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WO2025068461A1 - Guanfacine derivatives and their use in treating cancer - Google Patents

Guanfacine derivatives and their use in treating cancer Download PDF

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Publication number
WO2025068461A1
WO2025068461A1 PCT/EP2024/077218 EP2024077218W WO2025068461A1 WO 2025068461 A1 WO2025068461 A1 WO 2025068461A1 EP 2024077218 W EP2024077218 W EP 2024077218W WO 2025068461 A1 WO2025068461 A1 WO 2025068461A1
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alkyl
cycloalkyl
optionally substituted
radical
halogen
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French (fr)
Inventor
Stefano Crosignani
John Paul Watts
Joseph William WRIGGLESWORTH
Edward James COCHRANE
Thomas Fowler
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Negio Therapeutics
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Negio Therapeutics
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    • 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
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/22—Y being a hydrogen or a carbon atom, e.g. benzoylguanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/16—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D309/20—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hydrogen atoms and substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D309/22—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • Cancer is the second leading cause of death worldwide. Indeed, nearly 1 in 6 deaths is due to cancer. The prevalence of cancer is also extremely high as more than 15 million new cases are diagnosed each year, and the number of new cases is expected to rise by about 70% over the next 2 decades. Among the most common cancers, lung cancers account for 1.69 million deaths per year, colorectal cancer for 774 000 deaths per year, and breast cancer for 571 000 deaths per year. Many treatment options exist nowadays for cancer, including for example surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, immunotherapy and palliative care. The choice of the best treatments depends on the type, location and grade of the cancer as well as the patient's health and preferences.
  • the a2-AR are a family of G-protein-coupled receptors with 3 pharmacological subtypes, a2A, a2B, and a2C. They have been used for decades to treat common medical conditions such as hypertension; attention-deficit/hyperactivity disorder; various pain and panic disorders; symptoms of opioid, and alcohol withdrawal; and for sedation and to reduce anesthetic requirements.
  • Centrally acting alpha2-adrenergic receptors agonists stimulate a2-AR in the central nervous system (brain and spinal cord). When a2-AR are stimulated, sympathetic nervous system activity decreases. This decreased sympathetic activity leads to a drop in blood pressure and heart rate.
  • WO 2021/214129 and J. Zhu, et al. have currently shown that agonists of a2-AR, such as Guanabenz, Clonidine or Guanfacine, have surprisingly strong antitumor activity when used as monotherapies in multiple immunocompetent murine tumor models, including ICB-resistant models, but not in immunodeficient models. It was also observed striking effects in human tumor xenografts implanted in mice reconstituted with human peripheral blood mononuclear cells.
  • a2-AR such as Guanabenz, Clonidine or Guanfacine
  • a2-AR agonists were reverted by a2-AR antagonists, and were absent in a2-AR knockout mice, demonstrating on- target action exerted on host cells, not tumor cells.
  • Tumors from treated mice contained increased infiltrating CD8+ T lymphocytes and reduced infiltrating myeloid-derived suppressor cells (MDSC), which were more apoptotic.
  • MDSC myeloid-derived suppressor cells
  • a2-AR agonists are relevant and promising approaches for anti-cancer therapies. More particularly, it could significantly improve clinical efficacy of cancer immunotherapy.
  • many of the effects of centrally active a2-AR agonists are mediated by decreasing sympathetic activity and lead to side hypotensive and sedative effects that could be harmful to patients and/or limit the dose of a2- AR agonists that could be safely administered to patients, thereby potentially limiting the therapeutic anti-cancer benefit.
  • the inventors have provided new guanfacine derivatives as efficient a2-AR agonists while being not efficient in penetrating the BBB, demonstrating thereby the therapeutic interest of such derivatives in medicine, more particularly in anti-cancer therapies.
  • Ri represents a radical selected in a group consisting of:
  • a 3-14 membered ring saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
  • X is selected from the group consisting of -(CH2) m - with m is from 1 to 3 optionally substituted by at least one R a , -O-, -S-, -CO-, -C(O)-O-, -O-C(O)-, -NR a -, -CO-NR a -, -NRa-CO-, -SO-, -SO2-, -SO 2 -NRa, -NR a -SO2-, and -NRa-CO-NRa-, with R a being a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of: a
  • - a -CO-(Ci-C 6 )alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and R c may form together a N-heterocycloalkyl, a nitro, a cyano,
  • n is 0 or 1;
  • R 2 represents a radical selected in a group consisting of:
  • a 3-14 membered ring saturated, partially unsaturated, or unsaturated, selected in a group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl
  • said 3-14 membered ring is optionally substituted by at least one radical A selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, or a hydroxy, a cycloalkyl optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a hydroxy, a (C 2 -Ce)alkenyl, a (C 2 -Ce)alkynyl, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen, a cyano, a -NRaRe with Rd and Re represent independently a hydrogen,
  • Ri and Rj represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Ri and Rj may form together a N-heterocycloalkyl, a nitro, a cyano, - a -NH-CO-(Ci-C 6 )alkyl, a -CO-NH-(Ci-C 6 )alkyl, a -NH-CO-cycloalkyl; -CO-NH-cycloalkyl,
  • R3 represents a radical selected in a group consisting of:
  • Re represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2;
  • Rs may form together a 5-7 membered ring, partially unsaturated or saturated, N,N’ -heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (Ci-Ce)alkyl, a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, a - N((Ci-Ce)alkyl)2, and a ketone; and the isomers, stereoisomers and pharmaceutical acceptable salts thereof with the proviso that the compound is not a compound selected in the group consisting of:
  • the compound of formula (I) is such that n is 0. In a further particular embodiment, the compound of formula (I) is such that R4 and R5 represent H.
  • the compound of formula (I) is such that Re, R7, and Rs represent H.
  • the compound of formula (I) is such that Ri represents a halogen, preferably a chlorine or a bromine, more preferably a chlorine.
  • the compound of formula (I) is such that R2 represents a 3- 14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl, said 3-14 membered ring is optionally substituted by at least one radical A selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen,
  • R 2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of: o an aryl, particularly a phenyl, said aryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyloxy, particularly a methoxy or an ethoxy, a halogen, particularly a chlorine, and a -SO 2 -(Ci-C6)alkyl, particularly a -SO 2 -CH3, o a heteroaryl, particularly a pyrimidinyl, a pyrazolyl, or a pyridinyl, said heteroaryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyl, particularly a methyl, and a (Ci-Ce)alkyloxy, particularly a methoxy, o a cycloalkyl, particularly
  • the compound of formula (I) is such that R2 represents a radical selected in a group consisting of: o a (Ci-Ce)alkyl, particularly an isobutyl, and o a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
  • the compound of the invention has the following formula selected and a pharmaceutical acceptable salt thereof.
  • a further object of the invention is a compound of formula (I) as defined herein for use as a medicine.
  • a further object of the invention is a pharmaceutical composition comprising a compound of formula (I) as defined herein and a pharmaceutically acceptable excipient.
  • a further object of the invention is a pharmaceutical composition as defined herein for use for treating a cancer.
  • the cancer is selected in a group consisting of myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, glioblastoma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal mel
  • the pharmaceutical composition comprising a compound of formula (I) as defined herein is administered at a dose ranging from 0.001 mg/kg body weight to 30 mg/kg body weight.
  • the pharmaceutical composition is administered in combination with another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and/or radiotherapy, preferably immunotherapy.
  • Ci-Ce can also be used with lower numbers of carbon atoms such as C1-C2. If, for example, the term Ci-Ce is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms.
  • alkyl refers to a saturated, linear or branched aliphatic group.
  • (Ci- C6)alkyl more specifically means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, or hexyl.
  • alkenyl refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon double bound.
  • (C2-Ce)alkenyr more specifically means ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, or hexenyl.
  • alkynyl refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon triple bound.
  • (C2-Ce)alkynyr more specifically means ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, or hexynyl
  • alkoxy or “alkyloxy” corresponds to the alkyl group as above defined bonded to the molecule by an -O- (ether) bond.
  • (Ci-Ce)alkoxy or (Ci-Ce)alkyloxy includes methoxy or methyloxy, ethoxy or ethyloxy, propoxy or propyloxy, isopropoxy or isopropyloxy, butoxy or butyloxy, isobutoxy or isobutyloxy, pentoxy or pentyloxy, isopentoxy or isopentyloxy, and hexoxy or hexyl oxy.
  • 3-14 membered ring corresponds to a ring having between 3 and 14 atoms. Such a term includes, for instance, the term “5-14 membered ring” having between 5 and 14 atoms, and the term “5-7 membered ring” having between 5 and 7 atoms.
  • the term “ring” corresponds to a mono-, bi, or tricycle, which can be saturated, partially unsaturated or unsaturated, and optionally comprises at least one heteroatom. Particularly, the term “ring” includes a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl.
  • cycloalkyl corresponds to a saturated, partially unsaturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 14, preferably between 3 and 10 atoms of carbons. It also includes fused, bridged, or spiro-connected cycloalkyl groups.
  • cycloalkyl includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl.
  • heterocycloalkyl corresponds to a saturated, partially unsaturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen (N-heterocycloalkyl), oxygen (O-heterocycloalkyl), or sulphur atom (S-heterocycloalkyl). It also includes fused, bridged, or spiro-connected heterocycloalkyl groups.
  • heterocycloalkyl groups include, but are not limited to dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl.
  • Cycloalkyl and “heterocycloalkyl” also include cycloalkenyl and heterocycloalkenyl which correspond respectively to a partially unsaturated cycloalkyl and a partially unsaturated heterocycloalkyl such as cyclohexenyl, imidazolinyl, dihydropyranyl, for instance 3,6-dihydro- 2H-pyranyl and 3,4-dihydro-2H-pyranyl, pyrazolinyl, azetinyl, pyranyl, and tetrahydropyridinyl, for instance 1,2,3-6-tetrahydropyridinyl.
  • the partially unsaturated heterocycloalkyl group is 3,6-dihydro-2H-pyranyl.
  • heteroaryl refers to an aromatic, mono- or poly-cyclic group comprising between 3 and 20 atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulphur atom.
  • heteroaryl further includes the “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl”.
  • fused arylheterocycloalkyl and fused heteroarylcycloalkyl correspond to a bicyclic group in which an aryl as above defined or a heteroaryl is respectively bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons.
  • the aryl or the heteroaryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl.
  • Examples of such mono- and poly-cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroiso
  • a fused arylheterocycloalkyl is for instance an indolinyl (phenyl fused to a pyrrolidinyl) and a dihydrobenzofuranyl (phenyl fused to a dihydrofuranyl).
  • the heteroaryl group is a pyridinyl, a pyrimidinyl, or a pyridazinyl.
  • halogen corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, chlorine or bromine.
  • substituted by at least means that the radical is substituted by one or several groups of the list.
  • a (Ci-Ce)alkyl substituted by at least one halogen, preferably a fluorine may include a fluoromethyl (-CH2F), a difluoromethyl (-CHF2), or a trifluoromethyl (-CF3).
  • the “hydrates” are compounds further comprising at least one molecule of water. For instance, if the compound comprises one molecule of water, it corresponds to a monohydrate form. If the compound comprises two molecules of water, it corresponds to a dihydrate form.
  • the “pharmaceutically salts” include inorganic as well as organic acids salts.
  • suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like.
  • suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like.
  • Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002.
  • active principle As used herein, the terms "active principle”, “active ingredient”, “active pharmaceutical ingredient”, “medicine”, and “drug” are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect.
  • the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of a cancer. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the cancer, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the cancer to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.
  • the term “pharmaceutically acceptable excipient” refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients.
  • the term “immunotherapy”, “immunotherapeutic agent” or “immunotherapy treatment” refers to a cancer therapeutic treatment using the immune system to reject cancer. The therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells.
  • tumor antigens e.g., by administering a cancer vaccine
  • the patient's own immune system is trained to recognize tumor cells as targets to be destroyed
  • administration of molecules stimulating the immune system such as cytokines
  • administration of therapeutic antibodies as drugs in which case the patient's immune system is recruited by the therapeutic antibodies to destroy tumor cells.
  • antibodies are directed against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.
  • kit defines especially a "kit of parts” in the sense that the combination partners (a) and (b), as defined in the present application can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e., simultaneously or at different time points.
  • the parts of the kit of parts can then be administered simultaneously or chronologically staggered, that is at different time points for any part of the kit of parts.
  • the ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied.
  • the combination partners (a) and (b) can be administered by the same route or by different routes.
  • the term “simultaneous” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered simultaneously, i.e., at the same time.
  • the term “sequential” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered sequentially, i.e., one after the other.
  • the active ingredients are used or administered sequentially, i.e., one after the other.
  • all the active ingredients are administered in less than about an hour, preferably less than about 10 minutes, even more preferably in less than about a minute.
  • a 3-14 membered ring saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
  • - a -CO-(Ci-C 6 )alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and R c may form together a N-heterocycloalkyl, a nitro, a cyano,
  • a -NRkRi with Rk and Ri represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rk and Ri may form a N-heterocycloalkyl,
  • n is 0 or 1. If n is 1, X is present. If n is 0, X is absent.
  • n is 1.
  • X is selected from the group consisting of -(CH2) m - with m is from 1 to 3 optionally substituted by at least one R a , -O-, -S-, -CO-, -C(O)-O-, -O-C(O)-, -NRa-, -CO-NRa-, -NR a -CO-, -SO-, -SO2-, -SO 2 -NR a , -NRa-802-, and -NRa-CO-NRa-, with R a being a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of: a (Ci-Ce)alkyloxy, a
  • - a -CO-(Ci-C 6 )alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and R c may form together a N-heterocycloalkyl, a nitro, a cyano,
  • X is selected from the group consisting of -(CH 2 ) m - with m is from 1 to 3, particularly 1, -O-, -S-, -CO-, -C(O)-O-, -O-C(O)-, -SO-, and -SO 2 -.
  • X is selected from the group consisting of -(CH 2 ) m - with m is from 1 to 3 substituted by at least one R a , -NR a -, -CO-NRa-, -NR a -CO-, -SO 2 -NR a , - NRa-SO 2 -, and -NR a -CO-NRa-, with R a being a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
  • - a -CO-(Ci-C 6 )alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and R c may form together a N-heterocycloalkyl, a nitro, a cyano,
  • R a is a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or a heterocycloalkyl.
  • R a is a (Ci-Ce)alkyl substituted by at least one radical C, a cycloalkyl substituted by at least one radical C, or a heterocycloalkyl substituted by at least one radical C; said radical C being selected in a group as defined herein.
  • R a is a hydrogen.
  • X represents -NH-, -CO-NH-, -NH-CO-, -SO2-NH-, -NH-SO2-, or -NH-CO-NH-.
  • n is 0.
  • a compound of the invention has the following formula with Ri, R2, R3, R4, Rs, Re, R7, and Rs are as defined herein.
  • R4 and Rs represent independently a radical selected in a group consisting of:
  • a compound of formula (I) is such that n is 0, and R4, Rs,
  • R a is a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or a heterocycloalkyl.
  • R a is a (Ci-Ce)alkyl substituted by at least one radical C, a cycloalkyl substituted by at least one radical C, or a heterocycloalkyl substituted by at least one radical C; said radical C being selected in a group as defined herein.
  • R a is a hydrogen.
  • X represents -NH-, -CO-NH-, -NH-CO-, -SO2-NH-, -NH-SO2-, or -NH-CO-NH-.
  • the compounds of formula (ID), (IE) or (IF) are such that Ri represents a radical selected in a group consisting of a hydrogen, a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl, a halogen, a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and a (Ci-Ce)alkyloxy optionally substituted by at least one halogen.
  • Ri represents a radical
  • Ri represent a hydrogen, a (Ci-Ce)alkyl, a halogen, or a (Ci-Ce)alkyloxy.
  • Ri represents a (Ci-Ce)alkyl or a halogen.
  • Ri is selected from the group consisting of methyl, bromine, chlorine or fluorine, preferably methyl, chlorine or bromine, more preferably chlorine or bromine, even more preferably chlorine.
  • Ri represents a cyclopropyl, an optionally substituted phenyl (e.g., phenyl substituted by -(SO2)-(Ci-Ce)alkyl, (Ci-Ce)alkyloxy, or halogen, in particular -(SO2)-methyl, methoxy or chlorine), or an optionally substituted pyrazolyl or pyrimidinyl.
  • phenyl e.g., phenyl substituted by -(SO2)-(Ci-Ce)alkyl, (Ci-Ce)alkyloxy, or halogen, in particular -(SO2)-methyl, methoxy or chlorine
  • pyrazolyl or pyrimidinyl e.g., phenyl substituted by -(SO2)-(Ci-Ce)alkyl, (Ci-Ce)alkyloxy, or halogen, in particular -(SO2)-methyl, methoxy or chlorine
  • R3 represents a hydrogen, a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl, a halogen, a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, or a (Ci-Ce)alkyloxy optionally substituted by at least one halogen.
  • R3 represents a hydrogen, a (Ci-Ce)alkyl, a halogen, a cyclopropyl, an optionally substituted phenyl, or an optionally substituted pyrazolyl or pyrimidinyl.
  • R3 is selected from the group consisting of methyl, bromine, chlorine, fluorine, a phenyl substituted by -(SO2)-(Ci-Ce)alkyl, (Ci-Ce)alkyloxy or halogen, in particular by -(SO2)-methyl, methoxy or chlorine, or an optionally substituted pyrazolyl or pyrimidinyl.
  • R3 represents H.
  • a compound of formula (IE), (IF) or (IG) is such that R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of o an aryl, particularly a phenyl, said aryl is optionally substituted by at least one radical selected in a group consisting of a (Ci-Ce)alkyloxy, particularly a methoxy or an ethoxy, a halogen, particularly a chlorine, and a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3, o a heteroaryl, particularly a pyrimidinyl, a pyrazolyl, or a pyridinyl, said heteroaryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyl, particularly a methyl, and a (Ci-Ce)alkyloxy, particularly
  • a compound of formula (IE), (IF) or (IG) is such that R2 represents a 3-14 membered ring, which is an aryl or a heteroaryl, particularly a phenyl, a pyrazolyl, and pyridinyl, said aryl or heteroaryl is optionally substituted by at least one (Ci-Ce)alkyl, particularly a methyl, one halogen, particularly chlorine, and one -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
  • a compound of formula (IE), (IF) or (IG) is such that R2 represents a radical selected in a group consisting of: o a (Ci-Ce)alkyl, particularly an isobutyl, and o a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
  • a compound of formula (IE), (IF) or (IG) is such that: Ri represents a halogen, preferably a chlorine; R3 represents a hydrogen; and R2 represents an aryl or a heteroaryl, particularly a phenyl, a pyrazolyl, and pyridinyl, said aryl or heteroaryl is optionally substituted by at least one (Ci-Ce)alkyl, particularly a methyl, one halogen, particularly chlorine, and one -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
  • a preferred compound of formula (I) or (IA) or (IB) or (IC) or (ID) or (IE) or (IF) or (IG) according to the invention has the following formula selected in a group consisting of:
  • a preferred compound of the invention is selected in a group consisting of: -N-carbamimidoyl-2-[2-chloro-6-(3-chlorophenyl)phenyl]acetamide;
  • the present invention relates to a pharmaceutical or veterinary composition
  • a pharmaceutical or veterinary composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein.
  • the pharmaceutical composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient.
  • the present invention relates to the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein as a drug or a medicine.
  • the invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein, is administered to said subj ect in need thereof.
  • the invention also relates to the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein, for the manufacture of a medicine.
  • the invention also relates to a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC),
  • the present invention also concerns:
  • composition comprising a compound of formula (I), (IA), (IB), (IC), (ID),
  • kits comprising (a) a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein; and (b) an antitumor drug as a combined preparation for simultaneous, separate or sequential use, for preventing and/or treating cancer or for use for preventing and/or treating a cancer; and/or
  • a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, and an additional antitumor drug, for the manufacture of a medicament, a medicine or a drug for the prevention and/or the treatment of a cancer; and/or
  • a method for treating a cancer, in a subject in need thereof comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound;
  • a method for treating a cancer in a subject in need thereof, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, and an additional antitumor drug, optionally with radiotherapy;
  • a method for treating a cancer in a subject in need thereof, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound; the method further comprises chemotherapy, immunotherapy, hormonotherapy and/or radiotherapy, optionally before, simultaneously and/or after surgery (e.g., tumor resection).
  • cancer refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features.
  • the cancer may be solid tumor or hematopoietic tumor.
  • cancer include, but are not limited to, solid tumors and hematological cancers, including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies.
  • solid tumors and hematological cancers including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors
  • cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, lung cancer, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, bile duct cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, melanoma, skin cancer, thyroid cancer, neuroblastoma, osteosarcoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, oesophagal cancer, colon cancer, head and neck cancer, brain cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia, mastocytosis and any
  • the cancer is chosen among of myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, glioblastoma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, nonHodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma.
  • the cancer is resistant or has a low response to immunotherapy. More specifically, the cancer can be resistant to a treatment with a checkpoint inhibitor such as an antibody against PD-1, PD-L1, CTLA-4 and the like.
  • the administration route can be topical, transdermal, oral, rectal, sublingual, intranasal, intrathecal, intratumor or parenteral (including subcutaneous, intramuscular, intravenous and/or intradermal). Preferably, the administration route is parental, oral or topical.
  • the pharmaceutical composition is adapted for one or several of the above-mentioned routes.
  • the pharmaceutical composition, kit, product or combined preparation is preferably administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal.
  • the pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets or capsules that contain solid vehicles in a way known in the art.
  • Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion.
  • Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema.
  • Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances.
  • the formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients.
  • the carrier must be "acceptable” in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
  • the pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature.
  • compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration.
  • the treatment with the compound according to the invention or the pharmaceutical composition according to the invention starts no longer than a month, preferably no longer than a week, after the diagnosis of the disease.
  • the treatment starts the day of the diagnosis.
  • the compound according to the invention or the pharmaceutical composition according to the invention may be administered as a single dose or in multiple doses.
  • the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day.
  • the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day.
  • the duration of treatment with the compound according to the invention or the pharmaceutical composition according to the invention is preferably comprised between 1 day and 50 weeks, more preferably between 1 day and 30 weeks, still more preferably between 1 day and 15 weeks, even more preferably between 1 day and 10 weeks. In a particular embodiment, the duration of the treatment is of about 1 week. Alternatively, the treatment may last as long as the disease persists.
  • the amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient. In a particular embodiment, is administered at a dose ranging from 0.001 mg/kg body weight to 30 mg/kg body weight.
  • the compound of the invention can be used in combination with another antitumor drug or antineoplastic agent.
  • the additional antitumor drug can be selected in the non-exhaustive list of antitumor agents consisting of an inhibitor of topoisomerases I or II, an anti-mitotic agent, a DNA alkylating agent, an agent causing crosslinking of DNA, an anti-metabolic agent, a targeted agent such as a kinase inhibitor, a histone deacetylase inhibitor and an anti-EGFR agent and/or a therapeutical antibody designed to mediate cytotoxicity against the cancer cells or to modulate one of their key biological functions.
  • antitumor agents consisting of an inhibitor of topoisomerases I or II, an anti-mitotic agent, a DNA alkylating agent, an agent causing crosslinking of DNA, an anti-metabolic agent, a targeted agent such as a kinase inhibitor, a histone deacetylase inhibitor and an anti-EGFR agent and/or a therapeutical antibody designed to mediate cytotoxicity against the cancer cells or to modulate one of their key biological functions
  • Antimitotic agents include, but are not limited to, paclitaxel, docetaxel and analogs such as larotaxel (also called XRP9881; Sanofi-Aventis), XRP6258 (Sanofi-Aventis), BMS-184476 (Bristol-Meyer-Squibb), BMS-188797 (Bristol -Meyer- Squibb), BMS-275183 (Bristol -Meyer- Squibb), ortataxel (also called IDN 5109, BAY 59-8862 or SB-T-101131; Bristol-Meyer- Squibb), RPR 109881 A (Bristol-Meyer-Squibb), RPR 116258 (Bristol-Meyer-Squibb), NBT- 287 (TAPESTRY), PG-paclitaxel (also called CT-2103, PPX, paclitaxel poliglumex, paclitaxel polyglutamate or Xyo
  • Inhibitors of topoisomerases I and/or II include, but are not limited to etoposide, topotecan, camptothecin, irinotecan, amsacrine, intoplicin, anthracyclines such as doxorubicin, epirubicin, daunorubicin, idarubicin and mitoxantrone.
  • Inhibitors of topoisomerase I and II include, but are not limited to intoplicin.
  • the additional antitumor agent can be alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes.
  • alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes.
  • Non-exhaustive examples thereof include uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, cisplatin, carboplatin, fotemustine, oxaliplatin, thiotepa, streptozocin, dacarbazine, and temozolomide.
  • Anti-metabolic agents block the enzymes responsible for nucleic acid synthesis or become incorporated into DNA, which produces an incorrect genetic code and leads to apoptosis.
  • Non- exhaustive examples thereof include, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, and more particularly methotrexate, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, 5-fluorouracil, gemcitabine and capecitabine.
  • such an agent is gemcitabine.
  • the additional anti-tumor agent can also be a targeted agent, in particular a kinase inhibitor.
  • the kinase may be selected from the group consisting of intracellular tyrosine or serine/threonine kinases, receptors tyrosine or serine/threonine kinase.
  • the kinase could be selected among EGFR family, ALK, B-Raf, MEK, and mTOR.
  • the agents may have ability to inhibit angiogenesis based on the inhibitory activities on VEGFR and PDGFR kinases.
  • the targeted agent can be selected among the multiple kinase inhibitor drugs which are already approved: Gleevec®, which inhibits Bcr-Abl and c-Kit, and Iressa® and Tarceva®, which both inhibit EGFR, sorafenib (Nexavar®, BAY 43-9006) which inhibits Raf, dasatinib (BMS-354825) and nilotinib (AMN-107, Tasigna®) which also inhibits Bcr-Abl, lapatinib which also inhibits EGFR, temsirolimus (Torisel®, CCI-779) which targets the mTOR pathway, sunitinib (Student®, SU11248) which inhibits several targets including VEGFR as well as specific antibodies inactivating kinase receptors: Herceptin® and Avastin®.
  • Gleevec® which inhibits Bcr-Abl and c-Kit
  • the anti- EGFR agent can be selected among gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, clawartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS 1421373-98-9), poziotinib, WZ4002, preferably is erlotinib or cetuximab.
  • the ALK inhibitor can be selected among crizotinib, entrectinib, ceritinib, alectinib, brigatinib, lorlatinib, TSR-011, CEP-37440, and ensartinib.
  • the B-Raf inhibitor can be selected among vemurafenib, dabrafenib, regorafenib, and PLX4720.
  • the MEK inhibitor can be selected among cobimetinib, trametinib, binimetinib, selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733.
  • the antitumor agent can be IDO1 inhibitors such as epacadostat.
  • therapy refers to any type of treatment of cancer (i.e., antitumor therapy), including an adjuvant therapy and a neoadjuvant therapy.
  • Therapy comprises radiotherapy and therapies, preferably systemic therapies such as hormone therapy, chemotherapy, immunotherapy and monoclonal antibody therapy.
  • adjuvant therapy refers to any type of treatment of cancer given as additional treatment, usually after surgical resection of the primary tumor, in a patient affected with a cancer that is at risk of metastasizing and/or likely to recur.
  • adjuvant therapies comprise radiotherapy and therapy, preferably systemic therapy, such as hormone therapy, chemotherapy, immunotherapy and monoclonal antibody therapy.
  • hormone therapy or “hormonal therapy” or “hormonotherapy” refers to a cancer treatment having for purpose to block, add or remove hormones.
  • hormone therapy is given to block estrogen and a non-exhaustive list commonly used drugs includes: tamoxifen, toremifene, anastrozole, exemestane, letrozole, goserelin, leuprolide, megestrol acetate, and fluoxymesterone.
  • chemotherapeutic treatment or “chemotherapy” refers to a cancer therapeutic treatment using chemical or biological substances, in particular using one or several antineoplastic agents.
  • radiotherapeutic treatment or “radiotherapy” is a term commonly used in the art to refer to multiple types of radiation therapy including internal and external radiation therapies or radioimmunotherapy, and the use of various types of radiations including X-rays, gamma rays, alpha particles, beta particles, photons, electrons, neutrons, radioisotopes, and other forms of ionizing radiations.
  • therapeutic antibody refers to any antibody having an anti-tumoral effect.
  • the therapeutical antibody is a monoclonal antibody.
  • Therapeutic antibodies are generally specific for surface antigens, e.g., membrane antigens.
  • Most preferred therapeutic antibodies are specific for tumor antigens (e.g., molecules specifically expressed by tumor cells), such as CD20, CD52, ErbB2 (or HER2/Neu), CD33, CD22, CD25, MUC-1, CEA, KDR, aVb3, and the like.
  • the therapeutical antibody includes, but is not limited to, antibodies such as trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), alemtuzumab, gemtuzamab, cetuximab, pertuzumab, epratuzumab, basiliximab, daclizumab, labetuzumab, sevirumab, tuvurimab, palivizumab, infliximab, omalizumab, efalizumab, natalizumab, clenoliximab, and bevacizumab.
  • antibodies such as trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), alemtuzumab, gemtuzamab, cetuximab, pertuzumab, epratuzumab, basiliximab, daclizumab, labetuzuma
  • the antitumor agent can be an immunomodulator.
  • the immunomodulator can be a cancer vaccine, molecules stimulating the immune system such as cytokines, therapeutic antibodies, preferably monoclonal antibodies, in particular antibodies directed against antigens specifically presented or overexpressed at the membrane of tumor cells or directed against cell receptors which blockade prevent tumor growth, adoptive T-cell therapy, immune checkpoint inhibitor treatment, and any combination thereof.
  • the immunomodulator can be:
  • an immune checkpoint inhibitor preferably an inhibitor of of PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand), PD-L2, CTLA-4 (cytotoxic T lymphocyte associated protein 4), TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), LAG-3 (Lymphocyte-activation gene 3), NKG2D, NKG2L, KIR, VISTA, BTLA (B- and T-lymphocyte attenuator), or TIGIT (T cell immunoreceptor with Ig and ITIM domains), , especially an antibody directed against an anti-CTLA-4 such as ipilimumab, an antibody directed against PD-1 such as nivolumab, pembrolizumab, or BGB-A317, an antibody directed against PDL1 such as atezolizumab, avelumab, or durvalumab, an antibody directed against LAG-3 such as BMS-986016, an antibody directed against PD-1
  • an activator of a costimulatory molecule in particular an agonist of 0X40, CD2, CD27, CDS, ICAM-1, LFA-1 (CDl la/CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD 160, B7-H3 or CD83 ligand;
  • the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB- A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP -224 (Amplimmune).
  • the anti-PDl antibody can be selected from the group consisting of Pembrolizumab (also known as Keytruda lambrolizumab, MK-3475), Nivolumab (Opdivo, MDX-1106, BMS-936558, ONO-4538), Pidilizumab (CT-011), Cemiplimab (Libtayo), Camrelizumab, AUNP12, AMP-224, AGEN-2034, BGB-A317 (Tisleizumab), PDR001 (spartalizumab), MK-3477, SCH-900475, PF-06801591, JNJ-63723283, genolimzumab (CBT- 501), LZM-009, BCD-100, SHR-1201, BAT-1306, AK-103 (HX-008), MEDL0680 (also known as AMP-514) MED
  • BI-754091 CBT-501, INCSHR1210 (also known as SHR-1210), TSR-042 (also known as ANB011), GLS-010 (also known as WBP3055), AM-0001 (Armo), STI-1110 (see WO 2014/194302), AGEN2034 (see WO 2017/040790), MGA012 (see WO 2017/19846), or IBI308 (see WO 2017/024465, WO 2017/025016, WO 2017/132825, and WO 2017/133540), monoclonal antibodies 5C4, 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, described in WO 2006/121168.
  • Bifunctional or bispecific molecules targeting PD-1 are also known such as RG7769 (Roche), XmAb20717 (Xencor), MEDI5752 (AstraZeneca), FS118 (F-star), SL- 279252 (Takeda) and XmAb23104 (Xencor).
  • Antibodies directed against CTLA-4 and bifunctional or bispecific molecules targeting CTLA- 4 are also known such as ipilimumab, tremelimumab, MK-1308, AGEN-1884, XmAb20717 (Xencor), MEDI5752 (AstraZeneca).
  • Antibodies directed against TIGIT are also known in the art, such as BMS-986207 or AB 154, BMS-986207 CPA.9.086, CHA.9.547.18, CPA.9.018, CPA.9.027, CPA.9.049, CPA.9.057, CPA.9.059, CPA.9.083, CPA.9.089, CPA.9.093, CPA.9.101, CPA.9.103, CHA.9.536.1, CHAN.536.3, CHA.9.536.4, CHA.9.536.5, CHA.9.536.6, CHA.9.536.7, CHA.9.536.8,
  • Anti-TIGIT antibodies are also disclosed in WO 16028656, W016106302, WO16191643, W017030823, W017037707, WO17053748, WO17152088, WO18033798, WO18102536, WO18102746, W018160704, W018200430, WO18204363, W019023504, WO19062832, WO19129221, WO19129261, WO19137548, WO19152574, WO19154415, WO19168382 and WO19215728.
  • the LAG-3 inhibitor can be selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro).
  • Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839, which are incorporated herein by reference in their entirety.
  • the TIM-3 inhibitor can be MGB453 (Novartis) or TSR-022 (Tesaro).
  • Further known anti- TIM-3 antibodies include those described, e.g., in WO 2016/1 1 1947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US 9,163,087, which are incorporated herein by reference in their entirety.
  • the immunotherapy is selected from the group consisting of ipilimumab, nivolumab, BGB-A317, pembrolizumab, atezolizumab, avelumab, or durvalumab, BMS-986016, and epacadostat, or any combination thereof.
  • Apparatus Waters HClass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa; Column: Waters ACQUITY UPLC® CSH C18, 1.7 pm, 2.1 x 30 mm at 40 °C; Detection: UV at 210- 400 nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Formic in water / MeCN 98/2 to 0/100 over 2.5 minutes. Flow rate 0.77 mL/Min.
  • Apparatus Waters HClass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa; Column: Waters ACQUITY UPLC® BEH C18, 1.7 pm, 2.1 x 30 mm at 40 °C; Detection: UV at 210- 400 nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Ammonia in water / MeCN 98/2 to 0/100 over 2.5 minutes. Flow rate 0.77 mL/Min.
  • Apparatus Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:, G6150 MSD; Column: Waters Cortecs Cl 8, 30 x 2.1 mm, 2.7pm, at 40 °C; Detection: UV at 260nm +/- 90nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Formic in water / MeCN 98/2 to 0/100 over 2.5 minutes. Flow rate 1.35 mL/Min.
  • Apparatus Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:, G6150 MSD; Column: Phenomenex Evo Cl 8, 30 x 2.1 mm, 2.6pm, at 40 °C; Detection: UV at
  • NMR spectra were recorded using a Bruker 400MHz Avance Neo spectrometer fitted with a Bruker 5mm iProbe, or a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbeTM. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software. Abbreviations for multiplicities observed in NMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br (broad).
  • Solvents, reagents and starting materials were purchased and used as received from commercial vendors unless otherwise specified.

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Abstract

The present invention relates to guanfacine derivatives of formula (I), and the isomers and pharmaceutical acceptable salts thereof. The invention further relates to pharmaceutical compositions comprising such compounds of formula (I) and their use for treating a cancer.

Description

GUANFACINE DERIVATIVES AND THEIR USE IN TREATING CANCER
FIELD OF THE INVENTION
The present invention relates to the field of medicine, in particular guanfacine derivatives and their uses for treating diseases. More particularly, the invention provides alpha2-adrenergic receptor (a.2-AR) agonists for the treatment of cancer.
BACKGROUND OF THE INVENTION
Cancer is the second leading cause of death worldwide. Indeed, nearly 1 in 6 deaths is due to cancer. The prevalence of cancer is also extremely high as more than 15 million new cases are diagnosed each year, and the number of new cases is expected to rise by about 70% over the next 2 decades. Among the most common cancers, lung cancers account for 1.69 million deaths per year, colorectal cancer for 774 000 deaths per year, and breast cancer for 571 000 deaths per year. Many treatment options exist nowadays for cancer, including for example surgery, chemotherapy, radiation therapy, hormonal therapy, targeted therapy, immunotherapy and palliative care. The choice of the best treatments depends on the type, location and grade of the cancer as well as the patient's health and preferences.
The a2-AR are a family of G-protein-coupled receptors with 3 pharmacological subtypes, a2A, a2B, and a2C. They have been used for decades to treat common medical conditions such as hypertension; attention-deficit/hyperactivity disorder; various pain and panic disorders; symptoms of opioid, and alcohol withdrawal; and for sedation and to reduce anesthetic requirements. Centrally acting alpha2-adrenergic receptors agonists stimulate a2-AR in the central nervous system (brain and spinal cord). When a2-AR are stimulated, sympathetic nervous system activity decreases. This decreased sympathetic activity leads to a drop in blood pressure and heart rate.
WO 2021/214129 and J. Zhu, et al. (Nature, 618, 607-615 (2023)) have currently shown that agonists of a2-AR, such as Guanabenz, Clonidine or Guanfacine, have surprisingly strong antitumor activity when used as monotherapies in multiple immunocompetent murine tumor models, including ICB-resistant models, but not in immunodeficient models. It was also observed striking effects in human tumor xenografts implanted in mice reconstituted with human peripheral blood mononuclear cells. The anti-tumor effects of a2-AR agonists were reverted by a2-AR antagonists, and were absent in a2-AR knockout mice, demonstrating on- target action exerted on host cells, not tumor cells. Tumors from treated mice contained increased infiltrating CD8+ T lymphocytes and reduced infiltrating myeloid-derived suppressor cells (MDSC), which were more apoptotic. Single-cell RNA sequencing revealed upregulation of innate and adaptive immune response pathways in macrophages and T cells.
Consequently, the discovery and the synthesis of new a2-AR agonists are relevant and promising approaches for anti-cancer therapies. More particularly, it could significantly improve clinical efficacy of cancer immunotherapy. However, many of the effects of centrally active a2-AR agonists are mediated by decreasing sympathetic activity and lead to side hypotensive and sedative effects that could be harmful to patients and/or limit the dose of a2- AR agonists that could be safely administered to patients, thereby potentially limiting the therapeutic anti-cancer benefit.
Therefore, there remains a need to identify further a2-AR agonists having an efficient effect on a2-AR while limited CNS penetrance. The development of new peripherally restricted a2-AR agonists could be of interest as anti-cancer therapies and, more specifically anti-cancer immunotherapies. The present invention seeks to meet these and other needs.
SUMMARY OF THE INVENTION
In this context, the inventors have provided new guanfacine derivatives as efficient a2-AR agonists while being not efficient in penetrating the BBB, demonstrating thereby the therapeutic interest of such derivatives in medicine, more particularly in anti-cancer therapies.
The present invention thus provides new compounds of formula (I):
Figure imgf000003_0001
wherein: Ri represents a radical selected in a group consisting of:
• a hydrogen,
• a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl,
• a halogen,
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
• a (Ci-Ce)alkyloxy optionally substituted by at least one halogen; X is selected from the group consisting of -(CH2)m- with m is from 1 to 3 optionally substituted by at least one Ra, -O-, -S-, -CO-, -C(O)-O-, -O-C(O)-, -NRa-, -CO-NRa-, - NRa-CO-, -SO-, -SO2-, -SO2-NRa, -NRa-SO2-, and -NRa-CO-NRa-, with Ra being a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and Rc may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl, a -CO-NH-cycloalkyl, - a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a - NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl; n is 0 or 1; R2 represents a radical selected in a group consisting of:
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl, said 3-14 membered ring is optionally substituted by at least one radical A selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, or a hydroxy, a cycloalkyl optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a hydroxy, a (C2-Ce)alkenyl, a (C2-Ce)alkynyl, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen, a cyano, a -NRaRe with Rd and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rd and Re may form together a N-heterocycloalkyl, a nitro, a hydroxy, a ketone,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a - NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a - NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl,
- a -C(O)-O-(Ci-C6)alkyl, a -O-C(O)-(Ci-C6)alkyl, a - COOH, a -C(O)-O-cycloalkyl, -O-C(O)-cycloalkyl, a -CO-(Ci-Ce)alkyl, a -CO-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl, and • a radical selected in a group consisting of: o a (Ci-Ce)alkyl optionally substituted by at least one radical B or a cycloalkyl optionally substituted by at least one radical B, o a (C2-Ce)alkenyl optionally substituted by at least one radical B, o a (C2-Ce)alkynyl optionally substituted by at least one radical B, o a (Ci-Ce)alkyloxy optionally substituted by at least one radical B, o a cyano, o a -NRfRg’ with Rf and Rg’, represent independently a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg’ may form together a N-heterocycloalkyl, and o a -N(Rf)-CO-Rg, a-CO-N(Rf)-Rg, a -CO-Rf, a -C(O)-O-Rf, a -O- C(O)-Rf, a -SO2-Rf, a -SO-Rf, a -SO2-N(Rf)-Rg, a -N(Rf)-SO2-Rg, and a -N(Rh)-CO-NRfRg, with Rf, Rg, and Rh represent independently a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg may form together a N- heterocycloalkyl, said radical B being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRiRj with Ri and Rj represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Ri and Rj may form together a N-heterocycloalkyl, a nitro, a cyano, - a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl; -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a -NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl; R3 represents a radical selected in a group consisting of:
• a hydrogen,
• a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl,
• a halogen,
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
• a (Ci-Ce)alkyloxy optionally substituted by at least one halogen; R4 represents a radical selected in a group consisting of:
• a hydrogen,
• a halogen,
• a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a (Ci-Ce)alkyloxy optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a hydroxy,
• a -NRkRi with Rk and Ri represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rk and Ri may form a N-heterocycloalkyl,
• a nitro,
• a cyano,
• a -NH-(Ci-Ce)alkyl, a -NH-cycloalkyl; and
• a -NH-CO-(Ci-Ce)alkyl, and a -NH-CO-cycloalkyl; Rs represents a radical selected in a group consisting of:
• a hydrogen,
• a halogen, • a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a (Ci-Ce)alkyloxy optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a hydroxy,
• a -NRkRi with Rk and Ri represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rk and Ri may form a N-heterocycloalkyl,
• a nitro,
• a cyano,
• a -NH-(Ci-Ce)alkyl, a -NH-cycloalkyl; and
• a -NH-CO-(Ci-Ce)alkyl, and a -NH-CO-cycloalkyl; Re represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; R? represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; and Rs represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; or R? and Rs may form together a 5-7 membered ring, partially unsaturated or saturated, N,N’ -heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (Ci-Ce)alkyl, a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, a - N((Ci-Ce)alkyl)2, and a ketone; and the isomers, stereoisomers and pharmaceutical acceptable salts thereof with the proviso that the compound is not a compound selected in the group consisting of:
7V-(Aminoiminomethyl)-2-methoxybenzeneacetamide,
A-(Aminoiminomethyl)-2,4-dimethoxybenzeneacetamide, and A-(Aminoiminomethyl)-2,4-dimethylbenzeneacetamide.
In a particular embodiment, the compound of formula (I) is such that n is 0. In a further particular embodiment, the compound of formula (I) is such that R4 and R5 represent H.
In a further particular embodiment, the compound of formula (I) is such that Re, R7, and Rs represent H.
In a further particular embodiment, the compound of formula (I) is such that R3 represents H.
In a further particular embodiment, the compound of formula (I) is such that Ri represents a halogen, preferably a chlorine or a bromine, more preferably a chlorine.
In a further particular embodiment, the compound of formula (I) is such that R2 represents a 3- 14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl, said 3-14 membered ring is optionally substituted by at least one radical A selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen,
- a -CO-(Ci-C6)alkyl, and
- a -SO2-(Ci-C6)alkyl.
Particularly, R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of: o an aryl, particularly a phenyl, said aryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyloxy, particularly a methoxy or an ethoxy, a halogen, particularly a chlorine, and a -SO2-(Ci-C6)alkyl, particularly a -SO2-CH3, o a heteroaryl, particularly a pyrimidinyl, a pyrazolyl, or a pyridinyl, said heteroaryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyl, particularly a methyl, and a (Ci-Ce)alkyloxy, particularly a methoxy, o a cycloalkyl, particularly a cyclopropyl, and o a heterocycloalkyl, particularly a 3,6-dihydro-2H-pyran, a piperazinyl, or a morpholinyl, said heterocycloalkyl is optionally substituted by a - CO-(Ci-Ce)alkyl, particularly a -CO-CH3. In a further particular embodiment, the compound of formula (I) is such that R2 represents a radical selected in a group consisting of: o a (Ci-Ce)alkyl, particularly an isobutyl, and o a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3. In a particular embodiment, the compound of the invention has the following formula selected
Figure imgf000010_0001
and a pharmaceutical acceptable salt thereof. A further object of the invention is a compound of formula (I) as defined herein for use as a medicine. A further object of the invention is a pharmaceutical composition comprising a compound of formula (I) as defined herein and a pharmaceutically acceptable excipient.
A further object of the invention is a pharmaceutical composition as defined herein for use for treating a cancer. Preferably, the cancer is selected in a group consisting of myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, glioblastoma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma.
In a particular embodiment, the pharmaceutical composition comprising a compound of formula (I) as defined herein is administered at a dose ranging from 0.001 mg/kg body weight to 30 mg/kg body weight.
In a further particular embodiment, the pharmaceutical composition is administered in combination with another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and/or radiotherapy, preferably immunotherapy.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
According to the present invention, the terms below have the following meanings:
The terms mentioned herein with prefixes such as for example Ci-Ce, can also be used with lower numbers of carbon atoms such as C1-C2. If, for example, the term Ci-Ce is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 6 carbon atoms, especially 1, 2, 3, 4, 5, or 6 carbon atoms. If, for example, the term C1-C3 is used, it means that the corresponding hydrocarbon chain may comprise from 1 to 3 carbon atoms, especially 1, 2, or 3 carbon atoms. The term “alkyl” refers to a saturated, linear or branched aliphatic group. The term “(Ci- C6)alkyl” more specifically means methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, or hexyl.
The term “alkenyl” refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon double bound. The term “(C2-Ce)alkenyr more specifically means ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, or hexenyl.
The term “alkynyl” refers to an unsaturated, linear or branched aliphatic group comprising at least one carbon-carbon triple bound. The term “(C2-Ce)alkynyr more specifically means ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, pentynyl, or hexynyl
The term “alkoxy” or “alkyloxy” corresponds to the alkyl group as above defined bonded to the molecule by an -O- (ether) bond. (Ci-Ce)alkoxy or (Ci-Ce)alkyloxy includes methoxy or methyloxy, ethoxy or ethyloxy, propoxy or propyloxy, isopropoxy or isopropyloxy, butoxy or butyloxy, isobutoxy or isobutyloxy, pentoxy or pentyloxy, isopentoxy or isopentyloxy, and hexoxy or hexyl oxy.
The term “3-14 membered ring” corresponds to a ring having between 3 and 14 atoms. Such a term includes, for instance, the term “5-14 membered ring” having between 5 and 14 atoms, and the term “5-7 membered ring” having between 5 and 7 atoms. The term “ring” corresponds to a mono-, bi, or tricycle, which can be saturated, partially unsaturated or unsaturated, and optionally comprises at least one heteroatom. Particularly, the term “ring” includes a cycloalkyl, a heterocycloalkyl, an aryl, and a heteroaryl.
The term “cycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated mono-, bi- or tri-cyclic alkyl group comprising between 3 and 14, preferably between 3 and 10 atoms of carbons. It also includes fused, bridged, or spiro-connected cycloalkyl groups. The term “cycloalkyl” includes for instance cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl.
The term “heterocycloalkyl” corresponds to a saturated, partially unsaturated or unsaturated cycloalkyl group as above defined further comprising at least one heteroatom such as nitrogen (N-heterocycloalkyl), oxygen (O-heterocycloalkyl), or sulphur atom (S-heterocycloalkyl). It also includes fused, bridged, or spiro-connected heterocycloalkyl groups. Representative heterocycloalkyl groups include, but are not limited to dioxolanyl, benzo [1,3] dioxolyl, azetidinyl, oxetanyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1,4-dioxanyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1,4-dithianyl, pyrrolidinyl, oxozolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophenyl. In a particular embodiment, the heterocycloalkyl group is piperazinyl, or morpholinyl.
"Cycloalkyl" and "heterocycloalkyl" also include cycloalkenyl and heterocycloalkenyl which correspond respectively to a partially unsaturated cycloalkyl and a partially unsaturated heterocycloalkyl such as cyclohexenyl, imidazolinyl, dihydropyranyl, for instance 3,6-dihydro- 2H-pyranyl and 3,4-dihydro-2H-pyranyl, pyrazolinyl, azetinyl, pyranyl, and tetrahydropyridinyl, for instance 1,2,3-6-tetrahydropyridinyl. In a particular embodiment, the partially unsaturated heterocycloalkyl group is 3,6-dihydro-2H-pyranyl.
The term “aryl” corresponds to a mono- or bi-cyclic aromatic hydrocarbons having from 6 to 12 carbon atoms. For instance, the term “aryl” includes phenyl, biphenyl, naphthyl and anthracenyl. In a particular embodiment, the aryl is a phenyl.
The term “heteroaryl” as used herein corresponds to an aromatic, mono- or poly-cyclic group comprising between 3 and 20 atoms and comprising at least one heteroatom such as nitrogen, oxygen or sulphur atom. As used herein, the term “heteroaryl” further includes the “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl”. The terms “fused arylheterocycloalkyl” and “fused heteroarylcycloalkyl” correspond to a bicyclic group in which an aryl as above defined or a heteroaryl is respectively bounded to the heterocycloalkyl or the cycloalkyl as above defined by at least two carbons. In other terms, the aryl or the heteroaryl shares a carbon bond with the heterocycloalkyl or the cycloalkyl. Examples of such mono- and poly-cyclic heteroaryl group, fused arylheterocycloalkyl and fused arylcycloalkyl may be: pyridinyl, thiophenyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, furazanyl, thiadiazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolinyl, indanyl, quinolinyl, isoquinolinyl, benzimidazolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, triazinyl, thianthrenyl, benzofuranyl, dihydrobenzofuranyl, isobenzofuranyl, benzothiophenyl, isobenzothiophenyl, chromenyl, xanthenyl, phenoxanthinyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, indazolyl, purinyl, quinolizinyl, phtalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, P-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, indolinyl, isoindolinyl, oxazolidinyl, benzotri azolyl, benzoisoxazolyl, oxindolyl, benzoxazolyl, benzoxazolinyl, benzoxazinyl, benzothienyl, benzothiazolyl, benzodiazepinyl, benzazepinyl, benzoxazepinyl, isatinyl, dihydrobenzodi oxepinyl, dihydropyridyl, pyrimidinyl, s-triazinyl, oxazolyl, or thiofuranyl. A fused arylheterocycloalkyl is for instance an indolinyl (phenyl fused to a pyrrolidinyl) and a dihydrobenzofuranyl (phenyl fused to a dihydrofuranyl). In a particular aspect, the heteroaryl group is a pyridinyl, a pyrimidinyl, or a pyridazinyl.
The term “halogen” corresponds to a fluorine, chlorine, bromine, or iodine atom, preferably a fluorine, chlorine or bromine.
The expression “substituted by at least” means that the radical is substituted by one or several groups of the list. For instance, the expression “a (Ci-Ce)alkyl substituted by at least one halogen, preferably a fluorine” may include a fluoromethyl (-CH2F), a difluoromethyl (-CHF2), or a trifluoromethyl (-CF3).
The expression “optionally substituted” means that the radical is not substituted or substituted by one or several groups of the list.
The “stereoisomers” are isomeric compounds that have the same molecular formula and sequence of bonded atoms, but differ in the 3D-dimensional orientations of their atoms in space. The stereoisomers include enantiomers, diastereoisomers, cis-trans and E-Z isomers, conformers, and anomers. In a particular embodiment of the invention, the stereoisomers include diastereoisomers and enantiomers.
The “tautomers” are isomeric compounds that differ only in the position of the protons and the electrons.
The “hydrates” are compounds further comprising at least one molecule of water. For instance, if the compound comprises one molecule of water, it corresponds to a monohydrate form. If the compound comprises two molecules of water, it corresponds to a dihydrate form.
The “pharmaceutically salts” include inorganic as well as organic acids salts. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, maleic, methanesulfonic and the like. Further examples of pharmaceutically inorganic or organic acid addition salts include the pharmaceutically salts listed in J. Pharm. Sci. 1977, 66, 2, and in Handbook of Pharmaceutical Salts: Properties, Selection, and Use edited by P. Heinrich Stahl and Camille G. Wermuth 2002. In a particular embodiment, the salt is selected from the group consisting of maleate, chlorhydrate, bromhydrate, and methanesulfonate. The “pharmaceutically salts” also include inorganic as well as organic base salts. Representative examples of suitable inorganic bases include sodium or potassium salt, an alkaline earth metal salt, such as a calcium or magnesium salt, or an ammonium salt.
As used herein, the terms “treatment”, “treat” or “treating” refer to any act intended to ameliorate the health status of patients such as therapy, prevention, prophylaxis and retardation of a disease, in particular a cancer. In certain embodiments, such terms refer to the amelioration or eradication of the disease, or symptoms associated with it. In other embodiments, this term refers to minimizing the spread or worsening of the disease, resulting from the administration of one or more therapeutic agents to a subject with such a disease. In particular, such terms refer to decreased development of tumors, decreased tumor burden, tumor regression, and/or prevention or delay of metastasis occurrence and cancer relapse.
As used herein, the terms “subject”, “individual” or “patient” are interchangeable and refer to a mammal, even more preferably to a human, including adult, child, newborn and human at the prenatal stage. However, the term "subject" can also refer to non-human animals, in particular mammals such as dogs, cats, horses, cows, pigs, sheep and non-human primates, among others. In a particular embodiment, the subject is resistant to any other anticancer treatment. Optionally, the subject is a chemoresistant subject. In a particular aspect, the subject is resistant to immunotherapy. In other words, the cancer is immune-resistant.
The terms “quantity,” “amount,” and “dose” are used interchangeably herein and may refer to an absolute quantification of a molecule.
As used herein, the terms "active principle", "active ingredient", "active pharmaceutical ingredient", “medicine”, and “drug” are equivalent and refers to a component of a pharmaceutical composition having a therapeutic effect.
As used herein, the term “therapeutic effect” refers to an effect induced by an active ingredient, or a pharmaceutical composition according to the invention, capable to prevent or to delay the appearance or development of a cancer, or to cure or to attenuate the effects of a cancer.
As used herein, the term “effective amount” refers to a quantity of an active ingredient or of a pharmaceutical composition which prevents, removes or reduces the deleterious effects of a cancer. It is obvious that the quantity to be administered can be adapted by the man skilled in the art according to the subject to be treated, to the nature of the cancer, etc. In particular, doses and regimen of administration may be function of the nature, of the stage and of the severity of the cancer to be treated, as well as of the weight, the age and the global health of the subject to be treated, as well as of the judgment of the doctor.
As used herein, the term "pharmaceutically acceptable excipient" refers to any ingredient except active ingredients which are present in a pharmaceutical composition. Its addition may be aimed to confer a particular consistency or other physical or gustative properties to the final product. A pharmaceutically acceptable excipient must be devoid of any interaction, in particular chemical, with the active ingredients. As used herein, the term “immunotherapy”, “immunotherapeutic agent” or “immunotherapy treatment” refers to a cancer therapeutic treatment using the immune system to reject cancer. The therapeutic treatment stimulates the patient's immune system to attack the malignant tumor cells. It includes immunization of the patient with tumor antigens (e.g., by administering a cancer vaccine), in which case the patient's own immune system is trained to recognize tumor cells as targets to be destroyed, or administration of molecules stimulating the immune system such as cytokines, or administration of therapeutic antibodies as drugs, in which case the patient's immune system is recruited by the therapeutic antibodies to destroy tumor cells. In particular, antibodies are directed against specific antigens such as the unusual antigens that are presented on the surfaces of tumors.
The terms “kit”, “product” or "combined preparation", as used herein, defines especially a "kit of parts" in the sense that the combination partners (a) and (b), as defined in the present application can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners (a) and (b), i.e., simultaneously or at different time points. The parts of the kit of parts can then be administered simultaneously or chronologically staggered, that is at different time points for any part of the kit of parts. The ratio of the total amounts of the combination partner (a) to the combination partner (b) to be administered in the combined preparation can be varied. The combination partners (a) and (b) can be administered by the same route or by different routes.
As used herein, the term “simultaneous” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered simultaneously, i.e., at the same time.
As used herein, the term “sequential” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered sequentially, i.e., one after the other. Preferably, when the administration is sequential, all the active ingredients are administered in less than about an hour, preferably less than about 10 minutes, even more preferably in less than about a minute.
As used herein, the term “separate” refers to a pharmaceutical composition, a kit, a product or a combined preparation according to the invention in which the active ingredients are used or administered at distinct time of the day. Preferably, when the administration is separate, the active ingredients are administered with an interval of about 1 hour to about 24 hours, preferably with an interval of about 1 hour and 15 hours, more preferably with an interval of about 1 hour and 8 hours, even more preferably with an interval of about 1 hour and 4 hours. The present invention provides new compounds of the following formula (I), including isomers and pharmaceutical acceptable salts thereof, of therapeutic interest.
According to the invention, a compound has the following formula (I):
Figure imgf000017_0001
wherein: Ri represents a radical selected in a group consisting of:
• a hydrogen,
• a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl,
• a halogen,
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
• a (Ci-Ce)alkyloxy optionally substituted by at least one halogen; X is selected from the group consisting of -(CH2)m- with m is from 1 to 3 optionally substituted by at least one Ra, -O-, -S-, -CO-, -C(O)-O-, -O-C(O)-, -NRa-, -CO-NRa-, - NRa-CO-, -SO-, -SO2-, -SO2-NRa, -NRa-S02-, and -NRa-CO-NRa-, with Ra being a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and Rc may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a -
NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl; n is 0 or 1; R2 represents a radical selected in a group consisting of:
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl, said 3-14 membered ring is optionally substituted by at least one radical A selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, or a hydroxy, a cycloalkyl optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a hydroxy, a (C2-Ce)alkenyl, a (C2-Ce)alkynyl, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen, a cyano, a -NRaRe with Rd and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rd and Re may form together a N-heterocycloalkyl, a nitro, a hydroxy, a ketone,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a - NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a - NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl,
- a -C(O)-O-(Ci-C6)alkyl, a -O-C(O)-(Ci-C6)alkyl, a - COOH, a -C(O)-O-cycloalkyl, -O-C(O)-cycloalkyl, a -CO-(Ci-Ce)alkyl, a -CO-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl, and
• a radical selected in a group consisting of: o a (Ci-Ce)alkyl optionally substituted by at least one radical B or a cycloalkyl optionally substituted by at least one radical B, o a (C2-Ce)alkenyl optionally substituted by at least one radical B, o a (C2-Ce)alkynyl optionally substituted by at least one radical B, o a (Ci-Ce)alkyloxy optionally substituted by at least one radical B, o a cyano, o a -NRr Rg with Rf and Rg’, represent independently a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg’ may form together a N-heterocycloalkyl, and o a -N(Rf)-CO-Rg, a-CO-N(Rf)-Rg, a -CO-Rf, a -C(O)-O-Rf, a -O- C(O)-Rf, a -SO2-Rf, a -SO-Rf, a -SO2-N(Rf)-Rg, a -N(Rf)-SO2-Rg, and a -N(Rh)-CO-NRfRg, with Rf, Rg, and Rh represent independently a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg may form together a N- heterocycloalkyl, said radical B being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen, - a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRiRj with Ri and Rj represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Ri and Rj may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl; -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a -NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl; R3 represents a radical selected in a group consisting of:
• a hydrogen,
• a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl,
• a halogen,
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
• a (Ci-Ce)alkyloxy optionally substituted by at least one halogen; R4 represents a radical selected in a group consisting of:
• a hydrogen,
• a halogen,
• a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl, • a (Ci-Ce)alkyloxy optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a hydroxy,
• a -NRkRi with Rk and Ri represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rk and Ri may form a N-heterocycloalkyl,
• a nitro,
• a cyano,
• a -NH-(Ci-Ce)alkyl, a -NH-cycloalkyl; and
• a -NH-CO-(Ci-Ce)alkyl, and a -NH-CO-cycloalkyl; Rs represents a radical selected in a group consisting of:
• a hydrogen,
• a halogen,
• a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a (Ci-Ce)alkyloxy optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a hydroxy,
• a -NRkRi with Rk and Ri represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rk and Ri may form a N-heterocycloalkyl,
• a nitro,
• a cyano,
• a -NH-(Ci-Ce)alkyl, a -NH-cycloalkyl; and
• a -NH-CO-(Ci-Ce)alkyl, and a -NH-CO-cycloalkyl; Re represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; R7 represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; and Rs represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; or R? and Rs may form together a 5-7 membered ring, partially unsaturated or saturated, N,N’ -heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (Ci-Ce)alkyl, a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, a - N((Ci-Ce)alkyl)2, and a ketone; with the proviso that the compound is not a compound selected in the group consisting of: 7V-(Aminoiminomethyl)-2-methoxybenzeneacetamide,
A-(Aminoiminomethyl)-2,4-dimethoxybenzeneacetamide, and A-(Aminoiminomethyl)-2,4-dimethylbenzeneacetamide.
The following compounds A-(Aminoiminomethyl)-2-methoxybenzeneacetamide, N- (Aminoiminomethyl)-2,4-dimethoxybenzeneacetamide, and A-(Aminoiminomethyl)-2,4- dimethylbenzeneacetamide (CAS No. 39515-72-5, 1789315-10-1, and 773786-03-1, respectively) are therefore outside the scope of the present invention.
According to the invention, n is 0 or 1. If n is 1, X is present. If n is 0, X is absent.
In a particular embodiment, n is 1. According to this embodiment, X is selected from the group consisting of -(CH2)m- with m is from 1 to 3 optionally substituted by at least one Ra, -O-, -S-, -CO-, -C(O)-O-, -O-C(O)-, -NRa-, -CO-NRa-, -NRa-CO-, -SO-, -SO2-, -SO2-NRa, -NRa-802-, and -NRa-CO-NRa-, with Rabeing a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and Rc may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a - NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl.
In a more particular embodiment, X is selected from the group consisting of -(CH2)m- with m is from 1 to 3, particularly 1, -O-, -S-, -CO-, -C(O)-O-, -O-C(O)-, -SO-, and -SO2-.
In an alternative particular embodiment, X is selected from the group consisting of -(CH2)m- with m is from 1 to 3 substituted by at least one Ra, -NRa-, -CO-NRa-, -NRa-CO-, -SO2-NRa, - NRa-SO2-, and -NRa-CO-NRa-, with Rabeing a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and Rc may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a - NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl. In an embodiment, Rais a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or a heterocycloalkyl.
In an alternative embodiment, Ra is a (Ci-Ce)alkyl substituted by at least one radical C, a cycloalkyl substituted by at least one radical C, or a heterocycloalkyl substituted by at least one radical C; said radical C being selected in a group as defined herein.
In a more specific embodiment, Rais a hydrogen. According to this more specific embodiment, X represents -NH-, -CO-NH-, -NH-CO-, -SO2-NH-, -NH-SO2-, or -NH-CO-NH-.
In a particular embodiment, n is 0. According to this embodiment, a compound of the invention has the following formula
Figure imgf000024_0001
with Ri, R2, R3, R4, Rs, Re, R7, and Rs are as defined herein.
According to the invention, R4 and Rs represent independently a radical selected in a group consisting of:
• a hydrogen,
• a halogen,
• a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a (Ci-Ce)alkyloxy optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a hydroxy,
• a -NRkRi with Rk and Ri represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rk and Ri may form a N-heterocycloalkyl,
• a nitro,
• a cyano,
• a -NH-(Ci-Ce)alkyl, a -NH-cycloalkyl; and
• a -NH-CO-(Ci-Ce)alkyl, and a -NH-CO-cycloalkyl.
In a particular embodiment, R4 and R5 represent H. According to this embodiment, a compound of the invention has the following formula (IB):
Figure imgf000025_0001
with X, n, Ri, R2, R3, Re, R7, and Rs are as defined herein.
According to the invention, Re represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci-Ce)alkyl)2. In a particular embodiment, Re is a hydrogen.
According to the invention, R7 and Rs represent independently a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci- Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci-Ce)alkyl)2, or R7 and Rs may form together a 5- 7 membered ring, partially unsaturated or saturated, N,N’ -heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (Ci-Ce)alkyl, a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, a -N((Ci-Ce)alkyl)2, and a ketone. Optionally, R7 and/or Rs are a hydrogen.
In a particular embodiment, R7 and Rs are a hydrogen.
In a particular embodiment, R7 and Rs form together an imidazolinyl optionally substituted by at least one radical selected in a group consisting of a (Ci-Ce)alkyl, a hydroxy, a (Ci- Ce)alkyloxy, a -NH(Ci-Ce)alkyl, a -N((Ci-Ce)alkyl)2, and a ketone. In a specific embodiment, R7 and Rs form together an imidazolinyl substituted by a methyl and a ketone.
In a particular embodiment, Re, R7, and Rs represent H. According to this embodiment, a compound of the invention has the following formula (IC):
Figure imgf000025_0002
with X, n, Ri, R2, R3, R4, and Rs are as defined herein.
According to the invention, R3 represents a radical selected in a group consisting of • a hydrogen, • a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl,
• a halogen,
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
• a (Ci-Ce)alkyloxy optionally substituted by at least one halogen.
In a particular embodiment, R3 represents a hydrogen, a (Ci-Ce)alkyl, a halogen, a cyclopropyl, an optionally substituted phenyl, or an optionally substituted pyrazolyl or pyrimidinyl. Optionally, R3 is selected from the group consisting of a hydrogen, methyl, bromine, chlorine, fluorine, a phenyl substituted by -(SO2)-(Ci-Ce)alkyl, (Ci-Ce)alkyloxy or halogen, in particular by -(SO2)-methyl, methoxy or chlorine, or an optionally substituted pyrazolyl or pyrimidinyl.
In a more particular embodiment, R3 represents H. According to this embodiment, a compound of the invention has the following formula (ID):
Figure imgf000026_0001
(ID), with X, n, Ri, R2, R4, Rs, Re, R7, and Rs are as defined herein.
According to the invention, Ri represents a radical selected in a group consisting of:
• a hydrogen,
• a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl,
• a halogen,
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
• a (Ci-Ce)alkyloxy optionally substituted by at least one halogen. In a particular embodiment, Ri represents a hydrogen, a (Ci-Ce)alkyl, a halogen, or a (Ci- Ce)alkyloxy. Optionally, Ri represents a (Ci-Ce)alkyl or a halogen. Optionally, Ri is selected from the group consisting of methyl, bromine, chlorine or fluorine, preferably methyl, chlorine or bromine, more preferably chlorine or bromine, even more preferably chlorine.
Optionally, Ri represents a cyclopropyl, an optionally substituted phenyl (e.g., phenyl substituted by -(SO2)-(Ci-Ce)alkyl, (Ci-Ce)alkyloxy, or halogen, in particular -(SO2)-methyl, methoxy or chlorine), or an optionally substituted pyrazolyl or pyrimidinyl.
According to the invention, R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, optionally substituted by at least one radical A as defined herein, or a radical selected in a group consisting of a (Ci-Ce)alkyl, a cycloalkyl, a (C2-Ce)alkenyl, a (C2-Ce)alkynyl, or a (Ci-Ce)alkyloxy, optionally substituted by at least one radical B as defined herein, a cyano, and a -NRfRg’ with Rf and Rg’, represent independently a hydrogen, a (Ci- Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg’ may form together a N-heterocycloalkyl, a -N(Rf)-CO-Rg, a-CO-N(Rf)-Rg, a -C(O)-O- Rf, a -O-C(O)-Rf, a -SO2-Rf, a -SO-Rf, a -SO2-N(Rf)-Rg, a -N(Rf)-SO2-Rg, and a -N(Rh)-CO- NRfRg, with Rf, Rg, and Rh represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, a heterocycloalkyl, optionally substituted by at least one radical B as defined herein, or Rf and Rg may form together a N-heterocycloalkyl.
In a particular embodiment, R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl, said 3-14 membered ring is optionally substituted by at least one radical A selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, or a hydroxy, a cycloalkyl optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a hydroxy, a (C2-Ce)alkenyl, a (C2-Ce)alkynyl, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen, a cyano, a -NRaRe with Rd and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rd and Re may form together a N-heterocycloalkyl, a nitro, a hydroxy, a ketone,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a - NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a - NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl,
- a -C(O)-O-(Ci-C6)alkyl, a -O-C(O)-(Ci-C6)alkyl, a - COOH, a -C(O)-O-cycloalkyl, -O-C(O)-cycloalkyl, a -CO-(Ci-Ce)alkyl, a -CO-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, and a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl.
Particularly, said at least one radical A is selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen,
- a -CO-(Ci-C6)alkyl, and
- a -SO2-(Ci-C6)alkyl.
In a more particular embodiment, R2 represents a 3-14 membered ring which is an aryl or a heteroaryl optionally substituted by at least one radical A as defined herein.
In a more particular embodiment, R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of a phenyl, a pyrimidinyl, a pyrazolyl, an imidazolyl, a thiazolyl, an isoxazolyl, a pyridinyl, an indolyl, a pyridazinyl, a 1,3- benzoxazolyl, a benzimidazolyl, an indazolyl, a cyclopropyl, a cyclobutyl, an oxatenyl, a tetrahydrofuranyl, a 1,2,3,6-tetrahydropyridinyl, a piperidinyl, a 3,6-dihydro-2H-pyranyl, a 3,4- dihydro-2H-pyranyl, a tetrahydropyranyl, a pyrrolidinyl, a morpholinyl, and a piperazinyl, particularly a phenyl, a pyrimidinyl, a pyrazolyl, a pyridinyl, a cyclopropyl, a 3,6-dihydro-2H- pyranyl, a piperazinyl and morpholinyl, said radical being optionally substituted by at least one radical A as defined herein. Optionally, R2 represents a 3-14 membered ring selected in a group consisting of a phenyl, a pyrazolyl, and pyridinyl, said radical being optionally substituted by at least one radical A as defined herein.
In a specific embodiment, R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of: o an aryl, particularly a phenyl, said aryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyloxy, particularly a methoxy or an ethoxy, a halogen, particularly a chlorine, and a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3, o a heteroaryl, particularly a pyrimidinyl, a pyrazolyl, or a pyridinyl, said heteroaryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyl, particularly a methyl, and a (Ci-Ce)alkyloxy, particularly a methoxy, o a cycloalkyl, particularly a cyclopropyl, and o a heterocycloalkyl, particularly a 3,6-dihydro-2H-pyranyl, a piperazinyl, or a morpholinyl, said heterocycloalkyl is optionally substituted by a - CO-(Ci-Ce)alkyl, particularly a -CO-CH3.
In a more specific embodiment, R2 represents a 3-14 membered ring, which is an aryl or an heteroaryl, particularly a phenyl, a pyrazolyl, and pyridinyl, said aryl or heteroaryl is optionally substituted by at least one (Ci-Ce)alkyl, particularly a methyl, one halogen, particularly chlorine, and one -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
In a particular embodiment, R2 represents a radical selected in a group consisting of: o a (Ci-Ce)alkyl optionally substituted by at least one radical B or a cycloalkyl optionally substituted by at least one radical B, o a (C2-Ce)alkenyl optionally substituted by at least one radical B, o a (C2-Ce)alkynyl optionally substituted by at least one radical B, o a (Ci-Ce)alkyloxy optionally substituted by at least one radical B, o a cyano, o a -NRfRg’ with Rf and Rg’, represent independently a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg’ may form together a N-heterocycloalkyl, and o a -N(Rf)-CO-Rg, a-CO-N(Rf)-Rg, a -CO-Rf, a -C(O)-O-Rf, a -O- C(O)-Rf, a -SO2-Rf, a -SO-Rf, a -SO2-N(Rf)-Rg, a -N(Rf)-SO2-Rg, and a -N(Rh)-CO-NRfRg, with Rf, Rg, and Rh represent independently a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg may form together a N- heterocycloalkyl, said radical B being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRiRj with Ri and Rj represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Ri and Rj may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl; -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a -NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl.
Particularly, said at least one radical B is selected in a group consisting of:
- a (Ci-C6)alkyl a halogen,
- a -O-CO-(Ci-C6)alkyl, a hydroxy,
- a -SO2-(Ci-C6)alkyl, and
- a -NH-CO-(Ci-C6)alkyl.
In a more particular embodiment, R2 represents a radical selected in a group consisting of: o a (Ci-Ce)alkyl, particularly an isobutyl, and o a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
In an embodiment of the invention, a compound of formula (I) is such that R4, Rs, Re, R7, and Rs represent a hydrogen. According to this embodiment, a compound of the invention has the following formula (IE):
Figure imgf000031_0001
with X, n, Ri, R2, and R3 are as defined herein.
In an embodiment of the invention, a compound of formula (I) is such that n is 0, and R4, Rs,
Re, R7, and Rs represent a hydrogen. According to this embodiment, a compound of the invention has the following formula (IF):
Figure imgf000031_0002
with Ri, R2, and R3 are as defined herein.
In an embodiment of the invention, a compound of formula (I) is such that n is 1, and R4, Rs,
Re, R7, and Rs represent a hydrogen. According to this embodiment, a compound of the invention has the following formula (IG):
Figure imgf000031_0003
with X, Ri, R2, and R3 are as defined herein.
In a particular embodiment, a compound of formula (IE) or (IG) is such that X is selected from the group consisting of -(CH2)m- with m is from 1 to 3, particularly 1, -O-, -S-, -CO-, -C(O)-O- , -O-C(O)-, -SO-, and -SO2-.
In an alternative particular embodiment, X is selected from the group consisting of -(CH2)m- with m is from 1 to 3 substituted by at least one Ra, -NRa-, -CO-NRa-, -NRa-CO-, -SO2-NRa, - NRa-SO2-, and -NRa-CO-NRa-, with Rabeing a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and Rc may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a - NH-SCh-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SCh-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl.
In an embodiment, Rais a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or a heterocycloalkyl.
In an alternative embodiment, Ra is a (Ci-Ce)alkyl substituted by at least one radical C, a cycloalkyl substituted by at least one radical C, or a heterocycloalkyl substituted by at least one radical C; said radical C being selected in a group as defined herein. In a more specific embodiment, Rais a hydrogen. According to this more specific embodiment, X represents -NH-, -CO-NH-, -NH-CO-, -SO2-NH-, -NH-SO2-, or -NH-CO-NH-.
In a further particular embodiment, the compounds of formula (ID), (IE) or (IF) are such that Ri represents a radical selected in a group consisting of a hydrogen, a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl, a halogen, a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and a (Ci-Ce)alkyloxy optionally substituted by at least one halogen.
In a further particular embodiment, Ri represent a hydrogen, a (Ci-Ce)alkyl, a halogen, or a (Ci-Ce)alkyloxy. Optionally, Ri represents a (Ci-Ce)alkyl or a halogen. Optionally, Ri is selected from the group consisting of methyl, bromine, chlorine or fluorine, preferably methyl, chlorine or bromine, more preferably chlorine or bromine, even more preferably chlorine.
Optionally, Ri represents a cyclopropyl, an optionally substituted phenyl (e.g., phenyl substituted by -(SO2)-(Ci-Ce)alkyl, (Ci-Ce)alkyloxy, or halogen, in particular -(SO2)-methyl, methoxy or chlorine), or an optionally substituted pyrazolyl or pyrimidinyl.
In a further particular embodiment, R3 represents a hydrogen, a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl, a halogen, a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, or a (Ci-Ce)alkyloxy optionally substituted by at least one halogen.
Optionally, R3 represents a hydrogen, a (Ci-Ce)alkyl, a halogen, a cyclopropyl, an optionally substituted phenyl, or an optionally substituted pyrazolyl or pyrimidinyl. Optionally, R3 is selected from the group consisting of methyl, bromine, chlorine, fluorine, a phenyl substituted by -(SO2)-(Ci-Ce)alkyl, (Ci-Ce)alkyloxy or halogen, in particular by -(SO2)-methyl, methoxy or chlorine, or an optionally substituted pyrazolyl or pyrimidinyl. In a more particular embodiment, R3 represents H.
In a further particular embodiment, a compound of formula (IE), (IF) or (IG) is such that R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of o an aryl, particularly a phenyl, said aryl is optionally substituted by at least one radical selected in a group consisting of a (Ci-Ce)alkyloxy, particularly a methoxy or an ethoxy, a halogen, particularly a chlorine, and a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3, o a heteroaryl, particularly a pyrimidinyl, a pyrazolyl, or a pyridinyl, said heteroaryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyl, particularly a methyl, and a (Ci-Ce)alkyloxy, particularly a methoxy, o a cycloalkyl, particularly a cyclopropyl, and o a heterocycloalkyl, particularly a 3,6-dihydro-2H-pyranyl, a piperazinyl, or a morpholinyl, said heterocycloalkyl is optionally substituted by a - CO-(Ci-Ce)alkyl, particularly a -CO-CH3.
In a specific embodiment, a compound of formula (IE), (IF) or (IG) is such that R2 represents a 3-14 membered ring, which is an aryl or a heteroaryl, particularly a phenyl, a pyrazolyl, and pyridinyl, said aryl or heteroaryl is optionally substituted by at least one (Ci-Ce)alkyl, particularly a methyl, one halogen, particularly chlorine, and one -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
In a further particular embodiment, a compound of formula (IE), (IF) or (IG) is such that R2 represents a radical selected in a group consisting of: o a (Ci-Ce)alkyl, particularly an isobutyl, and o a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
In a further embodiment, a compound of formula (IE), (IF) or (IG) is such that: Ri represents a halogen, preferably a chlorine; R3 represents a hydrogen; and R2 represents an aryl or a heteroaryl, particularly a phenyl, a pyrazolyl, and pyridinyl, said aryl or heteroaryl is optionally substituted by at least one (Ci-Ce)alkyl, particularly a methyl, one halogen, particularly chlorine, and one -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
A preferred compound of formula (I) or (IA) or (IB) or (IC) or (ID) or (IE) or (IF) or (IG) according to the invention has the following formula selected in a group consisting of:
Figure imgf000035_0001
and a pharmaceutical acceptable salt thereof.
A preferred compound of the invention is selected in a group consisting of: -N-carbamimidoyl-2-[2-chloro-6-(3-chlorophenyl)phenyl]acetamide;
- N-carbamimidoyl-2-[2-chloro-6-(l-methylpyrazol-4-yl)phenyl]acetamide; - N-carbamimidoyl-2-[2-chloro-6-(3-methylsulfonylphenyl)phenyl]acetamide; and
- N-carbamimidoyl-2-[2-chloro-6-(4-pyridyl)phenyl]acetamide and a pharmaceutical acceptable salt therof.
Therapeutic applications
As illustrated by examples, the inventors have demonstrated the therapeutic interest of the new compounds of the invention. Accordingly, the present invention relates to a pharmaceutical or veterinary composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein. Preferably, the pharmaceutical composition further comprises a pharmaceutically or veterinary acceptable carrier or excipient. The present invention relates to the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein as a drug or a medicine. The invention further relates to a method for treating a disease in a subject, wherein a therapeutically effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein, is administered to said subj ect in need thereof. The invention also relates to the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein, for the manufacture of a medicine. The invention also relates to a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC),
(ID), (IE), (IF), or (IG) according to the invention or any particular compound as disclosed herein for use as a drug.
The present invention also concerns:
- a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound for preventing and/or treating or for use for preventing and/or treating a cancer; and/or
- a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC), (ID),
(IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, and an antitumor drug, in particular for the prevention and/or the treatment of cancer or for use in the prevention and/or the treatment of cancer; and/or
- a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for preventing and/or treating a cancer or for use for preventing and/or treating a cancer in combination with an antitumor drug such as chemotherapy, immunotherapy, and/or hormonotherapy, and/or with radiotherapy, optionally before, simultaneously and/or after surgery (e.g., tumor resection); and/or
- a kit comprising (a) a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein; and (b) an antitumor drug as a combined preparation for simultaneous, separate or sequential use, for preventing and/or treating cancer or for use for preventing and/or treating a cancer; and/or
- the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, a medicine or a drug for the prevention and/or the treatment of a cancer; and/or
- the use of a pharmaceutical composition comprising a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, and an additional antitumor drug, for the manufacture of a medicament, a medicine or a drug for the prevention and/or the treatment of a cancer; and/or
- the use of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined above including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, for the manufacture of a medicament, a medicine or a drug for the prevention and/or the treatment of a cancer in combination with a treatment with an antitumor drug such as chemotherapy, immunotherapy, and/or hormonotherapy, and/or with radiotherapy, optionally before, simultaneously and/or after surgery (e.g., tumor resection); and/or
- a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound;
- a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound, and an additional antitumor drug, optionally with radiotherapy;
- a method for treating a cancer, in a subject in need thereof, comprising administering an effective amount of a compound of formula (I), (IA), (IB), (IC), (ID), (IE), (IF), or (IG) as defined herein including any one of the disclosed embodiments and any particular compound as disclosed herein, or a pharmaceutical composition comprising such a compound; the method further comprises chemotherapy, immunotherapy, hormonotherapy and/or radiotherapy, optionally before, simultaneously and/or after surgery (e.g., tumor resection). The term “cancer”, as used herein, refers to the presence of cells possessing characteristics typical of cancer-causing cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological features. The cancer may be solid tumor or hematopoietic tumor. Examples of cancer include, but are not limited to, solid tumors and hematological cancers, including carcinoma, lymphoma, blastoma (including medulloblastoma and retinoblastoma), sarcoma (including liposarcoma and synovial cell sarcoma), neuroendocrine tumors (including carcinoid tumors, gastrinoma, and islet cell cancer), mesothelioma, schwannoma (including acoustic neuroma), meningioma, adenocarcinoma, melanoma, and leukemia or lymphoid malignancies. More particular examples of such cancers include chronic myeloid leukemia, acute lymphoblastic leukemia, Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL), squamous cell carcinoma, lung cancer, small-cell lung cancer, non-small cell lung cancer, glioma, gastrointestinal cancer, renal cancer, ovarian cancer, bile duct cancer, liver cancer, colorectal cancer, endometrial cancer, kidney cancer, prostate cancer, melanoma, skin cancer, thyroid cancer, neuroblastoma, osteosarcoma, pancreatic cancer, glioblastoma multiforme, cervical cancer, stomach cancer, bladder cancer, hepatoma, breast cancer, oesophagal cancer, colon cancer, head and neck cancer, brain cancer, gastric cancer, germ cell tumor, pediatric sarcoma, sinonasal natural killer, multiple myeloma, acute myelogenous leukemia (AML), chronic lymphocytic leukemia, mastocytosis and any symptom associated with mastocytosis.
In a particular aspect, the cancer is chosen among of myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, glioblastoma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, nonHodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma.
In a particular aspect, the cancer is resistant or has a low response to immunotherapy. More specifically, the cancer can be resistant to a treatment with a checkpoint inhibitor such as an antibody against PD-1, PD-L1, CTLA-4 and the like. The administration route can be topical, transdermal, oral, rectal, sublingual, intranasal, intrathecal, intratumor or parenteral (including subcutaneous, intramuscular, intravenous and/or intradermal). Preferably, the administration route is parental, oral or topical. The pharmaceutical composition is adapted for one or several of the above-mentioned routes. The pharmaceutical composition, kit, product or combined preparation is preferably administered by injection or by intravenous infusion or suitable sterile solutions, or in the form of liquid or solid doses via the alimentary canal.
The pharmaceutical composition can be formulated as solutions in pharmaceutically compatible solvents or as emulsions, suspensions or dispersions in suitable pharmaceutical solvents or vehicles, or as pills, tablets or capsules that contain solid vehicles in a way known in the art. Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Formulations for rectal administration may be in the form of a suppository incorporating the active ingredient and carrier such as cocoa butter, or in the form of an enema. Formulations suitable for parenteral administration conveniently comprise a sterile oily or aqueous preparation of the active ingredient which is preferably isotonic with the blood of the recipient. Every such formulation can also contain other pharmaceutically compatible and nontoxic auxiliary agents, such as, e.g. stabilizers, antioxidants, binders, dyes, emulsifiers or flavoring substances. The formulations of the present invention comprise an active ingredient in association with a pharmaceutically acceptable carrier therefore and optionally other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof. The pharmaceutical compositions are advantageously applied by injection or intravenous infusion of suitable sterile solutions or as oral dosage by the digestive tract. Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature.
Pharmaceutical compositions according to the invention may be formulated to release the active drug substantially immediately upon administration or at any predetermined time or time period after administration. Preferably, the treatment with the compound according to the invention or the pharmaceutical composition according to the invention starts no longer than a month, preferably no longer than a week, after the diagnosis of the disease. In a particular embodiment, the treatment starts the day of the diagnosis.
The compound according to the invention or the pharmaceutical composition according to the invention may be administered as a single dose or in multiple doses.
Preferably, the treatment is administered regularly, preferably between every day and every month, more preferably between every day and every two weeks, more preferably between every day and every week, even more preferably the treatment is administered every day. In a particular embodiment, the treatment is administered several times a day, preferably 2 or 3 times a day, even more preferably 3 times a day.
The duration of treatment with the compound according to the invention or the pharmaceutical composition according to the invention is preferably comprised between 1 day and 50 weeks, more preferably between 1 day and 30 weeks, still more preferably between 1 day and 15 weeks, even more preferably between 1 day and 10 weeks. In a particular embodiment, the duration of the treatment is of about 1 week. Alternatively, the treatment may last as long as the disease persists. The amount of compound according to the invention or of pharmaceutical composition according to the invention to be administered has to be determined by standard procedure well known by those of ordinary skills in the art. Physiological data of the patient (e.g. age, size, and weight) and the routes of administration have to be taken into account to determine the appropriate dosage, so as a therapeutically effective amount will be administered to the patient. In a particular embodiment, is administered at a dose ranging from 0.001 mg/kg body weight to 30 mg/kg body weight.
In one embodiment, the compound of the invention can be used in combination with another antitumor drug or antineoplastic agent.
The additional antitumor drug can be selected in the non-exhaustive list of antitumor agents consisting of an inhibitor of topoisomerases I or II, an anti-mitotic agent, a DNA alkylating agent, an agent causing crosslinking of DNA, an anti-metabolic agent, a targeted agent such as a kinase inhibitor, a histone deacetylase inhibitor and an anti-EGFR agent and/or a therapeutical antibody designed to mediate cytotoxicity against the cancer cells or to modulate one of their key biological functions.
Antimitotic agents include, but are not limited to, paclitaxel, docetaxel and analogs such as larotaxel (also called XRP9881; Sanofi-Aventis), XRP6258 (Sanofi-Aventis), BMS-184476 (Bristol-Meyer-Squibb), BMS-188797 (Bristol -Meyer- Squibb), BMS-275183 (Bristol -Meyer- Squibb), ortataxel (also called IDN 5109, BAY 59-8862 or SB-T-101131; Bristol-Meyer- Squibb), RPR 109881 A (Bristol-Meyer-Squibb), RPR 116258 (Bristol-Meyer-Squibb), NBT- 287 (TAPESTRY), PG-paclitaxel (also called CT-2103, PPX, paclitaxel poliglumex, paclitaxel polyglutamate or Xyotax™), ABRAXANE® (also called Nab-paclitaxel; ABRAXIS BIOSCIENCE), tesetaxel (also called DJ-927), IDN 5390 (INDENA), taxoprexin (also called docosahexanoic acid-paclitaxel; PROTARGA), DHA-paclitaxel (also called Taxoprexin®), and MAC-321 (WYETH). Preferably, antimitotic agents are docetaxel, paclitaxel, and is more preferably docetaxel.
Inhibitors of topoisomerases I and/or II include, but are not limited to etoposide, topotecan, camptothecin, irinotecan, amsacrine, intoplicin, anthracyclines such as doxorubicin, epirubicin, daunorubicin, idarubicin and mitoxantrone. Inhibitors of topoisomerase I and II include, but are not limited to intoplicin.
The additional antitumor agent can be alkylating agents including, without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, metal salts and triazenes. Non-exhaustive examples thereof include uracil mustard, chlormethine, cyclophosphamide (CYTOXAN®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, cisplatin, carboplatin, fotemustine, oxaliplatin, thiotepa, streptozocin, dacarbazine, and temozolomide. In a particular embodiment, the DNA alkylating agent is preferably cisplatin, carboplatin, temozolomide, fotemustine or dacarbazine.
Anti-metabolic agents block the enzymes responsible for nucleic acid synthesis or become incorporated into DNA, which produces an incorrect genetic code and leads to apoptosis. Non- exhaustive examples thereof include, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors, and more particularly methotrexate, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, 5-fluorouracil, gemcitabine and capecitabine. In a particular embodiment, such an agent is gemcitabine.
The additional anti-tumor agent can also be a targeted agent, in particular a kinase inhibitor. The kinase may be selected from the group consisting of intracellular tyrosine or serine/threonine kinases, receptors tyrosine or serine/threonine kinase. The kinase could be selected among EGFR family, ALK, B-Raf, MEK, and mTOR. For instance, the agents may have ability to inhibit angiogenesis based on the inhibitory activities on VEGFR and PDGFR kinases. In particular, the targeted agent can be selected among the multiple kinase inhibitor drugs which are already approved: Gleevec®, which inhibits Bcr-Abl and c-Kit, and Iressa® and Tarceva®, which both inhibit EGFR, sorafenib (Nexavar®, BAY 43-9006) which inhibits Raf, dasatinib (BMS-354825) and nilotinib (AMN-107, Tasigna®) which also inhibits Bcr-Abl, lapatinib which also inhibits EGFR, temsirolimus (Torisel®, CCI-779) which targets the mTOR pathway, sunitinib (Student®, SU11248) which inhibits several targets including VEGFR as well as specific antibodies inactivating kinase receptors: Herceptin® and Avastin®. The anti- EGFR agent can be selected among gefitinib, erlotinib, lapatinib, vandetanib, afatinib, osimertinib, neratinib, dacomitinib, brigatinib, canertinib, naquotinib, nazartinib, pelitinib, rociletinib, icotinib, AZD3759, AZ5104 (CAS
Figure imgf000042_0001
1421373-98-9), poziotinib, WZ4002, preferably is erlotinib or cetuximab. The ALK inhibitor can be selected among crizotinib, entrectinib, ceritinib, alectinib, brigatinib, lorlatinib, TSR-011, CEP-37440, and ensartinib. The B-Raf inhibitor can be selected among vemurafenib, dabrafenib, regorafenib, and PLX4720. The MEK inhibitor can be selected among cobimetinib, trametinib, binimetinib, selumetinib, PD-325901, CI-1040, PD035901, U0126, TAK-733. The antitumor agent can be IDO1 inhibitors such as epacadostat.
The term “therapy”, as used herein, refers to any type of treatment of cancer (i.e., antitumor therapy), including an adjuvant therapy and a neoadjuvant therapy. Therapy comprises radiotherapy and therapies, preferably systemic therapies such as hormone therapy, chemotherapy, immunotherapy and monoclonal antibody therapy.
The term “adjuvant therapy”, as used herein, refers to any type of treatment of cancer given as additional treatment, usually after surgical resection of the primary tumor, in a patient affected with a cancer that is at risk of metastasizing and/or likely to recur. The aim of such an adjuvant treatment is to improve the prognosis. Adjuvant therapies comprise radiotherapy and therapy, preferably systemic therapy, such as hormone therapy, chemotherapy, immunotherapy and monoclonal antibody therapy.
The term “hormone therapy” or “hormonal therapy” or “hormonotherapy” refers to a cancer treatment having for purpose to block, add or remove hormones. For instance, in breast cancer, the female hormones estrogen and progesterone can promote the growth of some breast cancer cells. So, in these patients, hormone therapy is given to block estrogen and a non-exhaustive list commonly used drugs includes: tamoxifen, toremifene, anastrozole, exemestane, letrozole, goserelin, leuprolide, megestrol acetate, and fluoxymesterone. As used herein, the term “chemotherapeutic treatment” or “chemotherapy” refers to a cancer therapeutic treatment using chemical or biological substances, in particular using one or several antineoplastic agents.
The term “radiotherapeutic treatment” or “radiotherapy” is a term commonly used in the art to refer to multiple types of radiation therapy including internal and external radiation therapies or radioimmunotherapy, and the use of various types of radiations including X-rays, gamma rays, alpha particles, beta particles, photons, electrons, neutrons, radioisotopes, and other forms of ionizing radiations.
The term “therapeutical antibody” refers to any antibody having an anti-tumoral effect.
Preferably, the therapeutical antibody is a monoclonal antibody. Therapeutic antibodies are generally specific for surface antigens, e.g., membrane antigens. Most preferred therapeutic antibodies are specific for tumor antigens (e.g., molecules specifically expressed by tumor cells), such as CD20, CD52, ErbB2 (or HER2/Neu), CD33, CD22, CD25, MUC-1, CEA, KDR, aVb3, and the like. The therapeutical antibody includes, but is not limited to, antibodies such as trastuzumab (anti-HER2 antibody), rituximab (anti-CD20 antibody), alemtuzumab, gemtuzamab, cetuximab, pertuzumab, epratuzumab, basiliximab, daclizumab, labetuzumab, sevirumab, tuvurimab, palivizumab, infliximab, omalizumab, efalizumab, natalizumab, clenoliximab, and bevacizumab.
In a particular aspect, the antitumor agent can be an immunomodulator. The immunomodulator can be a cancer vaccine, molecules stimulating the immune system such as cytokines, therapeutic antibodies, preferably monoclonal antibodies, in particular antibodies directed against antigens specifically presented or overexpressed at the membrane of tumor cells or directed against cell receptors which blockade prevent tumor growth, adoptive T-cell therapy, immune checkpoint inhibitor treatment, and any combination thereof.
For instance, the immunomodulator can be:
- an immune checkpoint inhibitor (ICI), preferably an inhibitor of of PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand), PD-L2, CTLA-4 (cytotoxic T lymphocyte associated protein 4), TIM-3 (T-cell immunoglobulin and mucin-domain containing-3), LAG-3 (Lymphocyte-activation gene 3), NKG2D, NKG2L, KIR, VISTA, BTLA (B- and T-lymphocyte attenuator), or TIGIT (T cell immunoreceptor with Ig and ITIM domains), , especially an antibody directed against an anti-CTLA-4 such as ipilimumab, an antibody directed against PD-1 such as nivolumab, pembrolizumab, or BGB-A317, an antibody directed against PDL1 such as atezolizumab, avelumab, or durvalumab, an antibody directed against LAG-3 such as BMS-986016, an antibody directed against TIM-3, an antibody directed against TIGIT, an antibody directed against BLTA, or a combination thereof; or
- an activator of a costimulatory molecule, in particular an agonist of 0X40, CD2, CD27, CDS, ICAM-1, LFA-1 (CDl la/CD18), ICOS (CD278), 4-1 BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD 160, B7-H3 or CD83 ligand;
In some embodiments, the PD-1 inhibitor is selected from PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB- A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), or AMP -224 (Amplimmune).
Several anti -PD-1 antibodies are already clinically approved and others are still in clinical developments. For instance, the anti-PDl antibody can be selected from the group consisting of Pembrolizumab (also known as Keytruda lambrolizumab, MK-3475), Nivolumab (Opdivo, MDX-1106, BMS-936558, ONO-4538), Pidilizumab (CT-011), Cemiplimab (Libtayo), Camrelizumab, AUNP12, AMP-224, AGEN-2034, BGB-A317 (Tisleizumab), PDR001 (spartalizumab), MK-3477, SCH-900475, PF-06801591, JNJ-63723283, genolimzumab (CBT- 501), LZM-009, BCD-100, SHR-1201, BAT-1306, AK-103 (HX-008), MEDL0680 (also known as AMP-514) MEDI0608, JS001 (see Si-Yang Liu et al., J. Hematol. Oncol.10: 136 (2017)), BI-754091, CBT-501, INCSHR1210 (also known as SHR-1210), TSR-042 (also known as ANB011), GLS-010 (also known as WBP3055), AM-0001 (Armo), STI-1110 (see WO 2014/194302), AGEN2034 (see WO 2017/040790), MGA012 (see WO 2017/19846), or IBI308 (see WO 2017/024465, WO 2017/025016, WO 2017/132825, and WO 2017/133540), monoclonal antibodies 5C4, 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, described in WO 2006/121168. Bifunctional or bispecific molecules targeting PD-1 are also known such as RG7769 (Roche), XmAb20717 (Xencor), MEDI5752 (AstraZeneca), FS118 (F-star), SL- 279252 (Takeda) and XmAb23104 (Xencor).
Antibodies directed against CTLA-4 and bifunctional or bispecific molecules targeting CTLA- 4 are also known such as ipilimumab, tremelimumab, MK-1308, AGEN-1884, XmAb20717 (Xencor), MEDI5752 (AstraZeneca).
Antibodies directed against TIGIT are also known in the art, such as BMS-986207 or AB 154, BMS-986207 CPA.9.086, CHA.9.547.18, CPA.9.018, CPA.9.027, CPA.9.049, CPA.9.057, CPA.9.059, CPA.9.083, CPA.9.089, CPA.9.093, CPA.9.101, CPA.9.103, CHA.9.536.1, CHAN.536.3, CHA.9.536.4, CHA.9.536.5, CHA.9.536.6, CHA.9.536.7, CHA.9.536.8,
CHAN.560.1, CHAN.560.3, CHA.9.560.4, CHA.9.560.5, CHA.9.560.6, CHA.9.560.7,
CHAN.560.8, CHA.9.546.1, CHA.9.547.1, CHA.9.547.2, CHA.9.547.3, CHA.9.547.4,
CHAN.547.6, CHA.9.547.7, CHA.9.547.8, CHA.9.547.9, CHA.9.547.13, CHA.9.541.1,
CHAN.541.3, CHAN.541.4, CHA.9.541.5, CHA.9.541.6, CHA.9.541.7, and CHA.9.541.8 as disclosed in WO 19232484. Anti-TIGIT antibodies are also disclosed in WO 16028656, W016106302, WO16191643, W017030823, W017037707, WO17053748, WO17152088, WO18033798, WO18102536, WO18102746, W018160704, W018200430, WO18204363, W019023504, WO19062832, WO19129221, WO19129261, WO19137548, WO19152574, WO19154415, WO19168382 and WO19215728.
The LAG-3 inhibitor can be selected from LAG525 (Novartis), BMS-986016 (Bristol-Myers Squibb), or TSR-033 (Tesaro). Further known anti-LAG-3 antibodies include those described, e.g., in WO 2008/132601, WO 2010/019570, WO 2014/140180, WO 2015/116539, WO 2015/200119, WO 2016/028672, US 9,244,059, US 9,505,839, which are incorporated herein by reference in their entirety.
The TIM-3 inhibitor can be MGB453 (Novartis) or TSR-022 (Tesaro). Further known anti- TIM-3 antibodies include those described, e.g., in WO 2016/1 1 1947, WO 2016/071448, WO 2016/144803, US 8,552,156, US 8,841,418, and US 9,163,087, which are incorporated herein by reference in their entirety.
Preferably, the immunotherapy is selected from the group consisting of ipilimumab, nivolumab, BGB-A317, pembrolizumab, atezolizumab, avelumab, or durvalumab, BMS-986016, and epacadostat, or any combination thereof.
Further aspects and advantages of the invention will be disclosed in the following experimental section, which should be regarded as illustrative and not limiting. EXAMPLES
I. CHEMISTRY EXAMPLES
The purity data provided in the examples described below were obtained using the following methods:
Method 1 - UPLC Acidic Method
Apparatus: Waters HClass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa; Column: Waters ACQUITY UPLC® CSH C18, 1.7 pm, 2.1 x 30 mm at 40 °C; Detection: UV at 210- 400 nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Formic in water / MeCN 98/2 to 0/100 over 2.5 minutes. Flow rate 0.77 mL/Min.
Method 2 - UPLC Basic Method
Apparatus: Waters HClass; Binary Solvent Pump, SM-FTN, CMA, PDA, QDa; Column: Waters ACQUITY UPLC® BEH C18, 1.7 pm, 2.1 x 30 mm at 40 °C; Detection: UV at 210- 400 nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Ammonia in water / MeCN 98/2 to 0/100 over 2.5 minutes. Flow rate 0.77 mL/Min.
Method 3 - LCMS Acidic Method
Apparatus: Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:, G6150 MSD; Column: Waters Cortecs Cl 8, 30 x 2.1 mm, 2.7pm, at 40 °C; Detection: UV at 260nm +/- 90nm unless otherwise indicated, MS by electrospray ionisation; Solvents and Gradient: 0.1% Formic in water / MeCN 98/2 to 0/100 over 2.5 minutes. Flow rate 1.35 mL/Min.
Method 4 - LCMS Basic Method
Apparatus: Agilent 1260; Binary Pump, HiP Sampler, Column Compartment, DAD:, G6150 MSD; Column: Phenomenex Evo Cl 8, 30 x 2.1 mm, 2.6pm, at 40 °C; Detection: UV at
260nm +/- 90nm unless otherwise indicated, MS by electrospray ionisation; 0.1% Ammonia in water / MeCN 98/2 to 0/100 over 2.5 minutes. Flow rate 1.35 mL/Min.
The NMR data provided in the examples described below were obtained as followed:
NMR spectra were recorded using a Bruker 400MHz Avance Neo spectrometer fitted with a Bruker 5mm iProbe, or a Bruker 500MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe™. Spectra were measured at 298 K, unless indicated otherwise, and were referenced relative to the solvent resonance. The chemical shifts are reported in parts per million. Data were acquired using Bruker TopSpin software and processed using MestreNova software. Abbreviations for multiplicities observed in NMR spectra are as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet), br (broad).
Solvents, reagents and starting materials were purchased and used as received from commercial vendors unless otherwise specified.
The intermediates and compounds described below were named using ChemDraw® version 21.0.0 (PerkinElmer).
1.1. GENERAL PROTOCOL FOR THE SYNTHESIS OF COMPOUNDS OF THE INVENTION
Protocol 1
Figure imgf000047_0001
Step 1
To a solution of bromide Pl-1 (1 eq), boronate Pl-2 (1.5 eq) and caesium or potassium carbonate (3 eq) in Acetonitrile/Water (4: 1 ratio) was added SPhos Pd G3 (10 mol%). Alternatively, PdChdppf or Pd(PPh3)2Ch was used. The reaction mixture was degassed with nitrogen and heated to 80 °C under nitrogen. After the reaction completion (LCMS), the mixture was allowed to cool and subjected to aqueous work up. The crude product was purified by column chromatography or used directly to afford Pl-3
Step 2
To a stirred suspension of guanidine hydrochloride (2-2.5 eq) in DMF (10-30 vol) at 35 °C was added sodium methoxide (2 eq of a 30% Wt solution in MeOH) or potassium /c/V-butoxide (2 eq). After, 5 mins the ester Pl-3 was added was added. If required, a further charge of reagents was added. After completion (LCMS), the mixture was quenched with water and the precipitate collected by filtration to afford crude material. This was purified by preparative HPLC or column chromatography to afford the product Pl-4.
1.2 EXAMPLES
Example 1: N-carbamimidoyl-2-[2-chloro-6-(3-chlorophenyl)phenyl]acetamide. TFA
Figure imgf000048_0001
The title compound was prepared from methyl 2-(2-bromo-6-chlorophenyl)acetate (Enamine) and (3-chlorophenyl)boronic acid using Protocol 1 and Pd(PPh3)2Ch in the Suzuki coupling. m/z 322.2 @ 1.31 min, Method 1. 'HNMR (400 MHz, DMSO) 5 11.92 (s, 1H), 8.28 (m, 3H), 7.57 (dd, J = 8.0, 1.3 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 7.35 (dt, J = 1.8, 1.1 Hz, 1H), 7.31 - 7.23 (m, 2H), 3.82 (s, 2H).
Example 2: N-carbamimidoyl-2-[2-chloro-6-(l-methylpyrazol-4-yl)phenyl]acetamide
Figure imgf000048_0002
The title compound was prepared from methyl 2-(2-bromo-6-chlorophenyl)acetate (Enamine) and l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole using Protocol 1 and Pd(PPh3)2Ch in the Suzuki coupling. m/z 292.1 @ 0.90 min, Method 2. JH NMR (400 MHz, DMSO) 5 7.80 (s, 1H), 7.47 (d, J= 0.9 Hz, 1H), 7.42 (dd, J= 7.5, 1.9 Hz, 1H), 7.36 - 7.27 (m, 2H), 3.88 (s, 3H), 3.84 (s, 2H), 3.64 (s, 3H)
Example 3: N-carbamimidoyl-2-[2-chloro-6-(3-methylsulfonylphenyl)phenyl]acetamide.
HCl
Figure imgf000049_0001
The title compound was prepared from methyl 2-(2-bromo-6-chlorophenyl)acetate (Enamine) and 3-(methylsulfonyl)phenylboronic acid using Protocol 1 and Pd PPhs^Ch in the Suzuki coupling, m/z'. 366.2 @ 1.02 min, Method 1. 'HNMR (400 MHz, DMSO) 5 12.00 (s, 1H), 8.25 (m, 4H), 8.00 (dt, J = 7.8, 1.5 Hz, 1H), 7.79 (t, J = 2.0 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.67 (dt, J = 7.7, 1.4 Hz, 1H), 7.61 (dd, J = 8.1, 1.3 Hz, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.36 (dd, J = 7.6, 1.3 Hz, 1H), 3.83 (s, 2H), 3.27 (s, 3H).
Example 4: N-carbamimidoyl-2-[2-chloro-6-(4-pyridyl)phenyl]acetamide. 2HC00H
Figure imgf000049_0002
The title compound was prepared from methyl 2-(2-bromo-6-chlorophenyl)acetate (Enamine) and pyridin-4-ylboronic acid using Protocol 1 and Pd(dppf)C12 in the Suzuki coupling. m/z 289.1 @ 0.89 min, Method 1. 'HNMR (400 MHz, DMSO) 5 8.67 - 8.58 (m, 2H), 8.15 (s, 2H), 7.54 - 7.48 (m, 1H), 7.42 - 7.32 (m, 3H), 7.22 (dd, J= 7.6, 1.4 Hz, 1H), 3.51 (s, 2H). (exchangeable guanidine NH peaks were not observed)
II. BIOLOGY EXAMPLES
II.1. ASSAYS FOR ADRENERGIC a2 FUNCTIONAL ACTIVITIES
II. LA. Stimulation of GTP binding in CHO cells
Materials
CHO-K1 cells stably transfected with plasmid containing the human sequence for adrenergic receptors: oi2A, G.2B and 012c were purchased from Perkin Elmer (EC-030-C, ES-31-C and ES- 032-C, respectively). Cells were maintained in Ham’s F12 (11765054, Gibco) with addition of 10 % (v/v) FBS and 0.4 mg/ml Geneticin (10131027, Gibco) at 37 °C, 5 % CO2 and passaged twice weekly. HTRF GTP binding kit was purchased from Perkin Elmer (62GTPPEC).
Methods
Membrane preparations
Cells were detached in Versene for up to 15 minutes with agitation. All collected cells were centrifuged at 300 xg for 5 minutes (RT) and supernatants were discarded. Cell pellets were resuspended in ice-cold HE buffer: 20 mM HEPES (H0887, Merck), 10 mM EDTA (E7889, Merck), pH 7.4. The cell suspension was then homogenised using a Dounce homogeniser with 20x strokes of pestle A, followed by 20x strokes with pestle B. Homogenates were centrifuged for 600 xg for 10 minutes at 4 °C. The supernatants were then transferred to high-speed centrifuge tubes (NC654, Appleton Woods). Pellets were again resuspended in ice-cold HE buffer: 20 mM HEPES (H0887, Merck), 10 mM EDTA (E7889, Merck), pH 7.4and homogenised using a Dounce homogeniser with 20x strokes of pestle A, followed by 20x strokes with pestle B, then centrifuged for 600 xg for 10 minutes at 4 °C. Supernatants were pooled and centrifuged at 40,000xg for 1 h at 4 °C. Each pellet was resuspended in 400 pl of 20 mM HEPES with 10 % (w/v) glycerol (332031000, ThermoScientific). All steps were performed on ice. Membrane suspensions were passed lOx through the insulin syringe (324892, BD Microfine), aliquoted and stored at -80 °C until further use. Protein content was established using the BCA kit (23225, ThermoFisher) with bovine serum albumin standards.
HTRF GTP binding assay
To evaluate the potential agonists of a2 adrenergic receptors (012A, 0.215 and 012c) HTRF GTP binding kit was used with some modification to the manufacturer’s protocol. Tested compounds were dispensed into 384 white ProxiPlates Plus (6008280, Perkin Elmer) using an ECHO acoustic dispenser with automatic DMSO backfill. Guanfacine (HU-17416, Medchemtronica AB) was used as a reference compound. All compounds were run in duplicates on each plate. For plate controls, 30 pM norepinephrine (N5785, Merck) and vehicle control (DMSO) were used. Then, the assay mix was prepared by mixing stimulation buffer #3, MgCh, lx GTP Eu Cryptate reagent, lx GTP d2 antibody and membrane preparation. MgCh concentration per well was 50 mM for a.2 \ and 012c, 8 mM for a.215. The amount of membrane proteins was established for each membrane preparation in a validation experiment (range 0.5-2 pg of protein per well). 10 pl of assay mix was added per well and assay plates were briefly centrifuged. Then plates were sealed with the optically clear plate seals (4311971, Applied Biosystems) and incubated for 6 h at room temperature. Plates were read on Pherastar FSX (BMG Labtech) using the Pherastar HTRF module. Fluorescence was read at two channels: 665 nm and 620 nm and the ratio between channels was calculated. Data was expressed as the percentage activation versus 30 pM norepinephrine.
Results. As evidenced in Table 1 below, the compounds of the present invention stimulate GTP binding on a2-overexpressing CHO cells.
Table 1 :
Figure imgf000051_0001
ND: Not Determined
III. PHARMACOKINETIC EXAMPLES
III.l. DETERMINATION OF PERMEABILITY AND EFFLUX IN CACO-2 CELLS
As mentioned in the introduction, the compounds of the invention have to exhibit a limited, if any, CNS penetrance, in order to avoid deleterious side effects that can occur if these compounds penetrate significantly into the brain.
The present assay aims at showing that the compounds of the invention do not have any significant CNS penetrance by showing that they are substrates of transporters that efflux them from brain.
Indeed, it is well known in the art that xenobiotics that are substrates of transporters such as P- Glycoprotein are not efficient in penetrating the Blood-Brain Barrier, and are thus less effective in the Central Nervous System (Alfred H. Schinkel, “P-Glycoprotein, a gatekeeper in the blood-brain barrier”, Advanced Drug Delivery Reviews 36 (1999) 179-194). The present assay thus aims at showing that the compounds of the present invention are substrates to such transporters present in the Caco-2 cell line and thus do not cross the Blood- Brain Barrier.
Protocol Summary
The permeability of test compounds across confluent Caco-2 monolayers were assessed using 96-well Transwell plates by adding compound into the apical and basolateral compartments (bidirectional) and determining test compound levels in the opposing compartment after 2 hours at 37°C in a CO2 incubator. Following sampling at T=0 and 2hrs from both compartments, the samples are analysed by UPLC-MS.
Experimental Procedure
The Caco-2 Permeability assay used cells purchased from EC ACC (86010202) and cultured inhouse. Caco-2 cells are plated on a 96-transwell permeable system as a single monolayer and allowed to differentiate for 21 days to phenotypically mimic intestinal epithelial cells. Dilutions of a 10 mM test compound DMSO stock solution were prepared in buffer (supplemented HBSS, pH6 or 7.4 for apical; supplemented HBSS, pH7.4 for basolateral)) so that the final DMSO concentration was 0.1% and the final test compound concentration tested was 10 uM. Following addition of test compound (in duplicate) into either the apical or basolateral compartment, the samples were incubated for 2 hours at 37°C in a CO2 incubator. Aliquots were sampled at T=0 and 2hrs and mixed with acetonitrile (containing internal standard). All the samples were mixed, centrifuged and the supernatants analysed by UPLC-MS with quantification against a calibration line prepared in matched HBSS buffer. Lucifer Yellow permeability was performed during the incubation period to assess monolayer integrity.
Data Analysis
Test Compound was quantified in each compartment and concentrations determined and against a calibration curve prepared in matched HBSS buffer.
The apparent permeability coefficient (Papp) was calculated using the following equation: Papp=VR/(Area* Time) * (CR/C0) wherein VR is the solution volume in the receiver chamber; Area is the surface area for the transport; Time is incubation time, expressed in seconds; CO is the initial concentration in the donor chamber; CR is the final concentrations in receiver chamber.
The efflux ratio was calculated using the following equation: Efflux ratio = Papp (A-B)ZPapp(B-A) where Papp (A-B) and Papp (B-A) are the Papp values of compound in Apical to Basolateral and Basolateral to Apical directional transport, respectively. Results. Compounds are considered to be P-Glycoprotein substrates when the value of efflux ratio is > 3. Compounds of the present invention typically have efflux ratios > 3 whereas guanfacine has an efflux ratio < 3 (1.5), as evidenced in Table 2 below.
Table 2:
Figure imgf000053_0001

Claims

1. A compound of formula (I):
Figure imgf000054_0001
wherein: Ri represents a radical selected in a group consisting of:
• a hydrogen,
• a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl,
• a halogen,
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
• a (Ci-Ce)alkyloxy optionally substituted by at least one halogen; X is selected from the group consisting of -(CH2)m- with m is from 1 to 3 optionally substituted by at least one Ra, -O-, -S-, -CO-, -C(O)-O-, -O-C(O)-, -NRa-, -CO-NRa-, - NRa-CO-, -SO-, -SO2-, -SO2-NRa, -NRa-S02-, and -NRa-CO-NRa-, with Ra being a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical C, a cycloalkyl optionally substituted by at least one radical C, or a heterocycloalkyl optionally substituted by at least one radical C; said radical C being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRbRc with Rb and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rb and Rc may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a -
NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl; n is 0 or 1; R2 represents a radical selected in a group consisting of:
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl, said 3-14 membered ring is optionally substituted by at least one radical A selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, or a hydroxy, a cycloalkyl optionally substituted by a halogen, a (Ci- Ce)alkyloxy, or a hydroxy, a (C2-Ce)alkenyl, a (C2-Ce)alkynyl, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen, a cyano, a -NRaRe with Rd and Re represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rd and Re may form together a N-heterocycloalkyl, a nitro, a hydroxy, a ketone, - a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a - NH-CO-cycloalkyl, a -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a - NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl,
- a -C(O)-O-(Ci-C6)alkyl, a -O-C(O)-(Ci-C6)alkyl, a - COOH, a -C(O)-O-cycloalkyl, -O-C(O)-cycloalkyl, a -CO-(Ci-Ce)alkyl, a -CO-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl, and
• a radical selected in a group consisting of: o a (Ci-Ce)alkyl optionally substituted by at least one radical B or a cycloalkyl optionally substituted by at least one radical B, o a (C2-Ce)alkenyl optionally substituted by at least one radical B, o a (C2-Ce)alkynyl optionally substituted by at least one radical B, o a (Ci-Ce)alkyloxy optionally substituted by at least one radical B, o a cyano, o a -NRfRg’ with Rf and Rg’, represent independently a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg’ may form together a N-heterocycloalkyl, and o a -N(Rf)-CO-Rg, a-CO-N(Rf)-Rg, a -CO-Rf, a -C(O)-O-Rf, a -O- C(O)-Rf, a -SO2-Rf, a -SO-Rf, a -SO2-N(Rf)-Rg, a -N(Rf)-SO2-Rg, and a -N(Rh)-CO-NRfRg, with Rf, Rg, and Rh represent independently a hydrogen, a (Ci-Ce)alkyl optionally substituted by at least one radical B, a cycloalkyl optionally substituted by at least one radical B, a heterocycloalkyl optionally substituted by at least one radical B, or Rf and Rg may form together a N- heterocycloalkyl, said radical B being selected in a group consisting of: a (Ci-Ce)alkyloxy, a halogen,
- a -O-C(O)-(Ci-C6)alkyl, a -C(O)-O-(Ci-C6)alkyl, a - COOH, a -O-C(O)-cycloalkyl, a -C(O)-O-cycloalkyl,
- a -CO-(Ci-C6)alkyl, a -CO-cycloalkyl, a hydroxy, a -NRiRj with Ri and Rj represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Ri and Rj may form together a N-heterocycloalkyl, a nitro, a cyano,
- a -NH-CO-(Ci-C6)alkyl, a -CO-NH-(Ci-C6)alkyl, a -NH-CO-cycloalkyl; -CO-NH-cycloalkyl,
- a -NH-SO2-(Ci-C6)alkyl, a -SO2-NH-(Ci-C6)alkyl, a -NH-SO2-cycloalkyl, a -SO2-NH-cycloalkyl, a -SO2-(Ci-Ce)alkyl, a -SO2-cycloalkyl, a -SO-(Ci-Ce)alkyl, and a -SO-cycloalkyl; R3 represents a radical selected in a group consisting of:
• a hydrogen,
• a (Ci-Ce)alkyl optionally substituted by a (Ci-Ce)alkyloxy, a hydroxy, at least one halogen, and a cycloalkyl,
• a halogen,
• a 3-14 membered ring, saturated, partially unsaturated, or unsaturated selected in a group consisting of a cycloalkyl, a heterocycloalkyl, an aryl, and an heteroaryl, said 3-14 membered ring is optionally substituted by a (Ci-Ce)alkyl, a hydroxy, a halogen, a -SO2-(Ci-Ce)alkyl, and a (Ci-Ce)alkyloxy, and
• a (Ci-Ce)alkyloxy optionally substituted by at least one halogen; R4 represents a radical selected in a group consisting of:
• a hydrogen,
• a halogen,
• a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a (Ci-Ce)alkyloxy optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a hydroxy, • a -NRkRi with Rk and Ri represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rk and Ri may form a N-heterocycloalkyl,
• a nitro,
• a cyano,
• a -NH-(Ci-Ce)alkyl, a -NH-cycloalkyl; and
• a -NH-CO-(Ci-Ce)alkyl, and a -NH-CO-cycloalkyl; Rs represents a radical selected in a group consisting of:
• a hydrogen,
• a halogen,
• a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a (Ci-Ce)alkyloxy optionally substituted by a halogen, a (Ci-Ce)alkyloxy, a hydroxy, or a cycloalkyl,
• a hydroxy,
• a -NRkRi with Rk and Ri represent independently a hydrogen, a (Ci-Ce)alkyl, a cycloalkyl, or Rk and Ri may form a N-heterocycloalkyl,
• a nitro,
• a cyano,
• a -NH-(Ci-Ce)alkyl, a -NH-cycloalkyl; and
• a -NH-CO-(Ci-Ce)alkyl, and a -NH-CO-cycloalkyl; Re represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; R7 represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; and Rs represents a hydrogen, or a (Ci-Ce)alkyl optionally substituted by a radical selected in a group consisting of a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, and a -N((Ci- Ce)alkyl)2; or R7 and Rs may form together a 5-7 membered ring, partially unsaturated or saturated, N,N’ -heterocycloalkyl optionally substituted by at least one radical selected in a group consisting of a (Ci-Ce)alkyl, a hydroxy, a (Ci-Ce)alkyloxy, a -NH(Ci-Ce)alkyl, a - N((Ci-Ce)alkyl)2, and a ketone; and the isomers, stereoisomers and pharmaceutical acceptable salts thereof with the proviso that the compound is not a compound selected in the group consisting of:
A-(Aminoiminomethyl)-2-methoxybenzeneacetamide,
A-(Aminoiminomethyl)-2,4-dimethoxybenzeneacetamide, and A-(Aminoiminomethyl)-2,4-dimethylbenzeneacetamide.
2. The compound according to claim 1, wherein n is 0.
3. The compound according to claim 1 or 2, wherein R4 and R5 represent H.
4. The compound according to any one of claims 1 to 3, wherein Re, R7, and Rs represent H.
5. The compound according to any one of claims 1 to 4, wherein R3 represents H.
6. The compound according to any one of claims 1 to 5, wherein Ri represents a halogen, preferably a chlorine or a bromine, more preferably a chlorine.
7. The compound according to any one of claims 1 to 6, wherein, R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of an aryl, a heteroaryl, a cycloalkyl, and a heterocycloalkyl, said 3-14 membered ring is optionally substituted by at least one radical A selected in a group consisting of: a (Ci-Ce)alkyl optionally substituted by a halogen, a (Ci-Ce)alkyloxy optionally substituted by a halogen, a halogen,
- a -CO-(Ci-C6)alkyl, and
- a -SO2-(Ci-C6)alkyl.
8. The compound according to any one of claims 1 to 7, wherein R2 represents a 3-14 membered ring, saturated, partially unsaturated, or unsaturated, selected in a group consisting of: o an aryl, particularly a phenyl, said aryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyloxy, particularly a methoxy or an ethoxy, a halogen, particularly a chlorine, and a -SO2-(Ci-C6)alkyl, particularly a -SO2-CH3, o a heteroaryl, particularly a pyrimidinyl, a pyrazolyl, or a pyridinyl, said heteroaryl is optionally substituted by at least one radical selected in a group consisting of: a (Ci-Ce)alkyl, particularly a methyl, and a (Ci-Ce)alkyloxy, particularly a methoxy, o a cycloalkyl, particularly a cyclopropyl, and o a heterocycloalkyl, particularly a 3,6-dihydro-2H-pyran, a piperazinyl, or a morpholinyl, said heterocycloalkyl is optionally substituted by a - CO-(Ci-Ce)alkyl, particularly a -CO-CH3.
9. The compound according to any one of claims 1 to 6, wherein R2 represents a radical selected in a group consisting of: o a (Ci-Ce)alkyl, particularly an isobutyl, and o a -SO2-(Ci-Ce)alkyl, particularly a -SO2-CH3.
10. The compound according to claim 1, wherein said compound has the following formula selected in a group consisting of:
Figure imgf000060_0001
Figure imgf000061_0001
11. The compound according to any one of claims 1 to 10, for use as a medicine.
12. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 10, and a pharmaceutically acceptable excipient.
13. The pharmaceutical composition according to claim 12, for use for treating a cancer.
14. The pharmaceutical composition for use according to claim 13, wherein the cancer is selected in a group consisting of myelofibrosis, acute lymphoblastic leukemia, acute myeloblastic leukemia adrenal gland carcinoma, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, glioblastoma, head and neck cancer, hepatocellular carcinoma, Hodgkin’s lymphoma, kidney cancer, lung cancer, melanoma, Merkel cell skin cancer, mesothelioma, multiple myeloma, myeloproliferative disorders, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer, prostate cancer, salivary gland cancer, sarcoma, squamous cell carcinoma, testicular cancer, thyroid cancer, urothelial carcinoma, and uveal melanoma.
15. The pharmaceutical composition for use according to claim 13 or 14, wherein the compound is administered at a dose ranging from 0.001 mg/kg body weight to 30 mg/kg body weight.
16. The pharmaceutical composition for use according to any one of claims 13 to 15, wherein said pharmceutical composition is administered in combination with another antitumoral drug, especially chemotherapy, immunotherapy, hormonotherapy and/or radiotherapy, preferably immunotherapy.
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