheng et al., Proct Natl Acad Sci.
  • AKT-1 amplifications have been found in human gastric cancers, fStaal et al., Proc Natl Acad Sci USA 1987, 84, 5034-5037).
  • Kinase activity of AKT-1 is found to be increased in prostate and breast cancers, and this is associated with poor prognosis (Sun et al., J. Pathol 2001, 159, 431-437).
  • the kinase activity of AKT-3 is found to be increased in different types of cancer including estrogen receptor-deficient breast cancers, androgen-sensitive prostate cancers (Makatani et al., J. Biol Chem 1999, 274, 21528- 21532J.
  • AKT protein kinases play a key role in the biology of many tumors and in particular in diseases with genetic abnormalities of the PI3K / AKT signal transduction pathway. Therefore, selective inhibition of one or more AKT isoenzyme (s) appears to be a promising approach for the treatment of cancer. Blocking the AKT kinase should inhibit the proliferation of tumor cells, make them susceptible to apoptosis and make them more sensitive to chemotherapy and radiotherapy.
  • inhibitors of kinases including AGC kinases.
  • AKT AKT
  • S6K S6K
  • Such inhibitors may be of particular interest in the treatment of cancer as antiproliferative, apoptosis-inducing, antimetastatic, anti-invasive, anti-angiogenic, radio-sensitizing and chemo-sensitizing agents.
  • R 3 may be a halogen atom, a group
  • X is SO 2 NH, SO 2 O, NHSO 2 or OSO 2 on the indazole ring and Z is alkyl, aryl, heteroaryl, heterocycloalkyl, optionally substituted cycloalkyl.
  • Z is alkyl, aryl, heteroaryl, heterocycloalkyl, optionally substituted cycloalkyl. The previous pattern is therefore not described either.
  • R 2 may be naphthalenyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl indazolyl, triazolyl, etc.
  • the group E as well as the 5 or 6 position on the indazole ring are not described therein.
  • halogen atom a fluorine, chlorine, bromine and iodine atom
  • alkyl group a saturated aliphatic hydrocarbon group, linear or branched, preferably having from 1 to 20 carbon atoms, preferably from 1 to 5 carbon atoms. Mention may especially be made of the following groups: methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl, octadecyl, isopropyl, isobutyl, tert-butyl, 2-ethylhexyl,
  • the following groups may be mentioned: allyl, pentenyl, hexenyl, octenyl;
  • alkyl group an alkyl group comprising one or more triple C liaisonC bond (s). Mention may be made in particular of the following groups: hexynyl, heptynyl, octynyl;
  • cycloalkyl group a cyclic alkyl group having 3 to 10 carbon atoms involved in the ring structure. There may be mentioned in particular the following groups: cyclopropyl, cyclopentyl, cyclohexyl;
  • aryl group an aromatic mono- or bicyclic group of 6 to 10 carbon atoms. Mention may in particular be made of the following groups: phenyl, naphthyl, indenyl, fluorenyl;
  • heteroaryl group a 5- to 10-membered aromatic mono- or bicyclic group comprising, as atoms forming the ring, one or more heteroatoms chosen from O, S or N.
  • the following groups may be mentioned in particular: pyrazinyl, thienyl, oxazolyl, furazanyl pyrrolyl, 1,2,4-thiadiazolyl, naphthyridinyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo [1,2-a] pyridine, rimidazo [2,1-b] thiazolyl, cinnolinyl, triazinyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, imidazopyridyl, benzoazaindole, 1, 2,
  • heterocycloalkyl group a cycloalkyl group as defined above further comprising as atoms forming the ring, one or more heteroatoms selected from N, O or S.
  • alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, cycloalkyl groups mentioned above may be optionally substituted with one or more substituents. These may be chosen from halogen atoms or alkyl, alkenyl, alkynyl, aryl, CN, NRR ', CF 3 , OR, COOR, CONRR', COR, heteroaryl, heterocycle, cycloalkyl, -SO 2 groups.
  • NRR ' which substituents may themselves be substituted by one or more substituents selected from halogen atoms, or an alkyl, alkenyl, alkynyl, aryl, CN, NRR', CF 3 , OR, COOR, CONRR 'group; , COR, heteroaryl, heterocycle, cycloalkyl, -SO 2 NRR 1 .
  • the invention relates to compounds of formula (I)
  • E may be more particularly one of the following groups: -NH-CO-O-, -NH-CO-NH-, -NH-CS-NH-, -NH-CO-Nalkyl-, preferably -NH-CO -NMe-, or -Nalkyl-CO-NH-, preferably -NMe-CO-NH-.
  • E denotes -NH-CO-O- (-NH- being attached to the indazole nucleus).
  • E can also be in the form of a 5- or 6-membered ring of formula (attached to the indazole nucleus by the nitrogen atom N 1 ).
  • E can be one of the following groupings:
  • R 1 represents one or more substituents (s), chosen independently of one another when there are several of them, from: a halogen atom, an alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, aryl group, heteroaryl, heterocycloalkyl, cycloalkyl, CN, NRR ', OR, NO 2 , COOR, CONRR', NRCOR '.
  • R and R ' which may be identical or different, denote independently of each other a hydrogen atom, an alkyl, aryl, heterocycloalkyl, cycloalkyl or heteroaryl group.
  • R 1 may especially be a CH 2 NHR group.
  • R 1 may be -C ⁇ CR.
  • R 1 may be a phenyl (Ph) group, optionally substituted by at least one substituent, for example chosen from -
  • R 1 may especially be -COOH or
  • R 1 may especially be -CONHPh or -CONH-CC 6 H 11 , the phenyl group possibly being optionally substituted, e.g. R 1 may be -CONH ⁇ - 1 Bu) Ph.
  • R 1 may especially be -CF 3 .
  • R 1 may especially be -OCF 3 .
  • R 1 may be one of those described in Table I.
  • R 2 represents a hydrogen atom, an alkyl group, alkenyl or alkynyl.
  • R 2 can be one of those described in Table I.
  • R 3 represents one or more substituents, selected independently of one another when there is more than one of: halogen, alkyl, alkenyl, alkynyl, haloalkoxy (e.g. OCF 3 ), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, -CN, -NRR ', - CF 3 , -OR, -NO 2 , -COOR, -CONRR', -NRCOR '.
  • R 3 denotes more particularly a halogen atom, in particular fluorine, or an alkyl group, especially the methyl group.
  • R 3 may be one of those described in Table I.
  • R 4 denotes a hydrogen or halogen atom, an alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl, -NR-CO-R ', -COOR, -NRR 1 , -CHO, -CONR (OR 1 ).
  • R 4 may be one of those described in Table I.
  • R 4 may be methyl or -CH 2 CH 2 Ph.
  • R 4 can be -C ⁇ CR where R is aryl or heteroaryl.
  • the aryl group is more particularly the phenyl group, optionally substituted by a fluorine atom at the 3 or 4 position.
  • the heteroaryl group may be the 3-pyridinyl group.
  • R 4 may be phenyl, optionally substituted with -SO 2 NH 2 in the 4-position.
  • R 4 may especially be the 2-, 3- or 4-pyridinyl group or the benzimidazolyl group.
  • R 4 can be the group -NH-CO-Ph.
  • R 4 can be -NH 2 .
  • R 1 represents one or more substituents, chosen independently of one another when there are several, among: a halogen atom, a group -COOR or -CONRR 1 ;
  • R 2 represents a hydrogen atom, an alkyl group, or alkenyl
  • R 3 represents a halogen atom
  • R 4 denotes a hydrogen or halogen atom, an alkyl, aryl, heteroaryl, -NR-CO-R 1 or -NRR 'group; • R and R ', which may be identical or different, designate independently of each other: a hydrogen atom, an alkyl or aryl group;
  • Fi 1 represents an integer ranging from 0 to 5 and n 3 an integer ranging from 0 to 3.
  • R 2 represents a hydrogen atom, an alkyl or alkenyl group
  • n 3 0
  • R 4 represents a hydrogen atom hydrogen or an alkyl group
  • R 2 may be an alkyl or alkenyl group, for example methyl or allyl
  • R 2 and R 4 can both be an alkyl group, for example methyl and methyl or methyl respectively and -CH 2 CH 2 Ph.
  • R 1 represents a halogen atom
  • R 2 represents a hydrogen atom or an alkyl group
  • n 3 0
  • R 4 represents a hydrogen atom.
  • R 1 represents a fluorine and / or chlorine atom.
  • R 2 may be the methyl group.
  • R 4 represents an aryl or heteroaryl group .
  • R 4 may be phenyl, optionally substituted with -SO 2 NH 2 in the 4-position.
  • R 4 may be 2-, 3- or 4-pyridinyl or the benzimidazolyl group.
  • R 2 may be the methyl group.
  • R 2 represents a hydrogen atom or an alkyl group
  • R may be the phenyl group, optionally substituted with a fluorine atom at the 3- or 4-position.
  • R may be the 3-pyridinyl group.
  • R 2 may be a methyl group.
  • R 2 represents a hydrogen atom or an alkyl group
  • R 3 represents a halogen atom or an alkyl group
  • R 4 represents a hydrogen atom, a group -NRR 'or -NR-CO-R.
  • R 4 can be -NH 2 .
  • R 4 may be the group -NH-CO-Ph.
  • n 3 1.
  • R 2 may be the methyl group.
  • R 3 may be a fluorine atom.
  • ⁇ O 1 1 or 2 and R 1 represents a halogen atom
  • R 2 represents a hydrogen atom or an alkyl group
  • n 3 0 or 1 and R 3 represents a halogen atom
  • R 4 represents -NH 2 , -CH 2 CH 2 Ph, a hydrogen atom or an alkyl, aryl group (preferably a phenyl group substituted by the SO 2 NH 2 in position 4), heteroaryl (preferably 2, 3 or 4-pyridinyl or benzimidazolyl), -C ⁇ CR, R denoting an aryl group (preferably phenyl, optionally substituted by a fluorine atom in position 3 or 4) or heteroaryl (preferably the 3-pyridinyl group).
  • E more particularly denotes -NH-CO-O- or -NH-CO-NH- and is attached by -NH- to indazole. Preferably also, it is attached in position 5.
  • the compounds can be chosen from the following list:
  • the compounds according to the invention may comprise at least two asymmetric carbons, they may therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and their mixtures are also part of the invention.
  • the compounds according to the invention may also exist in the form of hydrates or solvates, that is to say in the form of combinations or combinations with one or more molecule (s) of water or a solvent. These hydrates or solvates are also part of the invention.
  • the compounds according to the invention may also exist in the form of salts, that is to say additive compounds of the compounds according to the invention with acids or bases, organic or inorganic.
  • salts are used when the acids or bases are non-toxic and make it possible to retain the pharmacological properties of the compounds according to the invention.
  • the salts are prepared according to the techniques known to those skilled in the art (see, for example, H.Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6 th edition, 1995, pp.196 and 1456-1457).
  • the compounds according to the invention may also optionally exist in different tautomeric forms, which are included in the invention.
  • the compounds according to the invention may be in (i) racemic form, or enriched in a stereoisomer, or enriched in an enantiomer and / or (ii) salified and / or (iii) hydrated or solvated.
  • the compounds of the invention can be used for the preparation of a medicament, especially a medicament for preventing and / or treating a cancer (anticancer).
  • the invention also relates to a medicinal product comprising a compound according to the invention.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a compound according to the invention in combination with a pharmaceutically acceptable excipient (depending on the chosen mode of administration).
  • the dose of active ingredient administered will be adapted by the practitioner depending on the route of administration to the patient and the state of the latter.
  • the pharmaceutical composition may be in solid, liquid or liposome form depending on the chosen mode of administration.
  • the solid forms consist of powders, capsules or tablets.
  • the supports used for the solid forms consist in particular of mineral or organic supports.
  • the liquid forms consist of solutions, suspension or dispersion.
  • the compounds of the present invention may be administered alone or in admixture with at least one other anti-cancer agent. This can be chosen from:
  • Chemotherapeutic agents such as alkylating agents, platinum derivatives, antibiotic agents, antimicrotubule agents, taxoids, anthracyclines, group I and II topoisomerase inhibitors, fluoropyrimidines, cytidine analogues, analogs adenosine, enzymes, as well as estrogenic and androgenic hormones;
  • kinase inhibitors and in particular PI3K / AKT transduction pathway kinases (see Rapamycin and Temsirolimus analog), as well as tyrosine kinase receptor inhibitors with in particular EGFR (see Tarceva), HER2 and IGFR inhibitors of various signal transduction pathways with, in particular, inhibitors of the MAPK pathway such as MEK1 / 2 inhibitors, and inhibitors of other pathways playing a key role in the cancer process, such as the Notch pathway;
  • inhibitors of other biomolecules such as histone deacetylase inhibitors, COX-2 inhibitors, MMP inhibitors, proteasome inhibitors.
  • the invention relates to a process for preparing compounds according to the invention. These are obtained from the precursor compounds of formula (IA), (IB) or (IC) which are prepared according to one of the schemes described below.
  • A represents R 2 (except H) or a PG 1 protecting group.
  • B represents H or a PG 2 protective group.
  • the protective groups PG 1 and PG 2 are introduced to the protection step to avoid unwanted side reactions during one or more reaction steps and are removed during the deprotection step. Examples of protecting groups are found in TWGreene et al. "Protective Groups in Organic Synthesis", 3 "* edition, 1999, Wiley-Interscience or in JFW McOmie” Protective Groups in Organic Chemistry ", Plenum Press, 1973.
  • the two protective groups PG 1 and PG 2 may be identical or different
  • the deprotection step consists in removing the group (s) (s) protector (s) by application of suitable experimental conditions and known to those skilled in the art.
  • the agent may be, for example, phosgene, triphosgene or carbonate of N 1 N 1 - disuccinimidyl.
  • the reaction is carried out in a solvent such as dichloromethane (DCM) or acetonitrile, preferably in the presence of a base (eg triethylamine).
  • a base eg triethylamine.
  • the temperature is preferably between 0 ° C. and the boiling temperature of the reaction medium.
  • P 1 with the agent, then P 2 is added.
  • the compounds P 1 can be prepared according to the teaching of WO 2003/089411 or according to the method of Scheme 2 from an aldehyde (1) and an organomagnesium (2).
  • the reaction is carried out in an inert solvent (for example diethyl ether, tetrahydrofuran) at a temperature between -70 ° C. and 20 ° C.
  • an inert solvent for example diethyl ether, tetrahydrofuran
  • the aldehydes (1) can be commercial or prepared by application or adaptation of the methods described by Molander, Gary A. et al. Tetrahedron 2005, 61 (10), 2631-2643 or Yan, Lin et al., Bioorganic & Medicinal Chemistry Letters 2004, 14 (19), 4861-4866 or Balboni, Gianfranco et al., European Journal of Medicinal Chemistry 2000, 35 (11), 979-988 or Alibes, Ramon et al., Organic Letters 2004, 6 (11), 1813-1816.
  • the organomagnesium compounds (2) may be commercial or prepared by application or adaptation of the usual methods known to those skilled in the art.
  • the agent may be, for example, phosgene, triphosgene or N, N'-disuccinimidyl carbonate.
  • the reaction is carried out in a solvent such as DCM or acetonitrile, preferably in the presence of a base (eg triethylamine).
  • a base eg triethylamine
  • the temperature is preferably between 0 ° C. and the boiling temperature of the reaction medium.
  • the agent may be carbon disulfide (CS 2 ).
  • the reaction is carried out in a solvent such as ethanol, preferably in the presence of a base such as potassium hydroxide.
  • the temperature is between 0 ° C. and the boiling temperature of the reaction medium.
  • the methods described by Patel, H. et al., Indian Journal of Heterocyclic Chemistry 2006, 15 (3), 217-220, can also be used.
  • P 2 is contacted first with the agent, then P 3 is added.
  • the compounds P ' 2 can be prepared from P 2 by conversion of the amine -NH 2 function of the compounds P 2 as a function of the carbamate -NT-CO-OZ with the aid of the chloroformate ZO-COCI, preferably in the presence of a base (eg triethylamine).
  • the transformation reaction is carried out in a solvent such as THF at a temperature between 0 ° C. and the boiling temperature of the reaction medium. It is not necessary to isolate the compounds P ' 2 for the subsequent step.
  • the coupling between the compounds P ' 2 and P 3 can be carried out in a solvent such as acetonitrile or THF at a temperature of between 20 ° C.
  • the ⁇ -alkylation is carried out using a halide of A, in the presence of a base such as potassium carbonate, in a polar solvent such as acetonitrile at a temperature between 0 ° C. and the boiling point. of the reaction medium.
  • the alcohol function of P 1 can then be converted into a nucleofugal group, for example a chlorine, by the action of mesyl chloride in the presence of potassium carbonate in a chlorinated solvent such as DCM at a temperature between 0 ° C. and the temperature of 20 ° C. boiling of the reaction medium.
  • the nucleofuge group is then reacted with ammonia dissolved in methanol at a temperature between 0 ° C. and the boiling temperature of the reaction medium.
  • the compounds P 3 with T other than H can be prepared by ⁇ / -monoalkylation by applying the usual methods known to those skilled in the art.
  • the primary amine function NH 2 can be converted to the secondary amine NH-T (Scheme 7) by the action of a carbonyl derivative T'-CHO in the presence of a reducing agent such as lithium double hydride and aluminum (LiAlH 4 ) or sodium triacetoxyborohydride (NaBH (OAc) 3 ) in a solvent such as DMF or THF at a temperature between 0 0 C and the boiling temperature of the reaction medium.
  • a reducing agent such as lithium double hydride and aluminum (LiAlH 4 ) or sodium triacetoxyborohydride (NaBH (OAc) 3 ) in a solvent such as DMF or THF at a temperature between 0 0 C and the boiling temperature of the reaction medium.
  • n o may refer to: Deck, LM et al. Journal of Heterocyclic 680; _Lee, Chang Kiu et al., Bulletin of the Korean Chemical Society 1991, 12 (3), 343-7; Soliman, Raafat et al. Journal of Pharmaceutical Sciences 1981, 70 (8),
  • the reduction can be carried out according to a method customary for those skilled in the art, for example using ammonium formate in the presence of a palladium on charcoal catalyst (Ram, S. Tetra.Let. 25, 3415), using ferrous sulphate (Castellano, SJHet.Chem 2000, 37 (6), 949) or with the aid of tin chloride, using hydrogen in the presence of a catalyst such as palladium on carbon or Raney nickel.
  • a catalyst such as palladium on carbon or Raney nickel.
  • the reduction conditions given in the examples of application FR 2836914 can also be used.
  • the nitration can be carried out according to a method customary for those skilled in the art, for example using a nitric / sulfuric acid mixture at a temperature between 20 0 C and the boiling temperature of the reaction mixture.
  • a nitric / sulfuric acid mixture at a temperature between 20 0 C and the boiling temperature of the reaction mixture.
  • the compounds P 5 and P 6 can be obtained according to different synthetic routes. One of them is a cyclization respectively of the compounds P 7 and P 8 in the presence of hydrazine, followed optionally by the introduction of the protective group PG 2 (Scheme 11):
  • the cyclization reaction is preferably carried out in an inert solvent such as an alcohol (eg methanol, ethanol) at a temperature between 0 ° C. and the boiling temperature of the reaction mixture.
  • an inert solvent such as an alcohol (eg methanol, ethanol) at a temperature between 0 ° C. and the boiling temperature of the reaction mixture.
  • the compounds P 8 can be commercial or prepared by application or adaptation of the methods described in the following articles: Chem.Pharm.Bull. 1997, 45 (9), 1470, Kumazawa, E .; J. Med. 1991, 34 (5), 1545, Bellamy, FD; Synth. Common. 1991, 21 (4), 505, Deutsch, J .; J.HetChem. 1996, 33 (3), 831, Varvarescou, A. or in WO 93/22287.
  • Another method for obtaining the compounds P 5 or P 6 is to react respectively the compounds P 9 or P 10 with a nitrite RONO (sodium nitrite, terf-butyl, isoamyl for example) in the presence of an acid (eg acetic acid) or an acid anhydride (eg acetic anhydride), preferably at a temperature between 0 ° C and the boiling temperature of the reaction mixture (Scheme 12).
  • a nitrite RONO sodium nitrite, terf-butyl, isoamyl for example
  • an acid eg acetic acid
  • anhydride eg acetic anhydride
  • R 4 can be introduced before or after coupling, from a precursor of R 4 , denoted R ' 4 (Scheme 14).
  • R ' 4 a precursor of R 4
  • C designates one of the following groups: THN-; ZO-CO-NT-; XCN- or NO 2 -. (IA) or (IB) or (IC)
  • the reaction is carried out in the presence of a base at a temperature of between 0 ° C. and the boiling temperature of the reaction medium (see H. Kawakubo et al., Chem Pharm, Bull 1987, 35 (6)). 2292);
  • R 4 NHR, R representing a disubstituted alkyl group: by a reaction with an aldehyde or a ketone in the presence of a reducing agent (see MBSmith and J.March, Wiley Interscience, "Advanced Organic Chemistry “, 5th edition, p.1185);
  • R 4 alkyl, alkylene, alkynyl, aryl, heteroaryl, heterocycloalkyl, NR-CO-R ', COOR, NRR 1 , CHO,
  • CONR (OR ') can be obtained by reactions involving palladium chemistry (cf.
  • the diastereoisomers (2S, RS) and (2R, RS) of the compounds P 1 can also be obtained either by separation of the racemates, for example by chromatography on a silica column. They can also be obtained using the method of Scheme 15 from an enantiomerically pure aldehyde (1) (R or S).
  • the (2S 1 S), (2S 1 R), (2R 1 S) and (2R 1 R) enantiomers of the compounds P 1 can be obtained by separation of racemates or diastereoisomers (for example by chromatography on a silica column) ( Figure 16).
  • the (2S 1 S) and (2R 1 R) enantiomers of the compounds P 1 can also be obtained from the diastereoisomers by oxidation of the alcohol function followed by an enantioselective reduction (Diagram 17):
  • the compounds P 1 of configuration (2S, RS) or (2R, RS) are oxidized to ketone (2S) or (2R) respectively, according to the usual methods known to those skilled in the art using a d oxidation, e.g. oxalyl chloride in the presence of dimethylsulfoxide in a chlorinated solvent such as dichloromethane (DCM) at a temperature between -70 ° C. and
  • a d oxidation e.g. oxalyl chloride in the presence of dimethylsulfoxide in a chlorinated solvent such as dichloromethane (DCM) at a temperature between -70 ° C.
  • DCM dichloromethane
  • ketones are then reduced enantioselectively to alcohols (2S 1S) or
  • LC / MS analyzes were performed on a Waters Model ZQ device connected to an Alliance 2695. The abundance of products was measured using a Waters 996 PDA diode array detector over a waveband. 210-650 nm and a Sedex 85 light scattering detector. Mass spectra mass spectra were acquired over a range of 100 to 1000. The data were analyzed using the Waters MassLynx software. The separation was carried out on a Kromasil C18 column, 3.5 ⁇ m (50 ⁇ 2.0 mm), eluting with a linear gradient from 0 to 100% acetonitrile containing 0.05% (v / v) trifluoroacetic acid.
  • Spectra were obtained by LC / MS coupling in electrospray + and - (ES + and ES-) on a ZQ (Waters) or Quattro Premier (-Waters) spectrometer.
  • the chromatographic conditions are as follows: ZQ: ZQ X-Bridge C18 column 2.5 ⁇ m 3 ⁇ 50 mm; flow rate: 1100 ⁇ l / min; gradient: 5 to 100% B (CH 3 CN) in 5 min (A: H 2 O + 0.1% formic acid); Quattro Premier: Acquity C18 column 1, 7 ⁇ m 2.1 x 100 mm; flow rate: 600 ⁇ l / min; gradient: 5 to 100% B (MeOH) in 9 min (A: H 2 O + 0.1% formic acid).
  • the compound is prepared according to the prep. 1 from Fert -butyl (S) -2-formylpiperidine-1-carboxylate and (3,4-dichlorophenyl) magnesium bromide.
  • M-H + HCO 2 H] ' 404 tert-Butyl prep 4: (2R) -2 - [(S) - (3-chloro-5-fluorophenyl) (hydroxy) methyl] piperidine-1-carboxylate and (2R) -2 - [(R) - (3-Chloro-5-fluorophenyl) (hydroxy) methyl] piperidine-1-carboxylic acid tert-butyl ester
  • the compounds are obtained according to Preparation 4 by replacing tert-butyl (R) -2-formylpiperidine-1-carboxylate with tert-butyl (S) -2-formylpiperidine-1-carboxylate (19 g, 89 mmol) .
  • the tert-butyl (2S) -2 - [(R) - (3-chloro-5-fluorophenyl) (hydroxy) methyl] piperidine-1-carboxylate and (2S) -2- [(S) - are thus obtained.
  • the combined organic extracts are washed with distilled water (30 ml) and then with a saturated aqueous solution of NaCl (15 ml), dried over MgSO 4, filtered and concentrated to dryness under RP.
  • the isolated yellow oil is chromatographed on 100 g of silica gel 60, particle size 15-40 ⁇ m, contained in a column 3 cm in diameter, eluting with a mixture of cyclohexane / AcOEt 3/1 v / v, under a overpressure of 0.6 bar of argon.
  • Prep 10 (2S) -2 - [(S) - (3-Bromophenyl) -hydroxy-methyl] -piperidine-1-tert-butylcarboxylate
  • Prep 10a (S) -2- (3-Bromobenzovl) -piperidine Tert-Butylcarboxylate
  • the compound can be prepared as described in WO2008 / 018639 on page 105.
  • Preparation 10b (2S) -2 - [(S) - (3-Bromophenyl) -hydroxy-methyl] -piperidine 1-tert-butylcarboxylate
  • the compound is prepared according to Preparation 6b from (S) -2- (3-bromobenzoyl) -piperidine-1-carboxylic acid tert-butyl ester.
  • (M + Na) + 392.
  • Prep 11a (2S) -2- (N-Methoxy-N-methylcarbamoyl) -piperidine-1-tert-butylcarboxylate
  • the compound can be prepared as described in S.T.Tong et al. Tetrahedron Letters 2006, 47 (29), 5017-5020.
  • a second tricolor equipped with a magnetic stirrer and placed under nitrogen is introduced terf-butyl (2S) -2- (N-methoxy-N-methylcarbamoyl) -piperidine-1-carboxylate (8.5 g, 31, 2 mmol) and 125 ml of diethyl ether.
  • the solution obtained beforehand in the first three-neck is introduced dropwise.
  • the reaction medium is then maintained at -75 ° C. for 2 h and then the temperature is allowed to rise to 0 ° C. before adding 130 ml of a saturated aqueous solution of NaHCO 3.
  • the compound is prepared according to the preparation 11b from diiodobenzene (5.43 g, 0.0165 moles) and
  • (2S) -2 - [(3,4-dichlorophenyl) (hydroxy) methyl] piperidine-1-carboxylate of Fe / f-butyl (6 5 g, 18 mmol) is placed in solution in dioxane (20 mL).
  • a solution of 4N HCl in dioxane 55 mL, 220 mmol is added and the mixture is stirred at room temperature (RT) for 4 h.
  • the reaction medium is concentrated in vacuo to give 5.4 g of (3,4-dichlorophenyl) [(2S) -piperidin-2-yl]] methanol hydrochloride.
  • Prep 8b (S) - [(2S) -1-Allylpiperidin-2-yl] (3,4-dichlorophenyl) methanol and (R) - [(2S) -1-allylpiperidin-2-yl] (3,4) dichlorophenyl) methanol
  • This compound is prepared according to the process described in the prep. 8a from tert-butyl (2S) -2 - [(S) (3-chloro-5-fluorophenyl) (hydroxy) methyl] piperidine-1-carboxylate described in Preparation 6b (5.8 g, 16, 9 mmol). 5.1 g of (S) (3-chloro-5-fluorophenyl) [(2S) piperidin-2- (S) -yl] methanol are obtained.
  • Prep_9d 1 - [(S) - [(2S) -1-Allylpiperidin-2-yl] (3-chloro-5-fluorophenyl) methylamine
  • This compound is prepared according to the method described in the prep. 8d from (2S) -1-Allyl-2 - [(R) -chloro (3-chloro-5-fluorophenyl) methyl] piperidine (4.6 g, 15.2 mmol). 2.5 g of 1 - [(S) - [(2S) -1-allylpiperidin-2-yl] (3-chloro-5-fluorophenyl) methylamine are obtained.
  • 5-nitroindazole (2 g, 12.26 mmol) is dissolved in 60 mL of DCM.
  • Trimethylsilylethoxymethyl chloride (4.34 mL, 24.52 mmol) was added at 0 ° C and diisopropylethylamine (4.27 mL, 24.52 mmol) was added dropwise. After stirring for 3 h at RT, water is added and the medium is extracted with DCM.
  • 6-nitroindazole (2 g, 12.26 mmol) is dissolved in 60 mL of DCM.
  • the trimethylsilylethoxymethyl chloride (4.34 ml, 24.52 mmol) and diisopropylethylamine (4.27 ml, 24.52 mmol) are added dropwise at 0 ° C. After stirring for 4 h at RT, water is added and the medium is extracted with DCM.
  • 1,3-dimethylbarbituric acid (0.7 g, 4.5 mmol) and Pd (PPh 3 ) 4 (0.17 g, 0.15 mmol) are placed in solution in DCM (10 mL).
  • DCM 10 mL
  • the mixture is brought to reflux, supplemented with 1 - [(S) - [(2S) -1-allylpiperidin-2-yl] (3-chloro-5-fluorophenyl) methyl] -3- (1 - ⁇ [2 - trimethyldilyl) ethoxy] methyl ⁇ -1H-indazol-5-yl) urea dissolved in DCM (5 mL), and refluxed for 5 h.
  • the preparation compound 6b (0.21 g, 0.38 mmol) is treated with a solution of 4N HCl in dioxane (5 mL, 20 mmol) according to the conditions described in ex. 3c. After purification by chromatography on silica gel eluting with a DCM / MeOH / NH 4 OH mixture (98/2 / 0.2 to 96/4 / 0.4), 0.09 g of 1 - [(3-chloro) 5-fluorophenyl) (1-methylpiperidin-2-yl) methyl] -3- (1W-indazol-5-yl) urea is obtained. The hydrochloride is then carried out after treatment with 0.2N HCl in solution in ethyl ether and trituration in ethyl ether.
  • the compound is prepared following the method described in ex. 12th by replacing 4-methanesulfonylphenylboronic acid with 4-pyridylboronic acid.
  • the product obtained is treated with a molar excess of fumaric acid in ethanol.
  • the compound is prepared following the method described in ex. 12e by replacing 4-methanesulfonylphenylboronic acid with 3-pyridylboronic acid.
  • the product obtained is treated with a molar excess of fumaric acid in ethanol.
  • 3-iodo-5-nitro-1H-indazole (17.7 g, 61.3 mmol) is dissolved in 300 mL of DCM.
  • the trimethylsilylethoxymethyl chloride (11.9 mL, 67.4 mmol) is added at 0 ° C. and the diisopropylethylamine (12.8 mL, 73.6 mmol) is, in turn, added dropwise at 0 ° C.
  • the mixture is poured into water and extracted with DCM.
  • 5-nitro-1H-indazole-3-carboxylic acid (5.4 g, 26.07 mmol) is dissolved in 100 mL of DMF.
  • Dimethylhydroxylamine (3.18 g, 52.14 mmol), EDC (9.99 g, 52.14 mmol), HOBt (7.04 g, 52.14 mmol) and triethylamine (14.53 mL, 104.28 mmol) are added successively and the reaction mixture is then stirred for 8 days. After evaporation of the DMF, the medium is taken up in water and extracted with 1 AcOEt.
  • ⁇ -methoxy- ⁇ -methyl-5-nitro-1H-indazole-3-carboxamide (0.33 g, 1.32 mmol) is dissolved in 5 ml of DCM.
  • Trimethylsilylethoxymethyl chloride (0.47 mL, 2.64 mmol) was added at 0 ° C and diisopropylethylamine (0.46 mL, 2.64 mmol) was added dropwise. After stirring for 2 h at RT, water is added and the medium is extracted with DCM.
  • This compound is prepared according to the process described in Example 12d from 0.12 g of 3- (1H-benzimidazol-2-yl) -5-amino-1 - ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ indazole.
  • 0.066 g of 1- [3- (1H-benzimidazol-2-yl) -1 - ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ indazol-5-yl] -3 - [(1-methylpiperidin-2-yl)) (phenyl) methyl] urea ((S, 2S), (R, 2R)) is obtained.
  • (M + H) + 610.
  • Fd18d 3-Methyl-5 - ( ⁇ [(1-methylpiperidin-2-yl) (phenyl) methyl] carbamoyl ⁇ amino) indazol-1-carboxylic acid-butyl ester ((S, 2S), (R, 2R) )
  • tert-butyl 5-amino-3-methylindazole-1-carboxylate (0.25 g, 1.01 mmol) is dissolved in 10 ml of DCM at 0 ° C.
  • triethylamine (0.18 mL, 1.31 mmol) and triphosgene (0.2 g, 0.67 mmol) are added to the reaction medium.
  • 1- (1-methylpiperidin-2-yl) -1-phenylmethylamine ((S, 2S), (R, 2R)) (0.30 g, 1.52 mmol) is added in a bolus. .
  • the medium is then hydrolyzed with a saturated aqueous solution of sodium hydrogencarbonate (10 mL) and extracted twice with 20 mL of AcOEt. The combined organic extracts are washed with water (20 ml), dried over MgSO 4 , filtered and concentrated to dryness. The isolated solid is taken up in isopropyl ether (5 mL), filtered, washed and dried to give 0.12 g of N- (7-fluoro-5-nitro-1H-indazol-3-yl) benzamide in the form of a melting beige solid. PF (fumarate)> 260 ° C.
  • the solid deposit is chromatographed on silica gel (eluent: DCM / MeOH / NH 4 OH, 99/9/1 to 93/7 / 0.3) to give 0.37 g of 1- (3-amino-7-fluoro) 1H-indazol-5-yl) -3 - [(1-methylpiperidin-2-yl) (phenyl) methyl] urea ((S, 2S), (R, 2R)).
  • the product obtained is treated with a molar excess of fumaric acid in ethanol.
  • the reaction medium is neutralized with a 10% solution of NaOH and extracted with a 9/1 DCM / MeOH mixture. After evaporation of the organic phase, the residue is chromatographed on silica gel (eluent: DCM / MeOH / NH 4 OH, 99/9/1 to 92/8 / 0.2) to give 0.02 g of 1- ( 7-fluoro-1H-indazol-5-yl) -3 - [(1-methylpiperidin-2-yl) (phenyl) methyl] urea ((S, 2S), (R, 2R)). The product obtained is treated with a molar excess of fumaric acid in ethanol.
  • PdCl 2 (PPh 3 ) 2 (0.0264 g, 0.04 mmol) and triethylamine (0.17 mL, 1.25 mmol) and 3-fluorophenylacetylene (0.12 mL, 0.123 mmol) are added successively.
  • the reaction medium is heated at 90 ° C. for 15 hours.
  • the DMF is evaporated and the residue is partitioned between water and 1 AcOEt.
  • the compound was prepared from 1 - [(1-methylpiperidin-2-yl] -1-phenylmethylamine ((S, 2S), (R, 2R)) and 5-amino-1 - ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ -3-phenethylindazole prepared in Example 27a following the procedure described in Example 1.
  • Fert-butyl 3- (benzoylamino) -5 - ( ⁇ [(1-methylpiperidin-2-yl) (phenyl) methyl] carbamoyl ⁇ amino) -indazole-1-carboxylate ((S, 2S), (R, 2R)) (0.031 g, 0.05 mmol) is dissolved in 8 mL of dioxane.
  • a 4M solution of HCl in dioxane is added (0.53 mL, 0.5 mmol) and the reaction mixture is stirred for 2 hours.
  • Triethylamine (11.0 mL, 79.2 mmol), DMAP (1.4 g, 11.3 mmol) and di-tert-butyldicarbonate (17.3 g, 79.2 mmol) are added successively to the mixture. . After stirring for 18 h, DCM is added and washed with a saturated solution of NH 4 Cl and then with a saturated solution of NaCl.
  • tert-butoxycarbonylamino] -5-nitro-1H-indazole-1-carboxylic acid (9.5 g, 19.9 mmol) is dissolved in 200 ml of ethanol and 5% palladium on carbon (0.845 g) is added under N 2 .
  • the reaction medium is stirred under an atmosphere of hydrogen for 4 hours.
  • 8.6 g of tert-butyl 5-amino-3- [bis (tert-butoxycarbonyl) amino] -5-nitro-1H-indazole-1-carboxylate are recovered.
  • (M + H) + 449
  • N - [(1-methylpiperidin-2-yl) -phenylmethyl] formamide ((S, 2S), (R, 2R)) (0.4 g, 1.72 mmol) ) is dissolved in 15 mL of THF at 0 ° C.
  • the sodium aluminum hydride (0.327 g, 8.61 mmol) is added and the reaction medium is refluxed for 1 h. It is allowed to return to RT and the medium is treated with a solution of NaOH.
  • 5-amino-3-methylindazole-1-carboxylic acid (0.1 g, 0.43 mmol) is dissolved in 6 mL of DCM at 0 ° C.
  • Triethylamine (0.05 mL, 0.34 mmol) and triphosgene (0.064 g, 0.21 mmol) are added successively.
  • the methyl - [(1-methylpiperidin-2-yl) -phenylmethyl] amine ((S, 2S), (R, 2R)) (0.168 g, 0.77 mmol) solubilized in 3 mL of DCM is added.
  • acetic anhydride (1.6 mL, 17.08 mmol) is added to a solution of formic acid (0.64 mL, 17.08 mmol) in 20 mL of THF at 0 ° C. After stirring for 2 h, the reaction medium is cooled to -20 ° C. and 5-amino-1 - ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ indazole (1.5 g,
  • This compound is prepared according to the process described in ex. 17 g from 1-methyl-3 - [(1-methylpiperidin-2-yl) (phenyl) methyl] -1- (1 - ⁇ [2- (trimethylsilyl) ethoxy] methyl ⁇ - (indazol-5-yl) urea ((S, 2S), (R, 2R)) (0.043 g, 0.08 mmol) 0.014 g of 1- (1H-indazol-5-yl) -1-methyl-3 - [(1-methylpiperidine) -2-yl) (phenyl) methyl] urea ((S, 2S), (R, 2R)) is obtained The product obtained is treated with a molar excess of fumaric acid in ethanol.
  • the compound is prepared according to ex. 34a by substituting (2S) -2 - [(S) (3-chloro-5-fluorophenyl) 2 - [(3,5-dichlorophenyl) (hydroxy) methyl] piperidine-1-carboxylic acid-carboxylate ( hydroxy) methyl] piperidine-1-tert-butylcarboxylate (0.25 g, 0.73 mmol).
  • (M + H) + 633.5.
  • Triethylamine (8.95 ml, 64 mmol) is then added and the reaction medium is stirred for 4 hours at a temperature in the region of 20 ° C.
  • the reaction medium is concentrated to dryness and the evaporation residue is taken up with a saturated aqueous solution of sodium hydrogen carbonate (50 ml) and extracted with twice 40 ml of AcOEt. Persistent insoluble material is removed by filtration of the organic phases on a sintered glass. The filtrate is dried over MgSO 4, filtered and concentrated to dryness under RP to give the activated intermediate.
  • the 5-amino-indazole-1-carboxylate fertilizer is charged with butyl (3 g, 12.8 mmol) with DCM (125 mL) and triethylamine (2.7 mL, 19.1 mmol).
  • the activated intermediate is run in solution in DCM (40 mL) in about 10 minutes.
  • the reaction medium is stirred at around 20 ° C. for 16 hours.
  • the medium is hydrolyzed with saturated aqueous sodium hydrogencarbonate solution (80 mL), decanted and the aqueous layer re-extracted with DCM (30 mL).
  • the combined organic extracts are dried over MgSO 4 , filtered and concentrated to dryness under RP.
  • the isolated garnet oil is chromatographed on 420 g of silica gel 60, particle size 15-40 ⁇ m, contained in a column 5 cm in diameter, eluting with a mixture of cyclohexane / AcOEt 7/3 v / v, under overpressure.
  • tert-butyl 5 - [( ⁇ S (2 S) -1- (tert-butoxycarbonyl) piperidin-4-yl] -ethoxycarbonylphenylmethoxy] carbonylaminol-1H-indazole-1-carboxylate is charged with (1, 52 g, 2.4 mmol) prepared in Example 41a with lithium hydroxide, monohydrate (151 mg, 3.6 mmol), methanol (25 mL) and THF (25 mL). at around 20 ° C.
  • (2S) -2 - ⁇ [(1 / - / - indazol-5-ylcarbamoyl) oxy] [3- (methoxycarbonyl) phenyl] methyl ⁇ piperidine-1-carboxylate is charged.
  • the combined organic extracts are washed with distilled water (20 ml), a saturated aqueous solution of sodium hydrogen carbonate (15 ml) and then a saturated aqueous solution of NaCl (15 ml), dried over g 2 SC> 4 , filtered. and concentrated to dryness under PR.
  • the isolated residue is chromatographed on 45 g of silica gel 60, particle size 15-40 ⁇ m, contained in a column 2 cm in diameter, eluting with a mixture of AcOEt / cyclohexane 3/2 v / v, under an overpressure. 0.6 bar argon.
  • (2S) -2 - ( ⁇ 3 - [(4-tert-butylphenyl) carbamoyl] phenyl ⁇ [(1H-indazol-5-ylcarbamoyl) oxy] methyl is charged) piperidine-1-tert-butylcarboxylate (500 mg, 0.8 mmol) with 4M hydrochloric acid in solution in dioxane (7.2 mL, 28.8 mmol).
  • the combined organic extracts are washed with distilled water (20 ml), saturated aqueous sodium hydrogen carbonate solution (15 ml) and saturated aqueous NaCl solution (15 ml), dried over MgSO 4, filtered and concentrated to dryness. under PR.
  • the isolated residue is chromatographed on 30 g of silica gel 60, particle size 15-40 ⁇ m, contained in a column 2 cm in diameter, eluting with a mixture of cyclohexane / AcOEt 1/1 v / v, under an overpressure of 0.6 bar argon.
  • the compound is prepared according to ex. 38b from tert-butyl (S) -2 - [(S) - (3-bromo-phenyl) - (1H-indazol-5-ylcarbamoyloxy) -methyl] -piperidine-1-carboxylate (0.248 g, m.p. 39 mmol).
  • IC50 for AKT1 The inhibitory potential of the compounds is assessed by HTRF, a time-resolved fluorescence technique based on non-radiative energy transfer (FRET).
  • the AKT1 protein used in these studies does not contain the Pleckstrin homology domain (PH domain). It contains an aspartic acid instead of the Serine residue at position 473, the amino acid of the hydrophobic domain.
  • the AKT1 protein is phosphorylated by PDK1 at the Threonine 308 amino acid residue of the kinase domain. This phosphorylation activates the kinase activity of AKT1.
  • reaction buffer 50 mM Hepes, pH 7.5, 10 mM MgCl 2 (Prolabo reference 25.108.238), 0.015% triton-X100 ( 22686 USB reference), 2.5% glycerol (Prolabo reference 24388-295) and 10 mM DTT (reference Sigma ultra D5545) in 3% DMSO.
  • AAAGGGGGRPRAATFAE (reference Neosystem SP000560).
  • the plate is then covered with plastic paper, agitated and finally incubated at RT for 30 minutes.
  • the reaction is finally stopped by the addition of 50 ⁇ l of a mixture of 16.7 nM of steptavidin labeled with allophycocyanin XL665 (reference 611 SAXLA cisbio-international) and 0.998 nM of anti-phospho-threonine antibody coupled to europium cryptate (61 PTRKAZ cisbiointernational) in revealing buffer (100 mM Hepes-NaOH, 133 mM EDTA, 400 mM KF, BSA, 0.1% at pH 7.0 ).
  • the plate After a night of incubation at 40 ° C., the plate is read by an Ultra evolution spectrophotometer from Tecan.
  • the device settings are as follows: excitation at 320 nm, emission at 620 and 665 nm, latency time of 150 ⁇ s, integration time of 500 ⁇ s. All tests are performed in duplicate and the average of the two tests is calculated.
  • ⁇ F% ( ⁇ R / R white ) x 100 ⁇ F% is calculated by the Tecan Ultra Evolution.
  • IC50 are calculated from equation 205 of the XLFit4 software
  • IC50 for S6K1 The inhibitory potential of the compounds for S6K1 is evaluated in a substrate phosphorylation enzyme assay in Homogenous Time-Resolved Fluorescence (HTRF) format.
  • Human S4K1 (24-421) protein T412E is expressed in sf21 cells and purified by nickel-chelate column chromatography. It is activated by PDK1.
  • the test consists of two steps, both performed at TA.
  • the phosphorylation reaction takes place and during the second stage the revelation step is set up.
  • the enzyme (14.3 ⁇ M inhibitor or a range of concentrations in the reaction medium ranging from 14.3 ⁇ M to 0.00024 ⁇ M or 42.9 ⁇ M to 0.00073 ⁇ M (in steps of 3) added under 5 ⁇ l in DMSO-ED 30% (vol / vol) and 2.9 nM enzyme (or buffer kinase for the blank) added under 30 ⁇ l in kinase buffer (HEPES / 50 mM NaOH, 20 mM MgCl 2 , 1 mM DTT, 5% glycerol, 0.0025% Tween 20, pH 7.0), the kinase reaction is triggered by the addition of 15 ⁇ l of a mixture of two substrates (biot-A-AARARTSSFAEPG, called GSK3, ref
  • the compounds thus obtained during the incubation period range from 10 ⁇ M to 0.17 nM and the enzyme concentration is 2 nM
  • the reaction is stopped and the revelation initiated p by the addition of 30 ⁇ l of a mixture of streptavidin XL 665 Xlent, ref 611 SAXLB Cis international bio, and an anti-phospho-GSK3 antibody coupled to europium cryptate, ref 64CUSKAZ Cis bio international, dissolved in the revealing buffer (HEPES / 166.7 mM NaOH, 221 EDTA, 7 mM, 667.7 mM KF, 0.167% BSA, pH 7.0).
  • the reaction takes place in a half-well black plate ref 3694 Costar.
  • a mixture of the reaction medium after each addition of reagent is obtained by stirring for a few minutes at 700-1000 rpm on a Heidolph Titramax 100.
  • the reading is performed on a TECAN Ultra Evolution after at least one night and up to 3 nights at 4 0 C.
  • the read settings are: excitation wavelength 320 nm, emission wavelengths 620 and 665 nm, lag time 150 ⁇ s, integration time 500 ⁇ s.
  • the ⁇ F% is calculated as follows:
  • the activity of the compound is evaluated by the% inhibition of the enzymatic activity obtained in the presence of 10 ⁇ M of it during the incubation period (14.3 ⁇ M during preincubation).
  • the active compounds (% inhibition greater than 50% at 10 ⁇ M) are then reevaluated by determining their concentration capable of inhibiting the enzymatic activity by 50% (IC 50).
  • IC50s are calculated using equation 205 of XLfit4.
  • This assay is based on the incorporation of [ 14 C] -thymidine into cell DNA during the S phase of the cell cycle during cell division.
  • the cell line used in this assay is the MEF / 3T3 Tet-Off Clone 18 line obtained by stable transfection of the human IGF1 R receptor in MEF / 3T3 Tet-Off murine fibroblasts.
  • IGF1-dependent cell proliferation the cells were deprived of serum and cultured for 3 days in the serum-free culture medium in the presence of IGF1 growth factor which stimulates the proliferation of MEF-IGF1 cells.
  • the cells were seeded at 7500 cells per well in 96-well Cytostar microplates (Amersham (GE) RPNQ0162) in 200 ⁇ l of EMEM medium (EMEM, Biowhittaker, # BE12-662F) containing 10% calf serum.
  • EMEM EMEM, Biowhittaker, # BE12-662F
  • fetal SVF, Tet-BD Biosciences Tet System Approved US-Sourced FBS, # 8630-1
  • PSG Penicillin-Streptomycin-Glutamine (PSG), Gibco # 10378-016)
  • the cells were washed in the EMEM culture medium without FCS containing 1% PSG, and incubated in 170 ⁇ l of this serum-free culture medium at 37 ° C., 5% CO 2, for 24 hours.
  • the cells were incubated with 10 ⁇ l of IGFI (2 ⁇ g / ml in final concentration, recombinant human IGF-1, R & D Systems, # 291 -G1), 10 ⁇ l (0.1 ⁇ Ci) of [ 14 C] -Thymidine (NEN NEC-568) plus 10 ⁇ l of increasing concentrations of the test molecules, diluted in dimethylsulfoxide (DMSO, Sigma D2650).
  • the molecules were added in a volume of 10 ⁇ l of a solution concentrated 20 times in a final volume of 200 ⁇ l, the final percentage of DMSO being 0.1%.
  • the treated cells were incubated at 37 ° C., 5% CO 2 for 72 h.
  • [ 14 C] -Thymidine incorporation was quantified in cpm units (counts per minute) by counting the radioactivity 72 hours after the start of treatment, using a Micro-Beta radioactivity counter (Perkin-Elmer). The tests were performed in duplicate.
  • the CelITiter-GIo TM kit for the measurement of cell viability by luminescence is a homogeneous method for determining the number of viable cells in culture, based on the quantification of ATP present in the cells and which signs the presence of metabolically active cells.
  • the cell lines used in this assay were as follows: MIA PaCa-2 cells (human pancreatic carcinoma cells, ATCC 1 CRL-1420), C-433 cells (Ewing's sarcoma human cells, DSMZ, ACC 268), LNCaP cells clone FGC (human prostate carcinoma cells, ATCC, CRL-1740), MCF7 cells (human breast carcinoma cells, ECACC, # 86012803).
  • the MIAPaCa-2 and LNCaP cells were cultured in the D-MEM culture medium (Invitrogen Gibco, # 419656-039) containing 10% fetal calf serum (SVF, Invitrogen Gibco, # 10500-064) and 2 mM L Glutamine (Invitrogen Gibco, # 25030-024); C-433 cells were cultured in culture medium MCCoy's 5A (Invitrogen Gibco, # 26600-023) / RPMI 1640 (Gibco Invitrogen, # 31870-025) (50/50) containing 10% FCS and 2mM L-glutamine ; the MCF7 cells were cultured in the EMEM culture medium (EMEM, Biowhittaker, Lonza, # BE12-662F) containing 10% FCS and 2 mM L-Glutamine.
  • D-MEM culture medium Invitrogen Gibco, # 419656-039
  • C-433 cells were cultured in culture medium MCCo
  • CelITiter-GIo TM assay On day 1, the cells were seeded at 1000 (C-433), 2500 (MCF7) and 10,000 (LNCaP and MIA PaCa-2) cells per well. in 96-well black-bottomed microplates (Nunc fluoronunc, Fisherbioblock 2311 K) in 135 ⁇ l of complete culture medium and incubated at 37 ° C., 5% CO 2 , for 3 to 6 hours. The cells were then incubated with increasing concentrations of molecules diluted in dimethylsulfoxide (DMSO, Sigma D2650).
  • DMSO dimethylsulfoxide
  • the molecules were added in a volume of 15 ⁇ l of a solution 10 times concentrated in a final volume of 150 ⁇ l, the final percentage of DMSO being 0.1%.
  • Cells were incubated at 37 ° C, 5% CO 2 , for 96 h.
  • the CelITiter-GIo TM test was carried out following the instructions of the supplier (Celltiter-GIo Luminescent Kit, PROMEGA # G7571). Briefly, the cell plates were equilibrated for about 30 min at RT and 100 ⁇ l per well of added Celltiter-GLO reagent. Cells were incubated for 1 hour at RT for cell lysis and signal stabilization. Intracellular ATP was quantified by luminescence measurement in relative luminescence units, 96 hours after the initiation of treatment, using a luminescence counter (Wallac). The tests were carried out in six replicates.
  • IC50 were calculated by linear regression with the XLfit software (IDBS, UK) using the formula 205.
  • Table I are given the biochemical activities, i.e. IC50 on AKT1 and S6K1; in Table II, the antiproliferative activities of some of the compounds are given for certain cell lines. It is found that the compounds tested, generally have an IC 50 of less than 10000 nM according to the cell line.
  • Table I [A: IC50 ⁇ 100 nM; B: IC50 between 100 and 500 nM and C: IC50 between 500 and 2000 nM]

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US20100298377A1 (en) 2010-11-25
UY31166A1 (es) 2009-01-30
FR2917735B1 (fr) 2009-09-04
WO2009010660A3 (fr) 2009-04-16
FR2917735A1 (fr) 2008-12-26
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PE20090369A1 (es) 2009-04-30
AR067051A1 (es) 2009-09-30

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