WO2023036995A1 - Alkynylcarbinols with high cytotoxicity - Google Patents

Alkynylcarbinols with high cytotoxicity Download PDF

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WO2023036995A1
WO2023036995A1 PCT/EP2022/075358 EP2022075358W WO2023036995A1 WO 2023036995 A1 WO2023036995 A1 WO 2023036995A1 EP 2022075358 W EP2022075358 W EP 2022075358W WO 2023036995 A1 WO2023036995 A1 WO 2023036995A1
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group
alkyl
compound
alkynyl
formula
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PCT/EP2022/075358
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French (fr)
Inventor
Sébastien BRITTON
Stéphanie BALLEREAU
Patrick Calsou
Rémi Chauvin
Hafida Gaspard
Yves Genisson
Dymytrii LISTUNOV
Valérie MARAVAL
Pauline RULLIERE
Margaux BOSSUAT
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Centre National De La Recherche Scientifique
Universite Paul Sabatier Toulouse Iii
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Publication of WO2023036995A1 publication Critical patent/WO2023036995A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/16—Radicals substituted by singly bound hetero atoms other than halogen by oxygen atoms
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/28—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/28—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings
    • C07C33/30—Alcohols containing only six-membered aromatic rings as cyclic part with unsaturation outside the aromatic rings monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C33/00—Unsaturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
    • C07C33/40—Halogenated unsaturated alcohols
    • C07C33/46—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts
    • C07C33/48—Halogenated unsaturated alcohols containing only six-membered aromatic rings as cyclic parts with unsaturation outside the aromatic rings
    • C07C33/483—Monocyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/40—Radicals substituted by oxygen atoms
    • C07D307/42—Singly bound oxygen atoms

Definitions

  • the present invention relates to alkynylcarbinols.
  • Naturally occurring acetylenic lipids constitute a rich family of bioactive compounds. For example, more than 100 natural acetylenic lipids have been identified from diverse species of marine sponges and shown to display various biological activities, including for most of them a pronounced cytotoxicity against several tumor cell lines. More precisely, the presence of a terminal alkynylcarbinol unit has been correlated with the antitumor activity of such natural compounds.
  • an acetylenic lipid with a terminal dialkynylca rbinol unit which exhibits a cytotoxicity against HCT116 tumor cells 100 times higher than the one of its natural parent (S,Ej-icos-4-en-l-yn-3-ol, which is a lipidic alkenylalkynylcarbinol isolated from the marine sponge Cribrochalina vasculum.
  • alkynylcarbinol motif is found in various cytotoxic natural or synthetic lipids, but the mechanism of action of those potential therapeutic agents remains unknown.
  • the present invention satisfies this need by providing novel alkynylcarbinols having a pronounced cytotoxicity against several tumor cell lines.
  • HSD17B11 i.e. 17-beta- hydroxysteroid dehydrogenase 11
  • a short-chain dehydrogenase/reductase expressed in cancer cells oxidizes these novel alkynylcarbinols into the corresponding ketones in the.
  • the generated alkynylketones, also called alkynylcarbinones are able to react with lysine and cysteine side chains, and thus covalently modify several proteins, thereby triggering endoplasmic reticulum stress, proteasome inhibition and apoptosis.
  • cytotoxic alkynylcarbinone species are instable in biological medium. It explains why the cytotoxicity of the chemically synthetized alkynylcarbinones is low when they are directly in contact with the cells and why the novel alkynylcarbinols thus may constitute a reservoir of cytotoxic prodrugs that can be used for the treatment of cancer.
  • R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -al lenyl or a C 1 -C 6 -a Ikyl group,
  • Ar is selected from the group consisting of aryl and heteroaryl, wherein
  • - aryl is a phenyl, naphthyl, indanyl, tetralinyl, biphenylyl, fluorenyl or anthacenyl group,
  • - heteroaryl is an aziridine, azepine, azetidine, benzimidazole, benzofuran, benzo[l,4]dioxine,
  • Ar may be substituted with 1 to 7 substituents independently chosen from halogen, OCF 3 , CF 3 , CH 2 OH, CCSi(i-Pr) 3 , CH 3 , OH, CHFCH 2 F, -O(CH 2 CH 2 O) n Et with n an integer comprised between 1 and 6, AC n H 2n B with n an integer comprised between 1 and 20 and A being selected from the group consisting of CH 2 , CF 2 , O and S, B being selected from the group consisting of H, CH 3 , CH 2 F, CHFCH 2 F, CF 3 , CH 2 OH, O-C 1 -C 20 alkyl, CCSi(i-Pr) 3 or C 2 -alkynyl.
  • the compounds of the formula (2) are dialkynylcarbinols
  • the compounds of the formula (3) are alkenylalkynylcarbinols
  • the compounds of the formula (4) are allenylalkynylcarbinols
  • the compounds of the formula (5) are alkylalkynylcarbinols.
  • Halogen is understood as meaning fluorine, chlorine, bromine, or iodine.
  • Alkyl includes both branched and linear saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms.
  • C 1 -C n alkyl means an alkyl group having from 1 to n carbon atoms.
  • Alkenyl is a branched or linear unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon double bond without any carbon-carbon triple bond.
  • C 2 -alkenyl designates an ethenyl group.
  • Alkynyl is branched or linear unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon triple bond.
  • C2 alkynyl designates an ethynyl group.
  • the asymmetric carbon atom present in the compounds of the present invention can have a R configuration or a S configuration.
  • the compounds can be in the form of enantioenriched enantiomers or in the form of a racemic mixture.
  • the present invention relates to enantioenriched enantiomers and racemic mixtures.
  • the compounds of the present invention may be in all their stereoisomeric forms and mixtures thereof in any ratio, and also may be in the form of physiologically tolerable salts.
  • Physiologically tolerable salts of the compounds of the present invention are nontoxic salts that are physiologically acceptable, in particular pharmaceutically utilizable salts.
  • Possible salts correspond to ionic substituents of the Ar group, anionic (carboxylates, sulfinates, sulfonates, phosphinates, phosphonates, phosphates) or cationic (ammoniums), with biologically compatible counterions.
  • Salts of the compounds of the present invention can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the present invention with an inorganic or organic base in a solvent or diluent, or from other salts by cation exchange or anion exchange.
  • Ar is preferably selected from the group consisting of phenyl, naphthyl, furan, pyridine, pyrimidine, pyran, thiophene, pyrrole, 1,4-dioxine, dithiine, oxathiine, dihydropyrazine, 1,3-oxazine, 1,4-oxazine, 1,2,3-triazole and 1,2,4-triazole groups.
  • Ar is selected from the group consisting of phenyl, naphthyl, furan, and thiophene groups.
  • Ar is a thiophene group or a furan group that is substituted with 1 to 3 substituents, preferably with 1 substituent.
  • the thiophene group or the furan group may be substituted with a C 1 -C 20 -alkyl group (more preferably a C 4 -C 14 alkyl group).
  • the thiophene group or the furan group is substituted with a C 3 -C 20 -alkyl group (more preferably a C 4 -C 14 -alkyl group), the other substituent(s) if any being independently chosen from C 1 -C 20 -alkyl groups, preferably C 4 -C 14 -alkyl groups, F and OCF 3 .
  • R is preferably a C 2 -alkynyl group.
  • the compounds of the present invention are of the formula (6) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 9 or 11, and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -a llenyl or a C 1 -C 6 -al kyl group.
  • R is a C 2 -alkynyl group and thus preferred compounds are of the formula
  • n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 9 or 11.
  • the compounds are of the formula (8) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 6 or 9 and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -a I leny I or a C 1 -C 6 -a Iky I group.
  • R is a C2-alkynyl group and thus preferred compounds are of the formula (9) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 6 or 9.
  • Ar is a naphthyl group that is substituted with 1 to 7 substituents, at least one substituent having formula (a) AC n H 2n B as defined above, the other substituent(s), if any, being as defined above, preferably with 1 substituent.
  • naphthyl may be substituted with a C 1 -C 20 -alkyl group (more preferably a C 8 -alkyl group).
  • naphthyl is substituted with 1 to 7 substituents, one substituent being a C 3 -C 20 -alkyl group (more preferably a C 8 - alkyl group), the other substituent(s) if any being independently chosen from C 1 -C 20 -alkyl groups.
  • R is preferably a C 2 -alkynyl group.
  • the compounds are of the formula (10) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7 and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -alkyl group.
  • R is a C 2 -alkynyl group and thus preferred compounds are of the formula (11) :
  • n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7.
  • Ar may be a phenyl group that is substituted with 1 to 5 substituents, preferably with 1 to 3 substituents.
  • Ar is a phenyl group that is substituted with 1 to 5 substituents, at least one substituent having formula (a) AC n H 2n B as defined above, the other substituent(s), if any, being as defined above, preferably with 1 to 3 substituents.
  • the phenyl group is substituted with a group selected from the group consisting of C 3 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 - alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18.
  • the substituent is a C 3 -C 20 -alkyl, it is preferably in meta or para position and more preferably in para position.
  • the phenyl group is substituted with a C 4 -C 14 -alkyl (preferably C 8 ) in para position and optionally substituted with an halogen atom (preferably F) in meta position.
  • R 1 , R?, R 3 , R 4 and R 5 is chosen from C 3 -C 20 -alkyl (more preferably C 4 -C 14 - alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl and CF 2 -C 2 -C 20 -alkyl, the other substituents, identical or different, are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i- Pr) 3 , O
  • halogen
  • R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -a I kyl group.
  • R is a C 2 -alkynyl group.
  • the preferred compounds are of the formula (13) : in which at least one of R 1 , R 2 , R 3 , R 4 and R 5 is chosen from C 3 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl and CF 2 -C 2 -C 20 -alkyl, the other substituents, identical or different, and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 ) n -C 2 - alkynyl with n an integer comprised between 0 and
  • R 3 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18, and R 1 R 2 , R 4 and R 5 are identical or different and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i-Pr) 3 , O(CH 2 CH 2 O) n
  • R 3 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH2)n-C2 -alkynyl with n an integer comprised between 3 and 18 and R 1 R 2 , R 4 and R 5 are identical or different and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i-Pr) 3 , O(CH 2 CH 2 O) n Et
  • R 2 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 ) n -C 2 -alkynyl with n an integer comprised between 3 and 18 and R 1 R 3 , R 4 and R 5 are identical or different and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i-Pr) 3 , O(CH 2 CH 2 O)
  • halogen preferably F
  • R 2 is selected from the group consisting of -(CH 2 )nCH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 ) n -C 2 -alkynyl with n an integer comprised between 3 and 18 and R 1 R 3 , R 4 and R 5 are identical or different and are chosen independently of one another from hydrogen, C 1 -C 20 -alkyl (more preferably C 4 -C 14 -alkyl, most preferably C 8 -alkyl), (CH 2 )n-C 2 -alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF 3 , CHFCH 2 F, CF 3 , CH 2 OH, CCSi(i-Pr) 3 , O(CH 2 CH 2
  • Some preferred compounds of the formula (12) are compounds of the formula (14): in which R 3 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18.
  • R 1 , R 2 , R 4 and R 5 are hydrogen and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -a lleny I or a C 1 -C 6 -a I ky I group.
  • R is preferably a C 2 -alkynyl group or a C 2 - alkenyl group.
  • R is a C 2 -alkenyl group
  • preferred compounds are compounds of the formulas (15) and (16):
  • Some preferred compounds of (12) are compounds of the formula (17) : in which R 2 is selected from the group consisting of (CH 2 ) n CH 3 with n an integer comprised between 2 and 19, OCH 2 CH 2 OEt, O-C 2 -C 20 -alkyl, CF 2 -C 2 -C 20 -alkyl and (CH 2 )n-C 2 -alkynyl with n an integer comprised between 3 and 18.
  • R 1 , R 3 , R 4 and R 5 are hydrogen and R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -a I ky I group.
  • R is preferably a C 2 -alkynyl group or a C 2 - alkenyl group.
  • n is an integer comprised between 2 and 19, R 1 , R 2 , R 3 and R 4 are halogen
  • R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -a Ikyl group.
  • R is a C 2 -alkynyl group.
  • Some other preferred compounds of the compounds of the formula (12) are the compounds of the formulas (22) and (23) : in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7, R 2 and R 4 are halogen identical or different of one another (preferably F) and R 1 and R 3 are halogen identical or different of one another (preferably F), and R is a C 2 - alkynyl, a C 2 -alkenyl, a C 3 -allenyl or a C 1 -C 6 -alkyl group.
  • R is a C 2 -alkynyl group.
  • the compounds of the present invention are prepared according to any conventional methods and known for those of skill in the art. For example, two embodiments of the preparation of compounds according to the invention are here below disclosed in the experimental part.
  • the compounds of the present invention are valuable pharmacologically active compounds. As explained above, they may act as prodrug and especially exhibit a cytotoxicity that is suitable, for example, for the treatment of cancer.
  • a further subject of the present invention is a pharmaceutical composition, which comprises at least one compound of the present invention and/or a physiologically tolerable salt thereof and together with at least one pharmaceutically acceptable carrier.
  • composition of the invention comprises at least one compound of the formula (1), or physiologically tolerable salt thereof in which:
  • R is a C 2 -alkynyl, a C 2 -alkenyl, a C 3 -al lenyl or a C 1 -C 6 -a Ikyl group,
  • Ar is selected from the group consisting of aryl and heteroaryl, wherein
  • - aryl is a phenyl, naphthyl, indanyl, tetralinyl, biphenylyl, fluorenyl or anthacenyl group,
  • - heteroaryl is an aziridine, azepine, azetidine, benzimidazole, benzofuran, benzofl, 4]dioxine, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, chromane, cinnoline, dihydropyrazine, dithiine, 1,2-diazepine, 1,3- diazepine, 1,4-diazepine, 1,4-dioxine, furan, dioxole, imidazole, indazole, indole, isochromane, isoindole, isoquinoline, isothiazole, isoxazole, oxathiine, 1,2-oxazine, 1,3- oxazine, 1,4-oxazine, oxazole, 1,3-o
  • Ar being substituted with 1 to 7 substituents independently chosen from halogen, OCF 3 , CF 3 , CH 2 OH, CCSi(i-Pr) 3 , CH 3 , OH, CHFCH 2 F, -O(CH 2 CH 2 O) n Et with n an integer comprised between 1 and 6,
  • Carrier means a diluent, excipient, or vehicle with which at least one compound of the present invention is administered.
  • a “pharmaceutically acceptable carrier” means a substance, e.g., excipient, diluent, or vehicle, which is useful in preparing the pharmaceutical composition that is safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier” includes both one and more than one such carrier.
  • Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated.
  • the carrier can be inert or it can possess pharmaceutical benefits of its own.
  • the amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
  • Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
  • Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others.
  • Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils.
  • Optional active and/or inactive agents may be included in the pharmaceutical compositions, provided that such agents do not substantially interfere with the activity of the compounds of the present invention.
  • the optional active agent is an additional active agent that is not a compound or salt of the present invention.
  • the compounds of the present invention may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
  • the pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution.
  • Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
  • compositions are preferably formulated for oral administration.
  • compositions may contain between 0.1 % and 99 % by weight of a compound of the present invention.
  • a further subject of the present invention is a compound of the present invention and/or a physiologically tolerable salt thereof for use as a medicament.
  • a further subject of the present invention is a compound of the present invention and/or a physiologically tolerable salt thereof for use as a prodrug.
  • a further subject of the present invention is a compound of the present invention or a physiologically tolerable salt thereof for use in the treatment of a disease selected from the group consisting of cancer or metastasis thereof, bacterial, parasitic or fungal infections.
  • the cancer may be selected from the group consisting of colon cancer, renal-cell carcinoma, prostate cancer, testicular cancer, lung cancer, cancer of the small intestine and cancer of the esophagus, breast cancer, colon cancer, bone cancer, neuroblastoma, hematological malignancies such as B-cell lymphoid neoplasm, T-cell lymphoid neoplasm, non-Hodgkin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphoid neoplasm and myeloid cell lineage neoplasm including acute myeloid leukemia.
  • B-cell lymphoid neoplasm non-Hodgkin lymphoma
  • B-NHL non-Hodgkin lymphoma
  • B-NHL non-Hodgkin lymphoma
  • the cancer may be selected from the group consisting of lung cancer, breast cancer, colon cancer, bone cancer and neuroblastoma.
  • the bacterial infection may be selected from the group consisting of pneumonia, bacterial meningitis, cholera, diphtheria, tuberculosis, anthrax, botulism, brucellosis, campylobacteriosis, typhus, gonorrhea, listeriosis, lyme disease, rheumatic fever, pertussis (Whooping Cough), plague, salmonellosis, scarlet fever, shigellosis, syphilis, tetanus, trachoma, tularemia, typhoid fever, and urinary tract infections, or caused by Coxiella burnetii, Brucella abortus, Tropheryma whipplei, Mycobacterium tuberculosis and Mycobacterium canettii.
  • the parasitic infection may be selected from the group consisting of malaria, leishmaniasis, trypanosomiasis, chagas disease, cryptosporidiosis, fascioliasis, filariasis, amebic infections, giardiasis, pinworm infection, schistosomiasis, taeniasis, toxoplasmosis, trichi nellosis, and trypanosomiasis.
  • the fungal infection may be selected from the group consisting of candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis and tinea pedis.
  • Another application of the present invention is the use of at least one of the described compounds of the invention which contains a functional group, or one of these compounds on which at least one functional group would be added, to functionalize a protein of interest.
  • Functional groups may include, but are not limited to, a fluorophore, a biotin, a peptide, a drug or a "clickable" group, such as a C 2 -alkynyl group or an azido group.
  • This functional group can be added anywhere on the compound of the present invention, providing that it does not interfere with its bioactivation.
  • the HSD17Bll-mediated oxidation of the functionalized compound generates a protein reactive species which will covalently modify the protein of interest with the desirable functional group through Michael addition of one or several cysteine and lysine side chains with the functionalized bioactivated compound.
  • the use of "click- chemistry" reactions allows to subsequently modify the protein with another functional group, including large functional groups, providing that it carries a function amenable to the selected "click chemistry” reaction.
  • the protein of interest can be any protein with lysines and/or cysteines residues, but is preferably an antibody, and the functional group is preferentially a drug (i.e. an antibody-drug conjugates).
  • a further subject of the present invention is the use of at least one of the compounds of the present invention to select genome edited cells (i.e. by CRISPR/Cas9-mediated genome editing technology) through the co-inactivation of the HSD17B11 gene (i.e. knock-out or knock-in impacting on HSD17B11 catalytic activity) and of the gene(s) of interest in a target cell population.
  • the HSD17B11 gene coinactivation provides a resistance to some of the compounds described in the present invention which is used to enrich the edited cells and kill the unedited one by treating the cell population, comprising properly edited cells with non-edited ones, with the chosen compound(s).
  • the gene editing strategies amenable to this approach may comprise, but is not limited to, CRISPR/Cas9 genome editing.
  • Figure 1 is a scheme of the steps of a 1 st method for preparing compounds according to the present invention.
  • Figure 2 is a scheme of the steps of a 2 nd method for preparing compounds according to the present invention.
  • the starting compound of these two methods was a compound of the formula (X) : in which B is halogen (i.e. fluorine, chlorine, bromine, or iodine) and Ar has the meaning as above detailed.
  • B is halogen (i.e. fluorine, chlorine, bromine, or iodine) and Ar has the meaning as above detailed.
  • the 3 rd step of the 1 st method may be carried out according to a 1 st alternative (i.e. 3a) or a 2 nd alternative (i.e. 3'a).
  • step lb) of the 2 nd method was carried out as follows: [100] A Schlenk flask charged with Na 2 PdCI 4 (1 mol%), 2-(di-tert-butylphosphino)-N- phenylindole (PlntB, 2 mol%), Cul (2 mol%), propargyl alcohol (2.0 eq.), aryl halide of formula (X) (1.1 equiv), H2O (0.2 mL/mmol) and TMEDA (1.8 mL/mmol) was evacuated and backfilled with argon 3 times, and heated to 80 °C under stirring. After consumption of the compound of the formula (X), the reaction mixture was cooled to room temperature.
  • the 2 nd step of the 2 nd method may be carried out according to a 1 st alternative (i.e. 2b) or a 2 nd alternative (i.e. 2'b).
  • step 2'b) was carried out as below detailed if Ar of the compound of the formula (X) comprised a triisopropylsilyl-protected terminal alkyne.
  • the 3 rd step of the 2 nd method may be carried out according to a 1 st alternative (i.e. 3b) or a 2 nd alternative (i.e. 3'b) or a 3 rd alternative (i.e. 3"b) or a 4 th alternative (i.e. 3"'b).
  • the resulting mixture was stirred at room temperature for 45 minutes before dropwise addition of the propargylic aldehyde (1 eq.) in anhydrous CH 2 CI 2 (1 mL/mmol) (final concentration in starting terminal alkyne 0.3 M).
  • the reaction mixture was stirred at room temperature for 12 hours before being quenched by addition of aqueous saturated NH4CI solution and extracted 3 times with CH 2 CI 2 .
  • the combined organic layers were then washed with water and brine, dried over MgSO4 and concentrated under reduced pressure.
  • Example 8 l-(3-Nonylphenyl)penta-1,4-diyn-3-ol of the formula (36):
  • Example 10 l-(6-Octylnaphthalen-2-yl)penta-1,4-diyn-3-ol of the formula (40):
  • Example 11 l-(3-Fluoro-4-octylphenyl)penta-1,4-diyn-3-ol of the formula (42):
  • Example 12 l-(2-Fluoro-4-octylphenyl)penta-1,4-diyn-3-ol of the formula (44):
  • Example 15 l-(4-(2-(2-Ethoxyethoxy)ethoxy)phenyl)penta-1,4-diyn-3-ol of the formula (50):
  • Example 16 l-(4-(Heptyloxy)phenyl)penta-1,4-diyn-3-ol of the formula (52): [173] This compound (183 mg, 8 % yield from the starting compound (53)) was obtained in the form of a racemic mixture according to the 1 st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3 rd step) with the starting compound: l-lodo-4-(heptyloxy)benzene (CAS 116223-56-4 Commercial) of the formula (53):
  • Example 20 l-(5-Decylthiophen-2-yl)penta-1,4-diyn-3-ol of the formula (58):
  • Example 22 l-(4-(Oct-7-yn-l-yl)phenyl)penta-1,4-diyn-3-ol of the formula (62):
  • Example 27 1-(3-Fluoro-4-((6,6,6-trifluorohexyl)oxy)phenyl)penta-1,4-diyn-3-ol of the formula (71):
  • Example 28 l-(5-Decylfuran-2-yl)penta-1,4-diyn-3-ol of the formula (73):
  • Example 32 1-(4-Octylphenyl)hexa-4,5-dien-l-yn-3-ol of the formula (81): [226] This compound (42 mg, 35 % yield from the starting compound (28)) was obtained in the form of a racemic mixture according to the 2 nd method with the alternative 2b) for the 2 nd step, the alternative 3b) for the 3 rd step and 4b) for the 4 th step with the starting compound: l-Bromo-4-octyl benzene: (CAS 51554-93-9 Commercial) of the formula (28):
  • Wild-type human HCT116 colon cancer cells were seeded in 96-well plates together with the tested compound. Cells were grown and treated in DMEM 10% FBS. Two-fold serial dilutions were performed. After 72 hours, cell viability was measured using a MTT assay.
  • these 23 compounds of the present invention have all a high cytotoxicity (i.e. I C50 from 0.05 to 5 pM) and thus exhibit an antitumor activity on HCT116 cells;
  • the compound of the example 4 has the highest cytotoxicity ;
  • the compound of the example 6 has a cytotoxicity (i.e. IC 50 0.100 ⁇ M) 100 times higher than the compound of the comparative example A (i.e. IC 50 10 pM).
  • the compound of the example 6 only differs from the compound of the comparative example A in that it includes a further alkynyl group ;
  • the compound of the example 7 has a cytotoxicity (i.e. IC 50 0.400 pM) 125 times higher than the compound of the comparative example B (i.e. IC 50 50 pM).
  • the compound of the example 7 only differs from the compound of the comparative example B in that it includes a further alkynyl group.
  • Wild-type human HAP1 cells or HAP1 DACRWA4 (HSD17B11 carrying the S172L mutation) were seeded in 96-well plates (3500 cells/well) 24 hours before being treated for 72 hours with the tested compounds.
  • IC 50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
  • these 3 compounds of the present invention have all a high cytotoxicity (i.e. ICso from 0.85 to 0.187 pM) and thus exhibit an antitumor activity on HAP1 WT cells ;
  • the compound of the example 4 has the highest cytotoxicity ;
  • Wild-type human osteosarcoma cells U2OS or U2OS inactivated for HSD17B11 using CRISPR/Cas9 (clone #B3) were seeded in 96-well plates (1500 cells/well) 24 hours before being treated for 72 hours with the tested compounds.
  • IC 50 were computed from at least three independent experiments using the GraphPad Prism software using a nonlinear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
  • these 9 compounds of the present invention have all a high cytotoxicity (i.e. IC 50 from 0.040 to 1.552 pM) and thus exhibit an antitumor activity on U2OS cells ;
  • the compound of the example 4 has the highest cytotoxicity ;
  • IC 50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve [log[inhibitor] vs response; variable slope). Note that in complemented U2OS, HSD17B11 is overexpressed as compared to U2OS WT, explaining the lower (+)-PAC IC 50 in these cells.
  • the cytotoxicity of these 2 compounds of the present invention is much lower in U2OS cells inactivated for HSD17B11 and complemented with a control plasmid or a plasmid expressing the catalytically inactive S172L HSD17B11 mutant as compared to U2OS cells inactivated for HSD17B11 and complemented with the wild-type HSD17B11 enzyme.
  • SCLC Small Cell Lung Carcinoma
  • control cells were seeded in 96-well plates 24 hours before being treated for 72 hours with the compound of the example 4.
  • the plate was cooled down to room temperature and the CellTiterGlo® reagent (CTG, Promega) was added to each well and homogenized by pipetting. 100 pL of lysate was transferred to black plates and after a 15 minutes incubation at room temperature the luminescence was measured on a FLX800 plate reader. For normalization, the background value was subtracted to each value, the duplicates averaged and the value for the untreated condition set to 100% cell viability.
  • CCG CellTiterGlo® reagent
  • IC 50 were computed using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve ( log[i nhibitor] vs response; variable slope).
  • the compound of the example 4 exhibits high cytotoxicity for different lung cancer cell lines.
  • SCLC Small Cell Lung Carcinoma
  • HSD17B11 using CRISPR/Cas9 (KO HSD17B11 clone #1 and clone #6) were seeded in 96- well plates (2000 cells/well) 24 hours before being treated for 72 hours with the indicated molecules.
  • Cells were grown and treated in RPMI164010% FBS.
  • DMSO was at 0.5% final concentration in each well, including in the untreated conditions.
  • the plate was cooled down to room-temperature and the CellTiterGlo® reagent (Promega) was added to each well and homogenized by pipetting.
  • IC 50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[i nhibitor] vs response; variable slope).
  • the compound of the example 4 exhibits high cytotoxicity for NCI-H446 SCLC cells ;
  • I C 50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[in hibitor] vs response; variable slope).
  • the compound of the example 4 has a high cytotoxicity and thus exhibits an antitumor activity on neuroblastoma cell lines.
  • HSD17B13 (aka SCDR9 or SDR16C3) is the closest human homologue of HSD17B11 (63.3 % of sequence identity between them). Considering the high degree of sequence identity between HSD17B11 and HSD17B13, the selectivity for bioactivation by HSD17B11 over HSD17B13 was tested for a set of compounds of the invention.
  • IC50 were computed from at least three independent experiments using the GraphPad Prism software using a non- linear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
  • HSD17B13 can bioactivate some of the compounds described, albeit less efficiently than HSD17B11. These data also support that the specificity towards HSD17B11 versus HSD17B13 can be modulated by subtle structural modifications. Compound of the example 14 shows the highest selectivity among the tested compounds.

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Abstract

The present invention relates to compounds of the formula (1), or physiologically tolerable salt thereof in which R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-alkyl group, Ar is selected from the group consisting of aryl and heteroaryl. The compounds of the formula (1) are pharmacologically active compounds. They exhibit high cytotoxicity against cancer cells.

Description

Alkynylcarbinols with high cytotoxicity
[1] The present invention relates to alkynylcarbinols.
[2] Naturally occurring acetylenic lipids constitute a rich family of bioactive compounds. For example, more than 100 natural acetylenic lipids have been identified from diverse species of marine sponges and shown to display various biological activities, including for most of them a pronounced cytotoxicity against several tumor cell lines. More precisely, the presence of a terminal alkynylcarbinol unit has been correlated with the antitumor activity of such natural compounds.
[3] Given their unusual features and promising properties, in particular regarding their antitumor activity, these natural acetylenic lipids constitute a potential source of inspiration for designing new bio-inspired compounds that mimic their mechanism of action while exhibiting a similar or even stronger cytotoxicity than the natural compounds.
[4] For example, the publication of El Arfaoui et al., entitled "Identification of chiral alkenyl- and alkynylcarbinols as pharmacophores for potent cytotoxicity", ChemMedChem 2013, 8, 1779-1786 discloses the discovery of a bio-inspired synthetic compound (S)-heptadeca- l,4-diyn-3-ol (i.e. an acetylenic lipid with a terminal dialkynylca rbinol unit) which exhibits a cytotoxicity against HCT116 tumor cells 100 times higher than the one of its natural parent (S,Ej-icos-4-en-l-yn-3-ol, which is a lipidic alkenylalkynylcarbinol isolated from the marine sponge Cribrochalina vasculum.
[5] Thus, the alkynylcarbinol motif is found in various cytotoxic natural or synthetic lipids, but the mechanism of action of those potential therapeutic agents remains unknown.
[6] This explains the need for new alkynylcarbinols that exhibit an important cytotoxicity, in particular against specific tumor cell lines, and for understanding their mechanism of action.
[7] The present invention satisfies this need by providing novel alkynylcarbinols having a pronounced cytotoxicity against several tumor cell lines.
[8] Moreover, the inventors have discovered that the enzyme HSD17B11 (i.e. 17-beta- hydroxysteroid dehydrogenase 11), a short-chain dehydrogenase/reductase expressed in cancer cells, oxidizes these novel alkynylcarbinols into the corresponding ketones in the. The generated alkynylketones, also called alkynylcarbinones, are able to react with lysine and cysteine side chains, and thus covalently modify several proteins, thereby triggering endoplasmic reticulum stress, proteasome inhibition and apoptosis. Furthermore, and more generally, the inventors found that these cytotoxic alkynylcarbinone species are instable in biological medium. It explains why the cytotoxicity of the chemically synthetized alkynylcarbinones is low when they are directly in contact with the cells and why the novel alkynylcarbinols thus may constitute a reservoir of cytotoxic prodrugs that can be used for the treatment of cancer.
[9] Thus, a subject of the present invention are compounds of the formula (1),
Figure imgf000003_0001
(1), or physiologically tolerable salts thereof in which :
R is a C2-alkynyl, a C2-alkenyl, a C3-al lenyl or a C1-C6-a Ikyl group,
Ar is selected from the group consisting of aryl and heteroaryl, wherein
- aryl is a phenyl, naphthyl, indanyl, tetralinyl, biphenylyl, fluorenyl or anthacenyl group,
- heteroaryl is an aziridine, azepine, azetidine, benzimidazole, benzofuran, benzo[l,4]dioxine,
1.3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, chromane, cinnoline, dihydropyrazine, dithiine, 1,2-diazepine, 1,3-diazepine, 1,4-diazepine,
1.4-dioxine, furan, dioxole, imidazole, indazole, indole, isochromane, isoindole, isoquinoline, isothiazole, isoxazole, oxathiine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, oxazole, 1,3-oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidinyl, quinazoline, quinoline, quinoxaline, 1,2,3,4-tetrahydroisoquinoline, 1, 2,3,4- tetrahydroquinoline, thiadiazole, thiazole, 1,3-thiazole, thiophene, thiopyran, 1,2,3-triazole,
1.2.4-triazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine or 1,3,5- triazine group, Ar being substituted with 1 to 7 substituents, at least one substituent having formula (a) ACnH2nB with n being an integer comprised between 2 and 20, A being selected from the group consisting of CH2, CF2, O and S, and B being selected from the group consisting of H, CH3, CH2F, CHFCH2F, CF3, CH2OH, O-C1-C20 alkyl, CCSi(i-Pr)3 or C2-alkynyl, the other substituent(s), if any, being independently chosen from halogen, OCF3, CF3, CH2OH, CCSi(i- Pr)3, CH3, CH2CH3, OH, CHFCH2F, -O(CH2CH2O)nEt with n an integer comprised between 1 and 6, ACnH2nB with n an integer comprised between 2 and 20 and A being selected from the group consisting of CH2, CF2, O and S, B being selected from the group consisting of H, CH3, CH2F, CHFCH2F, CF3, CH2OH, O-C1-C20 alkyl, CCSi(i-Pr)3 or C2-alkynyl. In embodiments of the invention, Ar may be substituted with 1 to 7 substituents independently chosen from halogen, OCF3, CF3, CH2OH, CCSi(i-Pr)3, CH3, OH, CHFCH2F, -O(CH2CH2O)nEt with n an integer comprised between 1 and 6, ACnH2nB with n an integer comprised between 1 and 20 and A being selected from the group consisting of CH2, CF2, O and S, B being selected from the group consisting of H, CH3, CH2F, CHFCH2F, CF3, CH2OH, O-C1-C20 alkyl, CCSi(i-Pr)3 or C2-alkynyl.
[10] Thus, if R is a C2-alkynyl group, the compounds are of the formula (2):
Figure imgf000004_0002
if R is C3-a I le nyl group, the compounds are of the formula (4) :
Figure imgf000004_0001
and if R is a C1-C6-alkyl group, the compounds are of the formula (5) :
Figure imgf000005_0001
[11] The compounds of the formula (2) are dialkynylcarbinols, the compounds of the formula (3) are alkenylalkynylcarbinols, the compounds of the formula (4) are allenylalkynylcarbinols and the compounds of the formula (5) are alkylalkynylcarbinols.
[12] "Halogen" is understood as meaning fluorine, chlorine, bromine, or iodine.
[13] "Alkyl" includes both branched and linear saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms. The term "C1-Cn alkyl" means an alkyl group having from 1 to n carbon atoms.
[14] "Alkenyl" is a branched or linear unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon double bond without any carbon-carbon triple bond. For example, the term "C2-alkenyl" designates an ethenyl group.
[15] "Alkynyl" is branched or linear unsaturated hydrocarbon group having the specified number of carbon atoms and at least one carbon-carbon triple bond. For example, the term "C2 alkynyl" designates an ethynyl group.
[16] The asymmetric carbon atom present in the compounds of the present invention (i.e. the carbinol carbon atom) can have a R configuration or a S configuration. The compounds can be in the form of enantioenriched enantiomers or in the form of a racemic mixture. The present invention relates to enantioenriched enantiomers and racemic mixtures.
[17] The compounds of the present invention may be in all their stereoisomeric forms and mixtures thereof in any ratio, and also may be in the form of physiologically tolerable salts.
[18] Physiologically tolerable salts of the compounds of the present invention are nontoxic salts that are physiologically acceptable, in particular pharmaceutically utilizable salts. [19] Possible salts correspond to ionic substituents of the Ar group, anionic (carboxylates, sulfinates, sulfonates, phosphinates, phosphonates, phosphates) or cationic (ammoniums), with biologically compatible counterions.
[20] Salts of the compounds of the present invention can be obtained by customary methods known to those skilled in the art, for example by combining a compound of the present invention with an inorganic or organic base in a solvent or diluent, or from other salts by cation exchange or anion exchange.
[21] Ar is preferably selected from the group consisting of phenyl, naphthyl, furan, pyridine, pyrimidine, pyran, thiophene, pyrrole, 1,4-dioxine, dithiine, oxathiine, dihydropyrazine, 1,3-oxazine, 1,4-oxazine, 1,2,3-triazole and 1,2,4-triazole groups. Most preferably, Ar is selected from the group consisting of phenyl, naphthyl, furan, and thiophene groups.
[22] In some embodiments, Ar is a thiophene group or a furan group that is substituted with 1 to 3 substituents, preferably with 1 substituent. In embodiments of the invention, the thiophene group or the furan group may be substituted with a C1-C20-alkyl group (more preferably a C4-C14alkyl group). In preferred embodiments, the thiophene group or the furan group is substituted with a C3-C20-alkyl group (more preferably a C4-C14-alkyl group), the other substituent(s) if any being independently chosen from C1-C20-alkyl groups, preferably C4-C14-alkyl groups, F and OCF3. In these embodiments, R is preferably a C2-alkynyl group.
[23] In some embodiments in which Ar is a thiophene group, the compounds of the present invention are of the formula (6) :
Figure imgf000006_0001
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 9 or 11, and R is a C2-alkynyl, a C2-alkenyl, a C3-a llenyl or a C1-C6-al kyl group.
[24] Preferably , R is a C2-alkynyl group and thus preferred compounds are of the formula
(7) :
Figure imgf000007_0001
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 9 or 11.
[25] In some embodiments in which Ar is a furan group, the compounds are of the formula (8) :
Figure imgf000007_0002
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 6 or 9 and R is a C2-alkynyl, a C2-alkenyl, a C3-a I leny I or a C1-C6-a Iky I group.
[26] Preferably , R is a C2-alkynyl group and thus preferred compounds are of the formula (9) :
Figure imgf000007_0003
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 6 or 9.
[27] In some embodiments, Ar is a naphthyl group that is substituted with 1 to 7 substituents, at least one substituent having formula (a) ACnH2nB as defined above, the other substituent(s), if any, being as defined above, preferably with 1 substituent. In embodiments of the invention, naphthyl may be substituted with a C1-C20-alkyl group (more preferably a C8-alkyl group). In preferred embodiments, naphthyl is substituted with 1 to 7 substituents, one substituent being a C3-C20-alkyl group (more preferably a C8- alkyl group), the other substituent(s) if any being independently chosen from C1-C20-alkyl groups. In all these embodiments, R is preferably a C2-alkynyl group.
[28] In some embodiments in which Ar is a naphthyl group, the compounds are of the formula (10) :
Figure imgf000008_0001
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7 and R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-alkyl group.
[29] Preferably , R is a C2-alkynyl group and thus preferred compounds are of the formula (11) :
Figure imgf000008_0002
(11), in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7.
[30] In embodiments of the invention, Ar may be a phenyl group that is substituted with 1 to 5 substituents, preferably with 1 to 3 substituents. In some preferred embodiments of the invention. Ar is a phenyl group that is substituted with 1 to 5 substituents, at least one substituent having formula (a) ACnH2nB as defined above, the other substituent(s), if any, being as defined above, preferably with 1 to 3 substituents.
[31] In preferred embodiments, the phenyl group is substituted with a group selected from the group consisting of C3-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8- alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18. [32] If the substituent is a C3-C20-alkyl, it is preferably in meta or para position and more preferably in para position. In some preferred embodiments, the phenyl group is substituted with a C4-C14-alkyl (preferably C8) in para position and optionally substituted with an halogen atom (preferably F) in meta position.
[33] In embodiments in which Ar is a phenyl group, the compounds of the present invention are of the formula (12) :
Figure imgf000009_0001
in which :
- at least one of R1, R?, R3, R4 and R5 is chosen from C3-C20-alkyl (more preferably C4-C14- alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18, OCH2CH2OEt, O-C2-C20-alkyl and CF2-C2-C20-alkyl, the other substituents, identical or different, are chosen independently of one another from hydrogen, C1-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF3, CHFCH2F, CF3, CH2OH, CCSi(i- Pr)3, O(CH2CH2O)nEt with n an integer comprised between 1 and 6, O-C2-C20-alkyl and CF2- C2-C20-alkyl ;
- R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-a I kyl group.
[34] In some preferred embodiments, R is a C2-alkynyl group. Thus, the preferred compounds are of the formula (13) :
Figure imgf000010_0001
in which at least one of R1, R2, R3, R4 and R5 is chosen from C3-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18, OCH2CH2OEt, O-C2-C20-alkyl and CF2-C2-C20-alkyl, the other substituents, identical or different, and are chosen independently of one another from hydrogen, C1-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8-alkyl), (CH2)n-C2- alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF3, CHFCH2F, CF3, CH2OH, CCSi(i-Pr)3, O(CH2CH2O)nEt with n an integer comprised between 1 and 6, O-C2-C20-alkyl and CF2-C2-C20-alkyL
[35] In some preferred embodiments of the compounds of the formula (12), R3 is selected from the group consisting of (CH2)nCH3 with n an integer comprised between 2 and 19, OCH2CH2OEt, O-C2-C20-alkyl, CF2-C2-C20-alkyl and (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18, and R1 R2, R4 and R5 are identical or different and are chosen independently of one another from hydrogen, C1-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF3, CHFCH2F, CF3, CH2OH, CCSi(i-Pr)3, O(CH2CH2O)nEt with n an integer comprised between 1 and 6, O-C2-C20-alkyl and CF2-C2-C20-alkyL Preferably, R1 R2, R4 and R5 are hydrogen, with the proviso that at least one of R1 R2, R3, R4 and R5 has formula (a) ACnH2nB as defined above.
[36] In some preferred embodiments of the compounds of the formula (13), R3 is selected from the group consisting of (CH2)nCH3 with n an integer comprised between 2 and 19, OCH2CH2OEt, O-C2-C20-alkyl, CF2-C2-C20-alkyl and (CH2)n-C2 -alkynyl with n an integer comprised between 3 and 18 and R1 R2, R4 and R5 are identical or different and are chosen independently of one another from hydrogen, C1-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF3, CHFCH2F, CF3, CH2OH, CCSi(i-Pr)3, O(CH2CH2O)nEt with n an integer comprised between 1 and 6, O-C2-C20-alkyl and CF2-C2-C20-alkyL Preferably, R1 R2, R4 and R5 are hydrogen, with the proviso that at least one of R1 R2, R3, R4 and R5 has formula (a) ACnH2nB as defined above.
[37] In some preferred embodiments of the compounds of the formula (12), R2 is selected from the group consisting of (CH2)nCH3 with n an integer comprised between 2 and 19, OCH2CH2OEt, O-C2-C20-alkyl, CF2-C2-C20-alkyl and (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18 and R1 R3, R4 and R5 are identical or different and are chosen independently of one another from hydrogen, C1-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF3, CHFCH2F, CF3, CH2OH, CCSi(i-Pr)3, O(CH2CH2O)nEt with n an integer comprised between 1 and 6, O-C2-C20-alkyl and CF2-C2-C20-alkyL Preferably, R1 R3, R4 and R5 are hydrogen, with the proviso that at least one of R1 R2, R3, R4 and R5 has formula (a) ACnH2nB as defined above.
[38] In some preferred embodiments of the compounds of the formula (13), R2 is selected from the group consisting of -(CH2)nCH3 with n an integer comprised between 2 and 19, OCH2CH2OEt, O-C2-C20-alkyl, CF2-C2-C20-alkyl and (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18 and R1 R3, R4 and R5 are identical or different and are chosen independently of one another from hydrogen, C1-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF3, CHFCH2F, CF3, CH2OH, CCSi(i-Pr)3, O(CH2CH2O)nEt with n an integer comprised between 1 and 6, O-C2-C20-alkyl and CF2-C2-C20-alkyL Preferably, R1 R3, R4 and R5 are hydrogen, with the proviso that at least one of R1 R2, R3, R4 and R5 has formula (a) ACnH2nB as defined above.
[39] Some preferred compounds of the formula (12) are compounds of the formula (14):
Figure imgf000011_0001
in which R3 is selected from the group consisting of (CH2)nCH3 with n an integer comprised between 2 and 19, OCH2CH2OEt, O-C2-C20-alkyl, CF2-C2-C20-alkyl and (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18. In these embodiments of the invention, R1, R2, R4and R5 are hydrogen and R is a C2-alkynyl, a C2-alkenyl, a C3-a lleny I or a C1-C6-a I ky I group.
[40] For these compounds of the formula (14), R is preferably a C2-alkynyl group or a C2- alkenyl group.
[41] If R is a C2-alkenyl group, preferred compounds are compounds of the formulas (15) and (16):
Figure imgf000012_0001
[42] Some preferred compounds of (12) are compounds of the formula (17) :
Figure imgf000012_0002
in which R2 is selected from the group consisting of (CH2)nCH3 with n an integer comprised between 2 and 19, OCH2CH2OEt, O-C2-C20-alkyl, CF2-C2-C20-alkyl and (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18. In these embodiments of the invention, R1, R3, R4and R5 are hydrogen and R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-a I ky I group.
[43] For these compounds of the formula (17), R is preferably a C2-alkynyl group or a C2- alkenyl group.
[44] Some other preferred compounds of the compounds of the formula (12) are the compounds of the formulas (18) to (21) :
Figure imgf000013_0001
in which n is an integer comprised between 2 and 19, R1, R2, R3 and R4 are halogen
(preferably F) or OCF3, and R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-a Ikyl group.
[45] Preferably, for these compounds (18) to (21), R is a C2-alkynyl group.
[46] Some other preferred compounds of the compounds of the formula (12) are the compounds of the formulas (22) and (23) :
Figure imgf000013_0002
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7, R2 and R4 are halogen identical or different of one another (preferably F) and R1 and R3 are halogen identical or different of one another (preferably F), and R is a C2- alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-alkyl group.
[47] Preferably, for these compounds (22) and (23), R is a C2-alkynyl group.
[48] The most preferred compound of the invention is the compound of the formula (24) :
Figure imgf000014_0001
(24).
[49] The compounds of the present invention are prepared according to any conventional methods and known for those of skill in the art. For example, two embodiments of the preparation of compounds according to the invention are here below disclosed in the experimental part.
[50] The compounds of the present invention are valuable pharmacologically active compounds. As explained above, they may act as prodrug and especially exhibit a cytotoxicity that is suitable, for example, for the treatment of cancer.
[51] A further subject of the present invention is a pharmaceutical composition, which comprises at least one compound of the present invention and/or a physiologically tolerable salt thereof and together with at least one pharmaceutically acceptable carrier.
[52] Precisely, a pharmaceutical composition of the invention comprises at least one compound of the formula (1),
Figure imgf000014_0002
or physiologically tolerable salt thereof in which:
R is a C2-alkynyl, a C2-alkenyl, a C3-al lenyl or a C1-C6-a Ikyl group,
Ar is selected from the group consisting of aryl and heteroaryl, wherein
- aryl is a phenyl, naphthyl, indanyl, tetralinyl, biphenylyl, fluorenyl or anthacenyl group,
- heteroaryl is an aziridine, azepine, azetidine, benzimidazole, benzofuran, benzofl, 4]dioxine, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, chromane, cinnoline, dihydropyrazine, dithiine, 1,2-diazepine, 1,3- diazepine, 1,4-diazepine, 1,4-dioxine, furan, dioxole, imidazole, indazole, indole, isochromane, isoindole, isoquinoline, isothiazole, isoxazole, oxathiine, 1,2-oxazine, 1,3- oxazine, 1,4-oxazine, oxazole, 1,3-oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidinyl, quinazoline, quinoline, quinoxaline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, thiadiazole, thiazole, 1,3-thiazole, thiophene, thiopyran, 1,2,3-triazole, 1,2,4-triazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine group.
Ar being substituted with 1 to 7 substituents independently chosen from halogen, OCF3, CF3, CH2OH, CCSi(i-Pr)3, CH3, OH, CHFCH2F, -O(CH2CH2O)nEt with n an integer comprised between 1 and 6, ACnH2nB with n an integer comprised between 1 and 20 and A being selected from the group consisting of CH2, CF2, O and S, B being selected from the group consisting of H, CH3, CH2F, CHFCH2F, CF3, CH2OH, O-C1-C20 alkyl, CCSi(i-Pr)3 or C2 alkynyl, and together with at least one pharmaceutically acceptable carrier.
[53] "Carrier" means a diluent, excipient, or vehicle with which at least one compound of the present invention is administered. A "pharmaceutically acceptable carrier" means a substance, e.g., excipient, diluent, or vehicle, which is useful in preparing the pharmaceutical composition that is safe, non-toxic and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. A "pharmaceutically acceptable carrier" includes both one and more than one such carrier.
[54] Carriers include excipients and diluents and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient being treated. The carrier can be inert or it can possess pharmaceutical benefits of its own. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity of material for administration per unit dose of the compound.
[55] Classes of carriers include, but are not limited to binders, buffering agents, coloring agents, diluents, disintegrants, emulsifiers, flavorings, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one class, for example vegetable oil may be used as a lubricant in some formulations and a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, powdered tragacanth, malt, gelatin, talc, and vegetable oils. Optional active and/or inactive agents may be included in the pharmaceutical compositions, provided that such agents do not substantially interfere with the activity of the compounds of the present invention. The optional active agent is an additional active agent that is not a compound or salt of the present invention.
[56] The compounds of the present invention may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, via buccal administration, rectally, as an ophthalmic solution, or by other means, in dosage unit formulations containing conventional pharmaceutically acceptable carriers.
[57] The pharmaceutical composition may be formulated as any pharmaceutically useful form, e.g., as an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. Some dosage forms, such as tablets and capsules, are subdivided into suitably sized unit doses containing appropriate quantities of the active components, e.g., an effective amount to achieve the desired purpose.
[58] The pharmaceutical compositions are preferably formulated for oral administration.
[59] The pharmaceutical compositions may contain between 0.1 % and 99 % by weight of a compound of the present invention.
[60] A further subject of the present invention is a compound of the present invention and/or a physiologically tolerable salt thereof for use as a medicament.
[61] A further subject of the present invention is a compound of the present invention and/or a physiologically tolerable salt thereof for use as a prodrug.
[62] A further subject of the present invention is a compound of the present invention or a physiologically tolerable salt thereof for use in the treatment of a disease selected from the group consisting of cancer or metastasis thereof, bacterial, parasitic or fungal infections.
[63] The cancer may be selected from the group consisting of colon cancer, renal-cell carcinoma, prostate cancer, testicular cancer, lung cancer, cancer of the small intestine and cancer of the esophagus, breast cancer, colon cancer, bone cancer, neuroblastoma, hematological malignancies such as B-cell lymphoid neoplasm, T-cell lymphoid neoplasm, non-Hodgkin lymphoma (NHL), B-NHL, T-NHL, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), mantle cell lymphoma (MCL), NK-cell lymphoid neoplasm and myeloid cell lineage neoplasm including acute myeloid leukemia.
[64] Preferably, the cancer may be selected from the group consisting of lung cancer, breast cancer, colon cancer, bone cancer and neuroblastoma.
[65] The bacterial infection may be selected from the group consisting of pneumonia, bacterial meningitis, cholera, diphtheria, tuberculosis, anthrax, botulism, brucellosis, campylobacteriosis, typhus, gonorrhea, listeriosis, lyme disease, rheumatic fever, pertussis (Whooping Cough), plague, salmonellosis, scarlet fever, shigellosis, syphilis, tetanus, trachoma, tularemia, typhoid fever, and urinary tract infections, or caused by Coxiella burnetii, Brucella abortus, Tropheryma whipplei, Mycobacterium tuberculosis and Mycobacterium canettii.
[66] The parasitic infection may be selected from the group consisting of malaria, leishmaniasis, trypanosomiasis, chagas disease, cryptosporidiosis, fascioliasis, filariasis, amebic infections, giardiasis, pinworm infection, schistosomiasis, taeniasis, toxoplasmosis, trichi nellosis, and trypanosomiasis.
[67] The fungal infection may be selected from the group consisting of candidiasis, aspergillosis, coccidioidomycosis, cryptococcosis, histoplasmosis and tinea pedis.
[68] Another application of the present invention is the use of at least one of the described compounds of the invention which contains a functional group, or one of these compounds on which at least one functional group would be added, to functionalize a protein of interest. Functional groups may include, but are not limited to, a fluorophore, a biotin, a peptide, a drug or a "clickable" group, such as a C2-alkynyl group or an azido group. This functional group can be added anywhere on the compound of the present invention, providing that it does not interfere with its bioactivation.
[69] The HSD17Bll-mediated oxidation of the functionalized compound generates a protein reactive species which will covalently modify the protein of interest with the desirable functional group through Michael addition of one or several cysteine and lysine side chains with the functionalized bioactivated compound.
[70] In the case of compounds functionalized with clickable function, the use of "click- chemistry" reactions, such as the copper-catalyzed azide-alkyne cycloaddition (CuAAC), allows to subsequently modify the protein with another functional group, including large functional groups, providing that it carries a function amenable to the selected "click chemistry" reaction. The protein of interest can be any protein with lysines and/or cysteines residues, but is preferably an antibody, and the functional group is preferentially a drug (i.e. an antibody-drug conjugates).
[71] A further subject of the present invention is the use of at least one of the compounds of the present invention to select genome edited cells (i.e. by CRISPR/Cas9-mediated genome editing technology) through the co-inactivation of the HSD17B11 gene (i.e. knock-out or knock-in impacting on HSD17B11 catalytic activity) and of the gene(s) of interest in a target cell population. In that embodiment, the HSD17B11 gene coinactivation provides a resistance to some of the compounds described in the present invention which is used to enrich the edited cells and kill the unedited one by treating the cell population, comprising properly edited cells with non-edited ones, with the chosen compound(s). The gene editing strategies amenable to this approach may comprise, but is not limited to, CRISPR/Cas9 genome editing.
[72] The present invention is illustrated below with the aid of examples.
[73] Brief description of the figures:
[74] Figure 1 is a scheme of the steps of a 1st method for preparing compounds according to the present invention.
[75] Figure 2 is a scheme of the steps of a 2nd method for preparing compounds according to the present invention.
[76] EXAMPLES:
[77] I - PREPARATION OF COMPOUNDS OF THE PRESENT INVENTION:
[78] The below detailed compounds of the present invention have been prepared according to one of the two following methods : - a 1st method which was a 4-step method and which comprised for the 3rd step two alternatives (i.e. 3a) or 3'a)) as shown in the scheme of the figure 1 ;
- a 2nd method which was a 3-step or a 4-step method and which comprised for the 2nd step two alternatives (i.e. 2b) or 2'b)), for the 3rd step four alternatives (i.e. 3b), 3'b), 3"b) or 3"'b) and optionally a 4th step as shown in the scheme of the figure 2.
[79] The starting compound of these two methods was a compound of the formula (X) :
Figure imgf000019_0001
in which B is halogen (i.e. fluorine, chlorine, bromine, or iodine) and Ar has the meaning as above detailed.
[80] The 1st method was carried out according to the following steps la), 2a), 3a) or 3'a) and 4a).
[81] The step la) of the 1st method was carried out as follows:
[82] In a nitrogen-flushed two-necked flask equipped with a stirring bar, a reflux condenser and a rubber septum, were introduced Pd(PPh3)2CI 2( mol%) and copper(l) iodide (5 mol%). The flask was flushed with nitrogen, then, freshly distilled and degassed Et3N (0.7 mol/L) was added followed by the compound of the formula (X). Trimethylsilyl-acetylene (1.2 eq) was then slowly added dropwise and the solution was stirred at 80 °C for 15 hours. After cooling to room temperature, the reaction was quenched by addition of an aqueous HCI solution (1 mol/L) and the resulting mixture extracted 3 times with Et2O. The combined organic layers were washed with water and brine, before being dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the expected silylated alkyne (i.e. the compound shown in figure 1 after the end of step la)).
[83] The step 2a) of the 1st method was carried out as follows:
[84] A solution of the silylated alkyne in MeOH (0.06 mol/L) containing K2CO3 (0.2 equiv) was stirred at room temperature during 12 hours. CH2CI2 and water were added and the resulting mixture was extracted 3 times with CH2CI2. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the expected deprotected terminal alkyne (i.e. the compound shown in figure 1 after the end of step 2a)).
[85] As explained above, the 3rd step of the 1st method may be carried out according to a 1st alternative (i.e. 3a) or a 2nd alternative (i.e. 3'a).
[86] The step 3a) of the 1st method was carried out as follows:
[87] A flame-dried flask was charged with a solution of the starting terminal alkyne in THF (0.3 mol/L) under dry argon atmosphere at -78°C. To the stirred solution, n-butyllithium (1.2 eq., 2.5 mol/L in hexane) was added dropwise. The solution was stirred for 45 minutes at the same temperature, 3-(tri methylsily l)-2-propyna I (1.0 eq.) was then added dropwise and the mixture was stirred for 3 hours at room temperature. After addition of saturated aqueous NH4CI solution and water, the aqueous layer was extracted 3 times with CH2CI2. The combined organic layers were then washed with water and brine, dried over MgSCO4 and concentrated under reduced pressure.
[88] The crude product was purified by flash column chromatography on silica gel to afford the expected silylated dialkynylcarbinol in the form of a racemic mixture.
[89] And if the above obtained racemic mixture was resolved with preparative chiral supercritical fluid chromatography (Chiralpak IB 5 μm (20 x 250 mm) column, 90:10 ScCO2/MECN, 40 mL/min, 150 bar, 37 °C), the expected silylated dialkynylcarbinol was obtained in the form of an enantioenriched (R) or (S) silylated dialkynylcarbinol with more than 99% enantiomeric excess.
[90] In other words, depending on the method of purification/resolution of the product by chromatography, at the end of the alternative 3a), a silylated dialkynylcarbinol was obtained in the form of a racemic mixture or in the form of an enantioenriched (R) or (S) compound with more than 99% enantiomeric excess.
[91] The step 3'a) of the 1st method was carried out as follows:
[92] A flame-dried flask was charged with Zn(OTf)2 (4 eq.) and (+)- or (-)-N -methyl ephedrine (4 eq.) and dried under vacuum with stirring for 2 hours. Anhydrous CH2CI2 (0.4 mL/mmol) and freshly distilled Et3N (4 eq.) were added and the resulting mixture was stirred at room temperature for a further 2 hours. A solution of the deprotected terminal alkyne (1 eq.) in anhydrous CH2CI2 (1 mL/mmol, final concentration 0.4 M) was cannulated. The resulting mixture was stirred at room temperature for 45 minutes before dropwise addition of 3-(trimethylsilyl)-2-propynal (1 eq.) in anhydrous CH2CI2 (1 mL/mmol) (final concentration in deprotected terminal alkyne 0.3 mol/L). The reaction mixture was stirred at room temperature for 12 hours before being quenched by addition of aqueous saturated NH4CI solution and extracted 3 times with CH2CI2. The combined organic layers were then washed with water and brine, dried over MgSCO4 and concentrated under reduced pressure.
[93] The crude product was purified by flash column chromatography on silica gel to afford the expected enantioenriched (R)- or (S)-silylated dial kynylca rbi nol thus depending if the (-)- or (+)-/V-methyl ephedrine was respectively charged in the flame-dried flask.
[94] In other words, an enantioenriched (R)- or (S)-silylated dial kynylcarbi nol was always obtained with the alternative 3'a).
[95] The step 4a) of the 1st method was carried out as follows:
[96] A solution of the silylated dia Ikynylca rbinol in MeOH (0.06 mol/L) containing K2CO3 (0.2 equiv) was stirred at room temperature for 1 hour and 30 minutes. CH2CI2 and water were added and the resulting mixture was extracted 3 times with CH2CI2. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the expected dialkynylcarbinol of the present invention.
[97] To sum up, depending on the choice of the alternative 3a) or 3'a), and more precisely for the alternative 3a), depending on the choice of the method of purification/resolution of the product by chromatography, at the end of the 1st method, a dialkynylcarbinol according to the present invention was obtained in the form of a racemic mixture or in the form of an enantioenriched dialkynylcarbinol.
[98] The 2nd method was carried out according to the following steps lb), 2b) or 2'b), 3b) or 3'b) and then 4b) or 3"b) or 3"'b).
[99] The step lb) of the 2nd method was carried out as follows: [100] A Schlenk flask charged with Na2PdCI4 (1 mol%), 2-(di-tert-butylphosphino)-N- phenylindole (PlntB, 2 mol%), Cul (2 mol%), propargyl alcohol (2.0 eq.), aryl halide of formula (X) (1.1 equiv), H2O (0.2 mL/mmol) and TMEDA (1.8 mL/mmol) was evacuated and backfilled with argon 3 times, and heated to 80 °C under stirring. After consumption of the compound of the formula (X), the reaction mixture was cooled to room temperature. Water was added and the resulting mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over MgSCO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the expected propargylic alcohol (i.e. the compound shown in figure 2 after the end of step lb)).
[101] As explained above, the 2nd step of the 2nd method may be carried out according to a 1st alternative (i.e. 2b) or a 2nd alternative (i.e. 2'b).
[102] The step 2b) of the 2nd method was carried out as follows:
[103] To a solution of the propargylic alcohol in dry CH2CI2 (0.1 mol/L) was added Dess- Martin periodinane (DMP, 1.2 eq.). The reaction mixture was stirred at room temperature for 2 hours and a saturated solution of Na2S2O3 (10 mLfor 2 mL of CH2CI2) and a saturated solution of Na2CO3 (10 mL for 2 mL of CH2CI2) were added. The mixture was extracted 3 times with CH2CI2. The combined extracts were washed with brine, dried over MgSCO4 and concentrated. The residue was purified by flash column chromatography on silica gel to afford the expected propargylic aldehyde.
[104] The step 2'b) of the 2nd method was carried out as follows:
[105] The step 2'b) was carried out as below detailed if Ar of the compound of the formula (X) comprised a triisopropylsilyl-protected terminal alkyne.
[106] To a solution of the propargylic alcohol obtained at the end of step lb) and which comprised a triisopropylsilyl-protected terminal alkyne in dry THF (0.4 mol/L) was added at 0 °C TBAF (1 mol/L in THF, 1.8 eq.). After addition, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. After evaporation of the solvent, the residue was dissolved in Et2O. This organic layer was washed with water and brine, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography to afford the expected propargylic alcohol comprising a terminal alkyne. [107] Then to a solution of the thus obtained propargylic alcohol in dry CH2CI2 (0.1 mol/L) was added Dess-Martin periodinane (DMP, 1.2 eq.). The reaction mixture was stirred at room temperature for 2 hours and a saturated solution of Na2S2O3 (10 mL for 2 mL of CH2CI2) and a saturated solution of Na2CO3 (10 mL for 2 mL of CH2CI2) were added. The mixture was extracted 3 times with CH2CI2. The combined extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the expected propargylic aldehyde.
[108] As explained above, the 3rd step of the 2nd method may be carried out according to a 1st alternative (i.e. 3b) or a 2nd alternative (i.e. 3'b) or a 3rd alternative (i.e. 3"b) or a 4th alternative (i.e. 3"'b).
[109] The step 3b) of the 2nd method was carried out as follows:
[110] To a solution of the propargylic aldehyde in dry THF (0.1 mol/L) under dry argon atmosphere at 0 °C was added ethynyl magnesium bromide (0.5 mol/L in THF, 1.2 eq.). After 1 hour stirring at 0 °C, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Then a saturated aqueous solution of NH4CI (4 mL for 1 mL of THF) was added and the mixture was extracted with Et20. The combined extracts were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the expected dialkynylcarbinol of the present invention in the form of a racemic mixture.
[111] The step 3'b) of the 2nd method was carried out as follows:
[112] A flame-dried flask was charged with ZnfOTfh (4 eq.) and (+)- or (-)-N-methyl ephedrine (4 eq.) and dried under vacuum with stirring for 2 hours. Anhydrous CH2CI2 (0.4 mL/mmol) and freshly distilled Et3N (4 eq.) were added and the resulting mixture was stirred at room temperature for a further 2 hours. A solution of silylated acetylene (4 eq.) in anhydrous CH2CI2 (1 mL/mmol, final concentration 0.4 M) was cannulated. The resulting mixture was stirred at room temperature for 45 minutes before dropwise addition of the propargylic aldehyde (1 eq.) in anhydrous CH2CI2 (1 mL/mmol) (final concentration in starting terminal alkyne 0.3 M). The reaction mixture was stirred at room temperature for 12 hours before being quenched by addition of aqueous saturated NH4CI solution and extracted 3 times with CH2CI2. The combined organic layers were then washed with water and brine, dried over MgSO4 and concentrated under reduced pressure.
[113] The crude product was purified by flash column chromatography on silica gel to afford the expected enantioenriched (R)- or (S)-silylated dialkynylcarbinol depending if the (+)- or (-)-A/-methyl ephedrine was respectively charged in the flame-dried flask.
[114] In other words, an enantioenriched (R)- or (S)-silylated dialkynylcarbinol was always obtained with the alternative 3'b).
[115] Then, a solution of the silylated dialkynylcarbinol in MeOH (0.06 mol/L) containing K2CO3 (0.2 eq.) was stirred at room temperature for 1 hour and 30 minutes. CH2CI2 and water were added and the resulting mixture was extracted 3 times with CH2CI2. The combined organic layers were dried over MgSCO4, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel to afford the expected enantioenriched (R)- or (S)-dialkynylcarbinol of the present invention.
[116] The step 3"b) of the 2nd method was carried out as follows:
[117] To a solution of the propargylic aldehyde in dry THF (0.1 mol/L) under dry argon atmosphere at 0 °C was added vinyl magnesium bromide (1 mol/L in THF, 1,2 eq.). After 1 hour of stirring at 0 °C, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Then a saturated aqueous solution of NH4CI (4 mL per mL of THF) was added and the mixture was extracted with Et2O. The combined extracts were washed with brine, dried over MgSCO4 and concentrated. The residue was purified by flash chromatography to afford the expected alkenylalkynylcarbinol of the present invention in the form of a racemic mixture.
[118] The step 3"'b) of the 2nd method was carried out as follows:
[119] To a solution of the propargylic aldehyde in dry THF (0.1 mol/L) under dry argon atmosphere at 0 °C was added C1-C6 alkyl magnesium bromide (1 mol/L in THF, 1.2 eq.). After 1 hour of stirring at 0 °C, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. Then a saturated aqueous solution of NH4CI (4 mL per mL of THF) was added and the mixture was extracted with Et20. The combined extracts were washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography to afford the expected alkylalkynylcarbinol of the present invention in the form of a racemic mixture.
[120] The step 4b) of the 2nd method was carried out as follows:
[121] To an oven-dried reaction tube with a screw cap were added 3-5 mL of dry dioxane, Cul (0.1 eq.), paraformaldehyde (1.6 eq.), solution of the dial kynylcarbinol obtained at the end of step 3b) (1 eq.) in dioxane (0.1 mol/L) and iPr2NH (1.4 eq.) under an argon atmosphere. The obtained mixture was sealed with the screw cap and stirred at 130 °C. After stirring at this temperature overnight, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography to afford the expected allenylalkynylcarbinol of the present invention in the form of a racemic mixture.
[122] Example 1: l-(4-Hexylphenyl)penta-1,4-diyn-3-ol of the formula (25):
Figure imgf000025_0001
[123] This compound (258 mg, 34 % overall yield from the starting compound (26)) was obtained in the form of a mixture of enantiomers according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: l-Bromo-4-hexylbenzene (CAS 23703-22-2 Commercial) of the formula (26):
Figure imgf000025_0002
[124] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.40 - 7.35 (m, 2H), 7.15 - 7.10 (m, 2H), 5.34 (d, J = 2.3 Hz, 1H), 2.61 (d, J = 2.3 Hz, 1H), 2.58 (t, J = 7.9 Hz, 2H), 1.97 (br s, 1H, OH), 1.62 - 1.56 (m, 2H), 1.34 - 1.26 (m, 6H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 144.4, 131.9, 128.6, 125.9, 118.9, 85.2, 84.9, 81.1, 73.0, 52.7, 36.1, 31.8, 31.3, 29.0, 22.7, 14.2. HRMS (DCI-CH4): calcd for C17H21O [M+H]+: 241.1592 m/z, found: 241.1592 m/z. FTIR (cm 1) (neat): v 3357, 3291, 2961, 2926, 2854, 2246, 2195, 2119, 1508, 1299, 1021, 897, 832, 816, 645, 565, 544.
[125] Example 2: l-(4-Octylphenyl)penta-1,4-diyn-3-ol of the formula (27):
Figure imgf000026_0001
[126] This compound (104 mg, 35 % overall yield from the starting compound (28)) was obtained in the form of a mixture of enantiomers according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: l-Bromo-4-octylbenzene: (CAS 51554-93-9 Commercial) of the formula (28):
Figure imgf000026_0002
[127] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.38 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 5.34 (d, J = 2.4 Hz, 1H), 2.65 - 2.55 (m, 3H), 2.30 (br s, 1H, OH), 1.59 (p, J = 7.1 Hz, 2H), 1.35 - 1.15 (m, 10H), 0.87 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCI3) 5 (ppm) 144.4, 131.9, 128.6, 118.9, 85.2, 84.9, 81.1, 73.0, 52.7, 36.1, 32.0, 31.3, 29.6, 29.4, 22.8, 14.2. HRMS (DCI-CH4): calcd for CI9H25O [M+H]+: 269.1905 m/z, found: 269.1910 m/z. FTIR (cm -1) (neat): 1/ 3275, 3189, 2954, 2922, 2851, 2231, 2195, 2123, 1508, 1297, 1023, 889, 840, 825, 707.
[128] Example 3: (/?)-l-(4-Octylphenyl)penta-1,4-diyn-3-ol of the formula (29):
Figure imgf000026_0003
[129] This compound was obtained:
- according to the 1st method (220 mg, 15% yield from the starting compound (28)) (with the alternative 3a) and resolution with preparative chiral supercritical fluid chromatography (Chiralpak IB 5 μm (20 x 250 mm) column, 90:10 ScCO2/MECN, 40 mL/min, 150 bar, 37 °C) for the 3rd step), in the form of a pure enantiomer (R) with more than 99 % enantiomeric excess.
- according to the 1st method (115 mg, 41% yield from the starting compound (28)) with the alternative 3'a) with (+)-A/-methyl ephedrine as chiral inductor, in the form of a pure enantiomer (/?) with a 57 % enantiomeric excess, as measured by analytical chiral supercritical fluid chromatography (Chiralpak IG 3 μm (4.6 x 100 mm) column, 90:10 ScCO2/MeOH, 2 mL/min, 100 bar, 40 °C), with the starting compound l-bromo-4- octyl benzene: (CAS 51554-93-9 Commercial) of the above detailed formula (28).
[130] The characterisation data of the example 3 are identical to the characterisation data detailed for the example 2 except for optical rotation,
Figure imgf000027_0002
[131] Example 4: (S)-l-(4-Octylphenyl)penta-1,4-diyn-3-ol of the formula (24):
Figure imgf000027_0001
[132] This compound was obtained:
- according to the 1st method (265 mg, 15 % yield from the starting compound (28)) (with the alternative 3a) and resolution with preparative chiral supercritical fluid chromatography (Chiralpak IB 5 pm (20 x 250 mm) column, 90:10 ScCO2/MECN, 40 mL/min, 150 bar, 37 °C) for the 3th step), in the form of a pure enantiomer (S) with more than 99 % enantiomeric excess,
- according to the 1st method (272 mg, 39 % yield from the starting material (28)) with the alternative 3'a) with (-)-N -methyl ephedrine as chiral inductor, in the form of a pure enantiomer (S) with a 57 % enantiomeric excess, as measured by analytical chiral supercritical fluid chromatography (Chiralpak IG 3 μm (4.6 x 100 mm) column, 90:10 ScCO2/MeOH, 2 mL/min, 100 bar, 40 °C), - according to the 2nd method (41 mg, 34 % yield from the starting material (28)) with the alternative 2b) for the 2nd step and the alternative 3'b) for the 3rd step with (+)-A/-methyl ephedrine as chiral inductor, in the form of a enantio-enriched (S) sample with a 88 % enantiomeric excess, as measured by analytical chiral supercritical fluid chromatography (Chiralpak IG 3 pm (4.6 x 100 mm) column, 90:10 supercritical CO2/MeOH, 2 mL/min, 100 bar, 40 °C), with the starting compound l-bromo-4-octylbenzene: (CAS 51554-93-9 Commercial) of the above detailed formula (28).
[133] The characterisation data of the example 4 are identical to the characterisation data detailed for the example 2 except for optical rotation.
Figure imgf000028_0003
[134] Example 5: l-(4-Nonylphenyl)penta-1,4-diyn-3-ol of the formula (30) :
Figure imgf000028_0001
[135] This compound (100 mg, 17 % yield from the starting compound (31)) was obtained in the form of a mixture of enantiomers according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound : l-Bromo-4-nonylbenzene (CAS 51554-94-0 Commercial) of the formula (31):
Figure imgf000028_0002
[136] Characterisation data : 1H NMR (400 MHz, CDCI3) <5 (ppm) 7.38 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 5.35 (d, J = 4.9 Hz, 1H), 2.74 - 2.51 (m, 3H), 2.45 (br d, J = 7.0 Hz, 1H, OH), 1.65 - 1.50 (m, 2H), 1.40 - 1.20 (m, 12H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 144.4, 131.9, 128. 6, 118.9, 85.1, 84.9, 81.1, 72.9, 52.7, 36.0, 32.0, 31.3, 29.7, 29.6, 29.4, 29.4, 22.8, 14.2. HRMS (DCI-CH4): calcd for C20H27O [M+H]+: 283.2062 m/z, found 283.2070 m/z. FTIR (cm-1) (neat): v 3291 (br), 2923, 2853, 2227, 2132, 1511, 1296, 1027, 1022, 638. [137] Example 6: l-(4-Decylphenyl)penta-1,4-diyn-3-ol of the formula (32):
Figure imgf000029_0001
[138] This compound (90 mg, 31 % yield from the starting compound (33)) was obtained in the form of a racemic mixture of enantiomers according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: l-Bromo-4-decylbenzene (CAS 106418-67-1 Commercial) of the formula (33):
Figure imgf000029_0002
[139] Characterisation data: 1H NMR (400 MHz, CDCI3) 5 (ppm) 7.38 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 5.34 (dd, J = 7.6, 2.3 Hz, 1H), 2.61 (d, J = 2.3 Hz, 1H), 2.59 (t, J = 8.0 Hz, 2H), 2.32 (d, J = 7.6 Hz, 1H, OH), 1.65 - 1.50 (m, 2H), 1.35 - 1.20 (m, 18H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 144.4, 131.9, 128.6, 118.9, 85.2, 84.9, 81.0, 73.0, 52.7, 36.1, 32.0, 31.3, 29.7, 29.7, 29.6, 29.5, 29.4, 22.8, 14.3. HRMS (DCI-CH4): calcd for C21H29O [M+H]+: 297.2218 m/z, found 297.2223 m/z. FTIR (cm 1) (neat): v 3274, 2921, 2848, 2231, 2123, 1508, 1297, 1022, 707.
[140] Example 7: 1-(4-Dodecylphenyl)penta-1,4-diyn-3-ol of the formula (34):
Figure imgf000029_0003
[141] This compound (81 mg, 15 % yield from the starting compound (35)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: 1-Bromo-4-dodecylbenzene (CAS 126930-72-1 Commercial) of the formula (35):
Figure imgf000030_0001
[142] Characterisation data: 1H NMR (400 MHz, CDCI3) 6 (ppm) 7.38 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 5.34 (br s, 1H), 2.65 - 2.55 (m, 3H), 2.33 (br d, J = 6.1 Hz, 1H, OH), 1.65 - 1.50 (m, 2H), 1.35 - 1.20 (m, 18H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) 5 (ppm) 144.4, 131.9, 128.6, 118.9, 85.2, 84.9, 81.1, 73.0, 52.7, 36.1, 32.1, 31.3, 29.8, 29.8, 29.7, 29.6, 29.5, 29.4, 22.8, 14.3. HRMS (DCI-CH4): calcd for C23H33O [M+H]+: 325.2531 m/z, found: 325.2540 m/z. FTIR (cm 1) (neat): v3268 (br), 2954, 2918, 2849, 2240, 2113, 1469, 1296, 1026.
[143] Example 8: l-(3-Nonylphenyl)penta-1,4-diyn-3-ol of the formula (36):
Figure imgf000030_0002
[144] This compound (80 mg, 14 % yield from the starting compound (37)) was obtained in the form of a racemic mixture according to 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: l-Bromo-3-nonylbenzene (CAS 95902-12-8 ) of the formula (37):
Figure imgf000030_0003
[145] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.32 - 7.26 (m, 2H), 721 (td, J = 7.3, 1.0 Hz, 1H), 7.16 (dt, J = 7.6, 1.7 Hz, 1H), 5.34 (dd, J = 7.5, 2.3 Hz, 1H), 2.61 (d, J = 2.3 Hz, 1H), 2.57 (t, J = 7.5 Hz, 2H), 2.41 (d, J = 7.6 Hz, 1H, OH), 1.65 - 1.50 (m, 2H), 1.40 - 1.10 (m, 10H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ5 (ppm) 143.3, 132.0,
129.4, 129.3, 128.4, 121.6, 85.2, 85.1, 81.0, 73.0, 52.7, 35.8, 32.0, 31.4, 29.7, 29.6, 29.5,
29.4, 22.8, 14.3. HRMS (DCI-CH4): calcd for C20H27O [M+H]+: 283.2062 m/z, found 283.2059 m/z. FTIR (cm 1) (neat): v 3309, 3290, 2961, 2925, 2853, 2233, 2195, 2119, 1463, 1292, 1036, 792, 697. [146] Characterisation of the bromo-3-nonylbenzene: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.36 - 7.27 (m, 2H), 7.19 - 7.06 (m, 2H), 2.57 (t, J = 7.4 Hz 2H), 1.65 - 1.54 (m, 2H), 1.37 - 1.18 (m, 12H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 145.5, 131.6, 129.9, 128.8, 127.2, 122.5, 35.8, 32.0, 31.4, 29.7, 29.6, 29.5, 29.4, 22.8, 14.3.
[147] Example 9: l-(3-Decylphenyl)penta-1,4-diyn-3-ol of the formula (38):
Figure imgf000031_0001
[148] This compound (89 mg, 21 % yield from the starting compound (39)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound : Bromo-3-decylbenzene (CAS 1714947-67-7) of the formula (39)
Figure imgf000031_0002
[149] Characterisation data: 3H NMR (300 MHz, CDCI3) δ (ppm) 7.32 - 7.26 (m, 2H), 7.22 (td, J = 7.3, 1.0 Hz, 1H), 7.16 (dt, J = 7.5, 1.7 Hz, 1H), 5.34 (br s, 1H), 2.62 (d, J = 2.3 Hz, 1H), 2.57 (t, J = 7.5 Hz, 2H), 2.30 (br s, 1H, 1H, OH), 1.65 - 1.50 (m, 2H), 1.40 - 1.20 (m, 14H), 0.88 (t, J = 6.5 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 143.3, 132.0, 129.5, 129.3, 128.4, 121.6, 85.2, 85.1, 81.0, 73.0, 52.7, 35.8, 32.1, 31.4, 29.8, 29.7, 29.6, 29.5, 29.4, 22.8, 14.3. HRMS (DCI-CH4): calcd for C21H29O [M+H]+: 297.2213 m/z, found: 297.2218 m/z. FTIR (erm 3) (neat): 1/3398, 3303, 2922, 2853, 2233, 2192, 2122, 1306, 1014, 790, 693, 657, 637.
[150] Example 10: l-(6-Octylnaphthalen-2-yl)penta-1,4-diyn-3-ol of the formula (40):
Figure imgf000031_0003
[151] This compound (80 mg, 31 % yield from the starting compound (41)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: 2-Bromo-6-octylnaphtalene (CAS 100808-04-6 Commercial) of the formula
(41):
Figure imgf000032_0001
[152] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.96 (d, J = 1.1 Hz, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.58 (d, J = 1.0 Hz, 1H), 7.46 (dd, J = 8.4, 1.6 Hz, 1H), 7.35 (dd, J = 8.4, 1.6 Hz, 1H), 5.40 (dd, J = 7.6, 2.3 Hz, 1H), 2.76 (t, J = 7.7 Hz, 2H), 2.64 (d, J = 2.3 Hz, 1H), 2.37 (dd, J = 7.6, 1.7 Hz, 1H, OH), 1.70 - 1.60 (m, 2H), 1.45 - 1.20 (m, 10H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 142.2, 133.5, 132.1, 131.4, 128.4, 128.4, 127.8, 127.7, 126.4, 118.1, 85.5, 85.4, 78.7ff, 73.1, 52.8, 36.3, 32.0, 31.4, 29.6, 29.5, 29.4, 22.8, 14.3. HRMS (DCI-CH4): calcd for C23H26O [M]+ : 318.1984 m/z, found: 318.1982 m/z. FTIR (cm 1) (neat): v 3385 (br), 3279, 2956, 2919, 2851, 2240, 2119, 1471, 1031, 896, 826, 478.
[153] Example 11: l-(3-Fluoro-4-octylphenyl)penta-1,4-diyn-3-ol of the formula (42):
Figure imgf000032_0002
[154] This compound (13.6 mg, 17 % yield from the starting compound (43)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: 4-Bromo-2-fluoro-l-octylbenzene of the formula (43):
Figure imgf000032_0003
[155] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.17 (dd, J = 7.7, 1.4 Hz, 1H), 7.15 - 7.07 (m, 2H), 5.33 (dd, J = 7.6, 2.3 Hz, 1H), 2.62 (d, J = 2.3 Hz, 1H), 2.61 (t, J = 7.5 Hz, 2H), 2.32 (d, J = 7.7 Hz, 1H), 1.64 - 1.52 (m, 2H), 1.37 - 1.21 (m, 10H), 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 160.6 (d, J = 245.5 Hz), 131.5 (d, J = 16.3 Hz), 130.7 (d, J = 6.0 Hz), 127.7 (d, J = 3.4 Hz), 120.7 (d, J = 9.6 Hz), 118.6 (d, J = 24.5 Hz), 85.6, 83.9, 80.8, 73.2, 52.7, 32.0, 30.1 (d, J = 1.0 Hz), 29.5, 29.4, 29.4, 29.1 (d, J = 2.1 Hz), 22.8, 14.2. 19F NMR (282 MHz, CDCI3) δ (ppm) -118.4 (dd, J = 10.0, 7.3 Hz). HRMS (DCI-CH4): calcd for C19H24FO [M+H]+: 287.1811 m/z, found: 287.1818 m/z. FTIR (cm 1) (neat): v3361 (br) 3303, 2954, 2925, 2855, 2246, 2127, 1500, 1170, 1028.
[156] Characterisation of 4-bromo-2-fluoro-l-octylbenzene: 1H NMR (300 MHz, CDCI3) 5 (ppm) 7.22 - 7.14 (m, 2H), 7.05 (t, J = 8.1 Hz, 1H), 2.58 (t, J = 7.6 Hz, 1H), 1.63 - 1.50 (m, 2H), 1.40 - 1.10 (m, 10H), 0.88 (t, J = 7.2 Hz, 3H).13C NMR (75 MHz, CDCI3) δ (ppm) 161.1 (d, J = 249.2 Hz), 131.8 (d, J = 5.9 Hz), 129.0 (d, J = 16.3 Hz), 127.2 (d, J = 3.7 Hz), 119.3 (d, J = 9.6 Hz), 118.9 (d, J = 25.8 Hz), 32.0, 30.1, 29.5, 29.4, 28.8 (d, J = 2.0 Hz), 22.8, 14.2. 19F NMR (282 MHz, CDCI3) δ (ppm) -115.71 (d, J = 7.0 Hz). HRMS (DCI-CH4): calcd for C14H19BrF [M-H]+: 285.0654 m/z, found: 285.0646 m/z. FTIR (cm 1) (neat): 1/2954, 2925, 2855, 1610j, 1572, 1484, 878, 857.
[157] Example 12: l-(2-Fluoro-4-octylphenyl)penta-1,4-diyn-3-ol of the formula (44):
Figure imgf000033_0001
[158] This compound (31.5 mg, 27 % yield from the starting compound (45)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: 2-Fluoro-l-iodo-4-octylbenzene of the formula (45):
Figure imgf000033_0002
[159] 3H NMR (300 MHz, CDCI3) 5 (ppm) 7.34 (t, J = 7.7 Hz, 1H), 6.95 - 6.85 (m, 2H), 5.37 (dd, J = 7.7, 2.3 Hz, 1H), 2.62 (d, J = 2.2 Hz, 1H), 2.59 (t, J = 7.9 Hz, 2H), 2.45 - 2.30 (br s, 1H, OH), 1.65 - 1.50 (m, 2H), 1.40 - 1.20 (m, 10H), 0.88 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 163.1 (d, J = 252.2 Hz), 147.2 (d, J = 7.4 Hz), 133.5 (d, J = 1.7 Hz), 124.3 (d, J = 3.2 Hz), 115.5 (d, J = 20.3 Hz), 107.5 (d, J = 15.7 Hz), 89.9 (d, 7 = 3.2 Hz), 80.8, 78.7, 73.2, 52.8, 35.9 (d, J = 1.6 Hz), 32.0, 31.0, 29.5, 29.3, 29.3, 22.8, 14.2. 19F NMR (282 MHz, CDCI3) δ (ppm) -110.50 (dd, J = 10.4, 7.8 Hz). HRMS (DCI-CH4): calcd for C19H24FO [M+H]+: 287.1811 m/z, found: 287.1803 m/z. FTIR (cm-1) (neat): v 3364 (br), 3310, 3275, 2954, 2922, 2855, 2236, 2205, 2129, 1423, 1019.
[160] Characterisation of 2-Fluoro-l-iodo-4-octylbenzene: 1H NMR (300 MHz, CDCI3) 5 (ppm) 7.60 (dd, J = 8.0, 6.7 Hz, 1H), 6.89 (dd, J = 9.2, 2.0 Hz, 1H), 6.73 (dd, J = 8.1, 2.0f Hz, 1H), 2.56 (t, J = 7.3 Hz, 2H), 1.66 - 1.52 (m, 2H), 1.38 - 1.17 (m, 10H), 0.88 (t, J = 6.7 Hz, 3H). HRMS (DCI-CH4): calcd for C14H21FI [M+H]+: 335.0664 m/z, found: 335.0672 m/z. FTIR (cm 1) (neat): v2954, 2924, 2855.
[161] Example 13: l-(3,5-Difluoro-4-octylphenyl)penta-1,4-diyn-3-ol of the formula (46):
Figure imgf000034_0001
[162] This compound (69 mg, 36 % yield from the starting compound (47)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3b) forthe 3rd step with the starting compound: 5-Bromo-l,3- difluoro-2-octylbenzene of the formula (47):
Figure imgf000034_0002
[163] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.00 - 6.89 (m, 2H), 5.33 (d, J = 2.3 Hz, 1H), 2.64 (tt, J = 7.5, 1.4 Hz, 2H), 2.62 (d, J = 2.3 Hz, 1H), 2.55 - 2.40 (br s, 1H, OH), 1.55 (p, J = 7.3 Hz, 2H), 1.40 - 1.20 (m, 10H), 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (125 MHz, CDCI3) 6 (ppm) 161.2 (dd, J = 246.9, 10.4 Hz), 120.7 (t, J = 12.2 Hz), 120.4 (t, J = 20.7 Hz), 114.7 - 114.4 (m, 1C), 86.5, 82.9 (t, J = 3.8 Hz), 80.5, 73.4, 52.6, 32.0, 29.5, 29.4, 29.4, 29.3, 22.8, 22.5 (t, J = 2.3 Hz), 14.2. 19F NMR (282 MHz, CDCI3) δ (ppm) -115.4 (d, J = 6.9 Hz). HRMS (DCI-CH4): calcd for C19H23OF2 [M+H]+: 305.1717 m/z, found: 305.1711 m/z. FTIR (cm-1) (neat): v 3292, 3277, 2956, 2925, 2855, 2245, 2122, 1631, 1569, 1419, 1020. [164] Characterisation of 5-bromo-l,3-difluoro-2-octylbenzene: 1H NMR (300 MHz, CDCI3) δ (ppm) 6.97 - 7.07 (m, 2H), 2.60 (tt, J = 7.6, 1.4 Hz, 2H), 1.62 - 1.47 (m, 2H), 1.40 - 1.20 (m, 8H), 0.87 (t, J = 6.1 Hz, 3H). 13C NMR (125 MHz, CDCI3) 5 (ppm) 147.8, 134.5, 131.8, 129.9, 123.8, 120.5 (q, J = 257.3 Hz), 119.3, 31.8, 29.8, 29.4, 29.3, 29.3, 29.2, 22.7, 14.1. 19F NMR (282 MHz, CDCI3) 5 (ppm) -114.11 (d, J = 6.4 Hz). HRMS (DCI-CH4): calcd for C14H20BrF2 [M+H]+: 305.0711 m/z, found: 305.0691 m/z.
[165] Example 14: l-(4-Octyl-3-(trifluoromethoxy)phenyl)penta-1,4-diyn-3-ol of the formula (48):
Figure imgf000035_0001
[166] This compound (46 mg, 34 % yield from the starting compound (49)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3b) for the 3rd step with the starting compound: 4-Bromo-l- octyl-2-(trifluoromethoxy)benzene of the formula (49):
Figure imgf000035_0002
[167] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.37 - 7.32 (m, 2H), 7.24 (d, J = 8.3 Hz, 1H), 5.38 (dd, J = 7.6, 2.3 Hz, 1H), 2.68 (t, J = 7.6 Hz, 2H), 2.66 (d, J = 2.3 Hz, 1H), 2.41 (d, J = 7.6 Hz, 1H, OH), 1.67-1.55 (m, 2H), 1.40 - 1.25 (m, 10H), 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 147.3 ,137.0, 130.8, 130.3, 123.8, 120.7, 120.6 (q, J = 257.3 Hz), 86.0, 83.6, 80.7, 73.3, 52.6, 32.0, 29.9, 29.5, 29.3, 22.8, 14.2. 19F NMR (282 MHz, CDCI3) δ (ppm) -57.0. HRMS (DCI-CH4): calcd for C20H24O2F3 [M+H]+: 353.1728 m/z, found: 353.1726 m/z. FTIR (cm-1) (neat): 1/3292, 3277, 2956, 2925, 2855, 2245, 2122, 1631, 1569, 1419, 1291, 1160, 1119, 1020.
[168] Characterisation of 4-bromo-l-octyl-2-(trifluoromethoxy)benzene: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.40 - 7.30j (m, 2H), 7.13 (d, J = 8.0 Hz, 1H), 2.65 - 2.55 (m, 2H), 1.56 (p, J = 7.6 Hz, 2H), 1.40 - 1.15 (m, 10H), 0.88 (t, J = 7.2 Hz, 3H).13C NMR (125 MHz, CDCI3) δ (ppm) 161.1 (d, J = 249.2 Hz), 131.8 (d, J = 5.9 Hz), 129.0 (d, J = 16.3 Hz), 127.2 (d, J = 3.7 Hz), 119.3 (d, J = 9.6 Hz), 118.9 (d, J = 25.8 Hz), 32.0, 30.1, 29.5, 29.4, 28.8 (d, J = 2.0 Hz), 22.8, 14.2. 19F NMR (282 MHz, CDCI3) δ (ppm) -57.13. HRMS (DCI-CH4): calcd for C15H21OBrF3 [M+H]+: 353.0722 m/z, found: 353.0642 m/z.
[169] Example 15: l-(4-(2-(2-Ethoxyethoxy)ethoxy)phenyl)penta-1,4-diyn-3-ol of the formula (50):
Figure imgf000036_0001
[170] This compound (63 mg, 6 % yield from the starting compound (51)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: l-Bromo-4-(2-(2-ethoxyethoxy)ethoxy)benzene (CAS 1248916-41-7) of the formula (51):
Figure imgf000036_0002
[171] Characterisation data: 1H NMR (300 MHz, CDCI3) 5 (ppm) 7.37 (d, J = 9.0 Hz, 1H), 6.84 (d, J = 9.0 Hz, 1H), 5.33 (br s, 1H), 4.13 (dd, J = 5.5, 4.2 Hz, 2H), 3.86 (dd, J = 5.6, 4.2 Hz„ 2H), 3.74 - 3.67 (m, 2H), 3.65 - 3.58 (m, 2H), 3.53 (q, J = 7.1 Hz, 2H), 2.86 - 2.64 (m, 1H), 2.60 (d, J = 2.3 Hz, 1H), 1.21 (t, J = 7.0 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 159.4, 133.5, 114.7, 114.1, 84.8, 84.5, 81.3, 72.8, 71.0, 69.9, 69.7, 67.6, 66.9, 52.6, 15.3. HRMS (DCI-CH4): calcd for C17H21O4 [M+H]+: 289.1430 m/z, found: 289.1440 m/z. FTIR (cm -1) (neat): 1/3310, 2977, 2930, 2870, 2230, 2119, 1605, 1508, 1286, 1246, 1104, 1057, 1024, 832, 538.
[172] Example 16: l-(4-(Heptyloxy)phenyl)penta-1,4-diyn-3-ol of the formula (52):
Figure imgf000036_0003
[173] This compound (183 mg, 8 % yield from the starting compound (53)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: l-lodo-4-(heptyloxy)benzene (CAS 116223-56-4 Commercial) of the formula (53):
Figure imgf000037_0001
[174] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.42 - 7.36 (m, 2H), 6.86 - 6.80(m, 2H), 5.33 (dd, J = 7.0, 2.3 Hz, 1H), 3.95 (t, J = 6.6 Hz, 2H), 2.61 (d, J = 2.3 Hz, 1H), 2.31 (d, J = 7.44 Hz, 1H), 1.85 - 1.70 (m, 2H), 1.50 - 1.25 (m, 8H), 0.89 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) 5 (ppm) 159.9, 133.5, 114.6, 113.6, 85.1, 84.2, 81.2, 72.9, 68.2, 52.8, 31.9, 29.3, 29.2, 26.1, 22.7, 14.2. HRMS (DCI-CH4): calcd for C18H22O2 [M]+: 270.1612 m/z, found: 270.1620 m/z. FTIR (cm-1) (neat): v3297, 2958, 2923, 2857, 2236, 2027, 1605, 1508, 1286, 1244, 1172, 1018, 830, 643.
[175] Example 17: 5-(4-Octylphenyl)pent-l-en-4-yn-3-ol of the formula (54):
Figure imgf000037_0002
[176] This compound (32 mg, 16 % yield from the starting compound (28)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3"b) for the 3rd step with the starting compound: l-Bromo-4- octyl benzene: (CAS 51554-93-9 Commercial) of the formula (28):
Figure imgf000037_0003
[177] 1H NMR (300 MHz, CDCI3) δ (ppm) 7.36 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.5 Hz, 2H), 6.06 (ddd, J = 17.0, 10.1, 5.3 Hz, 1H), 5.54 (dt, J = 17.0, 1.3 Hz, 1H), 5.27 (dt, J = 10.1, 1.3 Hz, 1H), 2.59 (t, J = 7.6 Hz, 2H), 1.96 (d, J = 6.4 Hz, 1H), 1.65 - 1.52 (m, 2H), 1.36 - 1.21 (m, 10H), 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 144.0, 137.2, 131.8, 128.6, 119.6, 116.7, 87.1, 86.7, 63.9, 36.0, 32.0, 31.4, 29.6, 29.4, 22.8, 14.2. HRMS (DCI-CH4): calcd for C19H27O [M+H]+: 271.2062 m/z, found: 271.2055 m/z.
[178] Example 18: 5-(3-Fluoro-4-octylphenyl)pent-l-en-4-yn-3-ol of the formula (55):
Figure imgf000038_0001
[179] This compound (11 mg, 22 % yield from the starting compound (43)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3"b) for the 3rd step with the starting compound: 4-Bromo-2- fluoro-l-octylbenzene of the formula (43) characterized in example 11:
Figure imgf000038_0002
[180] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.17 - 7.06 (m, 3H), 6.05 (ddd, J = 17.0, 10.1, 5.3 Hz, 1H), 5.53 (dt, J = 17.0, 1.3 Hz, 1H), 5.28 (dt, J = 10.1, 1.2 Hz, 1H), 5.09 (ddt, J = 6.7, 5.3, 1.5 Hz, 1H), 2.61 (td, J = 7.6, 1.2 Hz, 2H), 1.99 (d, J = 6.3 Hz, 1H), 1.65 - 1.50 (m, 2H), 1.40 - 1.15 (m, 10H), 0.88 (t, J - 6.6 Hz, 3H). 13C NMR (100 MHz, CDCI3) 6 (ppm) 160.7 (d, J = 245.3 Hz), 136.9, 131.0 (d, J = 16.4 Hz), 130.7 (d, J = 6.0 Hz), 127.6 (d, J = 3.2 Hz), 121.4 (d, J = 9.6 Hz), 118.4 (d, J = 24.5 Hz), 116.9, 87.9, 85.5 (d, J = 3.1 Hz), 63.8, 32.0, 30.1, 29.5, 29.4, 29.4, 29.1 (d, J = 2.2 Hz), 22.8, 14.2. 19F NMR (282 MHz, CDCI3) 5 (ppm) -118.6 (dd, J = 10.4, 6.6 Hz). HRMS (DCI-CH4): calcd for C19H26OF [M+H]+: 289.1968 m/z, found: 289.1958 m/z. FTIR (cm 1) (neat): v 3330 (br) 3086, 2955, 2925, 2855, 2229, 1465, 1263, 1164, 1127.
[181] Example 19: l-(5-Dodecylthiophen-2-yl)penta-1,4-diyn-3-ol of the formula (56):
Figure imgf000039_0001
[182] This compound (89 mg, 38 % yield from the starting compound (57)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: 2-Bromo-5-dodecylthiophene (CAS 153561-74-1 Commercial) of the formula (57):
Figure imgf000039_0002
[183] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.08 (d, J = 3.6 Hz, 1H), 6.64 (d, J = 3.6 Hz, 1H), 5.34 (dd, J = 7.7, 2.3 Hz, 1H), 2.77 (t, J = 7.5 Hz, 2H), 2.61 (d, J = 2.3 Hz, 1H), 2.30 (d, J = 7.7 Hz, 1H), 1.65 (p, J = 7 A Hz, 2H), 1.28 (d, J = 14.2 Hz, 18H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 149.5, 133.4, 124.3, 118.8, 88.6, 80.7, 78.9, 73.2, 52.8, 32.1, 31.7, 30.3, 29.8, 29.8, 29.7, 29.5, 29.5, 29.2, 22.8, 14.3. HRMS (DCI-CH4): calcd for C21H31OS [M+H]+: 331.2096 m/z, found: 331.2091 m/z. FTIR (cm-1) (neat): v 3276, 3209 (br), 2955, 2913, 2849, 2230, 2179, 2124, 1469, 1021, 801.
[184] Example 20: l-(5-Decylthiophen-2-yl)penta-1,4-diyn-3-ol of the formula (58):
Figure imgf000039_0003
[185] This compound (43 mg, 20 % yield from the starting compound (59)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: 2-Bromo-5-decylthiophene (CAS 514188-72-8 Commercial) of the formula (59):
Figure imgf000040_0001
[186] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.08 (d, J = 3.6 Hz, 1H), 6.64 (dt, J = 3.6, 0.8 Hz, 1H), 5.34 (dd, J = 7.6, 2.3 Hz, 1H), 2.77 (t, J = 7 A Hz, 2H), 2.61 (d, J = 2.3 Hz, 1H), 2.34 (d, J = 7.6 Hz, 1H), 1.66 (p, J = 7.5 Hz, 2H), 1.40 - 1.19 (m, 14H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 149.5, 133.4, 124.3, 118.8, 88.6, 80.8, 79.0, 73.2, 52.8, 32.0, 31.7, 30.3, 29.7, 29.7, 29.5, 29.1, 22.8, 14.3. HRMS (DCI-CH4): calcd for C19H27OS [M+H]+: 303.1783 m/z, found: 303.1778 m/z. FTIR (cm-1) (neat): v3291 (br), 2955, 2924, 2866, 2175.
[187] Example 21: l-(5-Heptylfuran-2-yl)penta-1,4-diyn-3-ol of the formula (60):
Figure imgf000040_0002
[188] This compound (44 mg, 5 % yield from the starting compound (61)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: 2-Heptyl-5-iodofuran of the formula (61):
Figure imgf000040_0003
[189] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 6.57 (d, J = 3.3 Hz, 1H), 5.98 (d, J = 3.3 Hz, 1H), 5.36 (dd, J = 7.7, 2.3 Hz, 1H), 2.62 (d, J = 1.8 Hz, 1H), 2.60 (t, J = 7.5 Hz, 2H), 2.32 (d, J = 7.7 Hz, 1H), 1.63 (p, J = 7.5 Hz, 2H), 1.40 - 1.20 (m, 8H), 0.88 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCI3) 8 (ppm) 159.1, 133.9, 117.9, 106.5, 89.7, 80.4, 76.0, 73.4, 52.7, 31.9, 29.2, 29.1, 28.4, 28.0, 22.8, 14.2. HRMS (DCI-CH4): calcd for C16H21O2 [M+H]+: 245.1541 m/z, found: 245.1542 m/z. FTIR (cm-1) (neat): v3300, 2955, 2927, 2857, 2160, 2122, 1525, 1207, 1015, 786.
[190] Characterisation of 2-heptyl-5-iodofuran : 1H NMR (300 MHz, CDCI3) δ (ppm) 6.41 (d, J
= 3.1 Hz, 1H), 5.91 (d, J = 3.1 Hz, 1H), 2.63 (2H, t, J = 7.6 Hz), 1.61 (p, J = 7.5 Hz, 2H), 1.36- 1.21 (8H, m), 0.87 (t, J = 6.5 Hz, 3H). 13C NMR (100 MHz, CDCI3) 6 (ppm): 162.5, 120.8,
108.1, 84.3, 31.6, 29.1, 28.9, 28.4, 28.1, 22.8, 14.2.
[191] Example 22: l-(4-(Oct-7-yn-l-yl)phenyl)penta-1,4-diyn-3-ol of the formula (62):
Figure imgf000041_0001
[192] This compound (19 mg, 25 % yield from the starting compound (63)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2'b) for the 2nd step and alternative 3b) for the 3rd step with the starting compound: (8-(4- Bromophenyl)oct-l-yn-l-yl)triisopropylsilane (CAS 1429428-13-6) of the formula (63):
Figure imgf000041_0002
[193] Characterisation data: 3H NMR (300 MHz, CDCI3) δ (ppm) 7.38 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.5 Hz, 2H), 5.34 (dd, J = 7.6, 2.3 Hz, 1H), 2.61 (d, J = 2.3 Hz, 1H), 2.60 (t, J = 7.6 Hz, 2H), 2.30 (d, J = 7.6 Hz, 1H), 2.18 (td, J = 6.9, 2.5 Hz, 1H), 1.94 (t, J = 2.6 Hz, 1H), 1.70 - 1.20 (m, 6H). 13C NMR (125 MHz, CDCI3) δ (ppm) 144.2, 131.9, 128.6, 119.0, 85.1, 85.0, 84.8, 81.1, 73.0, 68.3, 52.8, 35.9, 31.1, 29.9, 28.8, z28.5, 18.5 HRMS (DCI-CH4): calcd for C19H21O [M-H]+: 265.1592 m/z, found: 265.1579 m/z. FTIR (cm-1) (neat): 1/3277, 3195, 2931, 2852, 2578, 2231, 1509, 1297, 1023.
[194] Example 23: (S) -1-(4-(Oct-7-yn-l-yl)phenyl)penta-1,4-diyn-3-ol of the formula (64):
Figure imgf000041_0003
[195] This compound was obtained by resolution of the racemic compound (62) with preparative chiral supercritical fluid chromatography (Chiralpak IG 5 μm (4.6 x 100 mm) column, 90:10 ScCO2/MeOH, 2 mL/min, 1740 psi, 40 °C). The expected compound was obtained in the form of an enantioenriched (S)-dialkynylcarbinol with more than 95% enantiomeric excess.
[196] Example 24 : l-(3-Hexylphenyl)penta-1,4-diyn-3-ol of the formula (65):
Figure imgf000042_0001
[197] This compound (89 mg, 18 % yield from the starting compound (66)) was obtained in the form of a racemic mixture according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3th step) with the starting compound: l-Bromo-3-hexylbenzene (CAS 38409-59-5 Commercial) of the formula (66):
Figure imgf000042_0002
[198] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.32 - 7.26 (m, 2H), 7.22 (td, J = 7.3, 1.0 Hz, 1H), 7.16 (dt, J = 7.5, 1.7 Hz, 1H), 5.34 (d, J = 2.3 Hz, 1H), 2.61 (d, J = 2.3 Hz, 1H), 2.57 (t, J = 7.5 Hz, 2H), 2.31 (br s, 1H, 1H, OH), 1.65 - 1.50 (m, 2H), 1.35 - 1.25 (m, 6H), 0.88 (t, J = 6.7 Hz, 3H). 13C NMR (75 MHz, CDCI3) δ (ppm) 143.3, 132.0, 129.4, 129.3, 128.4, 121.6, 85.2, 85.1, 81.0, 73.0, 52.7, 35.8, 31.8, 31.4, 29.0, 22.7, 14.2. HRMS (DCI- CH4): calcd for C17H21O [M+H]+: 241.1590 m/z, found: 241.1592 m/z. FTIR (cm-1) (neat): v3373, 3284, 2961, 2926, 2857, 2243, 2198, 2122, 1492, 1302, 1013, 790, 692, 638.
[199] Example 25: l-(4-Heptylphenyl)penta-1,4-diyn-3-ol of the formula (67):
Figure imgf000042_0003
[200] This compound was obtained in the form of a mixture of enantiomers according to the 1st method (with the alternative 3a) and purification by flash column chromatography on silica gel for the 3rd step) with the starting compound: l-Bromo-4-heptylbenzene: (CAS 76287-49-5 Commercial) of the formula (68):
Figure imgf000043_0001
[201] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.38 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H), 5.34 (d, J = 2.3 Hz, 1H), 2.61 (d, J = 2.3 Hz, 1H), 2.59 (t, J = 8.0 Hz, 2H), 1.59 (p, J = 7.1 Hz, 2H), 1.35 - 1.15 (m, 8H), 0.87 (t, J = 6.6 Hz, 3H). 13C NMR (75 MHz, CDCI3) 5 (ppm) 144.4, 131.9, 128.6, 118.9, 85.2, 84.9, 81.1, 73.0, 52.7, 36.0, 31.9, 31.3, 29.3, 29.3, 22.8, 14.2. HRMS (DCI-CH4): calcd for C18H23O [M+H]+: 255.1749 m/z, found: 255.1738 m/z.
Example 26: l-(3-Fluoro-4-(heptyloxy)phenyl)penta-1,4-diyn-3-ol of the formula (69):
Figure imgf000043_0002
[202] This compound (40 mg, 23 % yield from the starting compound (70)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3b) for the 3rd step with the starting compound: 4-Bromo-2- fluoro-l-(heptyloxy)benzene of the formula (70):
Figure imgf000043_0003
[203] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.22 - 7.18 (m, 1H), 7.18 - 7.14 (m, 1H), 6.87 (t, J = 8.5 Hz, 1H), 5.32 (d, J = 2.3 Hz, 1H), 4.02 (t, J = 6.6 Hz, 2H), 2.61 (d, J = 2.3 Hz, 1H), 2.39 (bs, 1H), 1.90 - 1.75 (m, 2H), 1.55 - 1.20 (m, 8H), 0.95-0.80 (m, 3H).13C NMR (75 MHz, CDCI3) δ (ppm) 151.9 (d, J = 246.9 Hz), 148.3 (d, J = 10.7 Hz), 128.6 (d, J = 3.8 Hz), 119.5 (d, J = 19.5 Hz), 114.2 (d, J = 3.0 Hz), 113.9 (d, J = 8.4 Hz), 84.7, 83.7 (d, J = 2.7 Hz), 80.8, 73.0, 69.4, 52.5, 31.8, 29.1, 29.0, 25.9, 22.6, 14.1. 19F NMR (282 MHz, CDCI3) 6 (ppm) -134.1. HRMS (DCI-CH4): calcd for C18H21FO2 [M+°]+: 288.1526 m/z, found: 288.1517 m/z. [204] Characterisation of 4-Bromo-2-fluoro-l-(heptyloxy)benzene: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.22 (dd, J = 10.6, 2.4 Hz, 1H), 7.16 (ddd, J = 8.7, 2.4, 1.5 Hz, 1H), 6.83 (t, J = 8.7 Hz, 1H), 3.99 (t, J = 6.6 Hz, 2H), 1.85 - 1.74 (m, 2H), 1.51 - 1.39 (m, 2H), 1.38 - 1.25 (m, 6H), 0.93-0.88 (m, 3H).13C NMR (75 MHz, CDCI3) δ (ppm) 152.6 (d, J = 250.5 Hz), 146.6 (d, J = 10.4 Hz), 127.1 (d, J = 3.8 Hz), 119.7 (d, J = 21.0 Hz), 116.0 (d, J = 2.3 Hz), 111.8 (d, J = 8.3 Hz), 69.7, 31.8, 29.1, 29.0, 25.4, 22.6, 14.1. 19F NMR (282 MHz, CDCI3) δ (ppm) -131.3. HRMS (DCI-CH4): calcd for C13H18FOBr [M+°]+: 288.0525 m/z, found: 288.0523 m/z.
[205] Example 27: 1-(3-Fluoro-4-((6,6,6-trifluorohexyl)oxy)phenyl)penta-1,4-diyn-3-ol of the formula (71):
Figure imgf000044_0001
[206] This compound (40 mg, 10 % yield from the starting compound (72)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3b) for the 3rd step with the starting compound: 4-Bromo-2- fluoro-l-((6,6,6-trifluorohexyl)oxy)benzene of the formula (72):
Figure imgf000044_0002
[207] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.24 - 7.21 (m, 1H), 7.21 - 7.17 (m, 1H), 6.89 (t, J = 8.6 Hz, 1H), 5.35 (s, 1H), 4.06 (t, J = 6.3 Hz, 2H), 2.64 (t, J = 6.6 Hz, 1H), 2.41 (bs, 1H), 2.27 - 2.00 (m, 2H), 1.95 - 1.80 (m, 2H), 1.75 - 1.56 (m, 4H).13C NMR (75 MHz, CDCI3) δ (ppm) 151.9 (d, J = 247.0 Hz), 148.1 (d, J = 10.7 Hz), 127.6 (q, J = 273.8 Hz), 128.6 (d, J = 3.0 Hz), 119.6 (d, J = 20.3 Hz), 114.3 (d, J = 2.3 Hz), 114.1, 84.8, 83.6 (d, J = 2.8 Hz), 80.8, 73.0, 68.9, 52.5, 33.7 (q, J = 28.5 Hz), 28.8, 25.2, 21.7 (q, J = 3.0 Hz). 19F NMR (282 MHz, CDCI3) 6 (ppm) -66.4, -134.0. HRMS (DCI-CH4): calcd for C17H17F4O2 [M+H]+: 329.1165 m/z, found: 329.1169 m/z.
[208] Characterisation of 4-Bromo-2-fluoro-l-((6,6,6-trifluorohexyl)oxy)benzene : 1H NMR (300 MHz, CDCI3) δ (ppm) 7.23 (dd, J = 10.5, 2.4 Hz, 1H), 7.17 (ddd, J = 8.7, 2.4, 1.5 Hz, 1H), 6.82 (t, J = 8.7 Hz, 1H), 4.01 (t, J = 6.6 Hz, 2H), 2.19-2.03 (m, 2H), 1.89 - 1.78 (m, 2H), 1.71 - 1.49 (m, 4H).13C NMR (75 MHz, CDCI3) δ (ppm) 152.6 (d, J = 250.7 Hz), 146.4 (d, J = 10.7 Hz), 127.3 (q, J = 276.3 Hz), 127.1 (d, J = 3.8 Hz), 119.8 (d, J = 21.0 Hz), 116.1 (d, J = 3.0 Hz), 112.1 (d, J = 8.2 Hz), 69.2, 33.7 (q, J = 28.5 Hz), 28.8, 25.2, 21.7 (q, J = 3.0 Hz). 19F NMR (282 MHz, CDCI3) 6 (ppm) -66.4, -131.3. HRMS (DCI-CH4): calcd for C12H14F4OBr [M+°]+: 329.0164 m/z, found: 329.0163 m/z.
[209] Example 28: l-(5-Decylfuran-2-yl)penta-1,4-diyn-3-ol of the formula (73):
Figure imgf000045_0001
[210] This compound (20 mg, 8 % yield from the starting compound (74)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3b) for the 3rd step with the starting compound: 2-Bromo-5- decylfuran of the formula (74):
Figure imgf000045_0002
[211] Characterisation data: 1H NMR (400 MHz, CDCI3) δ (ppm) 6.57 (d, J = 3.3 Hz, 1H), 5.98 (dt, J = 3.2, 0.9 Hz, 1H), 5.35 (dd, J = 7.7, 2.3 Hz, 1H), 2.61 (d, J = 2.3 Hz, 1H), 2.60 (t, J = 7.4 Hz, 2H), 2.32 (d, J = 7.9 Hz, 1H), 1.63 (p, J = 7.6 Hz, 2H), 1.35 - 1.20 (m, 14H), 0.88 (t, J = 6.8 Hz, 3H).13C NMR (100 MHz, CDCI3): 6 (ppm) 159.1, 133.9, 117.9, 106.5, 89.7, 80.4, 76.0,
73.4, 52.6, 32.0, 29.7, 29.7, 29.5, 29.3, 28.4, 28.0, 22.8, 14.3. HRMS (DCI-CH4): calcd for C19H26O2 [M]+: 286.1933 m/z, found: 286.1934 m/z. FTIR (cm-1) (neat): 3300, 2926, 2855, 1710, 1264, 734, 703.
[212] Characterisation of 2-Bromo-5-decylfuran: 1H NMR (300 MHz, CDCI3) δ (ppm) 6.17 (d, J = 3.1 Hz, 1H), 5.95 (dt, J = 3.2, 1.0 Hz, 1H), 2.58 (td, J = 7.5, 1.1 Hz, 2H), 1.60 (q, J = 7.5 Hz, 2H), 1.28 (bs, 14H), 0.88 (t, J = 9.0 Hz, 3H).13C NMR (100 MHz, CDCI3): δ (ppm) 152.6, 141.7,
110.4, 107.5, 32.0, 29.5, 29.4, 29.1, 27.6, 22.8, 14.2. HRMS (DCI-CH4): calcd for C14H24BrO [M+H]+: 287.1011 m/z, found: 287.1006 m/z. FTIR (cm-1) (neat): 2953, 2924, 2854, 2142, 1713, 1466, 1377, 1020, 786, 722.
[213] Example 29: l-(5-Decylfuran-3-yl)penta-1,4-diyn-3-ol of the formula (75):
Figure imgf000046_0001
[214] This compound (30 mg, 40 % yield from the starting compound (76)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3b) for the 3rd step with the starting compound: 3-lodo-5- decylfuran of the formula (76):
Figure imgf000046_0002
[215] Characterisation data: 1H NMR (400 MHz, CDCI3) δ (ppm) 7.51 (d, J = 0.9 Hz, 1H), 6.04 (q, J = 0.9 Hz, 1H), 5.29 (dd, J = 7.6, 2.3 Hz, 1H), 2.60 (d, J = 2.3 Hz, 1H), 2.57 (td, J = 7.6, 0.9 Hz, 2H), 2.26 (d, J = 7.6 Hz, 1H), 1.60 (p, J = 7.6 Hz, 2H), 1.35 - 1.20 (m, 14H)„ 0.88 (t, J = 6.8 Hz, 3H).13C NMR (100 MHz, CDCI3): 6 (ppm) 157.3, 145.0, 107.5, 106.6, 87.0, 81.0, 73.0, 52.7, 32.0, 29.7, 29.7, 29.5, 29.2, 27.9, 27.9, 22.8, 14.3. HRMS (DCI-CH4): calcd for C19H26O2 [M]+: 286.1933 m/z, found: 286.1934 m/z. FTIR (cm -1) (neat): 3303, 2925, 2854, 2123, 1264, 1158, 1137, 735, 704.
[216] Characterisation of 3-lodo-5-decylfuran: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.28 (d, J = 0.9 Hz, 1H), 6.07 (q, J = 0.9 Hz, 1H), 2.60 (td, J = 7.3, 0.9 Hz, 2H), 1.66-1.55 (m, 2H), 1.28 (bs, 14H), 0.88 (t, J = 6.9 Hz, 3H).13C NMR (75 MHz, CDCI3): δ (ppm) 158.5, 143.9, 112.0, 64.2, 32.0, 29.7, 29.7, 29.5, 29.2, 28.0, 27.9, 22.8, 14.3. HRMS (DCI-CH4) : calcd for C14H24OI [M]+: 335.0872 m/z, found: 335.0876 m/z. FTIR (cm 1) (neat): 3055, 2926, 2854, 1584, 1466, 1264, 1122, 911, 797, 734, 705, 590.
[217] Example 30: 1-(3,5-Difluoro-4-(7,7,7-trifluoroheptyl)phenyl)penta-1,4-diyn-3-ol of the formula (77):
Figure imgf000047_0001
[218] This compound (30 mg, 27 % yield from the starting compound (78)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3b) for the 3rd step with the starting compound: 5-Bromo-l,3- difluoro-2-(7,7,7-trifluoroheptyl)benzene of the formula (78):
Figure imgf000047_0002
[219] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.05 - 6.90 (m, 2H), 5.32 (d, J = 2.3Hz, 1H), 2.65 (t, J = 7.6 Hz, 2H), 2.63 (d, J = 2.2 Hz, 1H), 2.45 - 2.28 (bs, 1H), 2.15 - 1.95 (m, 2H), 1.70 - 1.45 (m, 4H), 1.45 - 1.30 (m, 4H).13C NMR (75 MHz, CDCI3) δ ( ppm) 161.2 (dd, J = 246.9, 10.3 Hz), 127.4 (q, J = 276.4 Hz), 120.9 (t, J = 12.1 Hz), 119.9 (t, J = 20.5 Hz), 115.2 - 144.4 (m), 86.7, 82.5 (t, J = 3.8 Hz), 80.4, 73.4, 52.4, 33.7 (q, J = 28.3 Hz), 29.0, 28.8, 28.4, 22.2 (t, J = 2.2 Hz), 21.8 (q, J = 2.9 Hz). 19F NMR (282 MHz, CDCI3) δ (ppm) -66.4, -115.4. HRMS (DCI-CH4): calcd for C18H18F5O [MH]+: 345.1278 m/z, found: 345.1277 m/z.
[220] Characterisation of 5-Bromo-1,3-difluoro-2-(7,7,7-trifluoroheptyl)benzene: 3H NMR (300 MHz, CDCI3) δ (ppm) 7.10 - 7.01 (m, 2H), 2.61 (tt, J = 7.7, 1.4 Hz, 2H), 2.15 - 1.95 (m, 2H), 1.65 - 1.50 (m, 4H), 1.45 - 1.30 (m, 4H). 13C NMR (75 MHz, CDCI3) δ (ppm) 161.5 (dd, J = 250.0, 10.2 Hz), 127.2 (q, J = 274.5 Hz), 118.9 (t, J = 12.8 Hz), 117.3 (t, J - 20.3 Hz), 115.2 - 114.8 (m, 2C), 33.7 (q, J = 28.3 Hz), 29.0, 28.7, 28.4, 22.0 (t, J = 2.1 Hz), 21.8 (q, J = 2.9 Hz). 19F NMR (282 MHz, CDCI3) δ (ppm) -66.4, -114.2. HRMS (DCI-CH4) : calcd for C13H15BrF5 [M+°]+: 345.0277 m/z, found: 345.0267 m/z.
[221] Example 31: 1-(4-(1,1-Difluorooctyl)phenyl)penta-1,4-diyn-3-ol of the formula (79):
Figure imgf000048_0001
[222] This compound (34 mg, 24 % yield from the starting compound (80)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step and the alternative 3b) for the 3rd step with the starting compound: l-Bromo-4- (l,l-difluorooctyl)benzene of the formula (78):
Figure imgf000048_0002
[223] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.54 - 7.48 (m, 2H), 7.44 - 7.38 (m, 2H), 5.36 (d, J = 2.4Hz, 1H), 2.63 (d, J = 2.3Hz, 1H), 2.54 - 2.26 (bs, 1H), 2.22 - 2.00 (m, 2H), 1.48 - 1.36 (m, 2H), 1.36 - 1.20 (m, 6H), 0.95-0.85 (m, 3H).13C NMR (75 MHz, CDCI3) δ (ppm) 138.2 (t, J = 27.0 Hz), 132.0, 125.2 (t, J = 6.2 Hz), 123.2 (t, J = 1.8 Hz), 122.9 (t, J = 240.8 Hz), 86.6, 84.0, 81.4, 73.3, 52.6, 39.1 (t, J = 27.0 Hz), 31.7, 29.3, 29.1, 22.7, 22.5 (t, J = 4.5 Hz), 14.2. 19F NMR (282 MHz, CDCI3) δ (ppm) -95.9. HRMS (DCI-CH4): calcd for C19H23F2O [M+H]+: 305.1717 m/z, found: 305.1730 m/z.
[224] Characterisation of l-Bromo-4-(l,l-difluorooctyl)benzene: 1H NMR 50.87 (t, J=6.8 Hz, 3H), 1.19-1.32 (m, 8H), 1.38 (m, 2H), 2.08 (m, 2H), 7.33 (d, J=8.6 Hz, 2H), 7.54 (d, J=8.7 Hz, 2H); 13C NMR 6 13.9, 22.3, 22.5, 28.9, 29.0, 31.5, 38.9 (t, JC-F=27.3 HZ), 122.7 (t, Jc F-242.3 HZ), 123.8, 126.6 (t, JC-F=6.1 HZ), 131.5, 136.5 (t, JC-F-27.4 HZ); 19F NMR δ -96.0 (t, JF-H=15.7 HZ). HRMS: calcd for C14H19BrF2 [M+, 81Br isotope]: 304.0638 m/z, found: 304.0640 m/z.
[225] Example 32: 1-(4-Octylphenyl)hexa-4,5-dien-l-yn-3-ol of the formula (81):
Figure imgf000048_0003
[226] This compound (42 mg, 35 % yield from the starting compound (28)) was obtained in the form of a racemic mixture according to the 2nd method with the alternative 2b) for the 2nd step, the alternative 3b) for the 3rd step and 4b) for the 4th step with the starting compound: l-Bromo-4-octyl benzene: (CAS 51554-93-9 Commercial) of the formula (28):
Figure imgf000049_0001
[227] Characterisation data: 1H NMR (300 MHz, CDCI3) δ (ppm) 7.35 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 5.48 (q, J = 6.4 Hz, 1H), 5.14 (bs, 1H), 5.01 (dd, J = 6.4, 2.5 Hz, 1H), 2.59 (t, J = 7.6 Hz, 1H), 2.07 (d, J = 6.3 Hz, 1H), 1. 65 - 1.50 (m, 2H), 1.35 - 1.15 (m, 10H), 0.86 (t, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCI3) δ (ppm) 207.7, 143.8, 131.7, 128.4, 119.4, 93.2, 87.3, 85.9, 78.9, 61.1, 35.9, 31.9, 31.2, 29.5, 29.3, 29.3, 22.7, 14.1. HRMS (DCI-CH4): calcd for C20H27O [M+H]+: 283.2062 m/z, found: 283.2064 m/z.
[228] II - CYTOTOXICITY OF COMPOUNDS OF THE PRESENT INVENTION :
[229] II - A - Experiments on HCT116 cells :
[230] Wild-type human HCT116 colon cancer cells were seeded in 96-well plates together with the tested compound. Cells were grown and treated in DMEM 10% FBS. Two-fold serial dilutions were performed. After 72 hours, cell viability was measured using a MTT assay.
[231] The here below table 1 details the IC50S using MTT assay on HCT116 cells for 16 compounds according to the present invention and two comparative compounds out of the scope of the present invention (i.e. comparative examples A and B):
Figure imgf000049_0002
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Table 1 of the IC50S using MTT assay on HCT116 cells for 23 compounds of the invention and 2 comparative compounds
[232] In view of the table 1:
- these 23 compounds of the present invention have all a high cytotoxicity (i.e. I C50 from 0.05 to 5 pM) and thus exhibit an antitumor activity on HCT116 cells;
- the compound of the example 4 has the highest cytotoxicity ;
- the compound of the example 6 has a cytotoxicity (i.e. IC50 0.100 μM) 100 times higher than the compound of the comparative example A (i.e. IC50 10 pM). The compound of the example 6 only differs from the compound of the comparative example A in that it includes a further alkynyl group ;
- the compound of the example 7 has a cytotoxicity (i.e. IC50 0.400 pM) 125 times higher than the compound of the comparative example B (i.e. IC5050 pM). The compound of the example 7 only differs from the compound of the comparative example B in that it includes a further alkynyl group.
[233] The comparison of the values of the IC50 of the compounds of the examples 6 and 7 in view of the values of the IC50 of the compounds of the comparative examples A and B shows the importance of the presence of the alkynyl group located between the hydroxyl function and the "Ar" moiety (as above defined) in the structure of the compounds of the present invention on their cytotoxicity.
[234] II - B - Experiments on HAP1 WT and HAP1 DACR#A4 (HSD17B11 S172L mutant) cells:
[235] Wild-type human HAP1 cells or HAP1 DACRWA4 (HSD17B11 carrying the S172L mutation) were seeded in 96-well plates (3500 cells/well) 24 hours before being treated for 72 hours with the tested compounds.
[236] Cells were grown and treated in IMDM 10% FBS. For each compound, 11 concentrations, corresponding to two-fold serial dilutions from the maximum concentration, were tested, with each concentration tested in duplicate. DMSO was at 0.5% final concentration in each well, including in the untreated conditions. At the end of the treatment, cells were fixed 1 hour at 4°C by addition of cold 10 % trichloroacetic acid to a final 3,33 % concentration, then washed 4 times with water.
[237] The plates were dried and the cells stained for 30 minutes with 0.057 % (wt/vol.) sulforhodamine B (SRB) in 1% acetic acid, then washed 4 times with 1% acetic acid and dried. The staining was resuspended by a 1 hour and 30 minutes incubation in 200 μL of 10 mM TrisBase and the absorbance at 490 nm measured with a plate reader (pquant, Bio-tek). For normalization, the background value was subtracted to each value, the duplicates averaged and the untreated condition set to 100% cell viability.
[238] IC50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
[239] The here below table 2 details the IC50S using SRB assay on HAP1 WT and HAP1 DACR#A4 (HSD17B11 S172L mutant) for 3 compounds according to the invention :
Figure imgf000053_0001
Figure imgf000054_0001
Table 2 of the IC50s using SRB assay on HAP1 WT and HAP1 DACR#A4 (HSD17B11 S172L mutant) for 3 compounds of the invention
[240] In view of the table 2 :
- these 3 compounds of the present invention have all a high cytotoxicity (i.e. ICso from 0.85 to 0.187 pM) and thus exhibit an antitumor activity on HAP1 WT cells ;
- the compound of the example 4 has the highest cytotoxicity ;
- the cytotoxicity of these 3 compounds is much lower for the HAP1 cells in which the enzyme HSD17B11 carries the inactivating S172L mutation.
[241] These experiments are a first example pointing out the relationship between the enzyme HSD17B11 and the cytotoxicity of compounds of the present invention, i.e. the importance of this enzyme so that the compounds of the present invention exhibit an antitumor activity.
[242] II - C- Experiments on U2OS and U2OS KO HSD17B11 cells:
[243] Wild-type human osteosarcoma cells U2OS or U2OS inactivated for HSD17B11 using CRISPR/Cas9 (clone #B3) were seeded in 96-well plates (1500 cells/well) 24 hours before being treated for 72 hours with the tested compounds.
[244] Cells were grown and treated in DMEM 10 % FBS. For each compound, 11 concentrations, corresponding to two-fold serial dilutions from the maximum concentration, were tested, with each concentration tested in duplicate. DMSO was at 0.5% final concentration in each well, including in the untreated conditions.
[245] At the end of the treatment, cells were fixed 1 hour at 4°C by addition of cold 10 % trichloroacetic acid to a final 3.33 % concentration, then washed four times with water. The plates were dried and the cells stained for 30 minutes with 0.057 % (wt/vol.) sulforhodamine B (SRB) in 1% acetic acid, then washed 4 times with 1% acetic acid and dried. The staining was resuspended by a 1 hour and 30 minutes incubation in 200 pL of 10 mM TrisBase and the absorbance at 490 nm measured with a plate reader (pquant,
Bio-tek).
[246] For normalization, the background value was subtracted to each value, the duplicates averaged and the untreated condition set to 100% cell viability. IC50 were computed from at least three independent experiments using the GraphPad Prism software using a nonlinear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
[247] The here below table 3 details the IC50S using SRB assay on U2OS and U2OS KO
HSD17B11 for 2 compounds according to the invention :
Figure imgf000055_0001
Figure imgf000056_0001
Table 3 of the IC50S using SRB assay on U20S and U20S KO HSD17B11 for 9 compounds of the invention
[248] In view of the table 3:
- these 9 compounds of the present invention have all a high cytotoxicity (i.e. IC50 from 0.040 to 1.552 pM) and thus exhibit an antitumor activity on U2OS cells ;
- the compound of the example 4 has the highest cytotoxicity ;
- the cytotoxicity of these 9 compounds is much lower for the U2OS cells in which the enzyme HSD17B11 has been inactivated.
[249] These experiments are a further example pointing out the relationship between the enzyme HSD17B11 and the cytotoxicity of compounds of the present invention, i.e. the importance of this enzyme so that the compounds of the present invention exhibit an antitumor activity.
[250] ll-D- Experiments on U2OS KO HSD17B11 cells stably complemented by a control plasmid or expressing HSD17B11 wild-type (WT) or a catalytic-dead mutant (S172L) :
[251] U2OS human osteosarcoma cells inactivated for HSD17B11 using CRISPR/Cas9 stably complemented with GFP (Ctrl), HSD17B11-WT-GFP or HSD17B11-S172L-GFP were seeded in 96-well plates (1500 cells/well) 24 hours before being treated for 72 hours with the tested compounds.
[252] Cells were grown and treated in DMEM 10 % FBS. For each molecule, 11 concentrations, corresponding to two-fold serial dilutions from the maximum concentration, were tested, with each concentration tested in duplicate. DMSO was at 0.5% final concentration in each well, including in the untreated conditions. At the end of the treatment, cells were fixed 1 hour at 4°C by addition of cold 10 % trichloroacetic acid to a final 3.33 % concentration, then washed 4 times with water. The plates were dried and the cells stained for 30 minutes with 0.057 % (wt/vol.) sulforhodamine B (SRB) in 1% acetic acid, then washed 4 times with 1% acetic acid and dried.
[253] The staining was resuspended by a 1 hour and 30 minutes incubation in 200 pL of 10 mM TrisBase and the absorbance at 490 nm measured with a plate reader (pquant, Bio- tek). For normalization, the background value was subtracted to each value, the duplicates averaged and the untreated condition set to 100% cell viability.
[254] IC50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve [log[inhibitor] vs response; variable slope). Note that in complemented U2OS, HSD17B11 is overexpressed as compared to U2OS WT, explaining the lower (+)-PAC IC50 in these cells.
[255] The here below table 4 details the IC50S using SRB assay on U2OS KO HSD17B11 stably complemented by a control plasmid or expressing HSD17B11 wild-type (WT) or a catalytic- dead mutant (S172L) for compounds according to the invention :
Figure imgf000057_0001
Table 4 ofIC50S using SRB assay on U2OS and U2OS KO HSD17B11 for 2 compounds of the invention
[256] In view of the table 4, the cytotoxicity of these 2 compounds of the present invention is much lower in U2OS cells inactivated for HSD17B11 and complemented with a control plasmid or a plasmid expressing the catalytically inactive S172L HSD17B11 mutant as compared to U2OS cells inactivated for HSD17B11 and complemented with the wild-type HSD17B11 enzyme.
[257] II - E- Experiments on SCLC and control cells : [258] Small Cell Lung Carcinoma (SCLC) or control cells were seeded in 96-well plates 24 hours before being treated for 72 hours with the compound of the example 4.
[259] Each cell line was grown and treated in the recommended medium. For each molecule, 11 concentrations, corresponding to two-fold serial dilutions from the maximum concentration, were tested, with each concentration tested in duplicate. DMSO was at 0.5% final concentration in each well, including in the untreated conditions.
[260] At the end of the treatment, the plate was cooled down to room temperature and the CellTiterGlo® reagent (CTG, Promega) was added to each well and homogenized by pipetting. 100 pL of lysate was transferred to black plates and after a 15 minutes incubation at room temperature the luminescence was measured on a FLX800 plate reader. For normalization, the background value was subtracted to each value, the duplicates averaged and the value for the untreated condition set to 100% cell viability.
[261] IC50 were computed using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve ( log[i nhibitor] vs response; variable slope).
[262] The here below table 5 details the IC50S using CTG assay on SCLC and control cells for the compound of the example 4.
Figure imgf000058_0001
Table 5 ofIC50S using CTG assay on SCLC and control cells for the compound of the example 4
[263] In view of the table 5, the compound of the example 4 exhibits high cytotoxicity for different lung cancer cell lines.
[264] II- F- Experiments on NCI-H446 SCLC cells wild-type (WT) or KO HSD17B11 :
[265] Small Cell Lung Carcinoma (SCLC) NCI-H446 cells, wild-type or inactivated for
HSD17B11 using CRISPR/Cas9 (KO HSD17B11 clone #1 and clone #6) were seeded in 96- well plates (2000 cells/well) 24 hours before being treated for 72 hours with the indicated molecules. Cells were grown and treated in RPMI164010% FBS. For each molecule, eleven concentrations, corresponding to two-fold serial dilutions from the maximum concentration, were tested, with each concentration tested in duplicate. DMSO was at 0.5% final concentration in each well, including in the untreated conditions. At the end of the treatment, the plate was cooled down to room-temperature and the CellTiterGlo® reagent (Promega) was added to each well and homogenized by pipetting. 100 pL of lysate was transferred to black plates and after a 15 min incubation at room-temperature the luminescence was measured on FLX800 plate reader. For normalization, the background value was subtracted to each value, the duplicates averaged and the value for the untreated condition set to 100% cell viability. IC50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[i nhibitor] vs response; variable slope).
[266] The here below table 6 details the IC50 using CTG assay on NCI-H446 SCLC cells wildtype (WT) or KO HSD17B11 for the compound of the example 4.
Figure imgf000059_0001
Table 6 of IC50 using CTG assay on NCI-H446 SCLC cells wild-type (WT) or KO HSD17B11 for the compound of the example 4
[267] In view of the table 6 :
- the compound of the example 4 exhibits high cytotoxicity for NCI-H446 SCLC cells ;
- the cytotoxicity of this compound is much lower for the NCI-H446 SCLC cells in which the enzyme HSD17B11 has been inactivated.
[268] These experiments are a further example pointing out the relationship between the enzyme HSD17B11 and the cytotoxicity of compounds of the present invention, i.e. the importance of this enzyme so that the compounds of the present invention exhibit an antitumor activity.
[269] II- G- Experiments on HepG2 (human hepatocellular carcinoma) cells :
[270] Human HepG2 hepatocellular carcinoma cells were seeded in 96-well plates (10000 cells/well) 24 hours before being treated for 72 hours with the compound of the example 4.
[271] Cells were grown in alpha-MEM with 10% FBS. For each molecule, 11 concentrations, corresponding to two-fold serial dilutions from the maximum concentration, were tested, with each concentration tested in duplicate. DMSO was at 0.5% final concentration in each well, including in the untreated conditions. At the end of the treatment, cells were fixed 1 hour at 4°C by addition of cold 10 % trichloroacetic acid to a final 3.33 % concentration, then washed four times with water. The plates were dried and the cells stained for 30 minutes with 0.057 % (wt/vol.) sulforhodamine B (SRB) in 1% acetic acid, then washed four times with 1% acetic acid and dried. The staining was resuspended by a 1 hour and 30 minutes incubation in 200 μL of 10 mM TrisBase and the absorbance at 490 nm measured with a plate reader (pquant, Bio-tek). For normalization, the background value was subtracted to each value, the duplicates averaged and the untreated condition set to 100% cell viability. I C50 were computed from at least three independent experiments using the GraphPad Prism software using a non-linear regression to a four-parameter logistic curve (log[in hibitor] vs response; variable slope).
[272] The here below table 7 details the IC50 using SRB assay on HepG2 (human hepatocellular carcinoma) for the compound of the example 4 :
Figure imgf000060_0001
Table 7 of the IC50 using SRB assay on HepG2 (human hepatocellular carcinoma) for the compound of the example 4
[273] In view of the table 7, the compound of the example 4 has a high cytotoxicity and thus exhibits an antitumor activity on HepG2 cells. [274] II- H - Experiments on neuroblastoma cell lines :
[275] Human neuroblastoma cell lines were seeded in 96-well plates together with the tested compounds. Two-fold serial dilutions were performed.
[276] After 72 hours, the cell viability was measured using a MTT assay.
[277] The here below table 8 details the IC50S using MTT assay on neuroblastoma cell lines for the compounds of the example 4.
Figure imgf000061_0001
Table 8 of the IC50S using MTT assay on neuroblastoma cell lines for the compounds of the example 4
In view of the table 8, the compound of the example 4 has a high cytotoxicity and thus exhibits an antitumor activity on neuroblastoma cell lines.
[278] II- 1- Experiments on U2OS KO HSD17B11 cells stably complemented with HSD17B11- GFP or HSD17B13-GFP treated with a compound of the invention :
[279] HSD17B13 (aka SCDR9 or SDR16C3) is the closest human homologue of HSD17B11 (63.3 % of sequence identity between them). Considering the high degree of sequence identity between HSD17B11 and HSD17B13, the selectivity for bioactivation by HSD17B11 over HSD17B13 was tested for a set of compounds of the invention.
[280] Human osteosarcoma cells inactivated for HSD17B11 using CRISPR/Cas9 and stably complemented with HSD17B11-WT-GFP (clone B11#A2) or HSD17B13-WT-GFP (clone B13#A2) were seeded in 96-well plates (1500 cel Is/well) 24 hours before being treated for 72 hours with the tested compounds.
[281] Cells were grown and treated in DMEM 10 % FBS. For each compound, 11 concentrations, corresponding to two-fold serial dilutions from the maximum concentration, were tested, with each concentration tested in duplicate. DMSO was at 0.5% final concentration in each well, including in the untreated conditions. [282] At the end of the treatment, cells were fixed 1 hour at 4°C by addition of cold 10 % trichloroacetic acid to a final 3.33 % concentration, then washed four times with water. The plates were dried and the cells stained for 30 minutes with 0.057 % (wt/vol.) sulforhodamine B (SRB) in 1% acetic acid, then washed 4 times with 1% acetic acid and dried. The staining was resuspended by a 1 hour and 30 minutes incubation in 200 pL of 10 mM TrisBase and the absorbance at 490 nm measured with a plate reader (pquant, Bio-tek).
[283] For normalization, the background value was subtracted to each value, the duplicates averaged and the untreated condition set to 100% cell viability. IC50 were computed from at least three independent experiments using the GraphPad Prism software using a non- linear regression to a four-parameter logistic curve (log[inhibitor] vs response; variable slope).
[284] The here below table 9 details, for selected compounds of the invention, the selectivity index (SI), which corresponds for each tested compound to the ratio of its IC50 on the HSD17B13 complemented cells over its IC50 on the HSD17B11 complemented cells.
Figure imgf000062_0001
Figure imgf000063_0001
[285] These data support that HSD17B13 can bioactivate some of the compounds described, albeit less efficiently than HSD17B11. These data also support that the specificity towards HSD17B11 versus HSD17B13 can be modulated by subtle structural modifications. Compound of the example 14 shows the highest selectivity among the tested compounds.

Claims

63
1. A compound of the formula (1),
Figure imgf000064_0001
or physiologically tolerable salt thereof in which :
R is a C2-alkynyl, a C2-alkenyl, a C3-a I leny I or a C1-C6-al kyl group,
Ar is selected from the group consisting of aryl and heteroaryl, wherein
- aryl is a phenyl, naphthyl, indanyl, tetralinyl, biphenylyl, fluorenyl or anthacenyl group,
- heteroaryl is an aziridine, azepine, azetidine, benzimidazole, benzofuran, benzo[l,4]dioxine, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, chromane, cinnoline, dihydropyrazine, dithiine, 1,2-diazepine, 1,3- diazepine, 1,4-diazepine, 1,4-dioxine, furan, dioxole, imidazole, indazole, indole, isochromane, isoindole, isoquinoline, isothiazole, isoxazole, oxathiine, 1,2-oxazine, 1,3- oxazine, 1,4-oxazine, oxazole, 1,3-oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidinyl, quinazoline, quinoline, quinoxaline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, thiadiazole, thiazole, 1,3-thiazole, thiophene, thiopyran, 1,2,3-triazole, 1,2,4-triazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine group,
Ar being substituted with 1 to 7 substituents, at least one substituent having formula (a) ACnH2nB with n being an integer comprised between 2 and 20, A being selected from the group consisting of CH2, CF2, O and S, and B being selected from the group consisting of H, CH3, CH2F, CHFCH2F, CF3, CH2OH, O-C1-C20 alkyl, CCSi(i-Pr)3 or C2 alkynyl, the other substituent(s) if any being independently chosen from halogen, OCF3, CF3, CH2OH, CCSi(i- Pr)3, CH3, CH2CH3, OH, CHFCH2F, -O(CH2CH2O)nEt with n an integer comprised between 1 and 6, ACnH2nB with n an integer comprised between 2 and 20 and A being selected from the group consisting of CH2, CF2, 0 and S, B being selected from the group consisting of H, CH3, CH2F, CHFCH2F, CF3, CH2OH, O-C1-C20 alkyl, CCSi(i-Pr)3 or C2 alkynyl.
2. A compound or salt as claimed in claim 1, wherein Ar is selected from the group consisting of phenyl, naphthyl, furan, pyridine, pyrimidine, pyran, thiophene, pyrrole, 1,4- dioxine, dithiine, oxathiine, dihydropyrazine, 1,3-oxazine, 1,4-oxazine, 1,2,3-triazole, and 1,2,4-triazole groups.
3. A compound or salt as claimed in claim 2, wherein Ar is a thiophene group or a furan group that is substituted with 1 to 3 substituents, one substituent being C3-C20-alkyl, preferably C4-C14 alkyl, the other substituent(s) if any being independently chosen from C1-C20-alkyl groups, preferably C4-C14alkyl groups, F and OCF3.
4. A compound or salt as claimed in claim 3 of the formula (6):
Figure imgf000065_0001
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 9 or 11, and R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-alkyl group, preferably a C2-alkynyl group.
5. A compound or salt as claimed in claim 3 of the formula (8) :
Figure imgf000065_0002
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 6 or 9, and R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-a I ky I group and preferably a C2-alkynyl group.
6. A compound or salt as claimed in claim 2, wherein Ar is a naphthyl group that is substituted with 1 to 7 substituents, one substituent being a C3-C20-alkyl group, the other substituent(s) if any being independently chosen from C1-C20-alkyl groups.
7. A compound or salt as claimed in claim 6 of the formula (10):
Figure imgf000066_0001
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7, and R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-alkyl group and preferably a C2-alkynyl group.
8. A compound or salt as claimed in claim 2 of the formula (12):
Figure imgf000066_0002
in which :
- at least one of R1, R2, R3, R4 and R5 is chosen from C3-C20-alkyl (more preferably C4-C14- alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18, OCH2CH2OEt, O-C2-C20-alkyl and CF2-C2-C20-alkyl, the other substituents, identical or different, are chosen independently of one another from hydrogen, C1-C20-alkyl (more preferably C4-C14-alkyl, most preferably C8-alkyl), (CH2)n-C2-alkynyl with n an integer comprised between 0 and 18, halogen (preferably F), OCF3, CHFCH2F, CF3, CH2OH, CCSi(i- Pr)3, O(CH2CH2O)nEt with n an integer comprised between 1 and 6, O-C2-C20-alkyl and CF2- C2-C20-alkyl ;
- R is a C2-alkynyl, a C2-alkenyl, a C3-al lenyl or a C1-C6-al kyl group, preferably a C2-alkynyl group.
9. A compound or salt as claimed in claim 8 of the formula (14):
Figure imgf000067_0001
in which R3 is selected from the group consisting of (CH2)nCH3 with n an integer comprised between 2 and 19, OCH2CH2OEt, O-C2-C20-alkyl, CF2-C2-C20-alkyl and (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18.
10. A compound or salt as claimed in claim 8 of the formula (17):
Figure imgf000067_0002
in which R2 is selected from the group consisting of -(CH2)nCH3 with n an integer comprised between 2 and 19, OCH2CH2OEt, O-C2-C20-alkyl, CF2-C2-C20-alkyl and (CH2)n-C2-alkynyl with n an integer comprised between 3 and 18.
11. A compound or salt as claimed in claim 8 of any one of the formulas (18) to (21):
Figure imgf000068_0001
in which n is an integer comprised between 2 and 19, R1, R2, R3 and R4 are halogen (preferably F) or OCF3, and R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-a Ikyl group, preferably a C2-alkynyl group.
12. A compound or salt as claimed in claim 8 of one of the formulas (22) and (23):
Figure imgf000068_0002
in which n is an integer comprised between 2 and 19, preferably between 3 and 13, most preferably 7, R2 and R4 are halogen identical or different of one another (preferably F) and R1 and R3 are halogen identical or different of one another (preferably F), and R is a C2- alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-a Ikyl group, preferably a C2-alkynyl group.
13. A compound as claimed in claim 8 of one of the formulas (15) and (16):
Figure imgf000069_0001
14. A compound as claimed in claim 8 of the formula (24):
Figure imgf000069_0002
(1), or physiologically tolerable salt thereof in which:
R is a C2-alkynyl, a C2-alkenyl, a C3-allenyl or a C1-C6-alkyl group,
Ar is selected from the group consisting of aryl and heteroaryl, wherein
- aryl is a phenyl, naphthyl, indanyl, tetralinyl, biphenylyl, fluorenyl or anthacenyl group.
- heteroaryl is an aziridine, azepine, azetidine, benzimidazole, benzofuran, benzo[l,4]dioxine, 1,3-benzodioxole, 4H-benzo[l,4]oxazine, benzoxazole, benzothiazole, benzothiophene, chromane, cinnoline, dihydropyrazine, dithiine, 1,2-diazepine, 1,3- diazepine, 1,4-diazepine, 1,4-dioxine, furan, dioxole, imidazole, indazole, indole, isochromane, isoindole, isoquinoline, isothiazole, isoxazole, oxathiine, 1,2-oxazine, 1,3- oxazine, 1,4-oxazine, oxazole, 1,3-oxazole, oxirane, piperazine, piperidine, phthalazine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyridoimidazole, pyridopyridine, pyridopyrimidine, pyrrole, pyrrolidinyl, quinazoline, quinoline, quinoxaline, 1,2,3,4-tetrahydroisoquinoline, 1,2,3,4-tetrahydroquinoline, thiadiazole, thiazole, 1,3-thiazole, thiophene, thiopyran, 1,2,3-triazole, 1,2,4-triazole, 1,2-thiazine, 1,3-thiazine, 1,4-thiazine, 1,2,3-triazine, 1,2,4-triazine or 1,3,5-triazine group,
Ar being substituted with 1 to 7 substituents independently chosen from halogen, OCF3, CF3, CH2OH, CCSi(i-Pr)3, CH3, OH, CHFCH2F, -O(CH2CH2O)nEt with n an integer comprised between 1 and 6, ACnH2nB with n an integer comprised between 1 and 20 and A being selected from the group consisting of CH2, CF2, O and S, B being selected from the group consisting of H, CH3, CH2F, CHFCH2F, CF3, CH2OH, O-Ci-C20 alkyl, CCSi(i-Pr)3 or C2 alkynyl, and together with at least one pharmaceutically acceptable carrier.
16. A compound or salt as defined in claim 15 for use as a medicament.
17. A compound or salt as defined in claim 15 for use as a prodrug.
18. A compound or salt as defined in claim 15 for use in the treatment of a disease selected from the group consisting of cancer or metastasis thereof, bacterial, parasitic or fungal infections.
19. A compound or salt as defined in claim 15 for use in the treatment of a disease as claimed in claim 18, wherein the cancer is selected from the group consiting of lung cancer, breast cancer, colon cancer, bone cancer and neuroblastoma.
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