WO2016087596A1

WO2016087596A1 - Securinine derivatives useful in the treatment of cancer

Info

Publication number: WO2016087596A1
Application number: PCT/EP2015/078551
Authority: WO
Inventors: Marc Perez; Virginie Vidal; Tahar AYAD; Jacques Fahy; Philippe Maillos
Original assignee: Pierre Fabre Medicament; Centre National De La Recherche Scientifique (Cnrs); Ecole Nationale Superieure De Chimie De Paris
Priority date: 2014-12-03
Filing date: 2015-12-03
Publication date: 2016-06-09

Abstract

The present invention relates to a compound of the following formula (I): or a pharmaceutically acceptable salt and/or solvate thereof, notably for use as a drug, notably in the treatment of cancer, as well as pharmaceutical compositions containing such a compound and process to prepare such a compound.

Description

SECURININE DERIVATIVES USEFUL IN THE TREATMENT OF CANCER

The present invention relates to novel derivatives of securinine, their methods of preparation, pharmaceutical compositions containing the same and their use as a drug, in particular in the treatment of cancer.

Securinine is a major alkaloid found in the plant leaves of Securinega suffruticosa, a subtropical semi-shrub that has been used in traditional Chinese folk medicine.

Securinine has been reported to have a wide range of pharmacological activities such as antagonist of Y-GABA_a receptor (Beutler et al (1985) Brain Res. 330: 135-40), therapeutic agent for the treatment of sequela of poliomyelitis, amyotrophic lateral sclerosis (ALS) and aplastic anemia, and macrophage activator against Coxiella burnetii, or an inhibitor of parasitic (Toxoplasma gondii) proliferation.

More recently, Securinine has been found to induce apoptosis in various human cancer cell lines including HL-60, SW480 (Xia et al. Fitoterapia 82 (201 1 ) 1258-1264) and p53-deficient colon cancer cells (Rana et al. (2010) FASEB 24:2126-2134), and promote differentiation in several acute myeloid leukemia (AML) cells lines such as HL-60, THP-1 and OCI-AMLT3, as well as cells from primary leukemic patients (Gupta et al. (201 1 ) Plos One e21203).

The present invention provides derivatives of securinine allowing improved anti-cancerous activity in comparison to securinine.

The present invention relates thus to a compound of following formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof, wherein:

• R-i is H, S1R2R3R4 or a group selected from

a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 6 carbon atoms,

a saturated or unsaturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms, an aryl, and

a heterocycle, said group being optionally substituted,

• R₂, R3 and R₄ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₅ and NR₆R₇, and

· R_5, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group.

For the purpose of the invention, the term "pharmaceutically acceptable" is intended to mean what is useful to the preparation of a pharmaceutical composition, and what is generally safe and non toxic, for a pharmaceutical use.

The term « pharmaceutically acceptable salt and/or solvate » is intended to mean, in the framework of the present invention, a salt and/or solvate of a compound which is pharmaceutically acceptable, as defined above, and which possesses the pharmacological activity of the corresponding compound.

The pharmaceutically acceptable salts comprise:

(1 ) acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulfuric, nitric and phosphoric acid and the like; or formed with organic acids such as acetic, benzenesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, hydroxynaphtoic, 2- hydroxyethanesulfonic, lactic, maleic, malic, mandelic, methanesulfonic, muconic, 2- naphtalenesulfonic, propionic, succinic, dibenzoyl-L-tartaric, tartaric, p-toluenesulfonic, trimethylacetic, or trifluoroacetic acid and the like, and

(2) salts formed when an acid proton present in the compound is either replaced by a metal ion, such as an alkali metal ion, an alkaline-earth metal ion, or an aluminium ion; or coordinated with an organic or inorganic base. Acceptable organic bases comprise diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases comprise aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

Acceptable solvates for the therapeutic use of the compounds of the present invention include conventional solvates such as those formed during the last step of the preparation of the compounds of the invention due to the presence of solvents. As an example, mention may be made of solvates made with water (these solvates are also called hydrates), methanol or ethanol.

The term "linear or branched, saturated hydrocarbon chain containing from 1 to 6 carbon atoms", as used in the present invention, includes, but is not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.

The term "linear or branched, unsaturated hydrocarbon chain containing from 1 to 6 carbon atoms", as used in the present invention, relates to a mono- or poly- unsaturated (i.e., having one on more carbon-carbon double or triple bonds) linear or branched hydrocarbon chain containing from 1 to 6 carbon atoms, including, but not limited to, ethenyl, ethynyl, propenyl, propadienyl butenyl, butynyl, butadienyl, butadiynyl, pentenyl, pentynyl, hexylenyl, hexylynyl and the like.

The term "saturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms", as used in the present invention, relates to a saturated hydrocarbon monocycle or bicycle containing from 3 to 10 carbon atoms, advantageously to a saturated hydrocarbon monocycle containing from 3 to 6, notably 3, 5 or 6 carbon atoms including, but not limited to, cyclopropyl, bicyclopropyl, cyclobutyl, bicyclobutyl, cyclopentyl, bicyclopentyl, cyclohexyl, bicyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Advantageously, the term "saturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms", as used in the present invention, refers to cyclopropyl, cyclopentyl or cyclohexyl.

The term "unsaturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms", as used in the present invention, relates to a mono- or poly- unsaturated (i.e., having one on more carbon-carbon double bonds) hydrocarbon monocycle or bicycle containing from 3 to 10 carbon atoms, advantageously to an unsaturated, preferably mono-unsaturated, hydrocarbon monocycle containing from 5 to 7, notably 5 or 6 carbon atoms, including, but not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like. Advantageously, the term "an unsaturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms", as used in the present invention, refers to cyclopentenyl or cyclohexenyl.

The term "(Ci-C₆)alkyl", as used in the present invention, refers to a straight or branched saturated hydrocarbon chain containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

The term "aryl", as used in the present invention, refers to an aromatic hydrocarbon group comprising preferably 6 to 10 carbon atoms and comprising one or more fused rings, such as, for example, a phenyl or naphtyl group. Advantageously, it will be a phenyl group.

The term "aryl-(Ci-C₆)alkyl", as used in the present invention, refers to an aryl group as defined above bound to the molecule via a (Ci-C₆)alkyl group as defined above. In particular, it is a benzyl group.

The term "heterocycle", as used in the present invention, refers to a saturated, unsaturated or aromatic hydrocarbon monocycle or bicycle in which one to three, preferably one or two, carbon atoms have been replaced with a heteroatom selected from O, N and S, preferably selected from O and N. Advantageously each cycle is a 3- to 7- membered, preferably 5- to 6- membered, cycle. In the case of a bicycle, the two cycles can be fused, bridged or have a spiro configuration. It includes notably the following cycles: aziridine, azetidine, oxetane, thiooxetane, pyrrolidine, pyrroline, tetrahydrofurane, dihydrofurane, tetrahydrothiophene, dihydrothiophene, piperidine, dihydropyridine, tetrahydropyridine, pyrane, dihydropyrane, tetrahydropyrane, thiopyrane, dihydrothiopyrane, tetrahydrothiopyrane, morpholine, thiomorpholine, piperazine, azepane, diazepane, imidadole, imidazoline, pyrrole, pyrazole, pyridine, pyrazine, pyridazine piperidazine, and pyrimidine.

The term "halo", as used in the present invention, refers to bromo (Br), chloro (CI), iodo (I) or fluoro (F).

In a particular embodiment of the invention, the compound according to the invention is not a compound of general formula (I) in which R-i is:

- H;

a methyl unsubstituted or substituted with one substituent selected from the group consisting in cyclopentyl, -N-(CH₃)₂, -N-(CH₂-CH₃)₂, -N-(n-propyl)₂, -N-(n-butyl)₂, -NH-CH₃, -NH-S0₂-

CH₃, -OH, -O-phenyl, -0-(n-propen-2-yl), -O-(t-butyl), -O-benzyl, -0-Si-(i-propyl)₃, phenyl and -S-phenyl;

a methyl disubstituted with -O-ethyl;

a n-propyl 3-substituted with cyano or CI;

- a n-butyl, i-butyl, t-butyl;

a n-octyl;

a 2-methylpropen-2-yl;

a cyclopropyl;

a cyclopentyl;

- a phenyl;

a phenyl para-substituted with one substituent selected from the group consisting in F, ethyl, n-butyl, t-butyl, phenyl, -CH₂-OH, -0-CH₃, -0-CF₃, -NH₂, -N-(CH₃)₂, -N₃, cyano, nitro, and a moiety of the following formula:

- a phenyl orirjo-substituted with methyl;

a phenyl meia-substituted with -0-CH₃;

a phenyl 3,5-disubstituted with F or CF₃;

a thien-3-yl;

a thien-2-yl;

- a 6-methoxynapht-2-yl; a 9-phenanthrenyl;

a cyclohexen-2-yl;

- -Si-(CH₃)₃;

a pyridin-3-yl;

- a pyridin-2-yl-A/-oxide; or

a pyridin-3-yl-A/-oxide.

a methyl substituted with -0-CH₃;

- an ethyl;

an i-propyl; or

a cyclohexyl.

In a particular embodiment of the invention, the compound of the invention is not a compound of general formula (I) in the form of a hydrochloride for which R-i is:

- H;

a methyl substituted with one substituent selected from the group consisting in -N-(CH₃)₂, -N-

(CH₂-CH₃)₂, -N-(n-propyl)₂, -N-(n-butyl)₂, -O-phenyl;

a n-propyl 3-substituted with cyano;

- a phenyl para-substituted with one substituent selected from the group consisting in t-butyl, phenyl, -NH₂, -N-(CH₃)₂, -N₃, and nitro;

a phenyl meia-substituted with -0-CH₃;

a thiophen-3-yl;

a thiophen-2-yl;

- a 6-methoxynapht-2-yl; or

a 9-phenanthrenyl.

In a particular embodiment of the invention, the compound of the invention is not a compound of general formula (I) in the form of a trifluoroacetate or a Mel salt in which R-i is 9- phenanthrenyl.

Advantageously, R-i is H, SiR₂R₃R₄ or a group selected from

a saturated or unsaturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms, - an aryl, and a heterocycle,

said group being optionally substituted with one or several groups selected from

- halo, OR₈, NR₉R₁₀, SRn, S(0)R₁₂, S0₂Ri₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂₁, CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, nitro (N0₂), cyano (CN), oxo (=0), notably halo, OR₈, NR₉R₁₀, SRn, S(0)R₁₂, S0₂R₁₃, S0₂NR₁₄R₁₅, OCOR₁₆,

NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂₁, CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, advantageously halo, OR₈, NR₉R₁₀, OCORi₆, NR₁₇CORi₈, NR₁₉C(O)OR₂₀, C0₂R₂i, CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, more advantageously halo, OR₈, NR₉R₁₀, NR₁₇CORis, NR₁₉C(O)OR₂₀, CONR₂₂R₂₃, OCONR₂₅R₂₆, even more advantageously halo, OR₈, NR₉R₁₀, NR₁₉C(O)OR₂₀, and

an aryl or (Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₂₈ and NR₂₉R₃₀, notably selected from halo, and

R₂ to R₄ and R₈ to R₃₀ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₅ and NR₆R₇, and

R_5, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, notably R₂ to R₄ and R₈ to R₃₀ are H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, in particular R₂, R₃, R₄ and R₈ to R₃₀ are H or (Ci-C₆)alkyl. More advantageously, R-i is H, SiR₂R₃R₄ or a group selected from

a saturated or unsaturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms, and

- an aryl,

said group being optionally substituted with one or several groups selected from:

- halo, OR₈, NR₉R₁₀, SRn, S(0)R₁₂, S0₂R₁₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂₁, CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, nitro (N0₂), cyano (CN), oxo (=0), and

- an aryl or (Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₂₈ and NR₂₉R₃₀, notably selected from halo, and

R_5, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, notably R₂ to R₄ and R₈ to R₃₀ are H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, in particular R₂ to R₄ and R₈ to R₃₀ are H or (Ci-C₆)alkyl.

Notably, R-i is H, SiR₂R₃R₄ or a group selected from:

an aryl,

- halo, OR₈, NR₉R₁₀, SRn, S(0)R₁₂, S0₂Ri₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈,

NR₁₉C(O)OR₂₀, C0₂R₂₁, CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, and

R₂ to R₄, R₈ to R-io and R₁₆ to R₂₇ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₅ and NR₆R₇, and

R_5, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, notably R₂ to R₄, R₈ to R₁₀ and R₁₆ to R₂₇ are H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, in particular R₂ to R₄, R₈ to R-io and R₁₆ to R₂₇ are H or (Ci-C₆)alkyl.

In a preferred embodiment, R-i is H, SiR₂R₃R₄ or a group selected from:

an aryl,

- halo, OR₈, NR₉R₁₀, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂₁, CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, and

In a particular embodiment of the invention, R-i is H, SiR₂R₃R₄ or a group selected from:

an aryl,

- halo, OR₈, NR₉R₁₀, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, CONR₂₂R₂3, OCONR₂₅R₂₆, notably halo, OR₈,

NR₉R₁₀, NR₁₉C(O)OR₂₀, and

an aryl or (Ci-C₆)alkyl group, notably a methyl, said group being optionally substituted with one or several groups selected from halo, OR₂₈ and NR₂₉R₃₀, notably selected from halo, and

R₂ to R₄, R₈ to R-io, R-I7 to R₂₀, R₂₂, R₂3, R_¾ and R₂₆ are, independently of one another, H or a (d- C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₅ and NR₆R₇, and

R_5, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, notably R₂ to R₄, R₈ to R₁₀, R17 to R₂₀, R₂₂, R₂3, R_¾ and R₂₆ are H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, in particular R₂ to R₄, R₈ to R₁₀, R17 to R₂₀, R₂₂, R₂3, R_¾ and R₂₆ are H or (Ci-C₆)alkyl.

Advantageously, R-i is H, SiR₂R₃R₄ or a group selected from:

a saturated or unsaturated hydrocarbon cycle containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl, and

a phenyl,

- halo, OR₈, NR₉R₁₀, SRn, S(0)R₁₂, S0₂R₁₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂₁, CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, nitro (N0₂), cyano (CN), oxo (=0), notably halo, OR₈, NR₉R₁₀, SRn, S(0)R₁₂, S0₂R₁₃, S0₂NR₁₄R₁₅, OCOR₁₆,

an aryl or (Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, and

R₂ to R₄, R₈ to R-io, R-17 to R₂o, R22, R23, R25 and R₂6 are, independently of one another, H or a (d- C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₅ and NR₆R₇, and

R_5, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, notably R₂ to R₄, R₈ to R₁₀, R17 to R₂o, R22, R23, R25 and R₂6 are H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, in particular R₂ to R₄, R₈ to R₁₀, R17 to R₂₀, R₂₂, R₂3, R_¾ and R₂₆ are H or (Ci-C₆)alkyl.

More advantageously, R-i is H, SiR₂R₃R₄ or a group selected from:

a saturated or unsaturated hydrocarbon cycle containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl,

a phenyl,

- halo, OR₈, NR₉R₁₀, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, CONR₂₂R₂₃, OCONR₂₅R₂₆, notably halo, OR₈, NR₉R₁₀, NR₁₉C(O)OR₂₀, and

R₂ to R₄, R₈ to R-io, R-I7 to R₂₀, R₂₂, R₂3, R_¾ and R₂₆ are, independently of one another H or a (d- C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, notably H or (CrC₆)alkyl.

In a particular embodiment, R-i can also be a heterocycle optionally substituted with one or several groups selected from:

- halo, OR₈, NR₉R₁₀, SRn , S(0)R₁₂, S0₂R₁₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂₁ , CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, nitro (N0₂), cyano (CN), oxo (=0; notably halo, OR₈, NR₉R₁₀, SRn , S(0)R₁₂, S0₂R₁₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂₁ , CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇; advantageously halo, OR₈, NR₉R₁₀, OCORi₆, NR₁₇CORi₈, NR₁₉C(O)OR₂₀, C0₂R₂i , CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇; more advantageously halo, OR₈, NR₉R₁₀, NR₁₇CORis, NR₁₉C(O)OR₂₀, CONR₂₂R₂₃, OCONR₂₅R₂₆; even more advantageously halo, OR₈, NR₉R₁₀, NR₁₉C(O)OR₂₀, and

R_5, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, notably R₂ to R₄ and R₈ to R₃₀ are H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group, in particular R₂, R3, R4 and R₈ to R₃₀ are H or (Ci-C₆)alkyl.

In the above definition, the heterocycle is preferably pyrrolyl, piperidinyl, pyrrolidinyl or pyridyl, in particular pyridyl.

In the above definitions of R-i, the linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 6 carbon atoms will be more particularly a (Ci-C₆)alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, n-pentyl or n-hexyl;

In the above definitions of R-i, the saturated or unsaturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms will be more particularly a saturated or unsaturated hydrocarbon cycle containing from 3 to 6, notably 3, 5 or 6, carbon atoms, in particular a cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl, notably a cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenyl, advantageously a cyclopropyl, cyclohexyl or cyclohexenyl;

In the above definitions of R-i, the aryl will be more particularly a phenyl or naphtyl, notably a phenyl.

The compound according to the present invention can be in particular selected from the compounds 1 to 22, preferably from 1 to 16 or from 17 to 22, of the examples below and the pharmaceutically acceptable salts and solvates thereof.

The present invention also relates to a compound of formula (I) as defined previously for use as a drug, notably intended for the treatment of cancer.

The present invention also pertains to the use of a compound of formula (I) as defined previously for the manufacture of a drug, notably intended for the treatment of cancer.

The present invention also pertains to a method for treating cancer comprising the administration to a person in need thereof of an effective amount of a compound of formula (I) as defined previously.

The cancer can be more particularly in this case a colon cancer, breast cancer, kidney cancer, liver cancer, pancreas cancer, prostate cancer, lung cancer, ovarian cancer, head and neck cancer, glioblastoma, neuroblastoma, lymphoma, leukaemia, inflammatory myofibroblastic tumour, myelodysplastic syndrome, or myelofibrosis. The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined previously and at least one pharmaceutically acceptable excipient.

The active principle can be administered in unitary dosage forms, in mixture with conventional pharmaceutical carriers, to animals and humans.

The pharmaceutical compositions according to the present invention are more particularly intended to be administered orally or parenterally (for ex. intravenously), notably to mammals including human beings.

Suitable unit forms for administration comprise the forms for oral administration, such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions.

When a solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. The tablets may be coated with sucrose or with other suitable materials, or they may be treated in such a way that they have a prolonged or delayed activity and they continuously release a predetermined amount of active principle.

A preparation in gelatin capsules can be obtained by mixing the active ingredient with a diluent and pouring the mixture obtained into soft or hard gelatin capsules.

A preparation in the form of a syrup or an elixir may contain the active ingredient together with a sweetener, an antiseptic, a taste enhancer or a suitable coloring agent.

The water-dispersible powders or granules may contain the active ingredient mixed with dispersing agents, wetting agents, or suspending agents, and with flavor correctors or sweeteners.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile and injectable solutions which contain pharmacologically compatible dispersing agents and/or wetting agents can be used.

The active principle may also be formulated in the form of microcapsules, optionally with one or more carrier additives.

The compounds of the invention can be used in a pharmaceutical composition at a dose ranging from 0.01 mg to 1000 mg a day, administered in only one dose once a day or in several doses along the day, for example twice a day. The daily administered dose is advantageously comprises between 5 mg and 500 mg, and more advantageously between 10 mg and 200 mg. However, it can be necessary to use doses out of these ranges, which could be noticed by the person skilled in the art.

The pharmaceutical compositions according to the present invention can further comprise at least another active principle, such as an anticancer agent.

The present invention also relates to a pharmaceutical composition comprising:

(i) at least one compound of formula (I) as defined previously, and

(ii) at least another active principle, such as an anticancer agent, as a combination product for a simultaneous, separate or sequential use.

The present invention also relates to a pharmaceutical composition as defined previously for use in the treatment of cancer.

The present invention also relates to a method for treating cancer comprising the administration to a person in need thereof of an effective amount of a pharmaceutical composition according to the invention.

The present invention also pertains to a process to prepare a compound of formula (I) as defined previously comprising the following steps:

1 ) reacting:

- a compound of following formula (II):

in which X is I, Br, CI or trifluoromethanesulfonate (OTf), and

- an alkyne of following formula (III):

in which R-i is as previously defined,

to give a compound of formula (I), and

2) optionally salifying and/or solvating the compound of formula (I) obtained in step 1 ) to give a pharmaceutically acceptable salt and/or solvate thereof.

Step 1):

Advantageously, X is I.

The compound of formula (II) can be prepared by methods well-known to the skilled person. In particular, when X is I, the compound of formula (II) can be prepared by reacting securinine with N-iodosuccinimide, as described notably below in the experimental part.

The compound of formula (III) can be prepared by methods well-known to the person skilled in the art.

Step 2):

The salifying step can be carry out by methods well-known to the skilled person, in presence of a pharmaceutically acceptable acid or base.

The solvating step can be carry out by methods weel-known to the skilled person, in the presence of pharmaceutically acceptable solvent, such as water, methanol or ethanol. Further protection / deprotection steps or functionalization steps can be carried out in the process described above, such steps and their reaction conditions being well known to the one skilled in the art.

The compound obtained can be separated from the reaction medium by methods well known to the person skilled in the art, such as by extraction, evaporation of the solvent or by precipitation or crystallisation (followed by filtration).

The compound can also be purified if necessary by methods well known to the person skilled in the art, such as by recrystallisation, by distillation, by chromatography on a column of silica gel or by high performance liquid chromatography (HPLC).

The present invention is illustrated by the following non-limitative examples.

EXAMPLES:

1. Synthesis of the compounds according to the invention:

The following abbreviations are used in the following exam c = concentration

CI, NH₃ = chemical ionization in ammonia

d = doublet

F = fusion

g = gram

HPLC = high performance liquid chromatography

Hz Hertz

J = coupling constant

m = multiplet

M Molar

[M+H]⁺ = parent mass spectrum peak plus H⁺

mg = milligram

mL = milliliter

mM = millimolar

μΜ = micromolar

mmol = millimole

MS = mass spectrum

NMR = Nuclear Magnetic Resonance

ppm = part per million

f = retention factor TLC thin-layer chromatography

°C degree Celcius

%mol molar percentage Synthesis of 14-iodosecurinine

14-iodosecurinine is prepared by adapting the preparation method disclosed in Tetrahedron 2012, 68, 3972-9.

A solution of securinine (1.66 g, 7.6 mmol) is prepared in methanol (50 mL; C=0.25 M) and then is cooled to 0 °C and placed away from light. N-iodosuccinimide (3.1 1 g, 13.8 mmol) is added to the solution by portion of 1.04 g in 5 minutes. The mixture is maintained at 0 °C during 1 hour and then heated to room temperature, the securinine consumption is followed by TLC (CH₂CI₂/acetone 95/5, Rf = 0.3), the reaction is completed in 5 hours.

Then methanol is evaporated, the obtained solid is dissolved in CH₂CI₂ (50 mL; C=0.25 M) and a saturated solution of NaHC0₃ (50 mL) is added, the mixture is stirred for 20 minutes.

The layers are separated, and then the aqueous layer is extracted with CH₂CI₂ (50 mL x 3). The organic layer is extracted with a saturated solution of NaHC0₃ (50 mL), and a saturated solution of NaCI (50 mL). the organic layer is dried over MgS0₄, filtered and concentrated to dryness. The obtained violet-brown solid is purified by flash chromatography on silica gel (CH₂CI₂/acetone gradient 100/0 to 80/20 then CH₂CI₂/MeOH gradient 99/1 to 90/10).

Yield : 860 mg (33 %).

Mass spectrometry (CI) : m/z = 343.8 [M+H]

NMR ¹H (300 MHz, CDCI₃) : δ = 6.97 (d, J = 5.6 Hz, 1 H), 5.56 (s, 1 H), 3.80 - 3.58 (m, 1 H), 2.97 (dt, J = 10.6, 3.8 Hz, 1 H), 2.51 (dt, J = 14.1 , 7.1 Hz, 2H), 2.18 (d, J = 1 1 .0 Hz, 1 H), 1.95 - 1.74 (m, 2H), 1.73 - 1.41 (m, 4H), 1.27 (ddd, J = 12.4, 1 1.1 , 4.7 Hz, 1 H).

NMR ¹³C (75 MHz, CDCI₃) : δ = 172.27, 170.75, 149.48, 1 10.77, 88.55, 84.51 , 62.85, 61.36, 48.67, 41.74, 27.07, 25.68, 24.22

General protocol for the synthesis of the compounds according to the invention

In a glass screw cap tube caped with a rubber septa, iodosecurinine (100 mg, 0.29 mmol), palladium on activated charcoal 10 % wt Pd (10 mg, 0.0094 mmol) and copper iodide (5.5 mg, 0.03 mmol) are successively introduced. Then, freshly distilled tetrahydrofuran (2 mL; C=0.15 M) is added. The mixture is degassed by 3 vacuum / argon cycles. 2 equivalents of distilled di-iso-propylamine and 1.3 equivalent of alkyne are successively introduced by syringe. The septa is replaced by a screw cap, and the mixture is stirred at room temperature. After the iodosecurinine has been consumed (following by TLC), the reaction mixture is filtered through a pad of Celite^® eluting with AcOEt (10 mL). The organic layer is extracted with a saturated aqueous solution of sodium hydrogen carbonate (10 mL) and brine (10 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification by flash chromatography on silica gel eluted by:

System A: petroleum ether/AcOEt gradient 100/0 to 70/30

System B: petroleum ether/AcOEt gradient 100/0 to 40/60

System C: petroleum ether/AcOEt gradient 100/0 to 80/20

Example 1 : (6S,11a/?,11 bS)-4-(hex-1 -yn-1 -yl)-6,8,9,10,11 ,11a-hexahydro-2H-6,11 b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 1 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being hex-1-yne. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 70-30) affords compound 1 as an oil (86 mg, yield: 98%).

TLC silica gel 60 F 254 Merck, CH₂CI₂-acetone: 99-1 , R_f=0.3.

NMR ¹H (CDCI₃) ppm: 6.50 (d, J = 5.5 Hz, 1 H), 5.66 (s, 1 H), 3.76 (t, J = 4.8Hz, 1 H), 2.99 - 2.87 (m,

1 H), 2.50 - 2.40 (m, 2H), 2.34 (t, J = 6.9 Hz, 2H), 2.12 (dd, J = 1 1.2, 2.2 Hz, 1 H), 1 .90 - 1.77 (m, 1 H),

1.73 (d, J = 9.3 Hz, 1 H), 1.66 - 1.36 (m, 8H), 1.27 - 1.10 (m, 1 H), 0.91 (t, J = 7.2 Hz, 3H).

NMR ¹³C (CDCI₃) ppm: 172.92, 170.49, 142.19, 1 17.83, 105.84, 93.70, 88.81 , 74.63, 62.59, 58.39,

48.64, 41.64, 30.39, 27.24, 25.80, 24.38, 21 .86, 18.86, 13.49.

MS (CI, NH₃) m/z 298.0 (M+H⁺), 315.0 (M+NH₄ ⁺)

Example 2: (6S,11a/?,11 bS)-4-(3,3-dimethylbut-1 -yn-1 -yl)-6,8,9,10,11 ,11a-hexahydro- 2H-6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 2 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 3,3-dimethylbut-1-yne. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 70-30) affords compound 2 as a solid (70 mg, yield: 81 %).

TLC silica gel 60 F 254 Merck, CH₂CI₂-acetone: 99-1 , R O.2. F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 6.51 (d, J = 5.5 Hz, 1 H), 5.67 (s, 1 H), 3.77 (t, J = 4.8 Hz, 1 H), 2.99 - 2.91 (m, 1 H), 2.54 - 2.44 (m, 2H), 2.20 - 2.13 (m, 1 H), 1.92 - 1.81 (m, 1 H), 1.76 (d, J = 9.3 Hz, 1 H), 1.67 - 1.48 (m, 4H), 1.28 - 1.23 (m, 9H fBu + 1 H).

NMR ¹³C (CDCI₃) ppm: 173.02, 170.66, 141 .95, 1 17.89, 105.91 , 101 .91 , 88.88, 73.15, 62.58, 58.47, 48.71 , 41.74, 30.76, 28.00, 27.31 , 25.89, 24.45.

MS (CI, NH₃) m/z 298.0 (M+H⁺), 315.0 (M+NH₄ ⁺) Example 3: (6S,11a ?,11 bS)-4-(5-chloropent-1 -yn-1 -yl)-6,8,9,10,11 ,11a-hexahydro-2H-

6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 3 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 5-chloropent-1-yne. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 70-30) affords compound 3 as a solid (84 mg, yield: 91 %).

TLC silica gel 60 F 254 Merck, CH₂CI₂-acetone: 99-1 , R_f=0.35. F= >250° C dec.

NMR ¹H (CDCI₃) ppm: 6.55 (d, J = 5.5 Hz, 1 H), 5.69 (s, 1 H), 3.79 (t, J = 4.5 Hz, 1 H), 3.67 (t, J = 6.3 Hz, 2H), 2.96 (dt, J = 10.5, 3.7 Hz, 1 H), 2.58 (t, J = 6.8 Hz, 2H), 2.53 - 2.46 (m, 2H), 2.15 (d, J = 9.9 Hz, 1 H), 2.07 - 1.98 (m, 2H), 1.92 - 1.82 (m, 1 H), 1 .76 (d, J = 9.3 Hz, 1 H), 1 .68 - 1.45 (m, 4H), 1.29 - 1.16 (m, 1 H).

NMR ¹³C (CDCI₃) ppm: 172.84, 170.18, 142.93, 1 17.54, 106.01 , 91.44, 88.84, 77.42, 77.00, 76.58, 75.63, 62.63, 58.45, 48.69, 43.45, 41.60, 31.00, 27.25, 25.83, 24.37, 16.68.

MS (CI, NH₃) m/z 317.9 (M+H⁺), 334.9 (M+NH₄ ⁺)

Example 4: (6S,11a/?,11 bS)-4-(cyclopropylethynyl)-6,8,9,10,11 ,11a-hexahydro-2H- 6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 4 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being ethynylcyclopropane. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 70-30) affords compound 4 as a solid (80 mg, yield: 98%).

TLC silica gel 60 F 254 Merck, CH₂CI₂-acetone: 99-1 , R_f=0.35. F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 6.50 (d, J = 5.5 Hz, 1 H), 5.67 (s, 1 H), 3.76 (t, J = 4.8 Hz, 1 H), 2.98 - 2.90 (m, 1 H), 2.50 - 2.41 (m, 2H), 2.12 (dd, J = 1 1 .2, 2.4 Hz, 1 H), 1.91 - 1.81 (m, 1 H), 1.73 (d, J = 9.3 Hz, 1 H), 1.65 - 1.47 (m, 5H), 1.45 - 1.21 (m, 1 H), 0.91 - 0.73 (m, 4H).

NMR ¹³C (CDCI₃) ppm: 172.98, 170.47, 142.29, 1 17.80, 105.90, 96.87, 88.85, 69.84, 62.66, 58.44, 48.72, 41.71 , 27.31 , 25.88, 24.48, 8.80, -0.02.

MS (CI, NH₃) m/z 281.9 (M+H⁺), 298.9 (M+NH₄ ⁺)

Example 5: (6S,11a/?,11 bS)-4-(3-hydroxyprop-1 -yn-1 -yl)-6,8,9,10,11 ,11a-hexahydro-2H- 6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 5 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being prop-2-yn-1-ol. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 70-30) affords compound 5 as a solid (50 mg, yield: 63%).

TLC silica gel 60 F 254 Merck, AcOEt, R O.3. F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 6.63 (d, J = 5.4 Hz, 1 H), 5.73 (s, 1 H), 4.44 (s, 2H), 3.80 (t, J = 4.5 Hz, 1 H), 3.01 - 2.92 (m, 1 H), 2.56 - 2.43 (m, 2H), 2.18 - 2.10 (m, 1 H), 1.90 - 1.72 (m, 2H), 1.61 - 1.17 (m, 5H).

NMR ¹³C (CDCI₃) ppm: 172.88, 169.64, 144.36, 1 16.89, 106.16, 88.85, 69.06, 62.65, 58.41 , 51.21 , 48.69, 41.53, 30.91 , 27.31 , 25.88, 24.43. MS (CI , NH₃) m/z 271 .9 (M+H⁺)

Example 6: (6S,11a/?,11 bS)-4-(3-hydroxy-3-methylbut-1 -yn-1 -yl)-6,8,9,10,11 ,11a- hexahydro-2H-6,11 b-methanofuro[2,3-c]pyrido[1 ,2-a]azepin-2-one

Compound 6 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 2-methylbut-3-yn-2-ol. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 40-60) affords compound 6 as a solid (80 mg, yield: 92%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 50-50,

F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 6.59 (d , J = 5.5 Hz, 1 H), 5.70 (s, 1 H), 3.79 (t, J = 4.8 Hz, 1 H), 2.98 - 2.90 (m, 1 H), 2.53 - 2.44 (m, 2H), 2.14 (dd , J = 1 1 .1 , 2.1 Hz, 1 H), 1 .90 - 1 .82 (m, 1 H), 1 .74 (d, J = 9.3 Hz, 1 H), 1 .61 - 1 .24 (m, 1 1 H).

NMR ¹³C (CDCI₃) ppm: 172.88, 169.87, 143.71 , 1 16.96, 106.04, 96.97, 88.84, 75.95, 65.36, 62.54, 58.40, 48.64, 41 .52, 31 .26, 27.24, 25.80, 24.34.

MS (CI , NH₃) m/z 299.9 (M+H⁺)

Example 7: (6S,11a/?,11 bS)-4-(5-hydroxypent-1 -yn-1 -yl)-6,8,9,10,11 ,11a-hexahydro-2H- -methanofuro[2,3-c]pyrido[1 ,2-a]azepin-2-one

Compound 7 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being pent-4-yn-1 -ol. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 40-60) affords compound 7 as a solid (58 mg, yield: 86%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 50-50, Rf=0.3. F=>250° C dec. NMR ¹H (CDCI₃) ppm: 6.53 (d, J= 5.5 Hz, 1H), 5.69 (s, 1H), 3.80 - 3.66 (m, 3H), 2.99 - 2.90 (m, 1H), 2.53-2.46 (m, 2H), 2.37 (t, J = 7.0 Hz, 2H), 2.13 (dd, J= 11.6, 2.8 Hz, 1H), 1.86- 1.73 (m, 4H), 1.60 -1.47 (m, 4H), 1.25 - 1.14 (m, 1H).

NMR ¹³C (CDCI₃) ppm: 173.06, 170.45, 142.66, 117.69, 105.92, 92.82, 88.93, 75.09, 62.64, 61.35, 58.44, 48.69, 41.64, 31.08, 27.26, 25.82, 24.39, 15.80.

MS (CI, NH₃) m/z 299.9 (M+H⁺)

Example 8: (6S,11a/?,11 bS)-4-(hept-1 -yn-1 -yl)-6,8,9,10,11 ,11a-hexahydro-2H-6,11 b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 8 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being hept-1-yne. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 80-20) affords compound 8 as a solid (81 mg, yield: 90%).

TLC silica gel 60 F 254 Merck, CH₂CI₂-acetone: 99-1 , R_f=0.3. F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 6.51 (d, J = 5.5 Hz, 1H), 5.67 (s, 1H), 3.76 (t, J = 4.8 Hz, 1H), 2.98 - 2.89 (m, 1H), 2.52-2.45 (m, 1H), 2.34 (t, J= 7.0 Hz, 2H), 2.13 (dd, J= 11.1, 2.1 Hz, 1H), 1.89 - 1.81 (m, 1H), 1.74 (d, J=9.3Hz, 1H), 1.62- 1.22 (m, 12H), 0.89 (t, J =7.0 Hz, 3H).

NMR ¹³C (CDCI₃) ppm: 172.95, 170.51, 142.21, 117.88, 105.89, 93.81, 88.84, 77.42, 77.00, 76.58, 74.64, 62.61, 58.42, 48.66, 41.64, 30.96, 28.07, 27.23, 25.79, 24.37, 22.07, 19.17, 13.89.

MS (CI, NH₃) m/z 312.0 (M+H⁺), 329.0 (M+NH₄ ⁺)

Example 9: (6S,11a?,11 bS)-4-(cyclohexylethynyl)-6,8,9,10,11 ,11a-hexahydro-2H-6,11 b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

In a glass screw cap tube caped with a rubber septa, iodosecurinine (150 mg, 0.44 mmol), palladium on activated charcoal 10 % wt Pd (15 mg, 0.015 mmol) and copper iodide (7.5 mg, 0.044 mmol) are successively introduced. Then, 3 mL of freshly distilled tetrahydrofuran is added. The mixture is degassed by 3 vacuum / argon cycles. 2 equivalents of distilled di-iso-propylamine and 1.3 equivalent of ethynylcyclohexane are successively introduced by syringe. The septa is replaced by a screw cap, and the mixture is stirred at room temperature. After the iodosecurinine has been consumed (following by TLC), the reaction mixture is filtered through a pad of Celite^® eluting with AcOEt (15 mL). The organic layer is extracted with a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and brine (15 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 80-20) affords compound 9 as a solid (126 mg, yield: 89%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 75-25, R O.62. F=>250° C dec.

NMR ¹H (CDCI3) ppm: 6.50 (d, J = 5.5 Hz, 1 H), 5.67 (s, 1 H), 3.76 (t, J = 4.5 Hz, 1 H), 2.97 - 2.89 (m, 1 H), 2.56 - 2.43 (m, 3H), 2.14 (d, J = 9.5 Hz, 1 H), 1.82 - 1.23 (m, 17H).

NMR ¹³C (CDCI3) ppm: 172.92, 170.59, 141 .97, 1 17.88, 105.87, 97.74, 88.81 , 74.55, 62.54, 58.42, 48.63, 41.63, 32.29, 29.39, 27.20, 25.68, 24.63, 24.31.

MS (CI, NH₃) m/z 324.1 (M+H⁺), 341.1 (M+NH₄ ⁺)

Example 10: (6S,11a ?,11 bS)-4-(cyclohex-1 -en-1 -ylethynyl)-6,8,9,10,11 ,11a-hexahydro- 2H-6,11 b-methanofuro[2,3-c]pyrido[1 ,2-a]azepin-2-one

In a glass screw cap tube caped with a rubber septa, iodosecurinine (150 mg, 0.44 mmol), palladium on activated charcoal 10 % wt Pd (15 mg, 0.015 mmol) and copper iodide (7.5 mg, 0.044 mmol) are successively introduced. Then, 3 mL of freshly distilled tetrahydrofuran is added. The mixture is degassed by 3 vacuum / argon cycles. 2 equivalents of distilled di-iso-propylamine and 1.3 equivalent of 1-ethynylcyclohex-1-ene are successively introduced by syringe. The septa is replaced by a screw cap, and the mixture is stirred at room temperature. After the iodosecurinine has been consumed (following by TLC), the reaction mixture is filtered through a pad of Celite^® eluting with AcOEt (15 mL). The organic layer is extracted with a saturated aqueous solution of sodium hydrogen carbonate (15 mL) and brine (15 mL). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 80-20) affords compound 10 as a solid (141 mg, yield: 99%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 75-25, R O.64. F=>250° C dec. NMR ¹H (CDCI3) ppm: 6.53 (d, J = 5.5 Hz, 1 H), 6.26 - 6.09 (m, 1 H), 5.67 (s, 1 H), 3.77 (t, J = 4.5 Hz, 1 H), 2.97 - 2.89 (m, 1 H), 2.51 - 2.42 (m, 2H), 2.16 - 2.08 (m, 5H), 1.91 - 1.78 (m, 1 H), 1.74 (d, J = 9.3 Hz, 1 H), 1.65 - 1.47 (m, 8H), 1.27 - 1.17 (m, 1 H).

NMR ¹³C (CDCI3) ppm: 172.81 , 170.1 1 , 142.24, 136.82, 1 19.87, 1 17.65, 105.87, 94.17, 88.76, 80.58, 62.57, 58.40, 48.63, 41.60, 28.85, 27.28, 25.84, 25.66, 24.43, 22.05, 21.22.

MS (CI, NH₃) m/z 322.1 (M+H⁺), 339.2 (M+NH₄ ⁺)

Example 11 : (6S,11a/?,11 bS)-4-((trimethylsilyl)ethynyl)-6,8,9,10,11 ,11a-hexahydro-2H- 6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 11 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being ethynyltrimethylsilane. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 80-20) affords compound 11 as a solid (75 mg, yield: 83%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 80-20, R O.45. F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 6.65 (d, J = 5.5 Hz, 1 H), 5.72 (s, 1 H), 3.80 (t, J = 4.5 Hz, 1 H), 3.00 - 2.92 (m, 1 H), 2.55 - 2.45 (m, 2H), 2.20 - 2.13 (m, 1 H), 1.92 - 1.82 (m, 1 H), 1.76 (d, J = 9.3 Hz, 1 H), 1.62 - 1.45 (m, 4H), 1.27 - 1.20 (m, 1 H), 0.30 - 0.20 (m, 9H).

NMR ¹³C (CDCI₃) ppm: 172.79, 169.62, 144.16, 1 17.47, 106.30, 98.37, 88.75, 62.56, 58.46, 48.69, 41.51 , 27.33, 25.89, 24.43, -0.28.

MS (CI, NH₃) m/z 313.9 (M+H⁺), 330.9 (M+NH₄ ⁺)

Example 12: (6S,11a/?,11 bS)-4-((4-fluorophenyl)ethynyl)-6,8,9,10,11 ,11a-hexahydro- 2H-6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 12 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 1-ethynyl-4-fluorobenzene. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 70-30) affords compound 12 as a solid (90 mg, yield: 93%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 75-25, R O.29. F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 7.48-7.42 (m, 2H), 7.08-7.01 (m, 2H), 6.69 (d, J= 5.5 Hz, 1H), 5.79 (s, 1H), 3.85 (t, J = 4.8 Hz, 1H), 3.02- 2.95 (m, 1H), 2.57 - 2.46 (m, 2H), 2.20 (dd, J = 11.2, 2.4 Hz, 1H), 1.92- 1.84 (m, 1H), 1.81 (d, J=9.4Hz, 1H), 1.70 - 1.43 (m, 4H), 1.29- 1.20 (m, 1H).

NMR ¹³C (CDCI₃) ppm: 172.76, 169.67, 162.83 (d, J¹C-F = 250 Hz), 143.59, 133.62 (d, fC-F = 8.5 Hz), 118.08, 117.26, 115.83 (d, J² C-F, 22.2Hz), 106.16, 91.07, 88.85, 82.85, 62.65, 58.49, 48.70, 41.56, 27.33, 25.88, 24.43.

MS (CI, NH₃) m/z 336.2 (M+H⁺), 353.2 (M+NH₄ ⁺)

Example 13: tert-butyl (3-((6S,11a/?,11 bS) -2 -oxo -6, 8,9,10,11 ,11a-hexahydro-2H-6,11 b- methanofuro[2,3-c]pyrido[1,2-a]azepin-4-yl)prop-2-yn-1-yl)carbamate

Compound 13 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being tert-butyl prop-2-yn-1-ylcarbamate. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 70-30) affords compound 13 as a solid (37 mg, yield: 35%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 50-50, R O.57. F=124° C dec.

NMR ¹H (CDCI₃) ppm: 6.60 (d, J = 5.5 Hz, 1 H), 5.70 (s, 1 H), 4.78 (s, br, NH), 4.09 (d, J = 5.5 Hz, 2H), 3.79 (d, J = 4.8Hz, 1H), 2.99 -2.91 (m, 1 H), 2.53 - 2.43 (m, 2H), 2.13 (dd, J = 11.2,2.3 Hz, 1H), 1.91 - 1.82 (m, 1H), 1.75 (d, J=9.3Hz, 1H), 1.59 - 1.15 (m, 5H + 9H).

NMR ¹³C (CDCI₃) ppm: 172.78, 169.66, 155.19, 144.03, 116.97, 106.15, 88.78, 80.27, 62.65, 58.40, 48.69, 41.55, 30.95, 29.66, 28.31 , 27.31 , 25.89, 24.44.

MS (+ESI) m/z 371.3 (M+H⁺) Example 14: (6S,11a/?,11 bS)-4-((4-(dimethylamino)phenyl)ethynyl)-6,8,9,10,11 ,11a- hexahydro-2H-6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 14 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 4-ethynyl-N,N-dimethylaniline. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 40-60) affords compound 14 as a solid (101 mg, yield: 97%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 40-60, R_f=0.3. F=157° C dec.

NMR ¹H (CDCI₃) ppm: 7.35 (d, J = 9.0 Hz, 2H), 6.64 (d, J = 9.1 Hz, 2H), 6.60 (d, J = 5.5 Hz, 1 H), 5.81 (s, 1 H), 3.83 (d, J = 4.5 Hz, 1 H), 3.00 (s, 6H), 2.93 - 2.97 (m, 1 H), 2.57 - 2.47 (m, 2H), 2.21 (dd, J = 1 1 .2, 2.2 Hz, 1 H), 1.92 - 1.85 (m, 1 H), 1.82 (d, J = 9.2 Hz, 1 H), 1.69 - 1.52 (m, 4H), 1.30 - 1.20 (m, 1 H).

NMR ¹³C (CDCI₃) ppm: 172.97, 170.38, 150.35, 141.34, 132.78, 1 17.95, 1 1 1 .59, 108.27, 105.87, 93.83, 88.85, 81.33, 62.62, 58.47, 48.68, 41.71 , 39.99, 27.32, 25.87, 24.48.

MS (CI) m/z 361.2 (M+H⁺)

Example 15 : (6S,11a/?,11 bS)-4-(p-tolylethynyl)-6,8,9,10,11 ,11a-hexahydro-2H-6,11 b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2-one

Compound 15 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 1-ethynyl-4-methylbenzene. Purification by flash chromatography on silica gel (petroleum ether-AcOEt, gradient 100-0 to 70-30) affords compound 15 as a solid (92 mg, yield: 96%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 70-30, R O.4. F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 7.37 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 7.9 Hz, 2H), 6.68 (d, J = 5.5 Hz, 1 H), 5.81 (s, 1 H), 3.85 (d, J = 4.5 Hz, 1 H), 3.04 - 2.94 (m, 1 H), 2.57 - 2.46 (m, 2H), 2.36 (s, 3H), 2.21 (dd, J = 1 1 .2, 2.4 Hz, 1 H), 1.94 - 1.84 (m, 1 H), 1.81 (d, J = 9.3 Hz, 1 H), 1.68 - 1.48 (m, 4H), 1.30 - 1.20 (m, 1 H).

NMR ¹³C (CDCI₃) ppm: 172.87, 169.92, 143.04, 139.30, 131 .54, 129.22, 1 18.89, 1 17.57, 106.13, 92.45, 88.86, 82.53, 62.65, 58.50, 48.71 , 41.62, 27.34, 25.89, 24.46, 21.51.

MS (CI, NH₃) m/z 332.2 [M+H]⁺, 349.2 [M+NH₄]⁺

Example 16 : (6S,11a/?,11 bS)-4-((2-(trifluoromethyl)phenyl)ethynyl)-9,10,11,11a- tetrahydro-8H-6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one

Compound 16 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 1-ethynyl-2- trifluoromethylbenzene. Purification by flash chromatography on silica gel (petroleum ether-AcOEt gradient, 100-0 to 70-30) affords compound 16 as a solid (66 mg, yield: 56%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 70-30, R_f=0.3. F=>250° C dec.

NMR ¹H (CDCI₃) ppm: 7.69 (d, J = 7.8 Hz, 1 H), 7.62 (d, J = 7.6 Hz, 1 H), 7.54 (t, J = 7.3 Hz, 1 H), 7.46 (t, J = 7.7 Hz, 1 H), 6.76 (d, J = 5.4 Hz, 1 H), 5.86 (s, 1 H), 3.87 (t, J = 4.6 Hz, 1 H), 3.00 (dt, J = 10.5, 3.6 Hz, 1 H), 2.57 - 2.48 (m, 2H), 2.23 (dd, J = 1 1 .3, 2.2 Hz, 1 H), 1 .91 - 1.82 (m, 2H), 1.70 - 1.49 (m, 3H), 1.34 - 1.21 (m, 2H).

NMR ¹³C (CDCI₃) ppm: 172.86, 169.20, 144.63, 133.94, 131 .55, 131.57 (q, J-CF= 30.0 Hz ), 128.73, 126.04, 125.99, 123.40 (q, J-CF = 273.5 Hz), 120.27, 1 17.12, 106.47, 88.85, 88.56, 87.87, 77.32, 77.00, 76.68, 62.64, 58.54, 48.72, 41 .44, 27.38, 25.93, 24.41.

MS (CI) m/z 386.23 [M+H]⁺

Example 17 : (6S,11a ?,11 bS)-4-((4-(A ,A -diethylaniline)ethynyl)-9,10,11 ,11a-tetrahydro- 8H-6,11 b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one

Compound 17 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being A/,A/-diethyl-4-ethynylaniline. Purification by flash chromatography on silica gel (petroleum ether-AcOEt gradient, 100-0 to 70-30) affords compound 17 as a yellow solid (94 mg, yield: 85%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 70-30, R_f=0.33. F= 177 °C.

NMR¹H (CDCI₃) ppm: 7.30 (d, J = 9.1 Hz, 2H), 6.60 - 6.57 (m, 3H), 5.80 (s, 1H), 3.83 (t, J = 4.7 Hz, 1H), 3.37 (q, J= 7.1 Hz, 4H), 3.00 - 2.93 (m, 1 H), 2.55 - 2.46 (m, 2H), 2.20 (dd, J = 11.2,2.4 Hz, 1H), 1.90- 1.78 (m,2H), 1.69-1.50 (m, 4H), 1.28- 1.22 (m, 1H), 1.17 (t, J = 7.1 Hz, 6H).

NMR¹³C (CDCI₃) ppm: 173.1, 170.5, 147.9, 141.1, 133.1, 118.1, 111.0, 107.2, 105.9, 94.1, 88.9, 81.1, 62.7, 58.5, 48.7, 44.3 , 41.8, 27.4, 25.9, 24.5, 12.5.

MS (CI/NH₃) m/z = 389.3 [M+H]⁺

Example 18 : (6S,11a?,11 bS)-4-((4-methoxyphenyl)ethynyl)-9,10,11 ,11a-tetrahydro-8H- 6,11b-methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one

Compound 18 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 1-ethynyl-4- methoxybenzene. Purification by flash chromatography on silica gel (petroleum ether-AcOEt gradient,

100-0 to 70-30) affords compound 18 as a yellow solid (76 mg, yield: 76%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 80-20, R O.13. F=153-5 °C.

NMR¹H (CDCI₃) ppm: 7.40 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.9 Hz, 2H), 6.65 (d, J = 5.5 Hz, 1H), 5.79 (s, 1H), 3.85-3.81 (m,4H), 2.97 (dt, J= 10.4, 3.5 Hz, 1H), 2.54- 2.45 (m, 2H), 2.19 (dd, J= 11.2, 2.4

Hz, 1H), 1.90- 1.75 (m, 2H), 1.67- 1.46 (m, 4H), 1.31 - 1.19 (m, 1H).

NMR ¹³C (CDCI₃) ppm: 172.9, 170.0, 160.1, 142.6, 133.1, 117.6, 114.1, 114.0, 106.0, 92.3, 88.8, 82.0, 62.6, 58.5, 55.3, 48.7, 41.6, 27.3, 25.9, 24.5.

MS (CI/NH₃) m/z = 348.2 [M+H]⁺

Example 19 : fert-butyl (5-((6S,11a?,11bS)-2-oxo-2,6,9,10,11,11a-hexahydro-8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-4-yl)pent-4-yn-1-yl)carbamate

Compound 19 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being ieri-butyl pent-4-yn-1- ylcarbamate. Purification by flash chromatography on silica gel (petroleum ether-AcOEt gradient, 100- 0 to 70-30) affords compound 19 as a yellow foam (90 mg, yield: 78%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 50-50, Rf=0.58. F< 50 °C.

NMR¹H (CDCI₃) ppm: 6.51 (d, J = 5.5 Hz, 1H), 5.67 (s, 1H), 4.75 (s, NH, 1H), 3.75 (t, J = 4.6 Hz, 1H), 3.20 (q, J= 6.5 Hz, 2H), 2.92 (dt, J= 10.4, 3.6 Hz, 1H), 2.49-2.32 (m, 4H), 2.09 (dd, J= 11.2, 2.3 Hz, 1H), 1.88- 1.66 (m, 4H), 1.62- 1.42 (m, 4H), 1.40 (s, 9H), 1.26- 1.11 (m, 1H).

NMR ¹³C (CDCI₃) ppm: 172.83, 170.21, 155.83, 142.72, 117.55, 105.86, 92.34, 88.75, 79.14, 75.22, 62.56, 58.32, 48.62, 41.60, 39.60, 28.65, 28.29 (3C), 27.24, 25.80, 24.38, 16.72.

MS (CI/NH3) m/z = 399.2 [M+H]⁺

Example 20 : fert-butyl (5-((6S,11a?,11bS)-2-oxo-2,6,9,10,11,11a-hexahydro-8H-6,11b- methanofuro[2,3-c]pyrido[1,2-a]azepin-4-yl)4-ethynylcyclohexyl)carbamate

Compound 20 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being ieri-butyl (4- ethynylcyclohexyl)carbamate. Purification by flash chromatography on silica gel (petroleum ether- AcOEt gradient, 100-0 to 70-30) affords compound 20 as a yellow visqueous oil (104 mg, yield: 82%). TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 70-30, Rf=0.26.

NMR¹H (CDCI₃) ppm: 6.49 (d, J= 5.5 Hz, 1H), 5.62 (s, 1H), 4.49 (brs, 1H), 3.82-3.66 (m, 1H), 3.39 (brs, 1H), 2.91 (dt, J= 10.3, 3.6 Hz, 1H), 2.44 (dd, J= 9.3, 3.9 Hz, 2H), 2.39-2.26 (m, 1H), 2.12 (d, J = 10.6 Hz, 1H), 2.02- 1.92 (m, 4H), 1.87- 1.77 (m, 1H), 1.71 (d, J= 9.3 Hz, 1H), 1.63- 1.40 (m, 6H), 1.38 (s, 9H), 1.24- 1.04 (m, 3H).

NMR ¹³C (CDCI₃) ppm: 172.75, 170.22, 155.04, 142.39, 117.59, 105.88, 96.56, 88.71, 79.04, 74.53, 62.45, 58.37, 48.55, 41.48, 32.19, 31.19, 29.10, 28.27, 27.08, 25.61, 24.16.

MS (CI/NH₃) m/z = 439.3 [M+H]⁺ Example 21 : (6S,11a/?,11 bS)-4-(phenylethynyl)-9,10,11 ,11a-tetrahydro-8H-6,11 b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one

Compound 21 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being ethynyllbenzene. Purification by flash chromatography on silica gel (petroleum ether-AcOEt gradient, 100-0 to 70-30) affords compound 21 as a glassy brown solid (88 mg, yield: 92%).

NMR¹H (CDCI₃) ppm: 7.50 - 7.43 (m, 2H), 7.38 - 7.31 (m, 3H), 6.70 (d, J = 5.5 Hz, 1H), 5.80 (s, 1H), 3.85 (t, J = 4.6 Hz, 1H), 2.98 (dt, J= 10.4, 3.6 Hz, 1H), 2.61 -2.39 (m, 2H), 2.21 (dd, J= 11.2,2.4 Hz, 1H), 1.92- 1.77 (m,2H), 1.70- 1.43 (m, 4H), 1.33- 1.18 (m, 1H).

NMR¹³C (CDCI₃) ppm: 172.77, 169.75, 143.47, 131.60 (2C), 128.96, 128.42 (2C), 121.94, 117.36, 106.11, 92.13, 88.82, 83.08, 62.61, 58.46, 48.67, 41.56, 27.32, 25.88, 24.43.

MS (CI/NH₃)m/z = 318.2 [M+H]⁺

Example 22 : (6S,11a/?,11 bS)-4-(pyridin-3-ylethynyl)-9,10,11 ,11a-tetrahydro-8H-6,11 b- methanofuro[2,3-c]pyrido[1,2-a]azepin-2(6H)-one

Compound 22 has been synthesized using the above recited general protocol for the synthesis of the compounds according to the invention, the alkyne being 3-ethynylpyridine.

Purification by flash chromatography on silica gel (petroleum ether-AcOEt gradient, 100-0 to 70-30) affords compound 22 as a brown glassy solid (44 mg, yield: 48%).

TLC silica gel 60 F 254 Merck, petroleum ether-AcOEt: 50-50, R O.29. F=>250° C dec.

NMR¹H (CDCI₃) ppm: 8.70 (dd, J = 2.1, 0.8 Hz, 1H), 8.57 (dd, J = 4.9, 1.7 Hz, 1H), 7.75 (dt, J = 7.9,

1.9 Hz 1H), 7.29 (ddd, J = 7.9, 4.9, 0.9 Hz, 1H), 6.75 (d, J = 5.5 Hz, 1H), 5.79 (s, 1H), 3.86 (t, J = 4.6

Hz, 1H), 2.99 (dt, J= 10.5, 3.6 Hz, 1H), 2.58-2.47 (m, 2H), 2.21 (dd, J= 11.2, 2.4 Hz, 1H), 1.93-

1.76 (m,2H), 1.68 - 1.45 (m, 4H), 1.29 - 1.18 (m, 1H). NMR ¹³C (CDCI₃) ppm: 172.61 , 169.23, 152.20, 149.23, 144.64, 138.51 , 123.10, 1 19.27, 1 16.86, 106.28, 88.81 , 88.60, 86.30, 62.64, 58.47, 48.70, 41.49, 27.37, 25.92, 24.44.

MS (CI/NH₃) m/z = 319.2 [M+H]⁺

1. Biological activity of the compounds according to the invention:

The antiproliferative activity of compounds was measured using the ATPIite assay (Perkin Elmer). HCT-1 16 cells (human colon cancer) were seeded in 96-well plates, incubated for 24 h and treated with 1 μΜ and 10 μΜ solution of test compounds. Cells were then incubated for 72 h at 37 °C under 5% C0₂. At the end of the experiment, cell viability was evaluated by determining the level of ATP released by viable cells. Results are expressed in percentage of growth inhibition compared to non-treated cells.

Inhibition

percentage

(HCT-1 16)

Example Structure 10 μΜ 1 μΜ

Securinine 50.6 7.6

O

1 98.1 7.5

OX) ^~~

Claims

1. A compound of the following formula (I):

or a pharmaceutically acceptable salt and/or solvate thereof, wherein:

• R-i is H, S1R2R3R4 or a group selected from

- a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 6 carbon atoms,

- a saturated or unsaturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms,

- an aryl, and

- a heterocycle,

said group being optionally substituted,

• R₅, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group.

2. The compound according to claim 1 , wherein:

• R-i is H, S1R2R3R4 or a group selected from:

- an aryl, and

- a heterocycle,

- halo, OR₈, NR₉R₁₀, SRn , S(0)R₁₂, S0₂Ri₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂₁ , CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, nitro (N0₂), cyano (CN), oxo (=0), and

- an aryl or (Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₂₈ and NR₂₉R₃₀, • R₂, 3, R4, Re R91 R101 R111 Ri2i Ri3i Ri4i Ri5i Ri7i Ri9> R20, R211 R22, R23, R24, R25, R∑6, R27, R28, R29 and R₃₀ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci- C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₅ and NR₆R₇, and

• R_5, R₆ and R₇ are, independently of one another, H, (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group.

The compound according to any one of claims 1 and 2, wherein:

• R-i is H, S1R2R3R4 or a group selected from

- a saturated or unsaturated hydrocarbon cycle or bicycle containing from 3 to 10 carbon atoms, and

- an aryl,

- halo, OR₈, NR₉R₁₀, SRn , S(0)R₁₂, S0₂Ri₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, CO2R21 , CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, nitro (N0₂), cyano (CN), oxo (=0), and

- an aryl or (Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₂₈ and NR₂₉R₃₀, and

• R₂, R3, R4, R₈, Rg, R10, R11 , Ri2> Ri3i Ri4i Ri5i Ri7i Ri9> R20, R21 R22, R23, R24, R25, R∑6, R27, R28, R29 and R₃₀ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci- C₆)alkyl group.

The compound according to any one of claims 1 to 3, wherein

• R-i is H, SiR₂R₃R₄ or a group selected from:

- an aryl,

- halo, OR₈, NR₉R₁₀, SRn , S(0)R₁₂, S0₂R₁₃, S0₂NR₁₄R₁₅, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂i , CONR₂₂R₂₃, OC0₂R₂₄, OCONR₂₅R₂₆, COR₂₇, and

- an aryl or (Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₂₈ and NR₂₉R₃₀, and • F¾, 3, R4, Re 101 111 i2i i3i i4i i5i i7i i9> R20, 21 R22, R23, R24, R25, R∑6, R27, R28, R29 and R₃₀ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci- C₆)alkyl group.

The compound according to any one of claims 1 to 4, wherein

• R-i is H, S1R2R3R4 or a group selected from:

- an aryl,

- halo, OR₈, NR₉R₁₀, OCOR₁₆, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, C0₂R₂i , CONR22R23, OC0₂R₂4, OCONR₂₅R₂6, COR₂₇, and

- an aryl or (Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo, OR₂8 and NR29R30, and

• R2, R3, R4, e 101 i i i9i R20, 211 R22, R23, R24, R25, R26, R27, R28, R29 and R30 are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group.

The compound according to any one of claims 1 to 5, wherein:

• R-i is H, S1R2R3R4 or a group selected from:

- an aryl,

- halo, OR₈, NR₉R₁₀, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, CONR₂₂R₂3, OCONR₂₅R₂6, and

• R₂, R3, R4, e, Rg, R10, R-I7, 18, i9, R20, R22, R23, R25, R26, R28, R29 and R₃₀ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group.

The compound according to any one of claims 1 to 6, wherein:

• R-i is H, S1R2R3R4 or a group selected from: - a linear or branched, saturated or unsaturated hydrocarbon chain containing from 1 to 6 carbon atoms,

- an aryl,

- halo, OR₈, NR₉R₁₀, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, CONR₂₂R₂3, OCONR₂₅R₂₆, and

- an aryl or (Ci-C₆)alkyl group, said group being optionally substituted with one or several groups selected from halo,

• R₂, R₃, R₄, R₈, R₉, R-io, R-I7, R-i₈, R19, R20, R22, R23, R25 and R₂₆ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group.

The compound according to any one of claims 1 to 7, wherein:

• R-i is H, SiR₂R₃R₄ or a group selected from:

- a saturated or unsaturated hydrocarbon cycle containing from 3 to 6 carbon atoms, such as cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl, or cyclohexenyl, and

- a phenyl,

- halo, OR₈, NR₉R₁₀, NR₁₇COR₁₈, NR₁₉C(O)OR₂₀, CONR₂₂R₂₃, OCONR₂₅R₂₆, and

• R₂, R₃, R₄, R₈, R₉, R-io, R-I7, Ri₈, R19, R₂o, R₂₂, R₂3, R₂5 and R₂₆ are, independently of one another, H or a (Ci-C₆)alkyl, aryl or aryl(Ci-C₆)alkyl group.

9. The compound according to any one of claims 1 to 8, wherein it is selected from the following compounds:

and the pharmaceutically acceptable salts and solvates thereof.

10. A compound according to any one of claims 1 to 9 for use as a drug.

1 1. A compound according to any one of claims 1 to 9 for use in the treatment of cancer.

12. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 9 and at least one pharmaceutically acceptable excipient.

13. The pharmaceutical composition according to claim 12, wherein it further comprises another active principle, such as an anticancer agent.

14. A pharmaceutical composition comprising:

a) at least one compound according to anyone of claims 1 to 9, and

b) at least one another active principle, such as an anticancer agent, as a combination product for simultaneous, separate or sequential use.

15. A process to prepare a compound according to any one of claims 1 to 9, comprising the following steps:

1 ) reacting:

- a compound of following formula (II):

in which X is I, Br, CI or OTf, and

- an alkyne of following formula (III)

in which R-i is as defined in any one of claims 1 to 8,

to give a compound of formula (I), and