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EP2411368A1 - Nicotinamide derivatives, preparation thereof, and therapeutic use thereof as anticancer drugs - Google Patents

Nicotinamide derivatives, preparation thereof, and therapeutic use thereof as anticancer drugs

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Publication number
EP2411368A1
EP2411368A1 EP10716566A EP10716566A EP2411368A1 EP 2411368 A1 EP2411368 A1 EP 2411368A1 EP 10716566 A EP10716566 A EP 10716566A EP 10716566 A EP10716566 A EP 10716566A EP 2411368 A1 EP2411368 A1 EP 2411368A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
fluoro
ureido
nicotinamide
ylmethyl
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Withdrawn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
EP10716566A
Other languages
German (de)
French (fr)
Inventor
Jérôme ARIGON
Claude Bernhart
Monsif Bouaboula
Romain Combet
Sandrine Hilairet
Samir Jegham
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 SA
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Filing date
Publication date
Application filed by Sanofi SA filed Critical Sanofi SA
Publication of EP2411368A1 publication Critical patent/EP2411368A1/en
Withdrawn legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to nicotinamide derivatives, the compositions containing them and their therapeutic application, especially as anti-cancer agents.
  • the invention also relates to the process for the preparation of these compounds as well as to some of the intermediate products.
  • Z represents a phenyl or indanyl group and not a pyridinyl group.
  • R 1 3 may be a 2-, 3- or 4-pyridinyl group
  • R 4 and R 5 represent a hydrogen atom, a group alkyl, alkoxy, -OH, -CF 3 or -CN.
  • halogen atom a fluorine, chlorine, bromine or iodine atom
  • Alkyl group a saturated aliphatic hydrocarbon group comprising from 1 to 6 carbon atoms (advantageously from 1 to 4 carbon atoms) obtained by removing a hydrogen atom from an alkane.
  • the alkyl group can be linear or branched.
  • alkoxy group a -O-alkyl group, where the alkyl group is as defined above; cycloalkyl group: a cyclic alkyl group comprising between 3 and 8 carbon atoms, all the carbon atoms being engaged in the ring structure.
  • heterocycloalkyl group a cycloalkyl group comprising at least one heteroatom (O, S, N) engaged in the ring and connected to the carbon atoms forming the ring.
  • heterocycloalkyl group a cycloalkyl group comprising at least one heteroatom (O, S, N) engaged in the ring and connected to the carbon atoms forming the ring.
  • pyrrolidinyl piperidinyl, piperazinyl or N- (C 1 -C 4 ) alkyl-piperazinyl, azepanyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxothiomorpholinyl groups.
  • the present invention relates to a compound of formula (I):
  • X is an integer equal to 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring;
  • R 1 represents a hydrogen atom, a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, phenyl group;
  • R 1 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group
  • R 2 represents:
  • R 3 represents at least one substituent of the pyridine ring chosen from a hydrogen or fluorine atom, a (C 1 -C 4 ) alkyl group or -NR c R d in which R c and R d represent a hydrogen atom or a (C 1 -C 4 ) alkyl group;
  • R 1 represents a hydrogen atom, a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl group, for example cyclopropyl, a phenyl group.
  • R ' 1 represents a hydrogen atom or a (C 1 -C 4 ) alkyl group. More particularly, R ' 1 represents a hydrogen atom.
  • R 1 and / or R ' 1 may be chosen from those described in Table I.
  • R 2 represents:
  • a (C 3 -C 6) cycloalkyl group such as for example the cyclopropyl or cyclopentyl group;
  • q 1 or 2.
  • the heterocycloalkyl group formed by R 3 and R b may be, for example, the pyrrolidinyl group
  • heterocycloalkyl group formed by R a and R b may be optionally substituted by one or more substituents, which are identical to or different from each other when there are several of them, chosen from: -OH; (C 1 -C 4 ) alkoxy: for example methoxy; (C 1 -C 4 ) alkyl: for example methyl.
  • substituents which are identical to or different from each other when there are several of them, chosen from: -OH; (C 1 -C 4 ) alkoxy: for example methoxy; (C 1 -C 4 ) alkyl: for example methyl.
  • the substituted heterocycloalkyl may be the 3-hydroxypiperidinyl group
  • the pyridine ring may comprise from 1 to 4 substituents R 3 chosen from a hydrogen or fluorine atom, a (C 1 -C 4 ) alkyl group or -NR c R d in which R c and R d represent a hydrogen atom or a (dC 4 ) alkyl group.
  • R 3 may be chosen from those described in Table I.
  • R 3 is in the 5 and / or 6 position on the pyridine ring.
  • the number of substituents R 3 is 1 and / or R 3 is in the 5 or 6 position on the pyridine ring as shown below:
  • R 3 is even more preferably in the 6-position.
  • R 3 represents a hydrogen atom or -NH 2 .
  • n is 1.
  • Z and Z ' represent N or CH.
  • Z and Z ' may respectively represent N and CH; CH and CH or N and N:
  • x is an integer of 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring. More particularly, x is 1.
  • R 1, R 1 , R 2 , R 3 and x are as previously defined.
  • R 1 represents a (C 1 -C 4 ) alkyl group
  • the compounds of the invention may exist in the form of bases or addition salts with acids. Such addition salts are also part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds also form part of the invention.
  • the compounds according to the invention may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
  • the compounds may have one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures are part of the invention.
  • the N-oxides of compounds containing an amine or a nitrogen atom are also part of the invention.
  • the invention provides the process for preparing compounds of to the invention as well as some of the reaction intermediates.
  • HaI represents a halogen atom (chlorine, bromine, iodine).
  • the coupling is carried out in the presence of a palladium complex (in the oxidation state (O) or (M)) in a basic medium.
  • the complex may be, for example, Pd (PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd (OAc) 2 , PdCl 2 (dppf) or bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium ( ll).
  • the most frequently used complexes are palladium (O) complexes.
  • the base can be for example K 2 CO 3 , NaHCO 3 , and 3 N, K 3 PO 4 , Ba (OH) 2 , NaOH, KF, CsF, Cs 2 CO 3.
  • the coupling can be carried out in a mixture an ethereal solvent and an alcohol, for example a dimethoxyethane (DME) / ethanol mixture; it can also be a toluene / water mixture.
  • the temperature is between 50 and 120oC.
  • the duration of the reaction can in some cases be long (see ex.1.3.).
  • K and K ' represent a hydrogen atom, an alkyl or aryl group, optionally linked together to form together with the boron atom and the two oxygen atoms a 5- to 7-membered ring optionally substituted by at least one (C 1 -C 4 ) alkyl group or to which is optionally attached to two consecutive carbon atoms of said ring a phenyl group.
  • one of the following groups can be used:
  • the compound of formula (I) is obtained by an amidification reaction starting from P 6 and the amine R 2 NH 2 or a salt of this amine, for example the hydrochloride (see ex .3.2).
  • the amidification can be carried out advantageously in the presence of an activator of acid (also called “coupling agent”) such as benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33-6, see also B.Castro., Dormoy, JR Tetrahedron Letter 1975, 16, 1219).
  • the reaction is preferably carried out in the presence of a base (such as triethylamine) at room temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).
  • Ps is obtained from P 7 acid by monosubstitution with an amine of formula R 1 R ' 1 NH.
  • the reaction may be carried out at ambient temperature and in a protic solvent such as an alcohol or water or in an aprotic solvent such as
  • P 7 is a 2,6-dihalogenonicotinic acid, for example 2,6-dichloronicotinic acid which is commercially available (see example 1.1);
  • Ps can also be obtained from the commercial compound 5-pyrimidinecarboxylic acid, 2,4- dichloro-, ethyl ester:
  • Pi is obtained from Ps acid by amidification using the amine R 2 NH 2 or a salt of this amine, for example the hydrochloride.
  • Amidification can advantageously be carried out in the presence of an acid activator (also called “coupling agent”) such as for example benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33- 6, see also Castro, B., Dormoy, JR Tetrahedron Letter 1975, 16, 1219).
  • the reaction is preferably carried out in the presence of a base (such as triethylamine) at room temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF). See ex.1 .2.
  • 2007/064931 3-F (4-amino-3-fluorophenylboronic acid pinacol ester, CAS No. 819058-34-9, Boron Molecular Inc., PO Box 12592, Research Triangle Park, NC 27709); 2-F (4-amino-2-fluorophenylboronic acid pinacol ester, CAS No. 819057-45-9, Boron Molecular, described on page 185 of WO 2007/064931); 2-F, 5-F (CAS No. 939807-75-7, compound described on page 184 of WO 2007/064931); 3-F, 5-F (CAS No. 939968-08-8, described on page 182 of WO
  • Amines R 2 NH 2 are commercial products or already described in published documents; for example :
  • Pyrrolidineethanamine CAS No. 7154-73-6, described in Anales de Quimica 1974, 70 (9-10), 733-737, sold by International Laboratory Ltd, 1067 Sneath Ln, San Bruno, CA94066, USA;
  • N- (2-aminoethyl) thiamorpholin-1-oxide CAS No. 1017791-77-3, sold by Sinova Inc. 3 Bethesda Metro Center, Suite 700, Bethesda, MD, 20814, USA.
  • a method for obtaining compounds for which R 2 represents a (C 1 -C 6 ) alkyl group substituted by the group -NR a R b in which R 3 and R b together with the nitrogen atom to which they are heterocycloalkyl (C 4 -C 6 ) group optionally comprising in the ring the group -S (O) q with q 0, 1 or 2 or the group -NH- or -N (C 1 -C 4 ) alkyl is described on Figure 6 which is inspired by scheme 3 of Bioorg. Med. Chem. 2007, 15, 365-373 or diagram 2 of Bioorg. Med. Chem. Lett. 2008, 18, 1378-1381:
  • P 5 can be either commercial or prepared according to methods known to those skilled in the art.
  • the hydrogenation conditions may be those described in ex.19 and 20 of WO 00/46179 or in Synlett 2001, 10, 1623-1625.
  • the compounds 3-picolylamine (CAS No. 3731-52-0), 3- (2-aminoethyl) pyridine (CAS No. 20173-24-4), 2-amino-5-aminomethylpyridine (CAS No. 156973-09- 0), 2-methyl-5-aminomethylpyridine (CAS No. 56622-54-9), 3-methyl-5-aminomethylpyridine (CAS No. 771574-45-9), 2- (BOC-amino) -5-aminomethyl -pyridine (CAS No. 187237-37-2), 2,5-diaminopyridine (CAS No. 4318-76-7) are commercial products.
  • 2-amino-5-aminomethylpyridine can also be prepared according to EP 0607804.
  • 5-Aminomethyl-2- (dimethylamino) pyridine (CAS No. 354824-17-2) is commercially available or can be prepared according to J.Agr.Food Chem . 2008, 56 (1), 204-212.
  • 2-Amino-3-methyl-5-aminomethylpyridine (CAS No. 187163-76-4) can be obtained by catalytic hydrogenation of the 6-amino-5-methyl-nicotinonitrile compound (CAS No. 183428-91-3), the amino function being doubly protected by the BOC.
  • Catalytic hydrogenation 6-methylamino-3-pyridinecarbonitrile (CAS No. 261715-36-0) provides access to 2-methylamino-5-aminomethylpyridine.
  • P 10 can be either commercial or prepared according to methods known to those skilled in the art.
  • trans-3- (3-pyridyl) acrylic acid is marketed by Sigma-Aldrich.
  • (6-Aminopyridin-3-yl) acrylic acid (CAS No. 234098-57-8, Compound E: CAS No. 167837-43-6) is described in J.Med.Chem. 2002, 45 (15), 3246-3256 (see diagram 4).
  • P 10 can be prepared from bromoaniline and acrylic acid according to the teachings of J.Med.Chem. 2002, 45 (15), 3246-3256.
  • P 10 can also be prepared according to J.Org.Chem. 1998, 63, 8785-8789 from the corresponding beta-formylpyridine or according to J.Med.Chem. 1989, 32 (3), 583-93 from 2-chloro-5-nitro-pyridine.
  • the acyl halide P '10 is obtained by a reaction known to those skilled in the art from the acid P 10 and an acylating agent such as for example SOCb or (COCI) 2 .
  • SOCb acylating agent
  • COCI COCI
  • P 4 is reacted with acryloyl chloride in the presence of a base such as, for example, triethylamine and at a temperature of between 0 ° C. and room temperature to obtain P 11 .
  • a base such as, for example, triethylamine
  • the solvent may be dichloromethane (DCM) (see Example 4.1).
  • P 11 is reacted with P 12 (Hal represents a halogen atom), in the presence of a palladium complex such as for example Pd (OAc) 2 , tri-orthotolylphosphine and a base such as for example diisopropylethylamine.
  • the solvent may be, for example, propionitrile.
  • the temperature is between room temperature and the reflux temperature of the solvent.
  • a protecting group to protect one or more chemical function (s), including a primary or secondary amine function.
  • R 3 and R b both represent a hydrogen atom
  • the amidification of Scheme 3 is carried out using for R 2 NH 2 the compound 2 HN- (Cr C ⁇ ) alkyl-NH-PG, where PG represents advantageously BOC (tert-butoxycarbonyl).
  • the heterocycloalkyl group formed by R 3 and R b represents the group piperazinyl can advantageously protect the function -NH- using
  • R 3 represents the group -NH 2 or -NHR C
  • the amine function can advantageously be protected by one or two PG group (s), preferably BOC or FMOC (9-fluorenylmethyl carbamate).
  • the compound P 5 can be used
  • the chemical function (s) is / are then obtained by a deprotection step (final or intermediate) whose conditions depend on the nature of the protected function (s) and protective group used.
  • a deprotection step final or intermediate
  • the deprotection step is carried out in acidic medium using, for example, HCl or trifluoroacetic acid (TFA).
  • the deprotection step is carried out in acidic medium using, for example, HCl or trifluoroacetic acid (TFA).
  • TFA HCl or trifluoroacetic acid
  • the salts are obtained during the deprotection step described above or by contacting the acid and the compound in its base form.
  • N-oxides of the compounds containing an amine or a nitrogen atom are prepared according to the methods known to those skilled in the art by reaction of the amine with peracids organic such as peracetic, trifluoroperacetic, performic, perbenzoic acids or its derivatives such as 3-chloroperbenzoic acid, at temperatures between 0oC and 90oC, preferably at temperatures below 50oC.
  • peracids organic such as peracetic, trifluoroperacetic, performic, perbenzoic acids or its derivatives such as 3-chloroperbenzoic acid
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined above in combination with a pharmaceutically acceptable excipient.
  • the excipient is selected from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired mode of administration.
  • the mode of administration can be, for example, orally or intravenously.
  • the subject of the invention is a medicinal product which comprises a compound as defined above as well as the use of a compound as defined above, for the manufacture of a medicament. It can be useful for treating a pathological condition, especially cancer.
  • the drug (as well as a compound according to the invention) may be administered in combination with one (or more) anticancer drugs. This treatment can be administered simultaneously, separately or sequentially. The treatment will be adapted by the practitioner according to the patient and the tumor to be treated.
  • the invention also relates to a method of treatment of pathologies indicated above which comprises administering to a patient an effective dose of a compound of the invention or a pharmaceutically acceptable salt or hydrates or solvates.
  • the compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection).
  • the apparatus used is composed of a Agilent chromatographic system equipped with an Agilent diode array detector and a ZQ Waters single quadrupole mass spectrometer or a Quattro-Micro Waters triple quadrupole mass spectrometer.
  • the compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection).
  • the apparatus used is composed of a chromatographic chain equipped with a diode array detector (HP1 1 10 Agilent or UPLC Acquity Waters) and a quadrupole mass spectrometer (ZQ, QM or SQD Waters).
  • the liquid chromatography / mass spectrometry (LC / MS) spectra were recorded in electrospray (ESI) positive mode, in order to observe the ions resulting from the protonation of analyzed compounds (MH + ) or the formation of adducts with other cations such as Na + , K + , etc.
  • the HPLC conditions are selected from one of the following methods:
  • Example 3 6- ⁇ 4-r3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl ⁇ -N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide (Compound No. 15 prepared according to Scheme 3) 3.1. 6- (4 - ⁇ [( ⁇ 6-rbis (tert-butoxycarbonyl) amino] pyridin-3-yl ⁇ methyl) carbamoyamino ⁇ -3-fluorophenyl) -2- (ethylamino) nicotinic acid
  • compound no. 28 (250 MHz) 1, 22 (t, 3), 1, 23 - 1, 6 (m, 6), 2.30 - 2.50 (m, 6), 2.75 (d, 3), 3.34 (m, 2), 3.52 (which, 2), 4.13 (d, 2), 6.39 (q, 1), 6.43 (d, 1), 6, 98 (t, 1), 7.16 (d, 1), 7.37 (dd, 1), 7.80 - 8.02 (m, 4), 8.28 (t, 1), 8.37 (t, 1), 8.41 (t, 1), 8.49 (d, 1).
  • compound no. 40 (400 MHz) 1, 22 (t, 3), 1, 30 - 1, 59 (m, 10), 2.23 (t, 2), 2.28 (s, 4), 3 23 (q, 2); 3.52 (which, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.99 (t, 1), 7.14 (d, 1), , 1), 7.34 (dd, 1), 7.82 - 8.00 (m, 4), 8.26 (t, 1), 8.43 (m, 2), 8.51 (if, 1).
  • the compounds described in Table I have been the subject of pharmacological tests for determining anticancer activity. They were tested in vitro on the tumor line HCT116 (ATCC-CCL247). Proliferation and cell viability were determined in a test using 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) according to Fujishita T. et al. Oncology 2003, 64 (4), 399-406. In this test, the mitochondrial capacity of living cells is measured to transform MTS into a colored compound after 72 hours of incubation of the test compound. The concentration of compound which leads to 50% loss of proliferation and cell viability is noted as IC 5 O.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to nicotinamide derivatives of formula (I), to compositions containing same, and to the therapeutic use thereof, in particular as anticancer drugs. The invention also relates to the method for preparing said compounds, as well as to some of the intermediate products.

Description

DERIVES DE NICOTINAMIDE, LEUR PREPARATION ET LEUR APPLICATION EN THERAPEUTIQUE COMME ANTICANCEREUX NICOTINAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION AS ANTICANCER
La présente invention se rapporte à des dérivés de nicotinamide, les compositions les contenant et leur application en thérapeutique, notamment comme anticancéreux. L'invention se rapporte aussi au procédé de préparation de ces composés ainsi qu'à certains des produits intermédiaires.The present invention relates to nicotinamide derivatives, the compositions containing them and their therapeutic application, especially as anti-cancer agents. The invention also relates to the process for the preparation of these compounds as well as to some of the intermediate products.
[L'art antérieur][The prior art]
La demande internationale WO 2005/051366 décrit des composés de formule générale (A) :The international application WO 2005/051366 describes compounds of general formula (A):
dans laquelle Z représente un groupe phényle ou indanyle et non un groupe pyridinyle. wherein Z represents a phenyl or indanyl group and not a pyridinyl group.
La demande internationale WO 2007/016538 décrit des composés de formule générale (B) :International Application WO 2007/016538 describes compounds of general formula (B):
dans laquelle Q peut représenter un groupe Ri3-NR12-C(=O)-, R13 pouvant être un groupe 2-, 3- ou 4- pyridinyle, R4 et R5 représentant un atome d'hydrogène, un groupe alkyle, alcoxy, - OH, -CF3 ou -CN. Ces composés sont utilisés dans le traitement de l'obésité. in which Q may represent a group R 1 -NR 12 -C (= O) -, R 1 3 may be a 2-, 3- or 4-pyridinyl group, R 4 and R 5 represent a hydrogen atom, a group alkyl, alkoxy, -OH, -CF 3 or -CN. These compounds are used in the treatment of obesity.
[Description de l'invention] Définitions utilisées[Description of the invention] Definitions used
Dans le cadre de la présente invention, on entend par :In the context of the present invention, the following terms mean:
• atome d'halogène : un atome de fluor, de chlore, de brome ou d'iode ;• halogen atom: a fluorine, chlorine, bromine or iodine atom;
• groupe alkyle : un groupe hydrocarboné aliphatique saturé comprenant de 1 à 6 atomes de carbone (avantageusement, de 1 à 4 atomes de carbone) obtenu en enlevant un atome d'hydrogène d'un alcane. Le groupe alkyle peut être linéaire ou ramifié. A titre d'exemples, on peut citer les groupes méthyle, éthyle, propyle, isopropyle, butyle, iso- butyle, tertio-butyle, pentyle, 2,2-diméthylpropyle, hexyle ; groupe alcoxy : un groupe -O-alkyle, où le groupe alkyle est tel que défini ci-dessus ; groupe cycloalkyle : un groupe alkyle cyclique comprenant entre 3 et 8 atomes de carbone, tous les atomes de carbone étant engagés dans la structure cyclique. A titre d'exemples, on peut citer les groupes cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle ; groupe hétérocycloalkyle : un groupe cycloalkyle comprenant au moins un hétéroatome (O, S, N) engagé dans le cycle et relié aux atomes de carbone formant le cycle. A titre d'exemples, on peut citer les groupes pyrrolidinyle, pipéridinyle, pipérazinyle ou N-(Cr C4)alkyle-pipérazinyle, azépanyle, thiomorpholinyle, 1-oxo-thiomorpholinyle, 1 ,1-dioxo- thiomorpholinyle.Alkyl group: a saturated aliphatic hydrocarbon group comprising from 1 to 6 carbon atoms (advantageously from 1 to 4 carbon atoms) obtained by removing a hydrogen atom from an alkane. The alkyl group can be linear or branched. As examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2,2-dimethylpropyl, hexyl; alkoxy group: a -O-alkyl group, where the alkyl group is as defined above; cycloalkyl group: a cyclic alkyl group comprising between 3 and 8 carbon atoms, all the carbon atoms being engaged in the ring structure. By way of examples, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups; heterocycloalkyl group: a cycloalkyl group comprising at least one heteroatom (O, S, N) engaged in the ring and connected to the carbon atoms forming the ring. By way of examples, mention may be made of pyrrolidinyl, piperidinyl, piperazinyl or N- (C 1 -C 4 ) alkyl-piperazinyl, azepanyl, thiomorpholinyl, 1-oxo-thiomorpholinyl, 1, 1-dioxothiomorpholinyl groups.
Selon un 1er aspect, la présente invention a pour objet un composé de formule (I) :According to a 1st aspect, the present invention relates to a compound of formula (I):
dans laquelle : in which :
• Z et Z' représentent N ou CH ;• Z and Z 'represent N or CH;
• x est un entier valant 1 ou 2, représentant le nombre d'atome(s) de fluor attaché(s) au noyau phényle central ; • L représente un groupe -CH=CH- ou -(CH2)nNH- dans lequel le groupe NH est rattaché au C=O et n est un entier valant 0, 1 ou 2 ;X is an integer equal to 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring; L represents a group -CH = CH- or - (CH 2 ) n NH- in which the NH group is attached to C = O and n is an integer of 0, 1 or 2;
• Ri représente un atome d'hydrogène, un groupe (CrC6)alkyle, (C3-C6)cycloalkyle, phényle ;R 1 represents a hydrogen atom, a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, phenyl group;
• R'i représente un atome d'hydrogène ou un groupe (CrC6)alkyle ; • R2 représente :R 1 represents a hydrogen atom or a (C 1 -C 6 ) alkyl group; • R 2 represents:
- un groupe (C3-C6)cycloalkyle ;a (C 3 -C 6 ) cycloalkyl group;
- un groupe (CrC6)alkyle, éventuellement substitué par : o un ou plusieurs groupes hydroxy ou (C1-C4)alcoxy ; o un groupe -NRaRb dans lequel R3 et Rb représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe (C1-C6)alkyle ou forment ensemble avec l'atome d'azote auquel ils sont reliés un groupe (C4-C6)hétérocycloalkyle comprenant éventuellement dans le cycle le groupe -S(O)q avec q= 0, 1 ou 2 ou le groupe -NH- ou -N(C1-C4)alkyle- et étant éventuellement substitué par un ou plusieurs substituant(s), identiques ou différents les uns des autres lorsqu'il y en a plusieurs, choisi(s) parmi un groupe - OH ; (C1-C4)alcoxy ou (C1-C4)alkyle ;a (CrC 6 ) alkyl group, optionally substituted by: one or more hydroxyl or (C 1 -C 4 ) alkoxy groups; a group -NR a R b in which R 3 and R b represent, independently of one another, a hydrogen atom or a (C 1 -C 6 ) alkyl group or together with the nitrogen atom to which they are connected a (C 4 -C 6 ) heterocycloalkyl group optionally comprising in the ring the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (C 1 -C 4 ) alkyl- and being optionally substituted with one or more substituents (s) ), identical or different from each other when there are several, selected from an --OH group; (C 1 -C 4 ) alkoxy or (C 1 -C 4 ) alkyl;
• R3 représente au moins un substituant du noyau pyridine choisi parmi un atome d'hydrogène ou de fluor, un groupe (C1-C4)alkyle ou -NRcRd dans lequel Rc et Rd représentent un atome d'hydrogène ou un groupe (C1-C4)alkyle ;R 3 represents at least one substituent of the pyridine ring chosen from a hydrogen or fluorine atom, a (C 1 -C 4 ) alkyl group or -NR c R d in which R c and R d represent a hydrogen atom or a (C 1 -C 4 ) alkyl group;
Ri représente un atome d'hydrogène, un groupe (CrC6)alkyle, (C3-C6)cycloalkyle, par exemple cyclopropyle, un groupe phényle. R'1 représente un atome d'hydrogène ou un groupe (C1-C4)alkyle. Plus particulièrement, R'1 représente un atome d'hydrogène. On pourra choisir R1 et/ou R'1 parmi ceux décrits dans le tableau I.R 1 represents a hydrogen atom, a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl group, for example cyclopropyl, a phenyl group. R ' 1 represents a hydrogen atom or a (C 1 -C 4 ) alkyl group. More particularly, R ' 1 represents a hydrogen atom. R 1 and / or R ' 1 may be chosen from those described in Table I.
R2 représente :R 2 represents:
- un groupe (C3-C6)cycloalkyle, tel que par exemple le groupe cyclopropyle ou cyclopentyle ;a (C 3 -C 6) cycloalkyl group, such as for example the cyclopropyl or cyclopentyl group;
- un groupe (CrC6)alkyle, éventuellement substitué par : o un ou plusieurs groupe(s) -OH ou (C1-C4)alcoxy, par exemple méthoxy ; o un groupe -NRaRb dans lequel R3 et Rb représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe (C1C6)alkyle ou forment ensemble avec l'atome d'azote auquel ils sont reliés un groupe (C4-C6)hétérocycloalkyle comprenant éventuellement dans le cycle le groupe -S(O)q avec q= 0, 1 ou 2 ou le groupe -NH- ou -N(C1-C4)alkyle-. De préférence, q= 1 ou 2.a (CrC 6 ) alkyl group, optionally substituted with: one or more (OH) or (C 1 -C 4 ) alkoxy groups, for example methoxy; a group -NR a R b in which R 3 and R b represent, independently of one another, a hydrogen atom or a (C 1 -C 6 ) alkyl group or together with the nitrogen atom to which they are connected to a heterocycloalkyl (C 4 -C 6 ) group optionally comprising in the ring the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (C 1 -C 4 ) alkyl-. Preferably, q = 1 or 2.
Le groupe hétérocycloalkyle formé par R3 et Rb peut être par exemple le groupe pyrrolidinyleThe heterocycloalkyl group formed by R 3 and R b may be, for example, the pyrrolidinyl group
ou N-(C1-C4)alkyle-pipérazinyle thiomorpholinyleor N- (C 1 -C 4 ) alkylpiperazinyl thiomorpholinyl
), 1-oxo-thiomorpholinyle -dioxo-thiomorpholinyle Le groupe hétérocycloalkyle formé par Ra et Rb peut être éventuellement substitué par un ou plusieurs substituant(s), identiques ou différents les uns des autres lorsqu'il y en a plusieurs, choisi(s) parmi : -OH ; (C1-C4)alcoxy : par exemple méthoxy ; (C1-C4)alkyle : par exemple méthyle. Ainsi, l'hétérocycloalkyle substitué pourra être le groupe 3-hydroxypipéridinyle ), 1-oxo-thiomorpholinyl dioxo-thiomorpholinyl The heterocycloalkyl group formed by R a and R b may be optionally substituted by one or more substituents, which are identical to or different from each other when there are several of them, chosen from: -OH; (C 1 -C 4 ) alkoxy: for example methoxy; (C 1 -C 4 ) alkyl: for example methyl. Thus, the substituted heterocycloalkyl may be the 3-hydroxypiperidinyl group
On pourra choisir R2 parmi l'un de ceux décrits dans le tableau I.We can choose R 2 from one of those described in Table I.
Le noyau pyridine peut comprendre de 1 à 4 substituants R3 choisi(s) parmi un atome d'hydrogène ou de fluor, un groupe (C1-C4)alkyle ou -NRcRd dans lequel Rc et Rd représentent un atome d'hydrogène ou un groupe (d-C4)alkyle. On pourra choisir R3 parmi ceux décrits dans le tableau I. De préférence, R3 est en position 5 et/ou 6 sur le noyau pyridine. De préférence, le nombre de substituants R3 est égal à 1 et/ou R3 est en position 5 ou 6 sur le noyau pyridine comme cela est représenté ci-dessous :The pyridine ring may comprise from 1 to 4 substituents R 3 chosen from a hydrogen or fluorine atom, a (C 1 -C 4 ) alkyl group or -NR c R d in which R c and R d represent a hydrogen atom or a (dC 4 ) alkyl group. R 3 may be chosen from those described in Table I. Preferably, R 3 is in the 5 and / or 6 position on the pyridine ring. Preferably, the number of substituents R 3 is 1 and / or R 3 is in the 5 or 6 position on the pyridine ring as shown below:
R3 est encore plus préférentiellement en position 6. De préférence, R3 représente un atome d'hydrogène ou -NH2.R 3 is even more preferably in the 6-position. Preferably, R 3 represents a hydrogen atom or -NH 2 .
L représente un groupe -CH=CH- ou -(CH2)nNH- dans lequel le groupe NH est rattaché au C=O et n est un entier valant 0, 1 ou 2. De préférence, n est égal à 1. L peut être l'un de ceux décrits dans le tableau I. On préfère aussi, dans le cas où L représente le groupe -CH=CH-, les isomères E plutôt que les isomères Z.L represents a group -CH = CH- or - (CH 2 ) n NH- in which the NH group is attached to C = O and n is an integer of 0, 1 or 2. Preferably, n is 1. L can be one of those described in Table I. It is also preferred, in the case where L represents the group -CH = CH-, the E isomers rather than the Z isomers.
Z et Z' représentent N ou CH. Par exemple, Z et Z' peuvent représenter respectivement N et CH ; CH et CH ou N et N :Z and Z 'represent N or CH. For example, Z and Z 'may respectively represent N and CH; CH and CH or N and N:
x est un entier valant 1 ou 2, représentant le nombre d'atome(s) de fluor attaché(s) au noyau phényle central. Plus particulièrement, x vaut 1. x is an integer of 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring. More particularly, x is 1.
On distingue le sous-groupe de formule (I') :There is a subgroup of formula (I '):
dans laquelle R-i, R'i, R2, R3 et x sont tels que définis précédemment. wherein R 1, R 1 , R 2 , R 3 and x are as previously defined.
On distingue le sous-groupe de formule (I") :We distinguish the subgroup of formula (I "):
dans laquelle Ri représentent un groupe (C1-C4)alkyle, R2 représente un groupe (C1-C6)alkyle éventuellement substitué par le groupe -NRaRb dans lequel Ra et Rb forment ensemble avec l'atome d'azote auquel ils sont reliés le groupe (C4-C6)hétérocycloalkyle comprenant éventuellement dans le cycle le groupe -S(O)q avec q= 0, 1 ou 2 ou le groupe -NH- ou -N(Cr C4)alkyle et R3 et x étant tels que définis précédemment. Plus particulièrement, x vaut 1. Plus particulièrement encore, x vaut 1 et l'atome de fluor est en position 3. in which R 1 represents a (C 1 -C 4 ) alkyl group, R 2 represents a (C 1 -C 6 ) alkyl group optionally substituted with the group -NR a R b in which R a and R b form together with the nitrogen atom to which they are connected the (C 4 -C 6 ) heterocycloalkyl group optionally comprising in the ring the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (Cr C 4 ) alkyl and R 3 and x being as defined above. More particularly, x is 1. More particularly, x is 1 and the fluorine atom is in the 3-position.
Parmi les composés objets de l'invention, on peut citer ceux du Tableau I.Among the compounds that are the subject of the invention, mention may be made of those of Table I.
Les composés de l'invention, y compris les composés exemplifiés, peuvent exister à l'état de bases ou de sels d'addition à des acides. De tels sels d'addition font également partie de l'invention. Ces sels sont avantageusement préparés avec des acides pharmaceutiquement acceptables, mais les sels d'autres acides utiles, par exemple, pour la purification ou l'isolement des composés font également partie de l'invention. Les composés selon l'invention peuvent également exister sous forme d'hydrates ou de solvats, à savoir sous forme d'associations ou de combinaisons avec une ou plusieurs molécules d'eau ou avec un solvant. De tels hydrates et solvats font également partie de l'invention. Les composés peuvent comporter un ou plusieurs atomes de carbone asymétriques. Ils peuvent donc exister sous forme d'énantiomères ou de diastéréoisomères. Ces énantiomères, diastéréoisomères, ainsi que leurs mélanges font partie de l'invention. Selon la présente invention, les N-oxydes des composés comportant une aminé ou un atome d'azote font également partie de l'invention.The compounds of the invention, including the exemplified compounds, may exist in the form of bases or addition salts with acids. Such addition salts are also part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for the purification or the isolation of the compounds also form part of the invention. The compounds according to the invention may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention. The compounds may have one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures are part of the invention. According to the present invention, the N-oxides of compounds containing an amine or a nitrogen atom are also part of the invention.
Selon un 2ème aspect, l'invention a pour objet le procédé de préparation des composés de l'invention ainsi que certains des intermédiaires réactionnels.According to a 2nd aspect, the invention provides the process for preparing compounds of to the invention as well as some of the reaction intermediates.
Préparation des composés de formule (I) ou (I') pour lesquels L = -(CH2)nNH-Preparation of compounds of formula (I) or (I ') for which L = - (CH 2 ) n NH-
On peut préparer ces composés selon l'un des Schémas 1-3 suivants.These compounds can be prepared according to one of the following Schemes 1-3.
Schéma 1Diagram 1
On réalise un couplage de type Suzuki de Pi et P2. HaI représente un atome d'halogène (chlore, brome, iode). Le couplage est réalisé en présence d'un complexe de palladium (à l'état d'oxydation (0) ou (M)) en milieu basique. Le complexe peut être par exemple Pd(PPh3)4, PdCI2(PPh3)2, Pd(OAc)2, PdCI2(dppf) ou le bis(di-tert-butyl(4- diméthylaminophényl)phosphine)dichloropalladium(ll). Les complexes les plus fréquemment utilisés sont des complexes de palladium(O). La base peut être par exemple K2CO3, NaHCO3, Et3N, K3PO4, Ba(OH)2, NaOH, KF, CsF, Cs2CO3... Le couplage peut être conduit dans un mélange d'un solvant éthéré et d'un alcool, par exemple un mélange diméthoxyéthane (DME)/éthanol ; il peut s'agir aussi d'un mélange toluène/eau. La température est comprise entre 50 et 120ºC. La durée de la réaction peut dans certains cas être longue (voir ex.1.3.).A Suzuki type coupling of Pi and P 2 is carried out . HaI represents a halogen atom (chlorine, bromine, iodine). The coupling is carried out in the presence of a palladium complex (in the oxidation state (O) or (M)) in a basic medium. The complex may be, for example, Pd (PPh 3 ) 4 , PdCl 2 (PPh 3 ) 2 , Pd (OAc) 2 , PdCl 2 (dppf) or bis (di-tert-butyl (4-dimethylaminophenyl) phosphine) dichloropalladium ( ll). The most frequently used complexes are palladium (O) complexes. The base can be for example K 2 CO 3 , NaHCO 3 , and 3 N, K 3 PO 4 , Ba (OH) 2 , NaOH, KF, CsF, Cs 2 CO 3. The coupling can be carried out in a mixture an ethereal solvent and an alcohol, for example a dimethoxyethane (DME) / ethanol mixture; it can also be a toluene / water mixture. The temperature is between 50 and 120ºC. The duration of the reaction can in some cases be long (see ex.1.3.).
On trouvera plus de détails sur le couplage de Suzuki, sur les conditions opératoires ainsi que sur les complexes de palladium utilisables dans : N.Miyaura et A.Suzuki, Chem. Rev. 1995,More details on the Suzuki coupling, the operating conditions as well as the palladium complexes usable in: N.Miyaura and A.Suzuki, Chem. Rev. 1995
95, 2457-2483; A.Suzuki dans "Metal-catalyzed cross-coupling reactions"; Diederich, F.;95, 2457-2483; A.Suzuki in "Metal-catalyzed cross-coupling reactions"; Diederich, F .;
Stang, PJ. Eds. Wiley-VCH: Weinhein, Germany, 1998, chap. 2, 49-97 ; Littke, A. et Fu, G., Angew. Chem. Int., Ed. 1999, 38, 3387-3388 et Chemler, S. R. Angew.Chem.Int.Ed. 2001 , 40, 4544.4568.Stang, PJ. Eds. Wiley-VCH: Weinhein, Germany, 1998, chap. 2, 49-97; Littke, A. and Fu, G., Angew. Chem. Int., Ed. 1999, 38, 3387-3388 and Chemler, SR Angew.Chem.Int.Ed. 2001, 40, 4544.4568.
K et K' représentent un atome d'hydrogène, un groupe alkyle ou aryle, éventuellement reliés entre eux pour former ensemble avec l'atome de bore et les deux atomes d'oxygène un cycle de 5 à 7 chaînons éventuellement substitué par au moins un groupe (C1-C4)alkyle ou auquel éventuellement est accolé sur deux atomes de carbone consécutifs dudit cycle un groupe phényle. Par exemple, on peut utiliser l'un des groupes suivants :K and K 'represent a hydrogen atom, an alkyl or aryl group, optionally linked together to form together with the boron atom and the two oxygen atoms a 5- to 7-membered ring optionally substituted by at least one (C 1 -C 4 ) alkyl group or to which is optionally attached to two consecutive carbon atoms of said ring a phenyl group. For example, one of the following groups can be used:
Schéma 2 Figure 2
Selon le Schéma 2, on réalise un couplage de Suzuki (voir plus haut) entre Pi et P3 pour obtenir P4, puis on fait réagir P4 avec P5 en présence d'un agent permettant d'introduire le motif "C=O" (par exemple le phosgène, le triphosgène ou le carbonate de N, N'- disuccinimidyle DSC). La réaction permettant d'introduire "C=O" est conduite de préférence en présence d'une base telle que par exemple la triéthylamine et à une température comprise entre -5°C et la température ambiante. Le solvant peut être le THF. Voir ex.1.4.According to Scheme 2, a Suzuki coupling (see above) is carried out between Pi and P 3 in order to obtain P 4 , then P 4 is reacted with P 5 in the presence of an agent making it possible to introduce the "C = O "(for example phosgene, triphosgene or N, N'-disuccinimidyl carbonate DSC). The reaction to introduce "C = O" is preferably carried out in the presence of a base such as for example triethylamine and at a temperature between -5 ° C and room temperature. The solvent may be THF. See ex.1.4.
Schéma 3Figure 3
Selon le Schéma 3, on obtient le composé de formule (I) par une réaction d'amidification à partir de P6 et de l'aminé R2NH2 ou d'un sel de cette aminé, par exemple le chlorhydrate (voir ex.3.2). L'amidification peut être conduite avantageusement en présence d'un activateur d'acide (aussi appelé « coupling agent ») comme par exemple le benzotriazol-1- yloxytris(dimethylamino)-phosphonium hexafluorophosphate (ou BOP, CAS N°56602-33-6, voir aussi B.Castro., Dormoy, J. R. Tetrahedron Letter 1975, 16, 1219). La réaction est conduite de préférence en présence d'une base (telle que la triéthylamine) à température ambiante, dans un solvant tel que le tétrahydrofurane (THF) ou le diméthylformamide (DMF).According to Scheme 3, the compound of formula (I) is obtained by an amidification reaction starting from P 6 and the amine R 2 NH 2 or a salt of this amine, for example the hydrochloride (see ex .3.2). The amidification can be carried out advantageously in the presence of an activator of acid (also called "coupling agent") such as benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33-6, see also B.Castro., Dormoy, JR Tetrahedron Letter 1975, 16, 1219). The reaction is preferably carried out in the presence of a base (such as triethylamine) at room temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).
Pβ est obtenu quant à lui par une réaction de couplage de type Suzuki entre P2 et le composé Ps de formule :Pβ is obtained by a Suzuki coupling reaction between P 2 and the compound Ps of formula:
selon un schéma similaire au Schéma 1. according to a scheme similar to Figure 1.
préparation de P1 preparation of P 1
Ps est obtenu à partir de l'acide P7 par monosubstitution par une aminé de formule R1R'1NH. Dans le cas d'une aminé aliphatique, la réaction peut être conduite à température ambiante et dans un solvant protique tel qu'un alcool ou de l'eau ou dans un solvant aprotique tel que lePs is obtained from P 7 acid by monosubstitution with an amine of formula R 1 R ' 1 NH. In the case of an aliphatic amine, the reaction may be carried out at ambient temperature and in a protic solvent such as an alcohol or water or in an aprotic solvent such as
THF. Dans le cas d'une aniline, on ajoute une base forte telle que par exemple le LiHMDSTHF. In the case of aniline, a strong base such as for example LiHMDS is added
(((CH3)3Si)2NLi) et la réaction est conduite à chaud. La monosubstitution est décrite en pages(((CH 3 ) 3 Si) 2 NLi) and the reaction is conducted under heat. Monosubstitution is described in pages
14-15 de FR 2917412 dans le cas où Z=N et Z'=CH mais peut s'appliquer à d'autres Z/Z'. Voir aussi ex.1 .1.14-15 of FR 2917412 in the case where Z = N and Z '= CH but can be applied to other Z / Z'. See also ex.1 .1.
Z=N, Z'=CH : P7 est un acide 2,6-dihalogénonicotinique, par exemple l'acide 2,6- dichloronicotinique qui est commercial (voir ex. 1.1 ) ;Z = N, Z '= CH: P 7 is a 2,6-dihalogenonicotinic acid, for example 2,6-dichloronicotinic acid which is commercially available (see example 1.1);
Z=N, Z'=N : P7 est un acide 2,4-dihalogéno-pyrimidine carboxylique, par exemple l'acide 2,4-dichloro-pyrimidine carboxylique qui est commercial (CAS N°37131-89-8) ; Z=CH, Z'=CH : P7 est un acide 2,4-dihalogéno-benzoïque, par exemple l'acide 2,4- dichloro-benzoïque qui est commercial (CAS N°50-84-0).Z = N, Z '= N: P 7 is a 2,4-dihalogenopyrimidine carboxylic acid, for example 2,4-dichloropyrimidine carboxylic acid which is commercial (CAS No. 37131-89-8); Z = CH, Z '= CH: P 7 is a 2,4-dihalo-benzoic acid, for example 2,4-dichlorobenzoic acid which is commercial (CAS No. 50-84-0).
Dans le cas où Z et Z' représentent tous les deux N et HaI représente un atome de chlore, Ps peut aussi être obtenu à partir du composé commercial 5-pyrimidinecarboxylic acid, 2,4- dichloro-, ethyl ester :In the case where Z and Z 'are both N and HaI represents a chlorine atom, Ps can also be obtained from the commercial compound 5-pyrimidinecarboxylic acid, 2,4- dichloro-, ethyl ester:
Le Schéma 5 utilisant une fonction ester transformée ensuite en fonction acide s'applique aussi au cas où Z=N et Z'=CH : voir les conditions dans Chem.Pharm.Bull. 2000, 48(12), 1847-1853 (réactions des tableaux 1 et 2).Scheme 5 using an ester function subsequently converted to an acidic function also applies to the case where Z = N and Z '= CH: see the conditions in Chem.Pharm.Bull. 2000, 48 (12), 1847-1853 (reactions of Tables 1 and 2).
Pi est obtenu à partir de l'acide Ps par amidification utilisant l'aminé R2NH2 ou un sel de cet aminé, par exemple le chlorhydrate. L'amidification peut être conduite avantageusement en présence d'un activateur d'acide (aussi appelé « coupling agent ») comme par exemple le benzotriazol-1-yloxytris(diméthylamino)-phosphonium hexafluorophosphate (ou BOP, CAS N°56602-33-6, voir aussi Castro, B., Dormoy, J. R. Tetrahedron Letter 1975, 16, 1219). La réaction est conduite de préférence en présence d'une base (telle que la triéthylamine) à température ambiante, dans un solvant tel que le tétrahydrofurane (THF) ou le diméthylformamide (DMF). Voir ex.1 .2.Pi is obtained from Ps acid by amidification using the amine R 2 NH 2 or a salt of this amine, for example the hydrochloride. Amidification can advantageously be carried out in the presence of an acid activator (also called "coupling agent") such as for example benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33- 6, see also Castro, B., Dormoy, JR Tetrahedron Letter 1975, 16, 1219). The reaction is preferably carried out in the presence of a base (such as triethylamine) at room temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF). See ex.1 .2.
préparation de P3 preparation of P 3
Les composés P3 pour lesquels K et K' forment le groupe suivant : sont commerciaux ou peuvent être préparés selon la réaction de couplage entre une bromo-aniline fluorée et le bis(pinacolato)diboron qui est décrite sur le schéma 2 en page 150-151 de WOCompounds P 3 for which K and K 'form the following group: are commercially available or can be prepared according to the coupling reaction between a fluorinated bromo-aniline and the bis (pinacolato) diboron which is described in Scheme 2 on page 150-151 of WO
2007/064931 : 3-F (4-amino-3-fluorophénylboronic acid pinacol ester, CAS N°819058-34-9, société Boron Molecular Inc, PO Box 12592, Research Triangle Park, NC 27709) ; 2-F (4- amino-2-fluorophénylboronic acid pinacol ester, CAS N°819057-45-9, Boron Molecular, décrit en page 185 de WO 2007/064931 ) ; 2-F, 5-F (CAS N°939807-75-7, composé décrit en page 184 de WO 2007/064931 ) ; 3-F, 5-F (CAS N°939968-08-8, décrit en page 182 de WO2007/064931: 3-F (4-amino-3-fluorophenylboronic acid pinacol ester, CAS No. 819058-34-9, Boron Molecular Inc., PO Box 12592, Research Triangle Park, NC 27709); 2-F (4-amino-2-fluorophenylboronic acid pinacol ester, CAS No. 819057-45-9, Boron Molecular, described on page 185 of WO 2007/064931); 2-F, 5-F (CAS No. 939807-75-7, compound described on page 184 of WO 2007/064931); 3-F, 5-F (CAS No. 939968-08-8, described on page 182 of WO
2007/064931 ).2007/064931).
Les composés P3 pour lesquels K et K' représentent un atome d'hydrogène peuvent être préparés à partir de la bromo-aniline fluorée par les réactions décrites dans Tetrahedron Letters 2003, 44, 7719-7722. préparation de P2Compounds P 3 for which K and K 'represent a hydrogen atom may be prepared from fluorinated bromoaniline by the reactions described in Tetrahedron Letters 2003, 44, 7719-7722. P2 preparation
Les composés P2 sont obtenus à partir des composés P3 et P5 en présence d'un agent permettant d'introduire le motif "C=O", selon une réaction telle que décrite précédemment.The compounds P 2 are obtained from the compounds P 3 and P 5 in the presence of an agent for introducing the "C = O" unit, according to a reaction as described above.
composés R2NH2 R 2 NH 2 compounds
Les aminés R2NH2 sont des produits commerciaux ou déjà décrits dans des documents publiés ; par exemple :Amines R 2 NH 2 are commercial products or already described in published documents; for example :
• 1-(2-aminoéthyl)pipéridine : CAS N°27578-60-5, décrit dans Justus Liebigs Annalen der Chemie 1950, 566, 210-44, commercialisé par ACROS ;1- (2-aminoethyl) piperidine: CAS No. 27578-60-5, described in Justus Liebigs Annalen der Chemie 1950, 566, 210-44, marketed by ACROS;
• 1-Pipéridinepropanamine : CAS N° 3529-08-6, décrit dans Bioorganic & Med. Chem.Lett. 2006, 16(7), 1938-1940 ;1-Piperidinepropanamine: CAS No. 3529-08-6, described in Bioorganic & Med. Chem.Lett. 2006, 16 (7), 1938-1940;
• 1-pipéridinebutanamine : CAS N°74247-30-6, décrit dans Bioorganic & Med. Chem.Lett. 2006, 16(7), 1938-1940 ; « 4-pipéridinol, 1-(2-aminoéthyl)- : CAS N°129999-60-6, décrit dans J.Med.Chem. 2005, 48(21 ), 6690-6695 ainsi qu'en page 17 de WO 2005/061453 (ref.ex.10) ;1-Piperidinebutanamine: CAS No. 74247-30-6, described in Bioorganic & Med. Chem.Lett. 2006, 16 (7), 1938-1940; "4-Piperidinol, 1- (2-aminoethyl) - CAS No. 129999-60-6, described in J.Med.Chem. 2005, 48 (21), 6690-6695 and on page 17 of WO 2005/061453 (ref.ex.10);
• 3-pipéridinol, 1-(2-aminoéthyl)- : CAS N°847499-95-0, décrit dans J.Med.Chem. 2005, 48(21 ), 6690-6695 ainsi qu'en page 16 de WO 2005/061453 (ref.ex.8) ;3-piperidinol, 1- (2-aminoethyl) - CAS No. 847499-95-0, described in J.Med.Chem. 2005, 48 (21), 6690-6695 and on page 16 of WO 2005/061453 (ref.ex.8);
• 2-(4-méthoxy-1-pipéridinyl)éthylamine : CAS N°91 1300-69-1 , décrit dans J.Med.Chem. 2007, 50(20), 4818-4831 ;2- (4-methoxy-1-piperidinyl) ethylamine: CAS No. 91 1300-69-1, described in J.Med.Chem. 2007, 50 (20), 4818-4831;
• pyrrolidineéthanamine : CAS N°7154-73-6, décrit dans Anales de Quimica 1974, 70(9-10), 733-737, commercialisé par International Laboratory Ltd, 1067 Sneath Ln, San Bruno, CA94066, USA ;Pyrrolidineethanamine: CAS No. 7154-73-6, described in Anales de Quimica 1974, 70 (9-10), 733-737, sold by International Laboratory Ltd, 1067 Sneath Ln, San Bruno, CA94066, USA;
• 1-pipérazineéthanamine : CAS N°140-31-8, décrit dans EP 151232 ; • azépan-1-yléthylamine : CAS N°51388-00-2, décrit dans Anales de Quimica 1974, 70(9-10), 733-737 ;1-piperazineethanamine: CAS No. 140-31-8, described in EP 151232; • azepan-1-ylethylamine: CAS No. 51388-00-2, described in Anales de Quimica 1974, 70 (9-10), 733-737;
• 2-(1 ,1-dioxothiomorpholin-4-yl)éthylamine : CAS N°89937-52-0, commercialisé par Intern. Lab. Ltd ;2- (1,1-dioxothiomorpholin-4-yl) ethylamine: CAS No. 89937-52-0, sold by Intern. Lab. Ltd;
• N-(2-aminoéthyl)thiamorpholine-1-oxide : CAS N°1017791-77-3, commercialisé par Sinova Inc. 3 Bethesda Métro Center, Suite 700, Bethesda, MD, 20814, USA.• N- (2-aminoethyl) thiamorpholin-1-oxide: CAS No. 1017791-77-3, sold by Sinova Inc. 3 Bethesda Metro Center, Suite 700, Bethesda, MD, 20814, USA.
Une méthode d'obtention des composés pour lesquels R2 représente un groupe (C1 -C6)alkyle substitué par le groupe -NRaRb dans lequel R3 et Rb forment ensemble avec l'atome d'azote auquel ils sont reliés le groupe (C4-C6)hétérocycloalkyle comprenant éventuellement dans le cycle le groupe -S(O)q avec q= 0, 1 ou 2 ou le groupe -NH- ou -N(C1-C4)alkyle est décrite sur le Schéma 6 qui s'inspire du schéma 3 de Bioorg. Med. Chem. 2007, 15, 365-373 ou du schéma 2 de Bioorg. Med. Chem. Lett. 2008, 18, 1378-1381 :A method for obtaining compounds for which R 2 represents a (C 1 -C 6 ) alkyl group substituted by the group -NR a R b in which R 3 and R b together with the nitrogen atom to which they are heterocycloalkyl (C 4 -C 6 ) group optionally comprising in the ring the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (C 1 -C 4 ) alkyl is described on Figure 6 which is inspired by scheme 3 of Bioorg. Med. Chem. 2007, 15, 365-373 or diagram 2 of Bioorg. Med. Chem. Lett. 2008, 18, 1378-1381:
Une autre méthode décrite sur le Schéma 6' s'inspire de la figure 2 de Bioorg. Med. Chem. Lett. 2006, 16, 1938-1940 :Another method described in Figure 6 'is based on Figure 2 of Bioorg. Med. Chem. Lett. 2006, 16, 1938-1940:
composés Pscompounds Ps
P5 peut être soit commercial soit préparé selon les méthodes connues de l'homme de l'art. On peut par exemple utiliser l'hydrogénation du composé cyano pour obtenir P5 avec n=1 :P 5 can be either commercial or prepared according to methods known to those skilled in the art. For example, the hydrogenation of the cyano compound can be used to obtain P 5 with n = 1:
Les conditions d'hydrogénation peuvent être celles décrites dans les ex.19 et 20 de WO 00/46179 ou dans Synlett 2001 , 10, 1623-1625.The hydrogenation conditions may be those described in ex.19 and 20 of WO 00/46179 or in Synlett 2001, 10, 1623-1625.
Les composés 3-picolylamine (CAS N°3731-52-0), 3-(2-aminoéthyl)pyridine (CAS N°20173- 24-4), 2-amino-5-aminométhylpyridine (CAS N° 156973-09-0), 2-méthyl-5- aminométhylpyridine (CAS N°56622-54-9), 3-méthyl-5-aminométhylpyridine (CAS N°771574- 45-9), 2-(BOC-amino)-5-aminométhyl-pyridine (CAS N°187237-37-2), 2,5-diaminopyridine (CAS N°4318-76-7) sont des produits commerciaux. Le 2-amino-5-aminométhylpyridine peut aussi être préparé selon EP 0607804. Le 5-aminométhyl-2-(diméthylamino)pyridine (CAS N°354824-17-2) est commercial ou peut être préparé selon J.Agr.Food Chem. 2008, 56(1 ), 204-212. Le 2-amino-3-méthyl-5-aminométhylpyridine (CAS N°187163-76-4) peut être obtenu par hydrogénation catalytique du composé 6-amino-5-méthyl-nicotinonitrile (CAS N°183428- 91-3), la fonction aminé étant doublement protégée par le BOC. L'hydrogénation catalytique du 6-méthylamino-3-pyridinecarbonitrile (CAS N°261715-36-0) permet d'accéder au 2- méthylamino-5-aminométhylpyridine.The compounds 3-picolylamine (CAS No. 3731-52-0), 3- (2-aminoethyl) pyridine (CAS No. 20173-24-4), 2-amino-5-aminomethylpyridine (CAS No. 156973-09- 0), 2-methyl-5-aminomethylpyridine (CAS No. 56622-54-9), 3-methyl-5-aminomethylpyridine (CAS No. 771574-45-9), 2- (BOC-amino) -5-aminomethyl -pyridine (CAS No. 187237-37-2), 2,5-diaminopyridine (CAS No. 4318-76-7) are commercial products. 2-amino-5-aminomethylpyridine can also be prepared according to EP 0607804. 5-Aminomethyl-2- (dimethylamino) pyridine (CAS No. 354824-17-2) is commercially available or can be prepared according to J.Agr.Food Chem . 2008, 56 (1), 204-212. 2-Amino-3-methyl-5-aminomethylpyridine (CAS No. 187163-76-4) can be obtained by catalytic hydrogenation of the 6-amino-5-methyl-nicotinonitrile compound (CAS No. 183428-91-3), the amino function being doubly protected by the BOC. Catalytic hydrogenation 6-methylamino-3-pyridinecarbonitrile (CAS No. 261715-36-0) provides access to 2-methylamino-5-aminomethylpyridine.
La préparation du 5-aminométhyl-2-(diméthylamino)pyridine (CAS N°779324-37-7) et du 5- aminométhyl-2-(diméthylamino)pyridine (CAS N°354824-17-2) sous forme de chlorhydrate est également décrite en page 106 de WO 2007/044449 (ex. 207 et 208).The preparation of 5-aminomethyl-2- (dimethylamino) pyridine (CAS No. 779324-37-7) and 5-aminomethyl-2- (dimethylamino) pyridine (CAS No. 354824-17-2) in the form of hydrochloride is also described on page 106 of WO 2007/044449 (eg 207 and 208).
Préparation des composés de formule (I) pour lesquels L = -CH=CH- Ces composés sont obtenus par une réaction d'amidification entre P4 et l'acide P10 ou l'halogénure d'acyle P'10, dérivé de P10. L'amidification utilisant P10 peut être réalisée avantageusement en présence d'un activateur d'acide comme par exemple le BOP.Preparation of compounds of formula (I) for which L = -CH = CH- These compounds are obtained by an amidification reaction between P 4 and the acid P 10 or the acyl halide P '10 , derived from P 10 . The amidation using P 10 can be carried out advantageously in the presence of an acid activator such as BOP.
P10 peut être soit commercial soit préparé selon les méthodes connues de l'homme de l'art. Par exemple, l'acide trans-3-(3-pyridyl)acrylique est commercialisé par Sigma-AIdrich. Le (6- aminopyridin-3-yl)acrylic acid (CAS N°234098-57-8 ; composé E : CAS N°167837-43-6) est décrit dans J.Med.Chem. 2002, 45(15), 3246-3256 (voir schéma 4). P10 peut être préparé à partir d'une bromo aniline et de l'acide acrylique selon l'enseignement de J.Med.Chem. 2002, 45(15), 3246-3256. On peut également utiliser un couplage utilisant une bromo aniline et un acrylate d'alkyle, puis saponifier la fonction ester en fonction acide (voir à ce propos, la méthode permettant de préparer le (6-aminopyridin-3-yl)acrylic acid décrite au paragraphe [483] de US 2008269220 ou [354] de EP1726580).P 10 can be either commercial or prepared according to methods known to those skilled in the art. For example, trans-3- (3-pyridyl) acrylic acid is marketed by Sigma-Aldrich. (6-Aminopyridin-3-yl) acrylic acid (CAS No. 234098-57-8, Compound E: CAS No. 167837-43-6) is described in J.Med.Chem. 2002, 45 (15), 3246-3256 (see diagram 4). P 10 can be prepared from bromoaniline and acrylic acid according to the teachings of J.Med.Chem. 2002, 45 (15), 3246-3256. It is also possible to use a coupling using bromoaniline and an alkyl acrylate, and then saponify the ester function in acid function (see, in this connection, the method for preparing the (6-aminopyridin-3-yl) acrylic acid described in US Pat. paragraph [483] of US 2008269220 or [354] of EP1726580).
P10 peut être aussi préparé selon J.Org.Chem. 1998, 63, 8785-8789 à partir de la béta- formylpyridine correspondante ou bien selon J.Med.Chem. 1989, 32(3), 583-93 à partir de la 2-chloro-5-nitro-pyridine. L'halogénure d'acyle P'10 est obtenu par une réaction connue de l'homme de l'art à partir de l'acide P10 et d'un agent acylant tel que par exemple SOCb ou (COCI)2. On peut également préparer ces composés selon le schéma 8 suivant Schéma 8P 10 can also be prepared according to J.Org.Chem. 1998, 63, 8785-8789 from the corresponding beta-formylpyridine or according to J.Med.Chem. 1989, 32 (3), 583-93 from 2-chloro-5-nitro-pyridine. The acyl halide P '10 is obtained by a reaction known to those skilled in the art from the acid P 10 and an acylating agent such as for example SOCb or (COCI) 2 . These compounds can also be prepared according to Scheme 8 according to Scheme 8
Selon le Schéma 8, on fait réagir P4 avec le chlorure d'acryloyle, en présence d'une base telle que par exemple la triéthylamine et à une température comprise entre 0ºC et la température ambiante pour obtenir P11. Le solvant peut être le dichlorométhane (DCM) (voir ex. 4.1 ). According to Scheme 8, P 4 is reacted with acryloyl chloride in the presence of a base such as, for example, triethylamine and at a temperature of between 0 ° C. and room temperature to obtain P 11 . The solvent may be dichloromethane (DCM) (see Example 4.1).
Puis on fait réagir P11 avec P12 (HaI représente un atome d'halogène), en présence d'un complexe de palladium tel que par exemple Pd(OAc)2, de tri-orthotolylphosphine et d'une base telle que par exemple la diisopropyléthylamine. Le solvant peut être par exemple le propionitrile. La température est comprise entre la température ambiante et la température de reflux du solvant.Then P 11 is reacted with P 12 (Hal represents a halogen atom), in the presence of a palladium complex such as for example Pd (OAc) 2 , tri-orthotolylphosphine and a base such as for example diisopropylethylamine. The solvent may be, for example, propionitrile. The temperature is between room temperature and the reflux temperature of the solvent.
Protection de la fonction aminé primaire ou secondaireProtection of the primary or secondary amine function
II peut être nécessaire d'utiliser à au moins une des étapes un groupe protecteur (PG) afin de protéger une ou plusieurs fonction(s) chimique(s), notamment une fonction aminé primaire ou secondaire. Par exemple, lorsque R3 et Rb représentent tous deux un atome d'hydrogène, l'amidification du Schéma 3 est réalisée en utilisant pour R2NH2 le composé 2HN-(Cr CβJalkyle-NH-PG, où PG représente avantageusement le BOC (tert-butoxycarbonyle). De même, lorsque le groupe hétérocycloalkyle formé par R3 et Rb représente le groupe pipérazinyle on peut en protéger avantageusement la fonction -NH- en utilisant It may be necessary to use at least one of the steps a protecting group (PG) to protect one or more chemical function (s), including a primary or secondary amine function. For example, when R 3 and R b both represent a hydrogen atom, the amidification of Scheme 3 is carried out using for R 2 NH 2 the compound 2 HN- (Cr Cβ) alkyl-NH-PG, where PG represents advantageously BOC (tert-butoxycarbonyl). Similarly, when the heterocycloalkyl group formed by R 3 and R b represents the group piperazinyl can advantageously protect the function -NH- using
le composé R2NH2 suivant où PG représente avantageusement le the following compound R 2 NH 2 where PG advantageously represents the
BOC. De même, lorsque R3 représente le groupe -NH2 ou -NHRC, on peut protéger avantageusement la fonction aminé par un ou deux groupe(s) PG, de préférence le BOC ou le FMOC (9-fluorénylméthyl carbamate). On peut par exemple utiliser le composé P5 BOC. Likewise, when R 3 represents the group -NH 2 or -NHR C , the amine function can advantageously be protected by one or two PG group (s), preferably BOC or FMOC (9-fluorenylmethyl carbamate). For example, the compound P 5 can be used
suivansuivan
La/les fonction(s) chimique(s) est/sont ensuite obtenue(s) par une étape de déprotection (finale ou intermédiaire) dont les conditions dépendent de la nature de la/des fonction(s) protégée(s) et de groupe protecteur utilisé. On pourra se reporter à « Protective groups in Organic Synthesis » de T.Greene, Wiley, 4eme éd., isbn = 978-0-471-69754-1 , notamment au chap.7 pour ce qui concerne les groupes protecteurs de la fonction aminé. Dans le cas de la protection des fonctions -NH2 ou -NH- par le BOC, l'étape de déprotection est conduite en milieu acide à l'aide par exemple de HCI ou de l'acide trifluoroacétique (TFA). On obtient ainsi le cas échéant le sel associé (chlorhydrate ou trifluoroacétate).The chemical function (s) is / are then obtained by a deprotection step (final or intermediate) whose conditions depend on the nature of the protected function (s) and protective group used. Reference may be made to "Protective groups in Organic Synthesis" of T.Greene, Wiley, 4 th ed., Isbn = 978-0-471-69754-1, especially for chap.7 regarding protecting groups amine function. In the case of the protection of the -NH 2 or -NH- functions by the BOC, the deprotection step is carried out in acidic medium using, for example, HCl or trifluoroacetic acid (TFA). The corresponding salt (hydrochloride or trifluoroacetate) is thus obtained, if appropriate.
Obtention des selsObtaining salts
Les sels sont obtenus lors de l'étape de déprotection décrite ci-dessus ou bien par mise en contact de l'acide et du composé sous sa forme base.The salts are obtained during the deprotection step described above or by contacting the acid and the compound in its base form.
Dans les Schémas précédents, les composés de départ et les réactifs, quand leur mode de préparation n'est pas décrit, sont disponibles dans le commerce ou décrits dans la littérature, ou bien peuvent être préparés selon des méthodes qui y sont décrites ou qui sont connues de l'homme du métier. L'homme du métier pourra aussi s'inspirer des conditions opératoires données dans les exemples qui sont décrits ci-après.In the above Schemes, the starting compounds and the reagents, when their method of preparation is not described, are commercially available or described in the literature, or they can be prepared according to methods described therein or which are known to those skilled in the art. Those skilled in the art may also be inspired by the operating conditions given in the examples which are described below.
Obtention des N-oxydesObtaining N-oxides
Les N-oxydes des composés comportant une aminé ou un atome d'azote sont préparés selon les méthodes connues de l'homme du métier par réaction de l'aminé avec des péracides organiques tels que les acides peracétiques, trifluoroperacétiques, performiques, perbenzoïques ou ses dérivés tel l'acide 3-chloroperbenzoïque, à des températures comprises entre 0ºC et 90ºC, de préférence à des températures inférieures à 50ºC.The N-oxides of the compounds containing an amine or a nitrogen atom are prepared according to the methods known to those skilled in the art by reaction of the amine with peracids organic such as peracetic, trifluoroperacetic, performic, perbenzoic acids or its derivatives such as 3-chloroperbenzoic acid, at temperatures between 0ºC and 90ºC, preferably at temperatures below 50ºC.
Selon un 3ème aspect, l'invention concerne une composition pharmaceutique comprenant un composé tel que défini précédemment en combinaison avec un excipient pharmaceutiquement acceptable. L'excipient est choisi parmi les excipients habituels connus de l'homme du métier selon la forme pharmaceutique et le mode d'administration souhaité. Le mode d'administration peut être par exemple par voie orale ou par intraveineuse.According to a 3rd aspect, the invention relates to a pharmaceutical composition comprising a compound as defined above in combination with a pharmaceutically acceptable excipient. The excipient is selected from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired mode of administration. The mode of administration can be, for example, orally or intravenously.
Selon un aspect, l'invention a pour objet un médicament qui comprend un composé tel que défini précédemment ainsi que l'utilisation d'un composé tel que défini précédemment, pour la fabrication d'un médicament. Il peut être utile pour traiter un état pathologique, en particulier le cancer. Le médicament (ainsi qu'un composé selon l'invention) peut être administré en association avec un (ou plusieurs) anticancéreux. Ce traitement peut être administré simultanément, séparément ou bien séquentiellement. Le traitement sera adapté par le praticien en fonction du malade et de la tumeur à traiter.According to one aspect, the subject of the invention is a medicinal product which comprises a compound as defined above as well as the use of a compound as defined above, for the manufacture of a medicament. It can be useful for treating a pathological condition, especially cancer. The drug (as well as a compound according to the invention) may be administered in combination with one (or more) anticancer drugs. This treatment can be administered simultaneously, separately or sequentially. The treatment will be adapted by the practitioner according to the patient and the tumor to be treated.
Selon un 5ème aspect, l'invention concerne également une méthode de traitement des pathologies indiquées précédemment qui comprend l'administration, à un patient, d'une dose efficace d'un composé selon l'invention ou un de ses sels pharmaceutiquement acceptables ou hydrates ou solvats.According to a 5th aspect, the invention also relates to a method of treatment of pathologies indicated above which comprises administering to a patient an effective dose of a compound of the invention or a pharmaceutically acceptable salt or hydrates or solvates.
[Exemples][Examples]
Les exemples suivants illustrent la préparation de certains composés conformes à l'invention. Les numéros des composés exemplifiés renvoient à ceux donnés dans le tableau ci-après, qui illustre les structures chimiques et les propriétés physiques de quelques composés selon l'invention.The following examples illustrate the preparation of certain compounds according to the invention. The numbers of the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.
Dans les exemples on utilise les abréviations suivantes : AcOEt : acétate d'éthyle MeOH : méthanol DIPEA : diisopropyléthylamineIn the examples, the following abbreviations are used: AcOEt: ethyl acetate MeOH: methanol DIPEA: diisopropylethylamine
Les composés ont été analysés par couplage HPLC-UV-MS (chromatographie liquide, détection d'ultraviolet (UV) et détection de masse). L'appareil utilisé est composé d'une chaine chromatographique Agilent équipé d'un détecteur à barrette de diodes Agilent et d'un spectromètre de masse simple quadripôle ZQ Waters ou un spectromètre de masse triple quadripôle Quattro- Micro Waters.The compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection). The apparatus used is composed of a Agilent chromatographic system equipped with an Agilent diode array detector and a ZQ Waters single quadrupole mass spectrometer or a Quattro-Micro Waters triple quadrupole mass spectrometer.
Les composés ont été analysés par couplage HPLC-UV-MS (chromatographie liquide, détection d'ultraviolet (UV) et détection de masse). L'appareil utilisé est composé d'une chaine chromatographique équipée d'un détecteur à barrette de diodes (HP1 1 10 Agilent ou UPLC Acquity Waters) et d'un spectromètre de masse quadripôlaire (ZQ, QM ou SQD Waters).The compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection). The apparatus used is composed of a chromatographic chain equipped with a diode array detector (HP1 1 10 Agilent or UPLC Acquity Waters) and a quadrupole mass spectrometer (ZQ, QM or SQD Waters).
conditions de spectrométrie de massemass spectrometry conditions
Les spectres de chromatographie phase liquide/spectromètre de masse (LC/MS) ont été enregistrés en mode électrospray (ESI) positif, afin d'observer les ions issus de la protonation de composés analysés (MH+) ou de la formation d'adduits avec d'autres cations tels que Na+, K+, etc .. Les conditions de HPLC sont choisies parmi l'une des méthodes suivantes :The liquid chromatography / mass spectrometry (LC / MS) spectra were recorded in electrospray (ESI) positive mode, in order to observe the ions resulting from the protonation of analyzed compounds (MH + ) or the formation of adducts with other cations such as Na + , K + , etc. The HPLC conditions are selected from one of the following methods:
Conditions de RMNNMR conditions
Les spectres 1H RMN sont enregistrés sur un spectromètre Bruker Avance 250 / Bruker Avance 400 ou Bruker Avance II 500. Le pic central du DMSL-d6 (2,50 ppm) est utilisé comme référence interne. Les abréviations suivantes sont utilisées : s : singulet ; d : doublet ; dd : doublet dédoublé ; t : triplet ; q : quadruplet ; m : massif/multiplet ; br.s : signal large. Exemple 1 : 6-{4-[3-(6-amino-pyridin-3-ylméthyl)-ureido]-3-fluoro-phényl}-2-éthylamino- N-(2-pipéridin-1-yl-éthyl)-nicotinamide (composé n°1 préparé selon le Schéma 2) 1 H NMR spectra are recorded on a Bruker Avance 250 / Bruker Avance 400 or Bruker Avance II 500 spectrometer. The central peak of DMSL-d6 (2.50 ppm) is used as an internal reference. The following abbreviations are used: s: singlet; d: doublet; dd: double doublet; t: triplet; q: quadruplet; m: massive / multiplet; br.s: wide signal. Example 1: 6- {4- [3- (6-amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) Nicotinamide (Compound No. 1 prepared according to Scheme 2)
1.1. acide 6-chloro-2-éthylamino-nicotiniαue 1.1. 6-chloro-2-ethylamino-nicotini acid
Dans un ballon, mélanger 26,1 g (0,136 M) d'acide 2,6-dichloro-nicotinique et 180 ml_ de solution aqueuse d'éthylamine à 70%. Agiter à température ambiante (TA) pendant 5 jours. Evaporer sous pression réduite (PR). Reprendre le résidu par 100 ml_ d'eau. Refroidir par un bain de glace et acidifier à pH 3 avec une solution HCI 5N. Filtrer le précipité, laver avec de l'eau froide et sécher sous vide sur P2O5 à 60ºC. On obtient 24,93 g (91 ,4%) de solide blanc. PF=157-159°C.In a flask, mix 26.1 g (0.136 M) of 2,6-dichloro-nicotinic acid and 180 ml of 70% aqueous ethylamine solution. Stir at room temperature (RT) for 5 days. Evaporate under reduced pressure (PR). Take up the residue with 100 ml of water. Cool with an ice bath and acidify to pH 3 with 5N HCl solution. Filter the precipitate, wash with cold water and dry under vacuum over P 2 O 5 at 60ºC. 24.93 g (91.4%) of white solid are obtained. Mp = 157-159 ° C.
1.2. 6-chloro-2-éthylamino-N-(2-pipéridin-1-yl-éthyl)-nicotinamide1.2. 6-chloro-2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
Dans un ballon, dissoudre 5,0 g (24,92 mM) d'acide 6-chloro-2-éthylamino-nicotinique dans 300 ml_ de THF. Ajouter 10,41 ml_ (74,77 mM) de triéthylamine, puis 7,08 ml_ (49,84 mM) deIn a flask, dissolve 5.0 g (24.92 mM) of 6-chloro-2-ethylamino-nicotinic acid in 300 ml of THF. Add 10.41 ml (74.77 mM) of triethylamine and then 7.08 ml (49.84 mM) of
1-(2-aminoéthyl)pipéridine et ensuite 11 ,02 g (24,92 mM) de BOP. Agiter à TA durant 15 h.1- (2-aminoethyl) piperidine and then 11.02 g (24.92 mM) BOP. Stir at RT for 15 h.
Evaporer le solvant et reprendre le résidu par de l'acétate d'éthyle. Laver la phase organique avec de l'eau puis une solution saturée en NaCI. Sécher sur Na2SO4, filtrer et évaporer. Le résidu est purifié par flah chromatographie (gradient DCM-MeOH 1 à 10%). On obtient 7,5 g (rdt : 96,8%) LCMS : M+ 310, tr (temps de rétention)=1 ,01 min.Evaporate the solvent and take up the residue with ethyl acetate. Wash the organic phase with water and saturated NaCl solution. Dry on Na 2 SO 4 , filter and evaporate. The residue is purified by flah chromatography (gradient DCM-MeOH 1 to 10%). 7.5 g (yield: 96.8%) LCMS: M + 310, tr (retention time) = 1.01 min.
1.3. 6-(4-amino-3-fluoro-phényl)-2-éthylamino-N-(2-pipéridin-1-yl-ethyl)-nicotinamide1.3. 6- (4-amino-3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
Dans un tricol d'1 litre, introduire 5 g (16,1 mmol) de 6-chloro-2-éthylamino-N-(2-pipéridin-1- yl-ethyl)-nicotinamide. Ajouter le 4-amino-3-fluorophénylboronic acid pinacol ester (1 ,1 éq, 4,2 g), 300 ml de 1 ,2-diméthoxyéthane, 60 ml d'éthanol et 120 ml d'une solution de NaHCO3 saturée. Faire buller de l'argon 15 min, puis ajouter le palladium tétrakis Pd(PPh)4 (0,1 éq, 1 ,86 g). Chauffer à reflux (~100°C) pendant 16 h. Concentrer, reprendre dans du DCM, laver avec H2O 2 fois, H2O/NaCI, sécher sur sulfate de sodium et concentrer. Chromatographie flash sur colonne de silice 400 g, gradient DCM/méthanol 99/1 jusqu'à 90/10. On obtient 4,8 g (rdt=78%) de 6-(4-amino-3-fluoro-phényl)-2-éthylamino-N-(2-pipéridin-1-yl-éthyl)- nicotinamide. LCMS(TFA3) : MH+ 386, tr=0,90 min.In a 1-liter tricolor, add 5 g (16.1 mmol) of 6-chloro-2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide. Add 4-amino-3-fluorophenylboronic acid pinacol ester (1.1 eq, 4.2 g), 300 ml of 1,2-dimethoxyethane, 60 ml of ethanol and 120 ml of saturated NaHCO 3 solution. Incubate argon for 15 min, then add palladium tetrakis Pd (PPh) 4 (0.1 eq, 1.86 g). Heat to reflux (~ 100 ° C) for 16 hours. Concentrate, continue in DCM, wash with H 2 O 2 times, H 2 O / NaCl, dry over sodium sulfate and concentrate. Flash column chromatography on silica 400 g, gradient DCM / methanol 99/1 up to 90/10. We obtain 4.8 6- (4-Amino-3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide g (rdt = 78%). LCMS (TFA3): MH + 386, tr = 0.90 min.
1.4. 6-{4-r3-(6-amino-pyridin-3-ylméthyl)-uréido1-3-fluoro-phényl>-2-éthylamino-N-(2- pipéridin-1-yl-éthyl)-nicotinamide1.4. 6- {4- (3- (6-amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl-2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
Dans 1 ballon de 1 litre, dissoudre 3,5 g (9,1 mmol) de 6-(4-amino-3-fluoro-phényl)-2- éthylamino-N-(2-pipéridin-1-yl-éthyl)-nicotinamide dans 300 ml de THF anhydre. Ajouter la DMAP (1 ,2 éq, 1 ,33 g) ainsi que le N,N'-disuccinimidyl carbonate ([74124-79-1], 1 ,2 éq, 2,8 g). Agiter à TA pendant 5 h. Ajouter alors la triéthylamine (3 éq, 3,8 ml) et la 2-(di-boc- amino)-5-(aminométhyl)pyridine (1 ,2 éq, 3,53 g) et agiter à TA une nuit. Concentrer. Reprendre avec du DCM, laver avec H2O 2 fois, H2O/NaCI, sécher et concentrer. Chromatographie Flash sur silice, gradient DCM/MeOH 95/5 jusqu'à 79/20 + 1 % NH4OH 20%. Après concentration, reprendre la fraction ainsi obtenue dans 200 ml de DCM, puis ajouter à froid 35 mL (50 éq) de TFA. Agitation à TA jusqu'à disparition du produit « di-boc- amino ». Concentrer, puis reprendre le résidu avec une solution de Na2COs 10%. Extraire la phase organique avec DCM, concentrer. Cristallisation à chaud dans l'acétate d'éthyle. Filtrer, rincer avec AcOEt, sécher à l'étuve. On obtient 3 g (rdt=63%) de 6-{4-[3-(6-amino-pyridin-3- ylméthyl)-uréido]-3-fluoro-phényl}-2-éthylamino-N-(2-pipéridin-1-yl-éthyl)-nicotinamide. LCMS(TFA3) : MH+ 535, tr=0,79 min ; 1H RMN (250 MHz, DMSO-d6) δ ppm 1 ,22 (t, 3 H), 1 ,29 - 1 ,68 (m, 6 H), 2,26 - 2,47 (m, 6 H), 3,28 -3,42 (m, 2 H), 3,43 - 3,62 (m, 2 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,97 (t, 1 H), 7,16 (d, 1 H), 7,35 (dd, 1 H), 7,79 - 8,07 (m, 4 H), 8,28 (t, 1 H), 8,33 - 8,46 (m, 2 H), 8,49 (s, 1 H). PF (point de fusion) = 175-177°C.In 1 liter flask, dissolve 3.5 g (9.1 mmol) of 6- (4-amino-3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) nicotinamide in 300 ml of anhydrous THF. Add DMAP (1, 2 eq, 1, 33 g) and N, N'-disuccinimidyl carbonate ([74124-79-1], 1.2 eq, 2.8 g). Stir at RT for 5 h. Then add triethylamine (3 eq, 3.8 ml) and 2- (di-Boc-amino) -5- (aminomethyl) pyridine (1.2 eq, 3.53 g) and stir at RT overnight. Focus. Resume with DCM, wash with H 2 O 2 times, H 2 O / NaCl, dry and concentrate. Flash chromatography on silica, gradient DCM / MeOH 95/5 up to 79/20 + 1% NH 4 OH 20%. After concentration, take up the fraction thus obtained in 200 ml of DCM, then add cold 35 ml (50 eq) of TFA. Stirring at RT until disappearance of the product "di-Boc-amino". Concentrate and then take up the residue with 10% Na 2 CO 2 solution. Extract the organic phase with DCM, concentrate. Hot crystallization in ethyl acetate. Filter, rinse with AcOEt, dry in an oven. 3 g (yield = 63%) of 6- {4- [3- (6-amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- piperidin-1-yl-ethyl) -nicotinamide. LCMS (TFA3): MH + 535, tr = 0.79 min; 1 H NMR (250 MHz, DMSO-d6) δ ppm 1, 22 (t, 3H), 1.29 - 1.68 (m, 6H), 2.26 - 2.47 (m, 6H) , 3.28 -3.42 (m, 2H), 3.43 - 3.62 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6. , 44 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.79 - 8.07 (m, 4 H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.49 (s, 1H). PF (melting point) = 175-177 ° C.
Exemple 2 : 6-{4-r3-(6-Amino-pyridin-3-ylmethyl)-ureido1-3-fluoro-phenyl>-2-ethylamino- N-(2-hvdroxy-ethyl)-nicotinamide (composé n°8 préparé selon le Schéma 1) 2.1. 6-chloro-2-(éthylamino)-N-(2-hvdroxyéthyl)nicotinamideExample 2 6- {4-r3- (6-aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl-2-ethylamino-N- (2-hydroxyethyl) -nicotinamide (Compound No. 8 prepared according to Scheme 1) 2.1. 6-Chloro-2- (ethylamino) -N- (2-hvdroxyéthyl) nicotinamide
Dissoudre 0,5 g (2,49 mM) d'acide 6-chloro-2-(éthylamino)nicotinique dans 30 mL de THF. Ajouter 1 ,04 mL (0,76 mM) de triéthylamine, 0,304 g (4,98 mM) de 2-hydroxyéthylamine et 1 ,10 g (2,49 mM) de BOP. Agiter 70 h à TA. Evaporer le solvant et reprendre le résidu par de l'acétate d'éthyle ; laver avec de l'eau puis une solution saturée en NaCI. Sécher sur Na2SU4, filtrer et évaporer. Purifier par chromatoflash (DCM/MeOH 1-5%). On obtient 600 mg (rdt=99%) LCMS(TFA3) : MH+ 244, tr=1 ,03 min. 5Dissolve 0.5 g (2.49 mM) of 6-chloro-2- (ethylamino) nicotinic acid in 30 mL of THF. Add 1.04 mL (0.76 mM) of triethylamine, 0.304 g (4.98 mM) of 2-hydroxyethylamine and 1.10 g (2.49 mM) BOP. Stir 70 hours at RT. Evaporate the solvent and take up the residue with ethyl acetate; wash with water and saturated NaCl solution. Dry over Na 2 SU 4 , filter and evaporate. Purify by chromatoflash (DCM / MeOH 1-5%). 600 mg (yield = 99%) LCMS (TFA3): MH + 244, tr = 1.03 min. 5
2.2. di-tert-butyl {5-r({r2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyllcarbamoyl}amino)méthyllpyridin-2-yl}imidodicarbonate2.2. di-tert-butyl {5 - ((2 R) -fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamoyl} amino) methyl-pyridin-2-yl} imidodicarbonate
Dissoudre 5,0 g (21 ,09 mM) de 2-fluoro-4-(4,4,5,5-tétraméthyl-1 ,3,2-dioxaborolan-2-yl)aniline0 et 3,09 g (25,31 mM) de DMAP (4-diméthylaminopyridine) dans 500 ml_ de THF. Ajouter 6,48 g (23,31 mM) de DSC et agiter à TA 18 h. Ajouter 8,81 ml_ (63,27 mM) de triéthylamine etDissolve 5.0 g (21.0 mM) of 2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline and 3.09 g (25, 31mM) of DMAP (4-dimethylaminopyridine) in 500 mL of THF. Add 6.48 g (23.31 mM) of DSC and stir at RT 18 h. Add 8.81 ml (63.27 mM) of triethylamine and
8,18 g (23,31 mM) de di-fert-butyl [5-(aminomethyl)pyridin-2-yl]imidodicarbonate. Agiter à TA8.18 g (23.31 mM) of di-tert-butyl [5- (aminomethyl) pyridin-2-yl] imidodicarbonate. Shake at TA
5 h. Evaporer le solvant et reprendre le résidu par DCM. Laver la phase organique avec de l'eau puis une solution saturée en NaCI. Sécher sur sulfate de sodium, filtrer et évaporer.5 Purifier par chromatoflash. On obtient 12 g de produit constitué par un mélange 50/50 d'ester pinacolique et d'acide boronique. LCMS(LS) MH+ 587 tr=6,17 min et MH+ 505, tr=4,97 min.5 h. Evaporate the solvent and take up the residue with DCM. Wash the organic phase with water and saturated NaCl solution. Dry over sodium sulfate, filter and evaporate. Purify by chromatoflash. 12 g of product consisting of a 50/50 mixture of pinacol ester and boronic acid are obtained. LCMS (LS) MH + 587 tr = 6.17 min and MH + 505, tr = 4.97 min.
2.3. di-tert-butyl r5-(m4-{6-(ethylamino)-5-r(2-hvdroxyethyl)carbamoyllpyridin-2-yl}-2- fluorophenyl)carbamoyllamino}methyl)pyridin-2-yllimidodicarbonate2.3. di-tert-butyl-5- (m4- {6- (ethylamino) -5- (2-hydroxyethyl) carbamoylpyridin-2-yl} -2-fluorophenyl) carbamoyllamino} methyl) pyridin-2-yl] imidicarbicarbonate
Q Q
Dans un tricol, placer 0,3 g (1 ,23 mM) de composé obtenu à l'étape 2.1 , 0,794 g (1 ,35 mM) de composé obtenu étape 2.2, 15 mL de solution saturée de NaHCOs, 38 ml de DME et 7 mL d'éthanol. Dégazer avec de l'argon puis ajouter 0,142 g (0,12 mM) de Pd(PPh3)4. Chauffer à reflux 6 h. Evaporer les solvants et reprendre le résidu par DCM. Laver avec de l'eau puis5 une solution saturée NaCI. Sécher sur Na2SO4, filtrer et évaporer. Purifier par chromatoflash (DCM/MeOH 0-15%). On obtient 600 mg (rdt=73%) LCMS(TFA3) : MH+ 668, tr=1 ,44 min. 2.4. 6-{4-r3-(6-Amino-pyridin-3-ylmethyl)-ureido1-3-fluoro-phenyl}-2-ethylamino-N-(2- hydroxy-ethyl)-nicotinamideIn a tricolor, place 0.3 g (1.23 mM) of the compound obtained in step 2.1, 0.794 g (1.35 mM) of compound obtained in step 2.2, 15 mL of saturated NaHCO 3 solution, 38 mL of DME. and 7 mL of ethanol. Degased with argon then add 0.142 g (0.12 mM) Pd (PPh 3 ) 4 . Heat to reflux 6 h. Evaporate the solvents and take up the residue with DCM. Wash with water and saturated NaCl solution. Dry on Na 2 SO 4 , filter and evaporate. Purify by chromatoflash (DCM / MeOH 0-15%). 600 mg (yield = 73%) LCMS (TFA3): MH + 668, tr = 1.44 min. 2.4. 6- {4-r3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-hydroxyethyl) -nicotinamide
Dissoudre 0,6 g (0,9 mM) du composé obtenu à l'étape 2.3 dans 20 ml_ de DCM. Refroidir par un bain de glace et ajouter 2,08 ml_ (27 mM) de TFA. Agiter 18 h à TA. Evaporer les solvants et reprendre le résidu par une solution Na2Cθ3. Filtrer, rincer avec de l'eau et sécher à l'étuve sur P2O5. On obtient 200 mg (rdt= 47,6%) LCMS(TFA3) : MH+ 468, tr=0,72 min ; 1H RMN (250 MHz, DMSO-d6) δ ppm 1 ,22 (t, 3 H), 3,31 (s, 2 H), 3,43 - 3,62 (m, 4 H), 4,13 (d, 2 H), 4,71 (t, 1 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,97 (t, 1 H), 7,16 (d, 1 H), 7,35 (dd, 1 H), 7,78 - 7,98 (m, 3 H), 8,01 (d, 1 H), 8,28 (t, 1 H), 8,34 - 8,47 (m, 2 H), 8,49 (d, 1 H). Dissolve 0.6 g (0.9 mM) of the compound obtained in step 2.3 in 20 ml of DCM. Cool with an ice bath and add 2.08 ml (27 mM) of TFA. Shake 18 h at RT. Evaporate the solvents and take up the residue with Na 2 CO 3 solution. Filter, rinse with water and dry in an oven on P 2 O 5 . 200 mg (yield = 47.6%) LCMS (TFA3): MH + 468, tr = 0.72 min; 1 H NMR (250 MHz, DMSO-d6) δ ppm 1, 22 (t, 3H), 3.31 (s, 2H), 3.43 - 3.62 (m, 4H), 4.13 (d, 2H), 4.71 (t, 1H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), (d, 1H), 7.35 (dd, 1H), 7.78 - 7.98 (m, 3H), 8.01 (d, 1H), 8.28 (t, 1H) , 8.34-8.47 (m, 2H), 8.49 (d, 1H).
Exemple 3 : 6-{4-r3-(6-Amino-pyridin-3-ylmethyl)-ureido1-3-fluoro-phenyl}-N-(2-azepan- 1 -yl-ethyl)-2-ethylamino-nicotinamide (composé n°15 préparé selon le Schéma 3) 3.1. 6-(4-{[({6-rbis(teft-butoxycarbonyl)amino1pyridin-3-yl}methyl)carbamovnamino}-3- fluorophenyl)-2-(ethylamino)nicotinic acidExample 3 6- {4-r3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide (Compound No. 15 prepared according to Scheme 3) 3.1. 6- (4 - {[({6-rbis (tert-butoxycarbonyl) amino] pyridin-3-yl} methyl) carbamoyamino} -3-fluorophenyl) -2- (ethylamino) nicotinic acid
Dans un tricol, placer 1 ,2 g (5,98 mM) d'acide 6-chloro-2-(éthylamino)nicotinique, 3,86 g (6,58 mM) de di-tert-butyl {5-[({[2-fluoro-4-(4,4,5,5-tetraméthyl-1 ,3,2-dioxaborolan-2- yl)phényl]carbamoyl}amino)méthyl]pyridin-2-yl}imidodicarbonate, 80 ml_ de DME, 15 ml_ d'éthanol et 40 ml_ de solution saturée NaHCO3. Dégazer avec de l'argon puis chauffer à reflux 18 h. Evaporer les solvants et reprendre le résidu par de l'eau. Filtrer, rincer avec de l'eau et sécher à l'étuve sur P2O5. Purifier par chromatoflash DCM/MeOH 1-20%. On obtient 1 ,8 g de mélange de composé mono et di-Boc. LCMS(LS) MH+ 525 tr=4,60 min et MH+ 625 tr=5,59 min. 3.2. 6-{4-r3-(6-Amino-pyridin-3-ylmethyl)-ureido1-3-fluoro-phenyl>-N-(2-azepan-1-yl- ethyl)-2-ethylamino-nicotinamideIn a tricolor, add 1.2 g (5.98 mM) of 6-chloro-2- (ethylamino) nicotinic acid, 3.86 g (6.58 mM) of di-tert-butyl {5 - [( {[2-fluoro-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] carbamoyl} amino) methyl] pyridin-2-yl} imidodicarbonate, 80 ml. DME, 15 ml ethanol and 40 ml saturated NaHCO 3 solution. Degas with argon then heat to reflux 18 h. Evaporate the solvents and take up the residue with water. Filter, rinse with water and dry in an oven on P 2 O 5 . Purify by DCM / MeOH chromatoflash 1-20%. 1.8 g of mono and di-Boc compound mixture are obtained. LCMS (LS) MH + 525 tr = 4.60 min and MH + 625 tr = 5.59 min. 3.2. 6- {4- (3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl-N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide
Dissoudre 0,2 g (0,32 mM) de composé obtenu à l'étape 3.1 dans 30 ml_ de THF. Ajouter 0,1 15 g (0,64 mM) de chlorhydrate de 2-azépan-1-yléthanamine, 0,18 ml_ (0,13 mM) de triéthylamine et 0,142 g (0,32 mM) de BOP. Agiter 18 h à TA. Evaporer, reprendre le résidu par DCM, laver avec de l'eau puis une solution saturée NaCI. Sécher sur Na2SU4, filtrer et évaporer. Purifier par chromatoflash DCM/MeOH 0-10%. On obtient 0,250 g de mélange de mono et diBoc. Dissoudre ce produit dans 15 ml_ DCM, refroidir par un bain de glace et ajouter 0,5 ml_ de TFA. Agiter 18 h à TA. Evaporer et reprendre le résidu par une solution Na2C03. Filtrer le précipité, laver à l'eau et sécher à l'étuve sur P2O5. On obtient 0,13 g (rdt=74%) LCMS (TFA3) MH+ 549, tr=0,85 min ; 1H RMN (400 MHz, DMSO-d6) δ ppm 1 ,22 (t, 3 H), 1 ,56 (m, 8 H), 2,67 (m, 6 H), 3,32 (m, 2 H), 3,45 - 3,63 (m, 2 H), 4,13 (d, 2 H), 5,84 (s, 2 H), 6,43 (d, 1 H), 6,97 (t, 1 H), 7,15 (d, 1 H), 7,34 (d, 1 H), 7,83 -8,00 (m, 4 H), 8,27 (t, 1 H), 8,35 (t, 1 H), 8,41 (t, 1 H), 8,49 (s, 1 H). Dissolve 0.2 g (0.32 mM) of the compound obtained in step 3.1 in 30 ml of THF. Add 0.1 g (0.64 mM) of 2-azepan-1-ylethanamine hydrochloride, 0.18 ml (0.13 mM) triethylamine and 0.142 g (0.32 mM) BOP. Shake 18 h at RT. Evaporate, take up the residue with DCM, wash with water and saturated NaCl solution. Dry over Na 2 SU 4 , filter and evaporate. Purify by chromatoflash DCM / MeOH 0-10%. 0.250 g of mixture of mono and diBoc is obtained. Dissolve this product in 15 ml DCM, cool with an ice bath and add 0.5 ml of TFA. Shake 18 h at RT. Evaporate and take up the residue with Na 2 CO 3 solution . Filter the precipitate, wash with water and dry in an oven on P 2 O 5 . 0.13 g (yield = 74%) LCMS (TFA3) MH + 549, tr = 0.85 min; 1 H NMR (400 MHz, DMSO-d6) δ ppm 1, 22 (t, 3H), 1.56 (m, 8H), 2.67 (m, 6H), 3.32 (m, 2 H), 3.45 - 3.63 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.43 (d, 1H), 6.97; (t, 1H), 7.15 (d, 1H), 7.34 (d, 1H), 7.83 -8.00 (m, 4H), 8.27 (t, 1H) , 8.35 (t, 1H), 8.41 (t, 1H), 8.49 (s, 1H).
Exemple 4 : 6-{4-r(E)-3-(6-amino-pyridin-3-yl)-acryloylamino1-3-fluoro-phenyl>-2- ethylamino-N-(2-piperidin-1-yl-ethyl)-nicotinamide (composé n° 43 préparé selon le Schéma 8)Example 4: 6- {4-r (E) -3- (6-amino-pyridin-3-yl) -acryloylamino] -3-fluoro-phenyl-2-ethylamino-N- (2-piperidin-1-yl) -ethyl) -nicotinamide (compound No. 43 prepared according to Scheme 8)
4.1. 6-(4-Acryloylamino-3-fluoro-phenyl)-2-ethylamino-N-(2-piperidin-1-yl-ethyl)- nicotinamide 4.1. 6- (4-Acryloylamino-3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
Dissoudre 0,385g (1 mM) de composé obtenu à l'étape 1.3 dans 2OmL de DCM ; ajouterDissolve 0.385 g (1 mM) of compound obtained in step 1.3 in 20 mL of DCM; add
0,28ml_ (2mM) de triethylamine et 0,11 1g (1 ,1 mM) de DMAP puis 0,2ml_ (2,2mM) de chlorure d'acryloyle. Agiter à température ambiante 18H. Evaporer les solvants et reprendre le résidu par du DCM. Laver avec une solution Na2CO3 puis une solution saturée en NaCI. Sécher sur sulfate de sodium, filrer puis évaporer le filtrat. Le résidu est purifié par chromatoflash (DCM -0.28 ml (2 mM) of triethylamine and 0.11 μg (1.1 mM) of DMAP followed by 0.2 ml (2.2 mM) of acryloyl chloride. Stir at room temperature 18H. Evaporate the solvents and take up the residue with DCM. Wash with Na 2 CO 3 solution and saturated NaCl solution. Dry over sodium sulfate, filter and evaporate the filtrate. The residue is purified by chromatoflash (DCM -
DCM/CH3OH/NH4OH 20% 95/5/0.2). On obtient 0,195g (44,4%).DCM / CH 3 OH / NH 4 OH 20% 95/5 / 0.2). 0.195 g (44.4%) is obtained.
LCMS (TFA3) MH+ 440, tr = 2,44 min.LCMS (TFA3) MH + 440, tr = 2.44 min.
4.2 6-{4-r(E)-3-(6-Amino-pyridin-3-yl)-acryloylamino1-3-fluoro-phenyl>-2- ethylamino-N-(2-piperidin-1-yl-ethyl)-nicotinamide4.2 6- {4-r (E) -3- (6-Amino-pyridin-3-yl) -acryloylamino] -3-fluoro-phenyl-2-ethylamino-N- (2-piperidin-1-yl-ethyl) ) nicotinamide
Dissoudre 0.187g (0.43mM) de composé obtenu à l'étape 4.1 dans 15mL de propionitrile ; ajouter 0,074g (0,43mM) de 2-amino-5-bromo pyridine et 0,11 mL (0,64mM) de DIPEA. Dégazer avec de l'argon pendant 30 minutes puis ajouter 0,01g (0,04mM) de Pd(OAc)2 etDissolve 0.187 g (0.43 mM) of the compound obtained in step 4.1 in 15 mL of propionitrile; add 0.074 g (0.43 mM) of 2-amino-5-bromo pyridine and 0.11 mL (0.64 mM) of DIPEA. Degasate with argon for 30 minutes then add 0.01g (0.04mM) Pd (OAc) 2 and
0,022g (0,07mM) de tri-orthotolyl phosphine. Porter à reflux 3H. Apres retour à température ambiante diluer avec du DCM et filtrer sur Whatman. Evaporer le filtrat et purifier le résidu par chromatoflash DCM - DCM/CH3OH/NH4OH 20% 85/15/0.2. On obtient 0,120g (53%).0.022 g (0.07 mM) of tri-orthotolyl phosphine. Bring to reflux 3H. After cooling to room temperature dilute with DCM and filter through Whatman. Evaporate the filtrate and purify the residue by chromatography DCM-DCM / CH 3 OH / NH 4 OH 20% 85/15 / 0.2. 0.120 g (53%) is obtained.
Exemple 5 : 2-Ethvlamino-6-r3-fluoro-4-((E)-3-pvridin-3-vl-acrylovlamino)-phenvn-N-(2- piperidin-1-yl-ethyl)-nicotinamide (composé n° 44)Example 5: 2-Ethylamino-6-r3-fluoro-4 - ((E) -3-pyridin-3-yl-acrylovamino) -phenyl-N- (2-piperidin-1-yl-ethyl) -nicotinamide (Compound n ° 44)
Dissoudre 0,25g (0,65mM) de composé obtenu à l'étape 1.3 dans 2OmL de DCM et ajouter 0,27mL (1 ,95mM) de triethylamine. Refroidir le milieu réactionnel par un bain de glace et ajouter goutte à goutte 0,163g (0,97mM) de (E)-3-Pyridin-3-yl-acryloyl chloride. Agiter à température ambiante 18H. Laver la solution organique avec une solution NaOH 10%, sécher sur Na2S04, filtrer et évaporer le filtrat. Purifier le résidu par chromatoflash SiO2 C18 CH3OH/H2O 50/50 - 90/10. On obtient 0,035g (10,4%). Exemple 6 : 6-{4-r3-(6-Amino-pvridin-3-vlmethvl)-ureido1-3-fluoro-phenvl>-2-ethylamino- N-[2-(1-oxy-piperidin-1-yl)-ethyl]-nicotinamide (composé n° 45)Dissolve 0.25 g (0.65 mM) of the compound obtained in step 1.3 in 20 mL of DCM and add 0.27 mL (1.95 mM) of triethylamine. Cool the reaction medium with an ice bath and add dropwise 0.163 g (0.97 mM) of (E) -3-pyridin-3-yl-acryloyl chloride. Stir at room temperature 18H. Wash the organic solution with 10% NaOH solution, dry over Na 2 S0 4 , filter and evaporate the filtrate. Purify the residue by chromatoflash SiO 2 C 18 CH 3 OH / H 2 O 50/50 - 90/10. 0.035 g (10.4%) is obtained. Example 6: 6- {4-R3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (1-oxy-piperidin-1-yl)} ) -ethyl] -nicotinamide (Compound No. 45)
6.1 5-r3-(4-{6-Ethylamino-5-r2-(1-oxy-piperidin-1-yl)-ethylcarbamovn-pyridin-2- yl}-2-fluoro-phenyl)-ureidomethvn-pyridin-2-yl}-carbamic acid tert-butyl ester6.1 5-R3- (4- {6-Ethylamino-5-r2- (1-oxy-piperidin-1-yl) -ethylcarbamoyl-pyridin-2-yl} -2-fluoro-phenyl) -ureidomethyl-pyridin-2 -yl} -carbamic acid tert-butyl ester
Mettre 0,35g (0,55mM) de [5-(3-{4-[6-ethylamino-5-(2-piperidin-1-yl-ethylcarbamoyl)-pyridin- 2-yl]-2-fluoro-phenyl}-ureidomethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester en suspension dans 35ml_ DCM et 1 OmL de CHCI3. Refroidir par un bain de glace et ajouter 0,105g (0,61 mM) d'acide meta chloro perbenzoïque. Agiter 0,5H à froid puis 2H à température ambiante. Laver la phase organique avec une solution NaHCO3 puis H2O puis une solution saturée NaCI. Sécher sur Na2SO4, filtrer et évaporer. Le résidu est purifié par chromatoflash sur AI2O3 neutre DCM/CH3OH - 98/2 à 92/8. On obtient 0,340g (94,7%).Put 0.35 g (0.55mM) of [5- (3- {4- [6-ethylamino-5- (2-piperidin-1-yl-ethylcarbamoyl) -pyridin-2-yl] -2-fluoro-phenyl } -ureidomethyl) -pyridin-2-yl] -carbamic acid tert-butyl ester suspended in 35 ml of DCM and 1 μl of CHCl 3 . Cool with an ice bath and add 0.105g (0.61 mM) of chlorobenzoic meta acid. Stir 0.5H cold then 2H at room temperature. Wash the organic phase with NaHCO 3 then H 2 O solution and saturated NaCl solution. Dry on Na 2 SO 4 , filter and evaporate. The residue is purified by chromatoflash on Al 2 O 3 neutral DCM / CH 3 OH - 98/2 to 92/8. 0.340 g (94.7%) is obtained.
LCMS (TFA3) MH+ 651 , tr = 2,07 min.LCMS (TFA3) MH + 651, tr = 2.07 min.
6.2 6-{4-r3-(6-Amino-pyridin-3-ylmethyl)-ureido1-3-fluoro-phenyl}-2- ethylamino-N-r2-(1 -oxy-piperidin-1 -yl)-ethyll-nicotinamide Dissoudre 0,328g (0,5mM) de composé obtenu à l'étape 6.1 dans 2OmL de CH2CI2. Refroidir par un bain de glace et ajouter 0,85mL (1 1 ,1 mM) de TFA. Agiter à température ambiante 44H. Evaporer et reprendre le résidu par une solution Na2CO3 10% et extraire DCM. Sécher sur Na2SO4, filtrer et évaporer. Le résidu est purifié par chromatoflash sur AI2O3 neutre DCIWCH3OH - 95/5 à 88/12. On obtient 0,213g (76,9%).6.2 6- {4-r3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-r2- (1-oxy-piperidin-1-yl) -ethyl nicotinamide Dissolve 0.328 g (0.5 mM) of compound obtained in step 6.1 in 20 mL of CH 2 Cl 2 . Cool with an ice bath and add 0.85mL (1 1, 1 mM) TFA. Stir at room temperature 44H. Evaporate and take up the residue with 10% Na 2 CO 3 solution and extract DCM. Dry on Na 2 SO 4 , filter and evaporate. The residue is purified by chromatoflash on AI 2 O 3 neutral DCIWCH 3 OH - 95/5 to 88/12. 0.213 g (76.9%) is obtained.
1H RMN des composés du tableau 1 1 H NMR of the compounds of Table 1
Les déplacements δ chimiques sont donnés en ppm. composé n°2 : (400 MHz) 1 ,22 (t, 3 H), 1 ,35 - 1 ,81 (m, 6 H), 2,54 - 3,16 (m, 6 H), 3,45 -3,57 (m, 4 H), 4,13 (d, 2 H), 5,88 (s, 2 H), 6,44 (d, 1 H), 7,02 - 7,14 (m, 2 H), 7,35 (dd, 1 H), 7,85 - 7,92 (m, 2 H), 7,98 (d, 1 H), 8,16 (dd, 1 H), 8,35 (t, 1 H), 8,61 (br. s., 1 H), 8,75 (s, 1 H).The chemical displacements δ are given in ppm. compound no. 2: (400 MHz) 1, 22 (t, 3H), 1, 35-1.81 (m, 6H), 2.54-3.16 (m, 6H), 3.45 -3.57 (m, 4H), 4.13 (d, 2H), 5.88 (s, 2H), 6.44 (d, 1H), 7.02-7.14 (m.p. , 2H), 7.35 (dd, 1H), 7.85 - 7.92 (m, 2H), 7.98 (d, 1H), 8.16 (dd, 1H), 8 35 (t, 1H), 8.61 (brs, 1H), 8.75 (s, 1H).
composé n°3 : (250 MHz) 1 ,22 (t, 3 H), 1 ,32 - 1 ,60 (m, 6 H), 2,40 - 2,65 (m, 6 H), 3,29 -3,46 (m, 2 H), 3,58 (m, 2 H), 4,13 (d, 2 H), 5,84 (s, 2 H), 6,44 (d, 1 H), 7,03 (t, 1 H), 7,35 (dd, 1 H), 7,88(d,Compound No. 3: (250 MHz) 1, 22 (t, 3H), 1.32 - 1.60 (m, 6H), 2.40 - 2.65 (m, 6H), 3.29 -3.46 (m, 2H), 3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H); , 7.03 (t, 1H), 7.35 (dd, 1H), 7.88 (d,
1 H), 8,00 - 8,19 (m, 2 H), 8,25 - 8,39 (m, 1 H), 8,50 - 8,63 (m, 2 H), 8,68 (s, 1 H), 8,75 (t, 1 H).1H), 8.00-8.19 (m, 2H), 8.25-8.39 (m, 1H), 8.50-8.63 (m, 2H), 8.68 (m.p. s, 1H), 8.75 (t, 1H).
composé n°4 : (250 MHz) 1 ,22 (t, 3 H), 1 ,32 - 1 ,60 (m, 6 H), 2,40 - 2,65 (m, 6 H), 3,29 -3,46 (m,Compound No. 4: (250 MHz) 1, 22 (t, 3H), 1.32 - 1.60 (m, 6H), 2.40 - 2.65 (m, 6H), 3.29 -3.46 (m,
2 H), 3,58 (m, 2 H), 4,13 (d, 2 H), 5,84 (s, 2 H), 6,44 (d, 1 H), 7,03 (t, 1 H), 7,35 (dd, 1 H), 7,88(d, 1 H), 8,00 - 8,19 (m, 2 H), 8,25 - 8,39 (m, 1 H), 8,50 - 8,63 (m, 2 H), 8,68 (s, 1 H), 8,75 (t, 1 H).2H), 3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.03 (t, 1H), 7.35 (dd, 1H), 7.88 (d, 1H), 8.00-8.19 (m, 2H), 8.25-8.39 (m, 1H). ), 8.50 - 8.63 (m, 2H), 8.68 (s, 1H), 8.75 (t, 1H).
composé n°5 : (250 MHz) 1 ,28 - 1 ,65 (m, 6 H), 2,32 - 2,47 (m, 6 H), 3,35 - 3,52 (m, 2 H), 4,13 (d, 2 H), 5,84 (s, 2 H), 6,44 (d, 1 H), 7,02 (t, 2 H), 7,26 - 7,52 (m, 4 H), 7,75 (d, 2 H), 7,82 - 8,04(m, 3 H), 8,16 (d, 1 H), 8,34 (t, 1 H), 8,53 (s, 1 H), 8,69 (t, 1 H), 11 ,06 (s, 1 H).Compound No. 5: (250 MHz) 1, 28 - 1.65 (m, 6H), 2.32 - 2.47 (m, 6H), 3.35 - 3.52 (m, 2H) , 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.02 (t, 2H), 7.26 - 7.52 (m). , 4H), 7.75 (d, 2H), 7.82 - 8.04 (m, 3H), 8.16 (d, 1H), 8.34 (t, 1H), 8. , 53 (s, 1H), 8.69 (t, 1H), 11.06 (s, 1H).
composé n°6 : (250 MHz) 0,97 (d, 6 H), 1 ,21 (t, 3 H), 1 ,57 (br. s., 1 H), 2,58 - 2,87 (m, 3H), 3,23 - 3,34 (m, 2 H), 3,43 - 3,61 (m, 2 H), 4,13 (d, 2 H), 5,84 (s, 2 H), 6,44 (d, 1 H), 6,99 (t, 1 H), 7,16 (d, 1 H), 7,35 (dd, 1 H), 7,80 - 8,10 (m, 4 H), 8,28 (t, 1 H), 8,34 - 8,48 (m, 2 H), 8,51 (d, 1 H).Compound No. 6: (250 MHz) 0.97 (d, 6H), 1.21 (t, 3H), 1. 57 (brs, 1H), 2.58-2.87 ( m, 3H), 3.23 - 3.34 (m, 2H), 3.43 - 3.61 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2). H), 6.44 (d, 1H), 6.99 (t, 1H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.80 - 8.10 (m, 4H), 8.28 (t, 1H), 8.34-8.48 (m, 2H), 8.51 (d, 1H).
composé n°7 : (250 MHz) 1 ,22 (t, 3 H), 2,66 (t, 2 H), 2,89 - 3,17 (m, 8 H), 3,31 - 3,42 (m, 2H), 3,45 - 3,61 (m, 2 H), 4,13 (d, 2 H), 5,84 (s, 2 H), 6,44 (d, 1 H), 6,98 (t, 1 H), 7,17 (d, 1 H), 7,35 (dd,1 H), 7,83 - 8,03 (m, 4 H), 8,28 (t, 1 H), 8,34 - 8,46 (m, 2 H), 8,50 (d, 1 H).compound no. 7: (250 MHz) 1, 22 (t, 3H), 2.66 (t, 2H), 2.89 - 3.17 (m, 8H), 3.31 - 3.42 (m, 2H), 3.45 - 3.61 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1H), 7.17 (d, 1H), 7.35 (dd, 1H), 7.83 - 8.03 (m, 4H), 8.28 (t, 1H), 8.34-8.46 (m, 2H), 8.50 (d, 1H).
composé n°9 : (250 MHz) 0,49 - 0,60 (m, 2 H), 0,77 - 0,94 (m, 2 H), 1 ,29 - 1 ,57 (m, 6 H), 2,28 - 2,48 (m, 6 H), 2,99 - 3,11 (m, 1 H), 3,31 - 3,42 (m, 2 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 7,03 (t, 1 H), 7,36 (dd, 1 H), 7,88 (d, 1 H), 8,05 - 8,23 (m, 2 H), 8,28 - 8,38 (m, 1 H), 8,50 - 8,64 (m, 2H), 8,69 (s, 1 H), 8,77 (d, 1 H).compound no. 9: (250 MHz) 0.49 - 0.60 (m, 2H), 0.77 - 0.94 (m, 2H), 1, 29 - 1.57 (m, 6H) , 2.28 - 2.48 (m, 6H), 2.99 - 3.11 (m, 1H), 3.31 - 3.42 (m, 2H), 4.13 (d, 2). H), 5.83 (s, 2H), 6.44 (d, 1H), 7.03 (t, 1H), 7.36 (dd, 1H), 7.88 (d, 1H), H), 8.05 - 8.23 (m, 2H), 8.28 - 8.38 (m, 1H), 8.50 - 8.64 (m, 2H), 8.69 (s, 1H), 8.77 (d, 1H).
composé n°10 : (250 MHz) 1 ,27 - 1 ,70 (m, 6 H), 2,49 - 2,87 (m, 6 H), 3,40 - 3,58 (m, 2 H), 4,14 (d, 2 H), 5,84 (s, 2 H), 6,44 (d, 1 H), 7,07 (t, 1 H), 7,15 (t, 1 H), 7,36 (dd, 1 H), 7,40 - 7,50 (m, 2 H), 7,77 (d, 2 H), 7,88 (d, 1 H), 8,03 (dd, 1 H), 8,13 (dd, 1 H), 8,38 (t, 1 H), 8,63 (d, 1 H), 8,81 - 9,04 (m, 2H), 11 ,15 (s, 1 H). composé n°11 : (250 MHz) 1 ,20 (t, 3 H), 1 ,29 - 1 ,66 (m, 6 H), 2,11 - 2,47 (m, 6 H), 3,25 -3,40 (m, 2 H), 3,42 - 3,62 (m, 2 H), 4,11 (d, 2 H), 5,76 (s, 2 H), 6,43 (d, 1 H), 6,61 (br. s., 1 H), 6,97 (d,1 H), 7,12 (d, 1 H), 7,35 (d, 1 H), 7,62 (d, 1 H), 7,77 - 8,05 (m, 3 H), 8,28 - 8,48 (m, 2 H), 8,91 (s, 1 H).Compound No. 10: (250 MHz) 1, 27-1.70 (m, 6H), 2.49-2.87 (m, 6H), 3.40-3.58 (m, 2H) , 4.14 (d, 2H), 5.84 (s, 2H), 6.44 (d, 1H), 7.07 (t, 1H), 7.15 (t, 1H). , 7.36 (dd, 1H), 7.40 - 7.50 (m, 2H), 7.77 (d, 2H), 7.88 (d, 1H), 8.03 (dd; , 1H), 8.13 (dd, 1H), 8.38 (t, 1H), 8.63 (d, 1H), 8.81-9.04 (m, 2H), 11, 15 (s, 1H). compound no. 11: (250 MHz) 1, 20 (t, 3H), 1, 29-1.66 (m, 6H), 2.11-2.47 (m, 6H), 3.25 -3.40 (m, 2H), 3.42 - 3.62 (m, 2H), 4.11 (d, 2H), 5.76 (s, 2H), 6.43 (d. , 1H), 6.61 (brs, 1H), 6.97 (d, 1H), 7.12 (d, 1H), 7.35 (d, 1H), 7, 62 (d, 1H), 7.77-8.05 (m, 3H), 8.28-8.48 (m, 2H), 8.91 (s, 1H).
composé n°12 : (250 MHz) 1 ,22 (t, 3 H), 1 ,57 - 1 ,86 (m, 4 H), 2,43 - 2,52 (m, 4 H), 2,57 (t, 2H), 3,29 - 3,43 (m, 2 H), 3,43 - 3,60 (m, 2 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,99 (t, 1 H), 7,15 (d, 1 H), 7,35 (dd, 1 H), 7,80 - 8,04 (m, 4 H), 8,28 (t, 1 H), 8,35 - 8,48 (m, 2 H), 8,51 (br. s., 1 H).Compound No. 12: (250 MHz) 1, 22 (t, 3H), 1.57-1.86 (m, 4H), 2.43 - 2.52 (m, 4H), 2.57. (t, 2H), 3.29 - 3.43 (m, 2H), 3.43 - 3.60 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.99 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.80-8, 04 (m, 4H), 8.28 (t, 1H), 8.35-8.48 (m, 2H), 8.51 (brs, 1H).
composé n°13 : (250 MHz) 1 ,22 (t, 3 H), 2,75 (d, 3 H), 3,43 - 3,66 (m, 2 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,98 (t, 1 H), 7,15 (d, 1 H), 7,35 (dd, 1 H), 7,82 - 8,04 (m, 4 H), 8,28 (t, 1 H), 8,35 - 8,62 (m, 3 H).compound no. 13: (250 MHz) 1, 22 (t, 3H), 2.75 (d, 3H), 3.43 - 3.66 (m, 2H), 4.13 (d, 2) H), 5.83 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), H), 7.82 - 8.04 (m, 4H), 8.28 (t, 1H), 8.35 - 8.62 (m, 3H).
composé n°14 : (250 MHz) 1 ,22 (t, 3 H), 3,27 (s, 3 H), 3,35 - 3,62 (m, 6 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,97 (t, 1 H), 7,15 (d, 1 H), 7,37 (dd, 1 H), 7,82 - 8,07 (m, 4 H), 8,28 (t, 1 H), 8,50 (br. s., 3 H).Compound No. 14: (250 MHz) 1, 22 (t, 3H), 3.27 (s, 3H), 3.35 - 3.62 (m, 6H), 4.13 (d, 2). H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.37 (dd, 1H), H), 7.82 - 8.07 (m, 4H), 8.28 (t, 1H), 8.50 (brs, 3H).
composé n°16 : (400 MHz) 1 ,22 (t, 3 H), 2,56 (t, 2 H), 2,66 - 2,75 (m, 4 H), 2,82 - 3,04 (m, 4H), 3,34 - 3,41 (m, 2 H), 3,45 - 3,60 (m, 2 H), 4,13 (d, 2 H), 5,87 (s, 2 H), 6,44 (d, 1 H), 6,99 (t, 1 H), 7,15 (d, 1 H), 7,35 (dd, 1 H), 7,82 - 7,99 (m, 4 H), 8,27 (t, 1 H), 8,34 - 8,47 (m, 2 H), 8,50 (d, 1 H).Compound No. 16: (400 MHz) 1, 22 (t, 3H), 2.56 (t, 2H), 2.66 - 2.75 (m, 4H), 2.82 - 3.04 (m, 4H), 3.34 - 3.41 (m, 2H), 3.45 - 3.60 (m, 2H), 4.13 (d, 2H), 5.87 (s, 2H), 6.44 (d, 1H), 6.99 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.82-7, 99 (m, 4H), 8.27 (t, 1H), 8.34-8.47 (m, 2H), 8.50 (d, 1H).
composé n°17: (250 MHz) 1 ,22 (t, 3 H), 1 ,29 - 1 ,62 (m, 6 H), 2,04 (s, 3 H), 2,29 - 2,47 (m, 6H), 3,30 - 3,41 (m, 2 H), 3,44 - 3,60 (m, 2 H), 4,13 (d, 2 H), 5,62 (s, 2 H), 6,96 (t, 1 H), 7,16 (d, 1 H), 7,22 (s, 1 H), 7,76 (s, 1 H), 7,82 - 8,06 (m, 3 H), 8,28 (t, 1 H), 8,33 - 8,46 (m, 2 H), 8,48 (d, 1 H).compound no. 17: (250 MHz) 1, 22 (t, 3H), 1, 29 - 1, 62 (m, 6H), 2.04 (s, 3H), 2.29 - 2.47 (m, 6H), 3.30 - 3.41 (m, 2H), 3.44 - 3.60 (m, 2H), 4.13 (d, 2H), 5.62 (s, 2H), 6.96 (t, 1H), 7.16 (d, 1H), 7.22 (s, 1H), 7.76 (s, 1H), 7.82-8, Δ (m, 3H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.48 (d, 1H).
composé n°18 : (250 MHz) 0,32 - 0,57 (m, 1 H), 0,78 (d, 6 H), 1 ,18 (t, 3 H), 1 ,35 - 1 ,70 (m,5 H), 2,39 (t, 2 H), 2,79 (d, 2 H), 3,22 - 3,38 (m, 2 H), 3,41 - 3,56 (m, 2 H), 4,09 (d, 2 H), 5,78 (s, 2 H), 6,39 (d, 1 H), 6,92 (t, 1 H), 7,11 (d, 1 H), 7,30 (dd, 1 H), 7,74 - 7,98 (m, 4 H), 8,23 (t, 1 H), 8,28 - 8,42 (m, 2 H), 8,44 (d, 1 H).compound no. 18: (250 MHz) 0.32 - 0.57 (m, 1H), 0.78 (d, 6H), 1.18 (t, 3H), 1.35 - 1.70 (m, 5H), 2.39 (t, 2H), 2.79 (d, 2H), 3.22 - 3.38 (m, 2H), 3.41 - 3.56 (m.p. , 2H), 4.09 (d, 2H), 5.78 (s, 2H), 6.39 (d, 1H), 6.92 (t, 1H), 7.11 (d, 1H), , 1H), 7.30 (dd, 1H), 7.74 - 7.98 (m, 4H), 8.23 (t, 1H), 8.28 - 8.42 (m, 2H), H), 8.44 (d, 1H).
composé n°19 : (250 MHz) 1 ,11 (d, 6 H), 1 ,02 - 1 ,32 (m, 3 H), 1 ,21 (t, 3 H), 1 ,39 - 1 ,73 (m,3 H)1 2,37 - 2,51 (m, 2 H), 2,59 - 2,78 (m, 2 H), 3,11 - 3,29 (m, 2 H), 3,42 - 3,59 (m, 2 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,97 (t, 1 H), 7,16 (d, 1 H), 7,35 (dd, 1 H), 7,83 - 8,01 (m, 4 H), 8,28 (t, 1 H), 8,35 - 8,59 (m, 3 H).compound no. 19: (250 MHz) 1, 11 (d, 6H), 1, 02 - 1, 32 (m, 3H), 1, 21 (t, 3H), 1, 39 - 1, 73 (m, 3H) 1 2.37 - 2.51 (m, 2H), 2.59 - 2.78 (m, 2H), 3.11 - 3.29 (m, 2H), 3 , 42 - 3.59 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1), H), 7.16 (d, 1H), 7.35 (dd, 1H), 7.83 - 8.01 (m, 4H), 8.28 (t, 1H), 8.35 8.59 (m, 3H).
composé n°20 : (250 MHz) 0,94 - 1 ,13 (m, 4 H), 1 ,22 (t, 3 H), 1 ,30 - 1 ,68 (m, 6 H), 2,41 -2,65 (m, 6 H), 3,31 - 3,68 (m, 4 H), 5,70 (s, 2 H), 6,43 (d, 1 H), 6,67 (br. s., 1 H), 7,16 (d, 1 H), 7,29 (d,1 H), 7,73 - 8,07 (m, 4 H), 8,19 - 8,34 (m, 1 H), 8,42 (br. s., 2 H), 8,54 (s, 1 H).Compound No. 20: (250 MHz) 0.94-1.3 (m, 4H), 1.22 (t, 3H), 1.30-1.68 (m, 6H), 2.41 -2.65 (m, 6H), 3.31 - 3.68 (m, 4H), 5.70 (s, 2H), 6.43 (d, 1H), 6.67 (brs), 1H), 7.16 (d, 1H), 7.29 (d, 1H), 7.73-8.07 (m, 4H), 8.19-8.34 (m, 1H). ), 8.42 (br s, 2H), 8.54 (s, 1H).
composé n°21 : (250 MHz) 1 ,13 (t, 3 H), 1 ,27 - 1 ,69 (m, 6 H), 2,16 - 2,47 (m, 6 H), 3,32 -3,43 (m, 4 H), 4,11 (d, 2 H), 5,81 (s, 2 H), 6,43 (d, 1 H), 6,61 - 6,82 (m, 2 H), 7,23 (d, 2 H), 7,35 (d, 1 H), 7,87 (s, 1 H), 7,92 (d, 1 H), 8,27 (br. s., 1 H), 8,41 (br. s., 1 H), 9,03 (s, 1 H).compound no. 21: (250 MHz) 1, 13 (t, 3H), 1, 27-1.69 (m, 6H), 2.16-2.47 (m, 6H), 3.32 -3.43 (m, 4H), 4.11 (d, 2H), 5.81 (s, 2H), 6.43 (d, 1H), 6.61-6.82 (m). , 2H), 7.23 (d, 2H), 7.35 (d, 1H), 7.87 (s, 1H), 7.92 (d, 1H), 8.27 (br. s, 1H), 8.41 (br s, 1H), 9.03 (s, 1H).
composé n°22 : (250 MHz) 1 ,19 (t, 3 H), 1 ,30 - 1 ,64 (m, 6 H), 2,31 - 2,50 (m, 6 H), 3,32 -3,42 (m, 2 H), 3,41 - 3,58 (m, 2 H), 4,13 (d, 2 H), 5,84 (s, 2 H), 6,44 (d, 1 H), 6,89 - 7,06 (m, 2 H), 7,35(dd, 1 H), 7,70 - 7,83 (m, 1 H), 7,88 (d, 1 H), 7,96 (d, 1 H), 8,09 (t, 1 H), 8,35 (t, 1 H), 8,43 (t, 1 H), 8,67(d, 1 H).compound no. 22: (250 MHz) 1, 19 (t, 3H), 1.30 - 1.64 (m, 6H), 2.31 - 2.50 (m, 6H), 3.32 -3.42 (m, 2H), 3.41 - 3.58 (m, 2H), 4.13 (d, 2H), 5.84 (s, 2H), 6.44 (d. , 1H), 6.89 - 7.06 (m, 2H), 7.35 (dd, 1H), 7.70 - 7.83 (m, 1H), 7.88 (d, 1H), H), 7.96 (d, 1H), 8.09 (t, 1H), 8.35 (t, 1H), 8.43 (t, 1H), 8.67 (d, 1H), H).
composé n°23: (250 MHz) 1 ,22 (t, 3 H), 1 ,33 - 1 ,68 (m, 6 H), 2,52 - 2,92 (m, 6 H), 3,15 -3,27 (m, 2 H), 3,34 - 3,50 (m, 2 H), 4,12 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,80 - 6,90 (m, 2 H), 6,94(t, 1 H), 7,35 (dd, 1 H), 7,48 (d, 1 H), 7,52 - 7,66 (m, 2 H), 7,78 - 7,93 (m, 2 H), 8,13 - 8,37 (m, 2 H), 8,43 (d, 1 H).compound no. 23: (250 MHz) 1, 22 (t, 3H), 1.33 - 1.68 (m, 6H), 2.52 - 2.92 (m, 6H), 3.15 -3.27 (m, 2H), 3.34 - 3.50 (m, 2H), 4.12 (d, 2H), 5.83 (s, 2H), 6.44 (d. , 1H), 6.80 - 6.90 (m, 2H), 6.94 (t, 1H), 7.35 (dd, 1H), 7.48 (d, 1H), 7. , 52-7.66 (m, 2H), 7.78-7.93 (m, 2H), 8.13-8.37 (m, 2H), 8.43 (d, 1H) .
composé n°24: (250 MHz) 0,39 - 0,51 (m, 2 H), 0,51 - 0,59 (m, 2 H), 0,59 - 0,75 (m, 2 H), 0,75compound no. 24: (250 MHz) 0.39 - 0.51 (m, 2H), 0.51 - 0.59 (m, 2H), 0.59 - 0.75 (m, 2H) , 0.75
- 0,90 (m, 2 H), 2,68 - 2,86 (m, 1 H), 2,86 - 3,09 (m, 1 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,98 (t, 1 H), 7,21 (d, 1 H), 7,35 (dd, 1 H), 7,83 - 8,13 (m, 4 H), 8,29 (t, 1 H), 8,38 - 8,65 (m, 3- 0.90 (m, 2H), 2.68 - 2.86 (m, 1H), 2.86 - 3.09 (m, 1H), 4.13 (d, 2H), , 83 (s, 2H), 6.44 (d, 1H), 6.98 (t, 1H), 7.21 (d, 1H), 7.35 (dd, 1H), 7. , 83-8.13 (m, 4H), 8.29 (t, 1H), 8.38-8.65 (m, 3)
H).H).
composé n°25: (250 MHz) 0,35 - 0,55 (m, 2 H), 0,69 - 0,84 (m, 2 H), 1 ,41 - 2,01 (m, 8 H), 2,85compound no. 25: (250 MHz) 0.35 - 0.55 (m, 2H), 0.69 - 0.84 (m, 2H), 1.41 - 2.01 (m, 8H) , 2.85
- 3,05 (m, 1 H), 4,13 (d, 2 H), 4,13 - 4,26 (m, 1 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,98 (t, 1 H), 7,22 (d, 1 H), 7,35 (dd, 1 H), 7,84 - 8,08 (m, 4 H), 8,22 - 8,37 (m, 2 H), 8,44 - 8,57 (m, 2 H)3.05 (m, 1H), 4.13 (d, 2H), 4.13-4.26 (m, 1H), 5.83 (s, 2H), 6.44 (d, 1H); , 1H), 6.98 (t, 1H), 7.22 (d, 1H), 7.35 (dd, 1H), 7.84 - 8.08 (m, 4H), 8 , 22 - 8.37 (m, 2H), 8.44 - 8.57 (m, 2H)
composé n°26: (250 MHz) 0,37 - 0,55 (m, 2 H), 0,71 - 0,83 (m, 2 H), 0,89 (t, 3 H), 1 ,18 -1 ,41 (m, 2 H), 1 ,41 - 1 ,63 (m, 2 H), 2,84 - 3,05 (m, 1 H), 3,21 (q, 2 H), 4,13 (d, 2 H), 5,86 (s, 2 H), 6,45 (d, 1 H), 6,98 (t, 1 H), 7,23 (d, 1 H), 7,36 (dd, 1 H), 7,83 - 8,09 (m, 4 H), 8,29 (t, 1 H), 8,39 - 8,68 (m, 3H)compound no. 26: (250 MHz) 0.37 - 0.55 (m, 2H), 0.71 - 0.83 (m, 2H), 0.89 (t, 3H), 1, 18 -1.41 (m, 2H), 1.41-1.63 (m, 2H), 2.84-3.05 (m, 1H), 3.21 (q, 2H), 4 , 13 (d, 2H), 5.86 (s, 2H), 6.45 (d, 1H), 6.98 (t, 1H), 7.23 (d, 1H), 7. , 36 (dd, 1H), 7.83-8.09 (m, 4H), 8.29 (t, 1H), 8.39-8.68 (m, 3H)
composé n°27: (250 MHz) 1 ,22 (t, 3 H), 1 ,29 - 1 ,58 (m, 6 H), 2,28 - 2,47 (m, 6 H), 3,30 -3,41 (m, 2 H), 3,43 - 3,62 (m, 2 H), 4,37 (d, 2 H), 7,16 (d, 1 H), 7,23 (t, 1 H), 7,39 (dd, 1 H), 7,69 - 7,79 (m, 1 H), 7,82 - 8,03 (m, 3 H), 8,26 (t, 1 H), 8,31 - 8,46 (m, 2 H), 8,49 (dd, 1 H), 8,56 (d, 1 H), 8,64 (d, 1 H).Compound No. 27: (250 MHz) 1, 22 (t, 3H), 1.29 - 1.58 (m, 6H), 2.28 - 2.47 (m, 6H), 3.30 -3.41 (m, 2H), 3.43 - 3.62 (m, 2H), 4.37 (d, 2H), 7.16 (d, 1H), 7.23 (t. , 1H), 7.39 (dd, 1H), 7.69-7.79 (m, 1H), 7.82-8.03 (m, 3H), 8.26 (t, 1H), H), 8.31-8.46 (m, 2H), 8.49 (dd, 1H), 8.56 (d, 1H), 8.64 (d, 1H).
composé n°28 : (250 MHz) 1 ,22 (t, 3), 1 ,23 - 1 ,6 (m, 6), 2,30 - 2,50 (m, 6), 2,75 (d, 3), 3,34 (m, 2), 3,52 (qui, 2), 4,13 (d, 2), 6,39 (q, 1 ), 6,43 (d, 1 ), 6,98 (t, 1 ), 7,16 (d, 1 ), 7,37 (dd,1 ), 7,80 - 8,02 (m, 4), 8,28 (t, 1 ), 8,37 (t, 1 ), 8,41 (t, 1 ), 8,49 (d, 1 ).compound no. 28: (250 MHz) 1, 22 (t, 3), 1, 23 - 1, 6 (m, 6), 2.30 - 2.50 (m, 6), 2.75 (d, 3), 3.34 (m, 2), 3.52 (which, 2), 4.13 (d, 2), 6.39 (q, 1), 6.43 (d, 1), 6, 98 (t, 1), 7.16 (d, 1), 7.37 (dd, 1), 7.80 - 8.02 (m, 4), 8.28 (t, 1), 8.37 (t, 1), 8.41 (t, 1), 8.49 (d, 1).
composé n°29 : (250 MHz) 1 ,22 (t, 3 H), 1 ,29 - 1 ,60 (m, 6 H), 2,31 - 2,47 (m, 6 H), 3,00 (s, 6H),compound no. 29: (250 MHz) 1, 22 (t, 3H), 1.29 - 1.60 (m, 6H), 2.31 - 2.47 (m, 6H), 3.00 (s, 6H),
3.26 - 3,42 (m, 2 H), 3,45 - 3,60 (m, 2 H), 4,18 (d, 2 H), 6,64 (d, 1 H), 7,01 (s, 1 H), 7,16 (d, 1 H), 7,49 (dd, 1 H), 7,81 - 8,01 (m, 3 H), 8,06 (d, 1 H), 8,28 (t, 1 H), 8,33 - 8,46 (m, 2 H), 8,51 (d, 1 H)3.26 - 3.42 (m, 2H), 3.45 - 3.60 (m, 2H), 4.18 (d, 2H), 6.64 (d, 1H), 7.01 ( s, 1H), 7.16 (d, 1H), 7.49 (dd, 1H), 7.81-8.01 (m, 3H), 8.06 (d, 1H), 8.28 (t, 1H), 8.33 - 8.46 (m, 2H), 8.51 (d, 1H)
composé n°30 : (250 MHz) 1 ,22 (t, 3 H), 1 ,30 - 1 ,63 (m, 6 H), 2,29 - 2,47 (m, 6 H), 3,29 -3,40 (m, 2 H), 3,44 - 3,63 (m, 2 H), 4,22 (d, 2 H), 5,32 (s, 2 H), 6,86 (s, 1 H), 7,03 - 7,22 (m, 2 H), 7,71(s, 1 H), 7,79 - 8,02 (m, 4 H), 8,28 (t, 1 H), 8,33 - 8,51 (m, 2 H), 8,58 (s, 1 H)compound no. 30: (250 MHz) 1, 22 (t, 3H), 1, 30 - 1, 63 (m, 6H), 2.29 - 2.47 (m, 6H), 3.29 -3.40 (m, 2H), 3.44 - 3.63 (m, 2H), 4.22 (d, 2H), 5.32 (s, 2H), 6.86 (s). , 1H), 7.03-7.22 (m, 2H), 7.71 (s, 1H), 7.79-8.02 (m, 4H), 8.28 (t, 1). H), 8.33 - 8.51 (m, 2H), 8.58 (s, 1H)
composé n°31 : (500 MHz) 1 ,23 (t, 3 H), 1 ,34 - 1 ,43 (m, 2 H), 1 ,45 - 1 ,57 (m, 4 H), 2,31 -2,49 (m, 6 H), 3,31 - 3,39 (m, 2 H), 3,46 - 3,59 (m, 2 H), 4,43 (d, 2 H), 7,17 (d, 1 H), 7,27 (t, 1 H), 7,62 -7,76 (m, 1 H), 7,88 (dd, 1 H), 7,91 - 8,02 (m, 2 H), 8,24 (t, 1 H), 8,38 (t, 1 H), 8,42 (t, 1 H), 8,46 (s, 1 H), 8,49 (d, 1 H), 8,69 (d, 1 H)Compound No. 31: (500 MHz) 1, 23 (t, 3H), 1, 34-1.43 (m, 2H), 1.45-1.57 (m, 4H), 2.31 -2.49 (m, 6H), 3.31 - 3.39 (m, 2H), 3.46 - 3.59 (m, 2H), 4.43 (d, 2H), 7. , 17 (d, 1H), 7.27 (t, 1H), 7.62 -7.76 (m, 1H), 7.88 (dd, 1H), 7.91-8.02 (m, 2H), 8.24 (t, 1H), 8.38 (t, 1H), 8.42 (t, 1H), 8.46 (s, 1H), 8.49 (t, 1H), (d, 1H), 8.69 (d, 1H)
composé n°32 : (400 MHz) 1 ,22 (t, 3 H), 1 ,33 - 1 ,61 (m, 6 H), 2,31 (s, 3 H), 2,51 (s, 6 H), 3,34 - 3,43 (m, 2 H), 3,46 - 3,60 (m, 2 H), 4,34 (d, 2 H), 7,16 (d, 1 H), 7,21 (t, 1 H), 7,54 (s, 1 H), 7,87(d,compound no. 32: (400 MHz) 1, 22 (t, 3H), 1, 33-1.61 (m, 6H), 2.31 (s, 3H), 2.51 (s, 6); H), 3.34 - 3.43 (m, 2H), 3.46 - 3.60 (m, 2H), 4.34 (d, 2H), 7.16 (d, 1H); , 7.21 (t, 1H), 7.54 (s, 1H), 7.87 (d,
1 H), 7,90 - 8,05 (m, 2 H), 8,21 - 8,29 (m, 1 H), 8,29 - 8,37 (m, 2 H), 8,37 - 8,49 (m, 2 H), 8,62 (d, 1 H)1H), 7.90 - 8.05 (m, 2H), 8.21 - 8.29 (m, 1H), 8.29 - 8.37 (m, 2H), 8.37 - 8.49 (m, 2H), 8.62 (d, 1H)
composé n°33 (250 MHz) 1 ,22 (t, 3 H), 1 ,31 - 1 ,59 (m, 6 H), 2,22 - 2,47 (m, 6 H), 3,29 -3,41 (m,compound no. 33 (250 MHz) 1, 22 (t, 3H), 1, 31-1.59 (m, 6H), 2.22-2.47 (m, 6H), 3.29 - 3.41 (m,
2 H), 3,53 (m, 2 H), 5,67 (s, 2 H), 6,45 (d, 1 H), 7,17 (d, 1 H), 7,51 (dd, 1 H), 7,80 - 8,05 (m, 4H),2H), 3.53 (m, 2H), 5.67 (s, 2H), 6.45 (d, 1H), 7.17 (d, 1H), 7.51 (dd, 1H), 7.80 - 8.05 (m, 4H),
8.27 (t, 1 H), 8,41 (d, 2 H), 8,70 (br. s., 2 H).8.27 (t, 1H), 8.41 (d, 2H), 8.70 (br.s, 2H).
composé n°34 : (400 MHz) 1 ,22 (t, 3 H), 1 ,40 (d, 2 H), 1 ,53 (quin, 4 H), 2,41 - 2,60 (m, 6H), 2,45 (s, 3 H), 3,34 - 3,42 (m, 2 H), 3,47 - 3,57 (m, 2 H), 4,32 (d, 2 H), 7,11 - 7,21 (m, 2 H), 7,23 (d, 1 H), 7,61 (dd, 1 H), 7,87 (d, 1 H), 7,90 - 8,03 (m, 2 H), 8,25 (t, 1 H), 8,41 (s, 3 H), 8,60 (d, 1 H)Compound No. 34: (400 MHz) 1, 22 (t, 3H), 1.40 (d, 2H), 1.53 (quin, 4H), 2.41 - 2.60 (m, 6H) ), 2.45 (s, 3H), 3.34 - 3.42 (m, 2H), 3.47 - 3.57 (m, 2H), 4.32 (d, 2H), 7.11-7.21 (m, 2H), 7.23 (d, 1H), 7.61 (dd, 1H), 7.87 (d, 1H), 7.90-8, 03 (m, 2H), 8.25 (t, 1H), 8.41 (s, 3H), 8.60 (d, 1H)
composé n°35 : (400 MHz) 1 ,22 (t, 3 H), 1 ,32 - 1 ,45 (m, 2 H), 1 ,64 - 1 ,78 (m, 2 H), 2,06 (t, 2H), 2,43 (t, 2 H), 2,64 - 2,77 (m, 2 H), 3,32 (s, 2 H), 3,37 - 3,48 (m, 1 H), 3,48 - 3,57 (m, 2 H), 4,13 (d, 2H), 4,52 (d, 1 H), 5,83 (s, 2 H), 6,43 (d, 1 H), 6,97 (t, 1 H), 7,15 (d, 1 H), 7,34 (dd, 1 H), 7,86 (d, 2 H), 7,89 - 7,99 (m, 2 H), 8,27 (t, 1 H), 8,33 - 8,45 (m, 2 H), 8,49 (d, 1 H)Compound No. 35: (400 MHz) 1, 22 (t, 3H), 1, 32-1.45 (m, 2H), 1.64-1.78 (m, 2H), 2.06 (t, 2H), 2.43 (t, 2H), 2.64 - 2.77 (m, 2H), 3.32 (s, 2H), 3.37 - 3.48 (m, 1H), 3.48 - 3.57 (m, 2H), 4.13 (d, 2H), 4.52 (d, 1H), 5.83 (s, 2H), 6.43 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.34 (dd, 1H), 7.86 (d, 2H), 7.89 (d, 1H), 7.99 (m, 2H), 8.27 (t, 1H), 8.33-8.45 (m, 2H), 8.49 (d, 1H)
composé n°36 : (250 MHz) 0,94 - 1 ,15 (m, 1 H), 1 ,22 (t, 3 H), 1 ,30 - 1 ,52 (m, 1 H), 1 ,52 -1 ,69 (m, 1 H), 1 ,69 - 1 ,97 (m, 3 H), 2,44 (t, 2 H), 2,62 - 2,77 (m, 1 H), 2,85 (dd, 1 H), 3,28 - 3,39 (m, 2H), 3,39 - 3,62 (m, 3 H), 4,13 (d, 2 H), 4,56 (d, 1 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,99 (t, 1 H), 7,16 (d, 1 H), 7,35 (dd, 1 H), 7,82 - 8,03 (m, 4 H), 8,28 (t, 1 H), 8,33 - 8,46 (m, 2 H), 8,51 (d, 1 H) composé n°37 : (400 MHz) 0,99 (d,12), 1 ,22 (t, 3), 2,51 (m, 2), 2,99 (m, 2), 3,19 (q, 2), 3,53 (qui, 2), 4,13 (d, 2), 5,83 (s, 2), 6,43 (d,1 ), 6.97 (t, 1 ), 7,15 (d, 1 ), 7,34 (dd, 1 ), 7,80 - 8,00 (massif, 4) ; 8,27 (t, 1 ), 8,37 (t, 1 ), 8,42 - 8,54 (massif, 2)Compound No. 36: (250 MHz) 0.94 - 1.15 (m, 1H), 1.22 (t, 3H), 1.30 - 1.52 (m, 1H), 1. 52 -1.69 (m, 1H), 1.69-1.77 (m, 3H), 2.44 (t, 2H), 2.62-2.77 (m, 1H), 2. , 85 (dd, 1H), 3.28 - 3.39 (m, 2H), 3.39 - 3.62 (m, 3H), 4.13 (d, 2H), 4.56 (b.p. d, 1H), 5.83 (s, 2H), 6.44 (d, 1H), 6.99 (t, 1H), 7.16 (d, 1H), 7.35 (d, 1H), dd, 1H), 7.82 - 8.03 (m, 4H), 8.28 (t, 1H), 8.33 - 8.46 (m, 2H), 8.51 (d, 1 H) compound no. 37: (400 MHz) 0.99 (d, 12), 1, 22 (t, 3), 2.51 (m, 2), 2.99 (m, 2), 3.19 (q, 12); , 2), 3.53 (which, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.97 (t, 1), 7.15 (d, 1), 7.34 (dd, 1), 7.80-8.00 (solid, 4); 8.27 (t, 1), 8.37 (t, 1), 8.42 - 8.54 (bulk, 2)
composé n°38 : (400 MHz) 1 ,22 (t, 3), 1 ,40 (m, 2), 1 ,82 (m , 2), 2,12 (t, 2), 2,44 (t, 2), 2,72 (m, 2), 3,15 (sep, 1 ), 3,22 (s, 3), 3,32 (m, 2), 3,52 (qui, 2), 4,15 (d, 2), 5,84 (s , 2), 6,43 (d,1 ), 6,97 (t, 1 ), 7,15 (d, 1 ), 7,34 (dd, 1 ), 7,80 - 8,00 (m, 4), 8,27 (t, 1 ), 8,37 (t, 1 ), 8,40 (t, 1 ), 8,49 (d,1 ).Compound No. 38: (400 MHz) 1, 22 (t, 3), 1.40 (m, 2), 1.82 (m, 2), 2.12 (t, 2), 2.44 (t , 2), 2.72 (m, 2), 3.15 (sep, 1), 3.22 (s, 3), 3.32 (m, 2), 3.52 (which, 2), 4 , (D, 2), 5.84 (s, 2), 6.43 (d, 1), 6.97 (t, 1), 7.15 (d, 1), 7.34 (dd, 1), 7.80 - 8.00 (m, 4), 8.27 (t, 1), 8.37 (t, 1), 8.40 (t, 1), 8.49 (d, 1), ).
composé n°39 : (250 MHz) 1 ,22 (t, 3 H), 1 ,30 - 1 ,57 (m, 6 H), 1 ,66 (t, 2 H), 2,18 - 2,41 (m, 6H), 3,16 - 3,29 (m, 2 H), 3,40 - 3,60 (m, 2 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d, 1 H), 6,97 (t, 1 H), 7,15 (d, 1 H), 7,35 (dd, 1 H), 7,81 - 8,03 (m, 4 H), 8,28 (t, 1 H), 8,36 - 8,58 (m, 3 H).compound no. 39: (250 MHz) 1, 22 (t, 3H), 1, 30 - 1, 57 (m, 6H), 1, 66 (t, 2H), 2.18 - 2.41 (m, 6H), 3.16 - 3.29 (m, 2H), 3.40 - 3.60 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 6.97 (t, 1H), 7.15 (d, 1H), 7.35 (dd, 1H), 7.81-8, 03 (m, 4H), 8.28 (t, 1H), 8.36 - 8.58 (m, 3H).
composé n°40 : (400 MHz) 1 ,22 (t, 3), 1 ,30 - 1 ,59 (m, 10), 2,23 (t, 2), 2,28 (si, 4), 3,23 (q, 2) ; 3,52 (qui, 2), 4,13 (d, 2), 5,83 (s, 2), 6,43 (d, 1 ), 6,99 (t, 1 ), 7,14 (d, 1 ), 7,34 (dd, 1 ), 7,82 - 8,00 (m, 4), 8,26 (t, 1 ), 8,43 (m, 2), 8,51 (si, 1 ).compound no. 40: (400 MHz) 1, 22 (t, 3), 1, 30 - 1, 59 (m, 10), 2.23 (t, 2), 2.28 (s, 4), 3 23 (q, 2); 3.52 (which, 2), 4.13 (d, 2), 5.83 (s, 2), 6.43 (d, 1), 6.99 (t, 1), 7.14 (d, 1), , 1), 7.34 (dd, 1), 7.82 - 8.00 (m, 4), 8.26 (t, 1), 8.43 (m, 2), 8.51 (if, 1).
composé n°41 : (400 MHz) 1 ,22 (t, 3 H), 2,14 (s, 3 H), 2,18 - 2,49 (m, 10 H), 3,31 - 3,39 (m, 2 H), 3,44 - 3,58 (m, 2 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,43 (d, 1 H), 6,97 (t, 1 H), 7,15 (d, 1 H), 7,34 (dd, 1 H), 7,81 - 7,89 (m, 2 H), 7,89 - 7,98 (m, 2 H), 8,27 (t, 1 H), 8,32 - 8,45 (m, 2 H), 8,49 (d, 1 H)compound no. 41: (400 MHz) 1, 22 (t, 3H), 2.14 (s, 3H), 2.18 - 2.49 (m, 10H), 3.31 - 3.39 (m, 2H), 3.44 - 3.58 (m, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.43 (d, 1H) , 6.97 (t, 1H), 7.15 (d, 1H), 7.34 (dd, 1H), 7.81-7.89 (m, 2H), 7.89-7. , 98 (m, 2H), 8.27 (t, 1H), 8.32 - 8.45 (m, 2H), 8.49 (d, 1H)
composé n°42 : (250 MHz) 1 ,22 (t, 3 H), 2,02 (br. s., 1 H), 2,27 - 2,38 (m, 4 H), 2,41 (t, 2H), 2,62 - 2,74 (m, 4 H), 3,22 - 3,41 (m, 2 H), 3,44 - 3,59 (m, 2 H), 4,13 (d, 2 H), 5,83 (s, 2 H), 6,44 (d,1 H), 7,00 (t, 1 H), 7,16 (d, 1 H), 7,35 (dd, 1 H), 7,82 - 8,02 (m, 4 H), 8,28 (t, 1 H), 8,33 - 8,46 (m, 2 H), 8,51 (d, 1 H)Compound No. 42: (250 MHz) 1, 22 (t, 3H), 2.02 (br s, 1H), 2.27 - 2.38 (m, 4H), 2.41 (b.p. t, 2H), 2.62 - 2.74 (m, 4H), 3.22 - 3.41 (m, 2H), 3.44 - 3.59 (m, 2H), 4.13. (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H), 7.00 (t, 1H), 7.16 (d, 1H), 7.35 (d, 1H), (dd, 1H), 7.82-8.02 (m, 4H), 8.28 (t, 1H), 8.33-8.46 (m, 2H), 8.51 (d, 1H), , 1H)
composé n°43 : 1 H NMR (500 MHz, DMSO-c/6) δ ppm 1.24 (t, 3 H), 1.35 - 1.44 (m, 2 H), 1.51 (quin, 4 H), 2.33 - 2.50(m, 6 H), 3.33 - 3.41 (m, 2 H), 3.50 - 3.59 (m, 2 H), 6.48 - 6.56 (m, 3 H), 6.86 (d, 1 H), 7.22 (d, 1 H),7.49 (d, 1 H), 7.66 (dd, 1 H), 7.90 - 8.06 (m, 3 H), 8.16 (d, 1 H), 8.31 (t, 1 H), 8.41 (q, 2 H), 9.88 (s, 1 H).Compound No. 43: 1 H NMR (500 MHz, DMSO-c / 6) δ ppm 1.24 (t, 3H), 1.35 - 1.44 (m, 2H), 1.51 (quin, 4H), 2.33 - 2.50 ( m, 6H), 3.33 - 3.41 (m, 2H), 3.50 - 3.59 (m, 2H), 6.48 - 6.56 (m, 3H), 6.86 (d, 1H), 7.22 (d, 1H). ), 7.49 (d, 1H), 7.66 (dd, 1H), 7.90-8.06 (m, 3H), 8.16 (d, 1H), 8.31 (t, 1H), 8.41 (q, 2H); ), 9.88 (s, 1H).
composé n°44 : 1 H NMR (250 MHz, DMSO-c/6) d ppm 1.23 (t, 3 H), 1.31 - 1.64 (m, 6 H), 2.23 - 2.47 (m, 6 H), 3.29 -3.41 (m, 2 H), 3.46 - 3.65 (m, 2 H), 7.21 (s, 1 H), 7.26 (d, 1 H), 7.51 (dd, 1 H), 7.69 (d, 1 H), 7.93 - 8.13(m, 4 H), 8.31 (t, 1 H), 8.37 - 8.47 (m, 2 H), 8.62 (d, 1 H), 8.85 (d, 1 H), 10.17 (s, 1 H).Compound No. 44: 1 H NMR (250 MHz, DMSO-c / 6) d ppm 1.23 (t, 3H), 1.31 - 1.64 (m, 6H), 2.23 - 2.47 (m, 6H), 3.29 - 3.41 (m, 2H), 3.46 - 3.65 (m, 2H), 7.21 (s, 1H), 7.26 (d, 1H), 7.51 (dd, 1H), 7.69 (d, 1H), 7.93 - 8.13 (m, 4H), 8.31 (t, 1H), 8.37 - 8.47 (m, 2H), 8.62 (d, 1H), 8.85 (d, 1H), 10.17 (s, 1H). ).
composé n°45 : 1 H NMR (250 MHz, DMSO-c/6) d ppm 1.22 (t, 7 H), 1.96 - 2.26 (m, 2 H), 3.16 (d, 4 H), 3.40 (t, 2 H),3.52 (ddt, 2 H), 3.71 (d, 2 H), 4.13 (d, 2 H), 5.83 (s, 2 H), 6.44 (d, 1 H), 7.07 (t, 1 H), 7.13 (d, 1 H), 7.35(dd, 1 H), 7.73 (d, 1 H), 7.80 - 7.96 (m, 3 H), 8.28 (t, 1 H), 8.55 (br. s., 2 H), 11.05 (br. s., 1 H) compound no. 45: 1H NMR (250 MHz, DMSO-c / 6) d ppm 1.22 (t, 7H), 1.96 - 2.26 (m, 2H), 3.16 (d, 4H), 3.40 (t, 2H), 3.52 (ddt, 2H), 3.71 (d, 2H), 4.13 (d, 2H), 5.83 (s, 2H), 6.44 (d, 1H). ), 7.07 (t, 1H), 7.13 (d, 1H), 7.35 (dd, 1H), 7.73 (d, 1H), 7.80 - 7.96 (m, 3H), 8.28 (t, 1H). ), 8.55 (ss, 2 hrs), 11.05 (ss, 1 hrs)
Les composés du Tableau I ont pour nom chimique (obtenus à partir du logiciel Autonom®) :The compounds of Table I have the chemical name (obtained from the Autonom ® software):
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-piperidin- 1-yl-ethyl)-nicotinamide (composé n°1 ) • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-2,5-difluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°2)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (Compound No. 1) • 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,5-difluoro-phenyl} -2-ethylamino-N- (2-piperidin) 1-yl-ethyl) -nicotinamide (No. 2)
• 2-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-4-ethylamino-pyrimidine-5- carboxylic acid (2-piperidin-1-yl-ethyl)-amide (n°3)2- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-ethylamino-pyrimidine-5-carboxylic acid (2-piperidin-1-yl) ethyl) -amide (No. 3)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-cyclopropylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°4)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-cyclopropylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (No. 4)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-phenylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°5)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-phenylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (No. 5)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2- isopropylamino-ethyl)-nicotinamide (n°6) • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-[2-(1 ,1-dioxo- thiomorpholin-4-yl)-ethyl]-2-ethylamino-nicotinamide (n°7)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-isopropylamino-ethyl) -nicotinamide (no. 6) ) 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2- (1,1-dioxothiomorpholin-4-yl)} -ethyl] -2-ethylamino-nicotinamide (No. 7)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-hydroxy- ethyl)-nicotinamide (n°8)6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-hydroxyethyl) -nicotinamide (no. 8) )
• 2-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-4-cyclopropylamino- pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide (n°9)2- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-cyclopropylaminopyrimidine-5-carboxylic acid (2-piperidin-1-yl) ethyl) -amide (No. 9)
• 2-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-4-phenylamino-pyrimidine-5- carboxylic acid (2-piperidin-1-yl-ethyl)-amide (n°10)2- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-phenylamino-pyrimidine-5-carboxylic acid (2-piperidin-1-yl) ethyl) -amide (No. 10)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-2-fluoro-phenyl}-2-ethylamino-N-(2-piperidin- 1-yl-ethyl)-nicotinamide (n°1 1 ) • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-pyrrolidin- 1-yl-ethyl)-nicotinamide (n°12)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (1, 1) • 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-pyrrolidin) -N yl-ethyl) -nicotinamide (no. 12)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-methyl- nicotinamide (n°13)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-methyl-nicotinamide (no. 13)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-methoxy- ethyl)-nicotinamide (n°14)6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-methoxyethyl) -nicotinamide (no. 14) )
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-(2-azepan-1-yl-ethyl)-2- ethylamino-nicotinamide (n°15)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide (No. 15)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(1-oxo- thiomorpholin-4-yl)-ethyl]-nicotinamide (n°16) • 6-{4-[3-(6-Amino-5-methyl-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°17) • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-[2-((cis-3,5-dimethyl- piperidin-1-yl)-ethyl]-2-ethylamino-nicotinamide (n°18)6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (1-oxothiomorpholin-4-yl)} ) -ethyl] -nicotinamide (No.16) • 6- {4- [3- (6-Amino-5-methyl-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino N- (2-piperidin-1-yl-ethyl) -nicotinamide (no. 17) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2 - ((cis-3,5-dimethyl-piperidin-1-one) yl) -ethyl] -2-ethylamino-nicotinamide (no. 18)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-[2-(cis-2,6-dimethyl- piperidin-1-yl)-ethyl]-2-ethylamino-nicotinamide (n°19) - 6-(4-{3-[2-(6-Amino-pyridin-3-yl)-ethyl]-ureido}-3-fluoro-phenyl)-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°20)6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2- (cis-2,6-dimethylpiperidin-1-yl) ) -ethyl] -2-ethylamino-nicotinamide (no. 19) - 6- (4- {3- [2- (6-Amino-pyridin-3-yl) -ethyl] -ureido} -3-fluoro-phenyl 2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (no. 20)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-2,6-difluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°21 )6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,6-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -Nicotinamide (No. 21)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-2,3-difluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°22)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,3-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -Nicotinamide (No. 22)
• 4'-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-ethylamino-3'-fluoro-biphenyl-4-carboxylic acid (2-piperidin-1-yl-ethyl)-amide (n°23)• 4 '- [3- (6-aminopyridin-3-ylmethyl) -ureido] -3-ethylamino-3'-fluoro-biphenyl-4-carboxylic acid (2-piperidin-1-yl-ethyl) -amide (No. 23)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-cyclopropyl-2- cyclopropylamino-nicotinamide (n°24) • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-cyclopentyl-2- cyclopropylamino-nicotinamide (n°25)6- {4- [3- (6-aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-cyclopropyl-2-cyclopropylamino-nicotinamide (No.24) • 6- {4 - [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-cyclopentyl-2-cyclopropylamino-nicotinamide (no. 25)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-butyl-2-cyclopropylamino- nicotinamide (n°26)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-butyl-2-cyclopropylamino-nicotinamide (no. 26)
• 2-Ethylamino-6-[3-fluoro-4-(3-pyridin-3-ylmethyl-ureido)-phenyl]-N-(2-piperidin-1-yl-ethyl)- nicotinamide (n°27)2-Ethylamino-6- [3-fluoro-4- (3-pyridin-3-ylmethyl-ureido) -phenyl] -N- (2-piperidin-1-yl-ethyl) -nicotinamide (No.27)
• 2-Ethylamino-6-{3-fluoro-4-[3-(6-methylamino-pyridin-3-ylmethyl)-ureido]-phenyl}-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°28)2-Ethylamino-6- {3-fluoro-4- [3- (6-methylamino-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide (No. 28)
• 6-{4-[3-(6-Dimethylamino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°29) • 6-{4-[3-(5-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-piperidin- 1-yl-ethyl)-nicotinamide (n°30)6- {4- [3- (6-Dimethylamino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (29) • 6- {4- [3- (5-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl) -ethyl) -nicotinamide (No. 30)
• 2-Ethylamino-6-{3-fluoro-4-[3-(5-fluoro-pyridin-3-ylmethyl)-ureido]-phenyl}-N-(2-piperidin-1- yl-ethyl)-nicotinamide (n°31 )2-Ethylamino-6- {3-fluoro-4- [3- (5-fluoro-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide (No. 31)
• 2-Ethylamino-6-{3-fluoro-4-[3-(5-methyl-pyridin-3-ylmethyl)-ureido]-phenyl}-N-(2-piperidin- 1-yl-ethyl)-nicotinamide (n°32)2-Ethylamino-6- {3-fluoro-4- [3- (5-methyl-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide (No. 32)
• 6-{4-[3-(6-Amino-pyridin-3-yl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-piperidin-1-yl- ethyl)-nicotinamide (n°33)6- {4- [3- (6-Amino-pyridin-3-yl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide (No. 33)
• 2-Ethylamino-6-{3-fluoro-4-[3-(6-methyl-pyridin-3-ylmethyl)-ureido]-phenyl}-N-(2-piperidin- 1-yl-ethyl)-nicotinamide (n°34) • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(4- hydroxy-piperidin-1-yl)-ethyl]-nicotinamide (n°35) • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(3- hydroxy-piperidin-1-yl)-ethyl]-nicotinamide (n°36)2-Ethylamino-6- {3-fluoro-4- [3- (6-methyl-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide (# 34) • 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-hydroxy) -benzoyl) piperidin-1-yl) -ethyl] -nicotinamide (no. 35) 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (3-hydroxy-piperidin-1-yl)} ) -ethyl] -nicotinamide (No 36)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-(2-diisopropylamino-ethyl)- 2-ethylamino-nicotinamide (n°37) • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(4- methoxy-piperidin-1-yl)-ethyl]-nicotinamide (n°38)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-diisopropylamino-ethyl) -2-ethylamino-nicotinamide (37) ) • 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-methoxy-piperidin-1-) yl) -ethyl] -nicotinamide (No. 38)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(3-piperidin- 1-yl-propyl)-nicotinamide (n°39)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (3-piperidin-1-yl-propyl) -nicotinamide (No. 39)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(4-piperidin- 1-yl-butyl)-nicotinamide (n°40)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (4-piperidin-1-yl-butyl) -nicotinamide (No. 40)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(4-methyl- piperazin-1-yl)-ethyl]-nicotinamide (n°41 )6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-methyl-piperazin-1-yl)} ) -ethyl] -nicotinamide (No 41)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-piperazin- 1-yl-ethyl)-nicotinamide (n°42) • 6-{4-[(E)-3-(6-Amino-pyridin-3-yl)-acryloylamino]-3-fluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide (n°43)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperazin-1-yl-ethyl) -nicotinamide (# 42) • 6- {4 - [(E) -3- (6-Aminopyridin-3-yl) -acryloylamino] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin) -1-yl-ethyl) -nicotinamide (No 43)
• 2-Ethylamino-6-[3-fluoro-4-((E)-3-pyridin-3-yl-acryloylamino)-phenyl]-N-(2-piperidin-1-yl- ethyl)-nicotinamide (n°44)2-Ethylamino-6- [3-fluoro-4 - ((E) -3-pyridin-3-yl-acryloylamino) -phenyl] -N- (2-piperidin-1-yl-ethyl) -nicotinamide (n 44)
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(1-oxy- piperidin-1-yl)-ethyl]-nicotinamide (n°45)6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (1-oxypiperidin-1-yl)} ) -ethyl] -nicotinamide (No 45)
Les composés décrits dans le Tableau I ont fait l'objet d'essais pharmacologiques permettant de déterminer l'activité anticancéreuse. Ils ont été testés in vitro sur la lignée tumorale HCT116 (ATCC-CCL247). La prolifération et la viabilité cellulaire ont été déterminées dans un test utilisant le 3-(4,5-diméthylthiazol-2-yl)-5-(3-carboxyméthoxyphényl)-2-(4-sulfophényl)-2H- tétrazolium (MTS) selon Fujishita T. et al. Oncology 2003, 64(4), 399-406. Dans ce test, on mesure la capacité mitochondriale des cellules vivantes à transformer le MTS en un composé coloré après 72 heures d'incubation du composé testé. La concentration en composé qui conduit à 50% de perte de prolifération et de viabilité cellulaire est notée IC5O-The compounds described in Table I have been the subject of pharmacological tests for determining anticancer activity. They were tested in vitro on the tumor line HCT116 (ATCC-CCL247). Proliferation and cell viability were determined in a test using 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) according to Fujishita T. et al. Oncology 2003, 64 (4), 399-406. In this test, the mitochondrial capacity of living cells is measured to transform MTS into a colored compound after 72 hours of incubation of the test compound. The concentration of compound which leads to 50% loss of proliferation and cell viability is noted as IC 5 O.
Pour les composés du Tableau I, on trouve une IC5o<1OOO nM (1 μM) sur la lignée HCT116. Certains composés (par ex. n°1 , 5, 11 , 19, 27) présentent même une activité <1 nM. For the compounds of Table I, there is an IC 5 o <1OOO nM (1 .mu.M) to the HCT116 line. Some compounds (eg Nos. 1, 5, 11, 19, 27) even have an activity <1 nM.

Claims

REVENDICATIONS
1. Composé de formule (I) :1. Compound of formula (I):
dans laquelle : in which :
• Z et Z' représentent N ou CH ;• Z and Z 'represent N or CH;
• x est un entier valant 1 ou 2, représentant le nombre d'atome(s) de fluor attaché(s) au noyau phényle central ;X is an integer equal to 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring;
• L représente un groupe -CH=CH- ou -(CH2)nNH - dans lequel le groupe NH est rattaché au C=O et n est un entier valant 0, 1 ou 2 ;• L represents a group -CH = CH- or - (CH 2 ) n NH - in which the NH group is attached to C = O and n is an integer of 0, 1 or 2;
• Ri représente un atome d'hydrogène, un groupe (C1-C6)alkyle, (C3-C6)cycloalkyle, phényle ;• Ri represents a hydrogen atom, a (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl, phenyl;
• R'i représente un atome d'hydrogène ou un groupe (C1-C6)alkyle ;R 'represents a hydrogen atom or a (C 1 -C 6 ) alkyl group;
• R2 représente : - un groupe (C3-C6)cycloalkyle ;R 2 represents: a (C 3 -C 6 ) cycloalkyl group;
- un groupe (C1-C6)alkyle, éventuellement substitué par : o un ou plusieurs groupes hydroxy ou (C1-C4)alcoxy ; o un groupe -NRaRb dans lequel R3 et Rb représentent indépendamment l'un de l'autre un atome d'hydrogène ou un groupe (C1-C6)alkyle ou forment ensemble avec l'atome d'azote auquel ils sont reliés un groupe (C4-C6)hétérocycloalkyle comprenant éventuellement dans le cycle le groupe -S(O)q avec q= 0, 1 ou 2 ou le groupe -NH- ou -N(C1-C4)alkyle- et étant éventuellement substitué par un ou plusieurs substituant(s), identiques ou différents les uns des autres lorsqu'il y en a plusieurs, choisi(s) parmi un groupe - OH ; (C1-C4)alcoxy ou (C1-C4)alkyle ;a (C 1 -C 6 ) alkyl group, optionally substituted with: one or more hydroxyl or (C 1 -C 4 ) alkoxy groups; a group -NR a R b in which R 3 and R b represent, independently of one another, a hydrogen atom or a (C 1 -C 6 ) alkyl group or together with the nitrogen atom to which they are connected a (C 4 -C 6 ) heterocycloalkyl group optionally comprising in the ring the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (C 1 -C 4 ) alkyl- and being optionally substituted by one or more substituents (s), identical or different from each other when there are several, selected from an --OH group; (C 1 -C 4 ) alkoxy or (C 1 -C 4 ) alkyl;
● R3 représente au moins un substituant du noyau pyridine choisi parmi un atome d'hydrogène ou de fluor, un groupe (C1-C4)alkyle ou -NRcRd dans lequel Rc et Rd représentent un atome d'hydrogène ou un groupe (C1-C4)alkyle.R 3 represents at least one substituent of the pyridine ring chosen from a hydrogen or fluorine atom, a (C 1 -C 4 ) alkyl group or -NR c R d in which R c and R d represent an atom of hydrogen or a (C 1 -C 4 ) alkyl group.
2. Composé selon la revendication 1 dans lequel Ri représente le groupe cyclopropyle, ou le groupe phényle ou un groupe (C1-C6)alkyle et R'1 représente un atome d'hydrogène.A compound according to claim 1 wherein R 1 is cyclopropyl, or phenyl or (C 1 -C 6 ) alkyl and R ' 1 is an atom hydrogen.
3. Composé selon la revendication 1 dans lequel R'i représente un atome d'hydrogène.3. The compound of claim 1 wherein R'i represents a hydrogen atom.
4. Composé selon la revendication 1 à 3 dans lequel R2 représente :4. Compound according to claim 1 to 3 wherein R 2 represents:
- le groupe cyclopropyle ou cyclopentyle ;cyclopropyl or cyclopentyl group;
- un groupe (C1-C6)alkyle, éventuellement substitué par : o un ou plusieurs groupe(s) -OH ou (C1-C4)alcoxy ;a (C 1 -C 6 ) alkyl group, optionally substituted by: one or more -OH or (C 1 -C 4 ) alkoxy group (s);
o le groupe pyrrolidinyle pipéridinyle pipérazinyle the pyrrolidinyl piperidinyl piperazinyl group
ou azépanyle or azepanyl
thiomorpholinyle 1-oxo-thiomorpholinyle ( thiomorpholinyl 1-oxo-thiomorpholinyl (
1 ,1-dioxo-thiomorpholinyle ( ,3-hydroxypipéridinyle ( 0 1, 1-dioxo-thiomorpholinyl (3-hydroxypiperidinyl (0
hydroxy-pipéridinyle 4-méthoxy-pipéridinyle hydroxy-piperidinyl 4-methoxy-piperidinyl
3,5-diméthyl-pipéridinyle ou cis-2,6-diméthyl-pipéridinyle 3,5-dimethyl-piperidinyl or cis-2,6-dimethyl-piperidinyl
5. Composé selon l'une des revendications précédentes dans lequel R3 est en position 5 et/ou 6 sur le noyau pyridine.5. Compound according to one of the preceding claims wherein R 3 is in position 5 and / or 6 on the pyridine ring.
6. Composé selon l'une des revendications précédentes dans lequel le nombre de substituants R3 est égal à 1 et/ou R3 est en position 5 ou 6 sur le noyau pyridine.6. Compound according to one of the preceding claims wherein the number of substituents R 3 is 1 and / or R 3 is in position 5 or 6 on the pyridine ring.
7. Composé selon l'une des revendications 1 à 6 dans lequel R3 est -NH2. 7. Compound according to one of claims 1 to 6 wherein R 3 is -NH 2 .
8. Composé selon l'une des revendications précédentes dans lequel n est égal à 1 ou L représente le groupe -CH=CH- sous forme E ou Z.8. Compound according to one of the preceding claims wherein n is 1 or L represents the group -CH = CH- in form E or Z.
9. Composé selon l'une des revendications précédentes dans lequel Z et Z' représentent respectivement N et CH ; CH et CH ou N et N.9. Compound according to one of the preceding claims wherein Z and Z 'respectively represent N and CH; CH and CH or N and N.
10. Composé selon l'une des revendications précédentes dans lequel x vaut 1.10. Compound according to one of the preceding claims wherein x is 1.
11. Composé selon la revendication 1 de formule (I") :11. Compound according to claim 1 of formula (I "):
dans laquelle Ri représentent un groupe (C1-C4)alkyle, R2 représente un groupe (Cr Cβjalkyle éventuellement substitué par un groupe -NRaRb dans lequel R3 et Rb forment ensemble avec l'atome d'azote auquel ils sont reliés le groupe (C4- Cβjhétérocycloalkyle comprenant éventuellement dans le cycle le groupe -S(O)q avec q= 0, 1 ou 2 ou le groupe -NH- ou -N(C1-C4)alkyle, x est un entier valant 1 ou 2, représentant le nombre d'atome(s) de fluor attaché(s) au noyau phényle central et R3 est tel que défini à l'une des revendications 1 , 5 à 7. wherein R 1 is (C 1 -C 4 ) alkyl, R 2 is (C 1 -C 4 ) alkyl optionally substituted with -NR a R b wherein R 3 and R b together with the nitrogen atom they are connected to the group (C 4 -C 8 ) heterocycloalkyl optionally comprising in the ring the group -S (O) q with q = 0, 1 or 2 or the group -NH- or -N (C 1 -C 4 ) alkyl, x is an integer of 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring and R 3 is as defined in any one of claims 1, 5 to 7.
12. Composé selon la revendication 11 dans lequel le groupe (C4- C6)hétérocycloalkyle est choisi parmi groupe pyrrolidinyle, pipéridinyle, pipérazinyle,The compound according to claim 11 wherein the (C 4 -C 6 ) heterocycloalkyl group is selected from pyrrolidinyl, piperidinyl, piperazinyl,
N-(C1-C4)alkyle-pipérazinyle, azépanyle, thiomorpholinyle, 1-oxo-thiomorpholinyle,N- (C 1 -C 4 ) alkyl-piperazinyl, azepanyl, thiomorpholinyl, 1-oxothiomorpholinyl,
1 ,1-dioxo-thiomorpholinyle, 3-hydroxypipéridinyle ou 4-hydroxy-pipéridinyle, 4- méthoxy-pipéridinyle, c/s-3,5-diméthyl-pipéridinyle ou cis-2,6-diméthyl-pipéridinyle .1,1-dioxothiomorpholinyl, 3-hydroxypiperidinyl or 4-hydroxy-piperidinyl, 4-methoxy-piperidinyl, cis-3,5-dimethyl-piperidinyl or cis-2,6-dimethyl-piperidinyl.
13. Composé selon l'une des revendications 1 à 12 dans lequel x vaut 1 et l'atome de fluor est en position 3.13. Compound according to one of claims 1 to 12 wherein x is 1 and the fluorine atom is in position 3.
14. Composé selon l'une quelconque des revendications précédentes sous forme de base ou d'un sel d'addition à un acide ou sous forme d'un hydrate ou d'un solvat.A compound according to any one of the preceding claims in base form or an acid addition salt or in the form of a hydrate or a solvate.
15. Composé selon la revendication 1 choisi parmi l'un des suivants : • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-piperidin- 1 -yl-ethyl)-nicotinamideThe compound of claim 1 selected from one of the following: 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-2,5-difluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide • 2-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-4-ethylamino-pyrimidine-5- carboxylic acid (2-pipeιïdin-1-yl-ethyl)-amide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,5-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) 2- (4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl-4-ethylamino-pyrimidine-5-carboxylic acid-2-piperidin-2-nicotinamide yl-ethyl) -amide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-cyclopropylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-cyclopropylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-phenylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-phenylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2- isopropylamino-ethyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-isopropylamino-ethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-[2-(1 ,1-dioxo- thiomorpholin-4-yl)-ethyl]-2-ethylamino-nicotinamide • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-hydroxy- ethyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2- (1,1-dioxothiomorpholin-4-yl) - ethyl] -2-ethylamino-nicotinamide • 6- {4- [3- (6-aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-hydroxy) ethyl) -nicotinamide
• 2-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-4-cyclopropylamino- pyrimidine-5-carboxylic acid (2-piperidin-1-yl-ethyl)-amide2- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-cyclopropylaminopyrimidine-5-carboxylic acid (2-piperidin-1-yl) ethyl) amide
• 2-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-4-phenylamino-pyrimidine-5- carboxylic acid (2-piperidin-1-yl-ethyl)-amide2- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -4-phenylamino-pyrimidine-5-carboxylic acid (2-piperidin-1-yl) ethyl) amide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-2-fluoro-phenyl}-2-ethylamino-N-(2-piperidin- 1 -yl-ethyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-pyrrolidin- 1 -yl-ethyl)-nicotinamide • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-methyl- nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-pyrrolidin-1-yl-ethyl) -nicotinamide 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N-methyl-nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-methoxy- ethyl)-nicotinamide6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-methoxyethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-(2-azepan-1-yl-ethyl)-2- ethylamino-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-azepan-1-yl-ethyl) -2-ethylamino-nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(1-oxo- thiomorpholin-4-yl)-ethyl]-nicotinamide6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (1-oxothiomorpholin-4-yl)} ) -ethyl] -nicotinamide
• 6-{4-[3-(6-Amino-5-methyl-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide - 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-[2-((cis-3,5-dimethyl- piperidin-1-yl)-ethyl]-2-ethylamino-nicotinamide • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-[2-(cis-2,6-dimethyl- piperidin-1-yl)-ethyl]-2-ethylamino-nicotinamide6- {4- [3- (6-Amino-5-methyl-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl) ethyl) -nicotinamide - 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2 - ((cis-3,5-dimethyl) piperidin-1-yl) -ethyl] -2-ethylamino-nicotinamide 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- [2- (cis-2,6-dimethylpiperidin-1-yl) ) -ethyl] -2-ethylamino-nicotinamide
- 6-(4-{3-[2-(6-Amino-pyridin-3-yl)-ethyl]-ureido}-3-fluoro-phenyl)-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-2,6-difluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide6- (4- {3- [2- (6-Amino-pyridin-3-yl) -ethyl] -ureido} -3-fluoro-phenyl) -2-ethylamino-N- (2-piperidin) -1- yl-ethyl) -nicotinamide • 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,6-difluoro-phenyl} -2-ethylamino-N- (2-piperidin) 1-yl-ethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-2,3-difluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -2,3-difluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) nicotinamide
• 4'-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-ethylamino-3'-fluoro-biphenyl-4-carboxylic acid (2-pipeιïdin-1-yl-ethyl)-amide• 4 '- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-ethylamino-3'-fluoro-biphenyl-4-carboxylic acid (2-piperadin-1-yl-ethyl) -amide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-cyclopropyl-2- cyclopropylamino-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N-cyclopropyl-2-cyclopropylamino-nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-cyclopentyl-2- cyclopropylamino-nicotinamide • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-butyl-2-cyclopropylamino- nicotinamide6- [4- [3- (6-aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl] -N-cyclopentyl-2-cyclopropylamino-nicotinamide • 6- {4- [3- ( 6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl-N-butyl-2-cyclopropylamino-nicotinamide
• 2-Ethylamino-6-[3-fluoro-4-(3-pyridin-3-ylmethyl-ureido)-phenyl]-N-(2-piperidin-1-yl-ethyl)- nicotinamide2-Ethylamino-6- [3-fluoro-4- (3-pyridin-3-ylmethyl-ureido) -phenyl] -N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 2-Ethylamino-6-{3-fluoro-4-[3-(6-methylamino-pyridin-3-ylmethyl)-ureido]-phenyl}-N-(2- piperidin-1-yl-ethyl)-nicotinamide2-Ethylamino-6- {3-fluoro-4- [3- (6-methylamino-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 6-{4-[3-(6-Dimethylamino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide6- {4- [3- (6-Dimethylamino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 6-{4-[3-(5-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-piperidin- 1 -yl-ethyl)-nicotinamide • 2-Ethylamino-6-{3-fluoro-4-[3-(5-fluoro-pyridin-3-ylmethyl)-ureido]-phenyl}-N-(2-piperidin-1- yl-ethyl)-nicotinamide6- {4- [3- (5-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide 2-Ethylamino-6- {3-fluoro-4- [3- (5-fluoro-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 2-Ethylamino-6-{3-fluoro-4-[3-(5-methyl-pyridin-3-ylmethyl)-ureido]-phenyl}-N-(2-piperidin- 1 -yl-ethyl)-nicotinamide2-Ethylamino-6- {3-fluoro-4- [3- (5-methyl-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-yl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-piperidin-1-yl- ethyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-yl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 2-Ethylamino-6-{3-fluoro-4-[3-(6-methyl-pyridin-3-ylmethyl)-ureido]-phenyl}-N-(2-piperidin- 1 -yl-ethyl)-nicotinamide2-Ethylamino-6- {3-fluoro-4- [3- (6-methyl-pyridin-3-ylmethyl) -ureido] -phenyl} -N- (2-piperidin-1-yl-ethyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(4- hydroxy-piperidin-1-yl)-ethyl]-nicotinamide - 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(3- hydroxy-piperidin-1-yl)-ethyl]-nicotinamide • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-N-(2-diisopropylamino-ethyl)- 2-ethylamino-nicotinamide6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-hydroxy-piperidin-1-yl)} ) -ethyl] -nicotinamide - 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (3-hydroxy) -piperidin-1-yl) -ethyl] -nicotinamide 6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -N- (2-diisopropylamino-ethyl) -2-ethylamino-nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(4- methoxy-piperidin-1-yl)-ethyl]-nicotinamide • 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(3-piperidin- 1 -yl-propyl)-nicotinamide6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-methoxy-piperidin-1-yl)} ) -ethyl] -nicotinamide • 6- {4- [3- (6-Aminopyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (3-piperidin) -1- yl-propyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(4-piperidin- 1 -yl-butyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (4-piperidin-1-yl-butyl) -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(4-methyl- piperazin-1-yl)-ethyl]-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (4-methyl-piperazin-1-yl)} ) -ethyl] -nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-(2-piperazin- 1 -yl-ethyl)-nicotinamide6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperazin-1-yl-ethyl) -nicotinamide
' 6-{4-[(E)-3-(6-Amino-pyridin-3-yl)-acryloylamino]-3-fluoro-phenyl}-2-ethylamino-N-(2- piperidin-1-yl-ethyl)-nicotinamide • 2-Ethylamino-6-[3-fluoro-4-((E)-3-pyridin-3-yl-acryloylamino)-phenyl]-N-(2-piperidin-1-yl- ethyl)-nicotinamide6- {4 - [(E) -3- (6-Amino-pyridin-3-yl) -acryloylamino] -3-fluoro-phenyl} -2-ethylamino-N- (2-piperidin-1-yl) -1- ethyl) -nicotinamide • 2-Ethylamino-6- [3-fluoro-4 - ((E) -3-pyridin-3-yl-acryloylamino) -phenyl] -N- (2-piperidin-1-yl-ethyl) nicotinamide
• 6-{4-[3-(6-Amino-pyridin-3-ylmethyl)-ureido]-3-fluoro-phenyl}-2-ethylamino-N-[2-(1-oxy- piperidin-1-yl)-ethyl]-nicotinamide sous forme de base ou d'un sel d'addition à un acide ou sous forme d'un hydrate ou d'un solvat.6- {4- [3- (6-Amino-pyridin-3-ylmethyl) -ureido] -3-fluoro-phenyl} -2-ethylamino-N- [2- (1-oxypiperidin-1-yl)} ) -ethyl] -nicotinamide in base form or an acid addition salt or in the form of a hydrate or a solvate.
16. Composé de formule :16. Compound of formula:
dans laquelle L représente un groupe -CH=CH- ou-(CH2)n-NH- dans lequel le groupe NH est rattaché au C=O, R3 est tel que défini à la revendication 1 , 5 à 7 et K et K' représentent un atome d'hydrogène, un groupe alkyle ou aryle, éventuellement reliés entre eux pour former ensemble avec l'atome de bore et les deux atomes d'oxygène un cycle de 5 à 7 chainons éventuellement substitué par au moins un groupe (Cr wherein L represents a group -CH = CH- or- (CH 2 ) n -NH- in which the NH group is attached to C = O, R 3 is as defined in claim 1, 5 to 7 and K and K 'represent a hydrogen atom, an alkyl or aryl group, optionally linked together to form together with the boron atom and the two oxygen atoms a 5- to 7-membered ring optionally substituted with at least one group ( Cr
C4)alkyle ou auquel éventuellement est accolé sur deux atomes de carbone consécutifs dudit cycle un groupe phényle. C 4 ) alkyl or to which is attached to two consecutive carbon atoms of said ring a phenyl group.
17. Composé selon la revendication 13 caractérisé en ce que -B(OK)(OK') représente l'un des groupes suivants :17. Compound according to claim 13, characterized in that -B (OK) (OK ') represents one of the following groups:
18. Composé de formule18. Formula compound
ou de formuleor formula
dans lesquelles Ri, R'i, R2, R3, Z, Z' et x sont tels que définis à l'une des revendications 1 à 10. in which R 1, R 1 , R 2 , R 3 , Z, Z 'and x are as defined in one of claims 1 to 10.
19. Médicament caractérisé en ce qu'il comprend un composé selon l'une des revendications 1 à 15.19. Medicinal product characterized in that it comprises a compound according to one of claims 1 to 15.
20. Composition pharmaceutique caractérisée en ce qu'elle comprend un composé selon l'un des revendications 1 à 15 ainsi qu'au moins un excipient pharmaceutiquement acceptable.20. Pharmaceutical composition characterized in that it comprises a compound according to one of claims 1 to 15 and at least one pharmaceutically acceptable excipient.
21. Composé selon la revendication 1 à 15 comme anticancéreux.21. Compound according to claim 1 to 15 as anti-cancer agents.
22. Utilisation d'un composé selon l'une des revendications 1 à 15 pour la fabrication d'un médicament destiné au traitement ou à la prévention d'un cancer.22. Use of a compound according to one of claims 1 to 15 for the manufacture of a medicament for the treatment or prevention of cancer.
23. Utilisation d'un composé choisi dans la liste suivante : en tant qu'intermédiaire dans la préparation d'un composé tel que défini à l'une des revendications 1 à 15. 23. Use of a compound selected from the following list: as an intermediate in the preparation of a compound as defined in one of claims 1 to 15.
EP10716566A 2009-03-24 2010-03-22 Nicotinamide derivatives, preparation thereof, and therapeutic use thereof as anticancer drugs Withdrawn EP2411368A1 (en)

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PCT/FR2010/050511 WO2010109122A1 (en) 2009-03-24 2010-03-22 Nicotinamide derivatives, preparation thereof, and therapeutic use thereof as anticancer drugs

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RU2617988C2 (en) 2010-09-03 2017-05-02 ФОРМА ТиЭм, ЭлЭлСИ New compounds and compositions for nampt inhibition
US9169209B2 (en) 2011-05-04 2015-10-27 Forma Tm, Llc Compounds and compositions for the inhibition of NAMPT
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US9938258B2 (en) 2012-11-29 2018-04-10 Karyopharm Therapeutics Inc. Substituted 2,3-dihydrobenzofuranyl compounds and uses thereof
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EA201890524A1 (en) 2015-08-18 2018-07-31 Кариофарм Терапевтикс Инк. (S, E) -3- (6-AMINOPYRIDIN-3-IL) -N - ((5- (4- (3-Fluoro-3-Methylpyrrolidin-1-Carbonyl) phenyl) -7- (4-Fluoro-phenyl) BENZOFURAN-2-IL) METHYL ACRYLAMIDE FOR THE TREATMENT OF CANCER
US10858347B2 (en) 2015-12-31 2020-12-08 Karyopharm Therapeutics Inc. Multicyclic compounds and uses thereof
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