Azaindole derivatives with a cyclo(hetero)aliphatic ring and their use as erk kinase inhibitors

Abstract

The present invention concerns a compound of formula (I) or one of its pharmaceutically acceptable salts, especially for use as inhibitors of the ERK kinase activity, in particular ERK2 activity.

Description

[0001] AZAINDOLE DERIVATIVES WITH A CYCLO(HETERO)ALIPHATIC RING AND THEIR USE AS ERK KINASE INHIBITORS

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to azaindole derivatives which are inhibitors of ERK kinases (ERK1 and ERK2), to the process for the preparation thereof and to the therapeutic use thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] ERK protein belongs to the RAS / RAF / MEK / ERK pathway which plays a major role in cell cycle, proliferation, growth, and survival. RAS / RAF / MEK / ERK pathway is activated by growth factors through their receptor tyrosine kinase that allows activation of GTPases RAS. In its turn, RAS activates RAF proteins. Then, RAF activates MEK, which activates ERK.

[0006] Finally, this enables phosphorylation of many substrates that have key roles in metabolism, protein synthesis, cell proliferation and survival.

[0007] RAF mutations lead specifically to an over-activation of this RAS / RAF / MEK / ERK pathway and are responsible for 7% of all human cancers (Davies et al., Nature. 2002; Garnett et al. , Cancer Cell. 2004).

[0008] Indeed, RAF mutations are frequently observed in melanomas (27-70%), thyroid cancers (36-53%), colorectal cancers (5-22%) and ovarian cancers (30%). Likewise, RAS mutations occur in almost 30% of cancers and are present in pancreatic (90%), lung (35%), colorectal (45%) and liver (30%) cancers (Downward, Nat. Rev. Cancer. 2003).

[0009] Thus, proteins of RAS / RAF / MEK / ERK pathway represent targets of interest for cancers treatment. Indeed, pharmaceutical companies are focusing on upstream kinases (RAF, MEK).

[0010] However, resistances ultimately appear after current treatment with RAF and MEK inhibitors (Lito et al., Nat. Med. 2013; Caunt et al., Nat. Rev. Cancer, 2015).

[0011] Moreover, most resistances to MEK or RAF inhibitors induce ERK reactivation, through different mechanisms such as MEK mutation, B-RAF amplification, C-RAF mutation... (Little et al. , Oncogene. 2013). Furthermore, RAF or MEK inhibition suppresses ERK negative feedback that restores upward signaling and finally ERK activity (Lito et al., Nat. Med., 2013).

[0012] Considering the resistance phenomena that emerged after current treatment with RAF and MEK inhibitors, it is essential to develop new therapeutic options.

[0013] Except for its key role in hyperproliferative diseases, ERK signaling has also been described as implied in neurodegenerative disorders such as in Parkinson’s, Alzheimer’s and Huntington’s diseases (Cheung et al., Sci. STKE. 2004; Bodai et al, Bioessays., 2012) and in inflammation such as in the pathogenesis of Rheumatoid Arthritis (Thalhamer et al., Rheumatology. 2008).

[0014] Thus, the present invention relates to ERK inhibitors development to treat a broad spectrum of diseases.

[0015] Some ERK inhibitors are already described in the prior art. Thus, US 8,697,697 B2 describes substituted pyrazole derivatives as inhibitors of ERK2 kinase activity.

[0016] Pyrrolo[2,3-b]pyrazine derivatives are also reported as ERK inhibitors in the international patent application WO 2014 / 060395 Al, and azaindole derivatives are reported as ERK inhibitors in the international patent application WO 2017 / 085230 Al.

[0017] However, there remains a need for efficient compounds able to selectively inhibit ERK1 and / or ERK2 kinases.

[0018] The present invention is precisely directed to novel compounds and their use as inhibitors of the ERK kinases activity.

[0019] The compounds of the present invention are novel azaindole derivatives with at least an enhanced anti-proliferative activity.

[0020] The compounds according to the invention are also characterized by their low toxicity, high permeability, and kinase inhibition selectivity.

[0021] Advantageously, compounds of the present invention present improved physicochemical properties, such as aqueous solubility, due to the presence of the (hetero)cycloalkyl group.

[0022] Overall, the compounds according to the invention are remarkable for their druglike properties.

[0023] A first subject of the invention concerns the compounds corresponding to the general formula (I): wherein:

[0024] - Cy is a 5- or 6-membered (hetero)cycloalkyl group, optionally substituted by one or more radicals selected from halogen atoms, (Ci-Ce)alkyl group, trifluoromethyl group, cyano group, (C3-Ce)cycloalkyl group and (C3-C6)heterocycloalkyl group, wherein said (Ci- Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group;

[0025] - Ri represents a (Ci-Ce)alkyl group;

[0026] - R2 represents a (Ci-Ce)alkyl group, a (C3-Ce)cycloalkyl group, or a (Ci-Ce)alkyl group substituted by one or more radicals selected from halogen atoms, cyano group, (Ci- Ce)alkoxy group and (C3-Ce)cycloalkyl group; or Ri and R2 form together with the nitrogen atom a 3- to 6-membered heterocyclic group;

[0027] - Re, R7, Rs and R9 represent, independently of each other, a hydrogen atom, a halogen atom, a (Ci-Ce)alkyl group, a trifluoromethyl group or a cyano group, wherein said (Ci-Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group; or one of its pharmaceutically acceptable salts.

[0028] After extensive searching of the ERK crystalline structure and structural screening tests, the inventors have identified that these new azaindole derivatives of formula (I) selectively target the active sites of the ERK kinases, and act as effective inhibitors of ERK kinases activity.

[0029] In the meaning of the present invention, a “kinase inhibitor" is intended to mean a compound that reduces or suppresses the activity of the targeted kinase, as compared with said activity determined without said inhibitor.

[0030] Within the meaning of the invention, the term “prevent” or “prevention” with respect to an event is intended to mean the decrease of a risk of occurrence of said event. As will be seen below, these compounds have utility in the treatment of conditions or diseases in which modification of the activity of ERK would have a positive therapeutic outcome, in particular cancers.

[0031] Another subject concerns the compounds of general formula (I) for their use especially in medicaments or in pharmaceutical compositions.

[0032] A further subject concerns the compounds according to the invention for use as inhibitors of the ERK kinases activity, particularly for use as inhibitors of the ERK1 and / or ERK2 kinases activity.

[0033] ABBREVIATIONS AND DEFINITIONS

[0034] In the context of the present invention, the following abbreviations and empirical formulae are used:

[0035] ATP adenosine 5 ’-triphosphate

[0036] Brij-35 Polyoxyethyleneglycol dodecyl ether

[0037] Boc tert-butyloxycarbonyl

[0038] CS2CO3 Cesium carbonate

[0039] DMF Dimethylformamide

[0040] DMEM Dulbecco’s Modified Eagle Medium

[0041] DMSO Dimethylsulfoxide

[0042] °C Degree Celsius

[0043] DCM Dichloromethane

[0044] EGTA Egtazic acid

[0045] Et2O Diethyl ether

[0046] EtOH Ethanol

[0047] FBS Fetal bovine serum g gram(s) h hour(s)

[0048] HC1 Hydrochloric acid

[0049] HEPES (4-(2 -hydroxy ethyl)- 1 -piperazineethanesulfonic acid

[0050] K2CO3 Potassium carbonate

[0051] LiHMDS Lithium bis(trimethylsilyl)amide

[0052] M Mole(s) per liter MeCN Acetonitrile

[0053] MeOH Methanol mg Milligram(s)

[0054] Ms Mesyl pl Microliter(s) ml Milliliter(s) mmol Millimole(s) mol Mole(s)

[0055] Na2CC>3 Sodium carbonate

[0056] NaOH Sodium hydroxide

[0057] PG Protecting group

[0058] RuPhos 2-Dicy cl ohexylphosphino-2’, 6’ -diisopropoxybiphenyl

[0059] RuPhos Pd G2 Chloro(2-dicyclohexylphosphino-2’,6’-diisopropoxy-l,r-bi- phenyl)[2-(2’ -amino- 1,1’ -biphenyl)]palladium(II)

[0060] SDS Sodium dodecyl sulfate

[0061] TBAF Tetrabutylammonium fluoride

[0062] THF Tetrahydrofuran

[0063] TIPS Triisopropyl silyl

[0064] TMS Trimethyl silyl

[0065] Ts Tosyl

[0066] In the context of the present invention, the following definitions apply:

[0067] - a halogen atom: a fluorine, a chlorine, a bromine, or an iodine atom. The halogen atoms may be more particularly chosen among chlorine and fluorine atoms.

[0068] - Ct-Cz: a carbon-based chain possibly containing from t to z carbon atoms in which t and z may take values from 1 to 10; for example, C1-C3 is a carbon-based chain possibly containing from 1 to 3 carbon atoms.

[0069] - an alkyl: a linear or branched saturated aliphatic group, in particular comprising from 1 to 6 carbon atoms. Examples that may be mentioned include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, etc...

[0070] - an alkoxy: a radical -O-alkyl in which the alkyl group is as defined previously.

[0071] - a cyano group: a radical -ON. - a trifluoromethyl group: a radical -CF3.

[0072] - a (hetero)cycloalkyl group: a cycloalkyl group or a heterocycloalkyl group.

[0073] - a cycloalkyl group: a non-aromatic mono- or bicyclic saturated or partially saturated or unsaturated ring containing 3 to 8 carbon atoms. Examples of cycloalkyl group that may be mentioned include cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane or cyclohexene.

[0074] - a heterocycloalkyl group or a heterocyclic group: a monocyclic saturated ring containing at least one heteroatom.

[0075] - a 5- or 6-membered (hetero)cycloalkyl group: examples of 5- or 6-membered (hetero)cycloalkyl group that may be mentioned include cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranyl, 1,2- dioxanyl, 1,4-dioxanyl, tetrahydropyranyl.

[0076] - 3- to 6-membered heterocyclic group: examples of 3- to 6-membered heterocyclic group that may be mentioned include aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, 2-oxa-6- azaspiro[3.3]heptanyl.

[0077] Other features, properties and advantages of the invention will emerge more clearly from the description and examples that follow.

[0078] COMPOUNDS OF THE INVENTION

[0079] As above-mentioned, the compounds according to the invention correspond to general formula (I): wherein: - Cy is a 5- or 6-membered (hetero)cycloalkyl group, optionally substituted by one or more radicals selected from halogen atoms, (Ci-Ce)alkyl group, trifluoromethyl group, cyano group, (C3-Ce)cycloalkyl group and (C3-C6)heterocycloalkyl group, wherein said (Ci- Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group;

[0080] - Ri represents a (Ci-Ce)alkyl group;

[0081] - R2 represents a (Ci-Ce)alkyl group, a (C3-Ce)cycloalkyl group, or a (Ci-Ce)alkyl group substituted by one or more radicals selected from halogen atoms, cyano group, (Ci- Ce)alkoxy group and (C3-Ce)cycloalkyl group; or Ri and R2 form together with the nitrogen atom a 3- to 6-membered heterocyclic group;

[0082] - Re, R7, Rs and R9 represent, independently of each other, a hydrogen atom, a halogen atom, a (Ci-Ce)alkyl group, a trifluoromethyl group or a cyano group, wherein said (Ci-Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group; or one of its pharmaceutically acceptable salts.

[0083] The compounds of formula (I) may comprise one or more asymmetric carbon atoms. They may thus exist in the form of enantiomers or diastereoisomers. These enantiomers and diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

[0084] According to a preferred embodiment, the asymmetric carbon bearing the group -CH2NR1R2 of the compounds of formula (I) is of R configuration.

[0085] The compounds of formula (I) may also exist in the form of free bases or of acidaddition salts. These salts may be prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purifying or isolating the compounds of formula (I) also form part of the invention.

[0086] The compounds of formula (I) may also exist in the form of hydrates or solvates, i.e. in the form of associations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates also form part of the invention.

[0087] According to an embodiment, Cy is a 5-membered (hetero)cycloalkyl group.

[0088] According to an embodiment, Cy is a 5-membered cycloalkyl group, i.e. Cy is a cyclopentyl group.

[0089] According to an embodiment, Cy is a 5-membered heterocycloalkyl group, in particular chosen from a pyrrolidinyl, a tetrahydrofuranyl or a tetrahydropyranyl group. According to an embodiment, Cy is a 5-membered (hetero)cycloalkyl group substituted in 3-position by one or more radicals, in particular selected from halogen atoms, (Ci-Ce)alkyl group, trifluoromethyl group, cyano group, (C3-Ce)cycloalkyl group and (C3- C6)heterocycloalkyl group, wherein said (Ci-Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group.

[0090] According to an embodiment, Cy is a 6-membered (hetero)cycloalkyl group.

[0091] According to an embodiment, Cy is a 6-membered cycloalkyl group, i.e. Cy is a cyclohexyl group.

[0092] According to an embodiment, Cy is a 6-membered heterocycloalkyl group, in particular chosen from a piperidinyl, a morpholinyl, a thiomorpholinyl, a piperazinyl, a 1,2- dioxanyl, a 1,4-dioxanyl, or a tetrahydropyranyl group, and preferably a tetrahydropyranyl group.

[0093] According to an embodiment, Cy is a 6-membered (hetero)cycloalkyl group selected from a cyclohexyl group and a tetrahydropyran group.

[0094] According to an embodiment, Cy is a 6-membered (hetero)cycloalkyl group, in particular substituted in meta position, preferably by a radical selected from halogen atoms, trifluoromethyl group and (C3-C6)heterocycloalkyl group.

[0095] According to a preferred embodiment, Cy is a cyclohexyl group or a tetrahydropyran group.

[0096] According to a preferred embodiment, Cy is a cyclohexyl group.

[0097] According to a preferred embodiment, Cy is a cyclohexyl group substituted in meta position, by one or two halogen atoms, preferably fluorine atoms, a trifluoromethyl group or an oxetanyl.

[0098] According to a preferred embodiment, Cy is a tetrahydropyran group.

[0099] According to an embodiment, Ri represents a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, in particular Ri represents a methyl group, an ethyl group, or a propyl group, and preferably Ri represents a methyl group or an ethyl group.

[0100] According to a preferred embodiment, Ri represents a methyl group.

[0101] According to a preferred embodiment, R2 represents a (Ci-Ce)alkyl group.

[0102] According to an embodiment, R2 represents a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, or a hexyl group, in particular R2 represents a methyl group, an ethyl group or a propyl group, and preferably R2 represents a methyl group or an ethyl group.

[0103] Preferably, R2 represents a methyl group.

[0104] According to another embodiment, R2 represents a (C3-Ce)cycloalkyl group, and preferably a cyclopropyl group.

[0105] According to another embodiment, R2 represents a (Ci-Ce)alkyl group substituted by one or more radicals selected from halogen atoms, cyano group, (Ci- Ce)alkoxy group and (C3-Ce)cycloalkyl group.

[0106] Preferably, R2 represents a (Ci-Ce)alkyl group, in particular a methyl group or an ethyl group, a cyclopropyl group, -CH2-CF2, -CH2-CN, -CH2-CH2-O-CH3 or -CH2- cyclopropyl.

[0107] According to another embodiment, Ri and R2 form together with the nitrogen atom an aziridinyl group.

[0108] According to a preferred embodiment, both Ri and R2 represent a methyl group.

[0109] According to a preferred embodiment, Re represents a hydrogen atom or a (Ci- Ce)alkyl group.

[0110] More particularly, Re represents a hydrogen atom or a methyl group.

[0111] According to a preferred embodiment, Re represents a hydrogen atom.

[0112] According to another preferred embodiment, Re represents a (Ci-Ce)alkyl group, in particular a methyl group or an ethyl group, and preferably a methyl group.

[0113] According to a preferred embodiment, R7 represents a hydrogen atom or a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom.

[0114] More particularly, R7 represents a hydrogen atom, a chlorine atom, or a fluorine atom.

[0115] According to a preferred embodiment, R7 represents a hydrogen atom.

[0116] According to another preferred embodiment, R7 represents a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom, and preferably a fluorine atom.

[0117] According to a preferred embodiment, both Re and R7 represent a hydrogen atom. According to a preferred embodiment, Rs represents a hydrogen atom or a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom.

[0118] More particularly, Rs represents a hydrogen atom, a chlorine atom, or a fluorine atom.

[0119] According to a preferred embodiment, Rs represents a hydrogen atom.

[0120] According to another preferred embodiment, Rs represents a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom, and preferably a fluorine atom.

[0121] According to a preferred embodiment, R9 represents a hydrogen atom, a halogen atom or a trifluoromethyl group.

[0122] More particularly, R9 represents a hydrogen atom or a trifluoromethyl group.

[0123] According to a preferred embodiment, R9 represents a hydrogen atom.

[0124] According to another preferred embodiment, R9 represents a trifluoromethyl group.

[0125] According to a preferred embodiment, all of Re, R7, Rs and R9 represent a hydrogen atom.

[0126] According to a preferred embodiment, both Ri and R2 represent a methyl group, and all of Re, R7, Rs and R9 represent a hydrogen atom.

[0127] According to a preferred embodiment, both Ri and R2 represent a methyl group, all of Re, R7, Rs and R9 represent a hydrogen atom, and Cy is an unsubstituted cyclohexyl group.

[0128] According to another preferred embodiment, both Ri and R2 represent a methyl group, all of Re, R7, Rs and R9 represent a hydrogen atom, and Cy is a cyclohexyl group substituted in meta position, by one or two halogen atoms, preferably fluorine atoms, a trifluoromethyl group or an oxetanyl.

[0129] It is clear that features of the above-mentioned embodiments may be combined with each other, unless specifically noted otherwise.

[0130] Among the compounds of formula (I) mention may be made especially of the following compounds: or one of their pharmaceutically acceptable salts.

[0131] APPLICATIONS

[0132] As specified previously, the compounds according to the present invention are useful as inhibitors of the ERK kinases activity.

[0133] According to a first aspect, the compounds of the invention are used as inhibitors of the ERK2 kinase activity, preferably as selective inhibitors of the ERK2 kinase activity.

[0134] More specifically, the compounds of the invention are used for preventing and / or inhibiting and / or treating a disease or a condition mediated by ERK kinases activity, in particular by ERK2 kinase activity.

[0135] The present invention therefore provides a method for preventing and / or treating a disease or a condition mediated by ERK kinases activity, comprising at least a step of administering to an individual in need thereof at least an effective amount of at least one compound in accordance with the invention.

[0136] The present invention also provides the compounds of the invention for their use for preventing and / or inhibiting and / or treating, preferably for preventing and / or treating, more preferably for treating, a disease or a condition mediated by ERK kinases activity, preferably ERK2 kinases activity.

[0137] The present invention also provides the use of compounds of the invention for preventing and / or inhibiting and / or treating, preferably for preventing and / or treating, more preferably for treating, a disease or a condition mediated by ERK kinases activity, preferably ERK2 kinases activity.

[0138] According to one embodiment, the disease or the condition may be chosen among cancers, metastases and the Human Immunodeficiency Virus (HIV), and preferably chosen among cancers and metastases.

[0139] More specifically, the disease or the condition may be chosen among glioblastomas, multiple myelomas, carcinomas, leukemia, in particular myeloid (AML), lymphocytic, myelocytic, myelogenous (CML) or lymphoblastic leukemias, myelodysplastic syndromes, Kaposi’s sarcomas, cutaneous angiosarcomas, solid tumours, lymphomas, in particular non-hodgkin’s lymphomas, melanomas, in particular malignant melanomas, bladder cancers, breast cancers, gastric cancers, colon cancers, colorectal cancers, endometrial cancers, lung cancers, including non-small-cell cancers, pancreatic cancers, prostate cancers, rectal cancers, kidney cancers, head and neck cancers, liver cancers, ovarian cancers, in particular serous ovarian cancers, seminoma cancers, cancers of the respiratory tract and chest, thyroid cancers, in particular papillary or follicular thyroid cancers, or other tumours expressing ERK.

[0140] According to another embodiment, the disease or condition may be chosen among a neoplastic disorder, an allergy disorder, an inflammatory disorder, an autoimmune disorder, a Plasmodium related disease, a mast cell associated disease, a graft- versus -host disease, a metabolic syndrome, a CNS related disorder, a neurodegenerative disorder, a pain condition, a substance abuse disorder, a prion disease, a heart disease, a fibrotic disease, idiopathic arterial hypertension (IP AH), or primary pulmonary hypertension (PPH). According to yet another embodiment, the compounds of the invention may be used for preventing and / or inhibiting and / or treating the Human Immunodeficiency Virus (HIV).

[0141] The compounds of the present invention may be used alone or combined with chemotherapeutic agents or radiotherapeutic regimen.

[0142] Thus, according to one embodiment, a method of the invention may comprise the step of administering a compound of formula (I) in accordance with the invention, separately, sequentially, or simultaneously with a chemotherapeutic agent.

[0143] As examples of chemotherapeutic agents that may be suitable for the invention, one may mention chemotherapeutic agents chosen from alkylating agents, intercalating agents, antimicrotubule agents, antimitotics, antimetabolites, antiproliferative agents, antibiotics, immunomodulatory agents, anti-inflammatories, kinases inhibitors, anti- angiogenic agents, antivascular agents, oestrogenic and androgenic hormones.

[0144] A radiotherapeutic regimen may be administrated by exposing an individual in need thereof to a source of ionizing radiation such as X-ray, gamma-ray or beta-ray.

[0145] According to another of its aspects, the present invention relates to a pharmaceutical composition comprising at least one compound according to the invention or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0146] The compounds according to the invention may be used for the preparation of medicaments, in particular of medicaments for inhibiting the activity of ERK kinases preferably ERK2 kinases activity.

[0147] Thus, according to yet another of its aspects, the present invention relates to a medicament comprising at least one compound according to the invention, or a pharmaceutically acceptable salt thereof.

[0148] The term “pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes what is acceptable for veterinary as well as human pharmaceutical use.

[0149] The pharmaceutical compositions may contain more particularly an effective dose of at least one compound according to the invention. An “ effective dose" means an amount sufficient to induce a positive modification in the condition to be regulated or treated, but low enough to avoid serious side effects. An effective amount may vary with the pharmaceutical effect to obtain or with the particular condition being treated, the age and physical condition of the end user, the severity of the condition being treated / prevented, the duration of the treatment, the nature of other treatments, the specific compound or composition employed, the route of administration, and like factors.

[0150] A compound of formula (I) according to the invention may be administered in an effective dose by any of the accepted modes of administration in the art.

[0151] In one embodiment, a compound of the invention may be used in a composition intended to be administrated by oral, nasal, sublingual, aural, ophthalmic, topical, rectal, vaginal, urethral, or parenteral injection route.

[0152] The route of administration and the galenic formulation will be adapted by one skilled in the art pursuant to the desired pharmaceutical effect.

[0153] One of ordinary skill in the art of therapeutic formulations will be able, without undue experimentation and in reliance upon personal knowledge, to ascertain a therapeutically effective dose of a compound of the invention for a given indication.

[0154] A pharmaceutical composition of the invention may be formulated with any known suitable pharmaceutically acceptable excipients according to the dose, the galenic form, the route of administration and the likes.

[0155] As used herein, ^pharmaceutically acceptable excipients’" include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. Except insofar as any conventional excipient is incompatible with the active compounds, its use in a medicament or pharmaceutical composition of the invention is contemplated.

[0156] A medicament or pharmaceutical composition of the invention may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, sprays, ointments, gels, creams, sticks, lotions, pastes, soft and hard gelatine capsules, suppositories, sterile injectable solutions, sterile packages powders and the like.

[0157] According to one embodiment, a pharmaceutical composition of the invention may be intended to be administered separately, sequentially, or simultaneously with an agent useful for the prevention and / or the treatment of a disease condition, in particular a cancer condition, said agent being different from the compound of formula (I) of the invention.

[0158] The applications also include a novel kit-of-parts that is suitable for use in the treatment of cancers.

[0159] A kit-of-part according to the invention may comprise (i) a compound of formula (I) according to the invention, and (ii) at least one agent useful for the prevention and / or the treatment of a cancer condition, said agent being different from said compound of formula (I). An agent useful for the prevention and / or treatment of a cancer condition may be a chemotherapeutic agent or a radiotherapeutic agent.

[0160] PREPARATION OF THE COMPOUNDS OF THE INVENTION

[0161] Compounds of the invention can be prepared according to methods as illustrated below.

[0162] According to a first embodiment, the synthesis of synthetic intermediates of compounds of the present invention may be accomplished according to the Schemes 1 and 2 below.

[0163] More precisely, synthetic intermediates of formula (V) may be prepared according to Scheme 1, wherein Rs and R9 are as defined above in formula (I) and PG is a protecting group chosen from -Tosyl, -Mesyl, -Brosyl, -Nosyl, -Trifyl, -tertbutyloxycarbonyl, -trimethylsilylethoxymethyl, -Trimethylsilyl, -Triisopropyl silyl, preferably a group -Tosyl.

[0164] Scheme 1

[0165] 5-Morpholino-7-azaindole derivatives of formula (III), as shown in scheme 1, can be obtained from commercially available compounds of formula (II), by carrying out a Buchwald-Hartwig coupling reaction, with a base such as LiHMDS, a catalyst like RuPhos and a RuPhos ligand such as RuPhos Pd G2 (Step a). Other RuPhos ligands such as RuPhos Pd G3 or RuPhos Pd G4 could also be used to obtain compounds of formula (III). This reaction is generally performed in anhydrous solvent such as THF and at a temperature of 60-70°C.

[0166] Then, compounds of formula (IV) can be obtained by performing a protection of the pyrrolyl moiety of the 7-azaindole core with a protecting group, such as Ts or another sulfonyl group, and using a base, such as NaH or K2CO3, in an anhydrous solvent, such as DMF, DCM or THF (Step b). This reaction could also be performed with another protecting group such as Boc, trimethylsilylethoxymethyl, TMS or TIPS.

[0167] Finally, compounds of formula (V) can be obtained by a selective borylation of the azaindole core in position 3 (Step c), using (l,5-cyclooctadiene)(methoxy)iridium(I), in presence of a ligand, such as 4,4’-di- / c / 7-butylbiphenyl, and a source of boron, such as bis(pinacolato)diboron. This reaction is generally performed in methyl-THF at reflux for 30 min to several hours under argon.

[0168] Among the compounds of formula (V) mention may be made especially of the following compound (Va):

[0169] According to an embodiment, compounds of general formula (V) wherein Rs and R9 are as defined in formula (I) and PG is a protecting group as defined above may be prepared by a process wherein the following steps are carried out in that order, starting from compounds of formula (II): a) a Buchwald-Hartwig coupling reaction to obtain 5-morpholino-7-azaindoles of formula (III), b) a protection of the pyrrolyl moitey of the 7-azindole core to obtain compounds of formula (IV), c) a selective borylation of the azaindole core in position 3 to finally obtain compounds of formula (V). Synthetic intermediates of formula (XI) may be prepared according to Scheme 2, wherein Ri, R2, Cy, Re and R7 are as defined above, X is Cl, Br or OMs, and Y is a halogen atom.

[0170] Scheme 2

[0171] Compounds of formula (VII) can be obtained by direct olefination of commercially available aldehydes of formula (VI). The reaction is generally performed with methyltriphenylphosphonium bromide in presence of a base such as NaH, and in an anhydrous solvent such as Et2O, DCM or THF (Step 1).

[0172] Then, alkenes of formula (VII) can be converted to the corresponding epoxides of formula (VIII) typically using the couple NBS / AcOH at 0°C followed by a NaOH solution (Step 2). Epoxide formation could also be performed with other reageants such as peroxides or NaOCl.

[0173] Selective epoxide opening of compounds of formula (VIII) is then carrying out with commercially available disubstituted amines HNR1R2 (Step 3). The reaction is preferably performed in EtOH 96% at room temperature for 24h to obtain the best regioselectivity but could also be done in an EtOH / water mixture, and / or heating for few hours.

[0174] Benzylalcohol derivatives of formula (IX) can be then converted to the corresponding benzyl chlorides or mesylate derivatives of formula (X) using MsCl at 0°C in an anhydrous solvent such as DCM (Step 4). Benzylbromides of formula (X) could also be prepared with thionyl bromide instead of MsCl in DCM at 0°C.

[0175] Compounds of formula (XI) can be finally obtained by a substitution of the halogen or the OMs moiety, using commercially available 4-halogenopyridin-2-ones in the presence of a base such as K2CO3 or Na2CC>3, in DMF or DMA. The reaction could also be done in another solvent such as THF, Et2O, DCM or acetone and with other bases like NaOH or tBuOK, but a higher presence of (9-alkylated by-product formation could be observed

[0176] (Step 5).

[0177] According to a preferred embodiment, in formula (XI), Cy is a 5-membered (hetero)cycloalkyl group.

[0178] According to a preferred embodiment, in formula (XI), Cy is a 6-membered (hetero)cycloalkyl group.

[0179] According to a preferred embodiment, in formula (XI), Cy is a 6-membered cycloalkyl group, i.e. Cy is a cyclohexyl group.

[0180] According to a preferred embodiment, in formula (XI), Cy is a 6-membered heterocycloalkyl group, in particular chosen from a piperidinyl, a morpholinyl, a thiomorpholinyl, a piperazinyl, a 1,2-dioxanyl, a 1,4-dioxanyl, or a tetrahydropyranyl group, and preferably a tetrahydropyranyl group.

[0181] According to a preferred embodiment, in formula (XI), Cy is a 6-membered (hetero)cycloalkyl group selected from a cyclohexyl group and a tetrahydropyran group.

[0182] According to a preferred embodiment, in formula (XI), Cy is a 6-membered (hetero)cycloalkyl group, in particular substituted in meta position, preferably by a radical selected from halogen atoms, trifluoromethyl group and (C3-C6)heterocycloalkyl group.

[0183] According to a preferred embodiment, in formula (XI), Cy is a cyclohexyl group or a tetrahydropyran group.

[0184] According to a preferred embodiment, in formula (XI), Cy is a cyclohexyl group.

[0185] According to a preferred embodiment, in formula (XI), Cy is a cyclohexyl group substituted in meta position, by one or two halogen atoms, preferably fluorine atoms, a trifluoromethyl group or an oxetanyl.

[0186] According to a preferred embodiment, in formula (XI), Cy is a tetrahydropyran group.

[0187] According to a preferred embodiment, in formula (XI), Y is a bromine atom or an iodine atom.

[0188] According to an embodiment, compounds of general formula (XI) wherein Cy, Ri, R2, Re and R7 are as defined in formula (I), and Y is a halogen atom may be prepared by a process wherein the following steps are carried out in that order, starting from commercially available compounds of formula (VI):

[0189] 1) an olefination of the aldehydes to give the corresponding alkenes of formula (VII),

[0190] 2) an epoxidation of the olefins to obtain the compounds of formula (VIII),

[0191] 3) a regioselective ring opening to conduct to the benzyl alcohols of formula (IX),

[0192] 4) a conversion of the alcohols into their corresponding halogeno- or mesylate derivatives to give compounds of formula (X), directly followed by,

[0193] 5) a V-alkylation of commercially available 4-halogenopyridin-2-ones to finally give the compounds of formula (XI).

[0194] Finally, compounds of formula (I) may be prepared according to Scheme 3, wherein Cy, Ri, R2, Re, R7, Rs and R9 are as defined above in formula (I), Y is a halogen atom, and PG is a protecting group chosen from -Tosyl, -Mesyl, -Brosyl, -Nosyl, -Trifyl, - tert-butyloxycarbonyl, -trimethylsilylethoxymethyl, -Trimethyl silyl, -Triisopropyl silyl, preferably a group -Tosyl.

[0195] Scheme 3

[0196]

[0197] Compounds of formula (XII) can be prepared by coupling synthetic intermediates of formula (V) and (XI) previously described in scheme 1 and 2 (Step i). The Suzuki coupling reaction is typically performed in the presence of a base like K2CO3 or Na2CC>3 (in powder or in aqueous solution), a palladium II catalyst such as bis(triphenylphosphine)palladium dichloride in MeCN, at a temperature comprised between 60°C and 110°C. Other conditions can be used for this step, for example other solvents, such as 1,4-di oxane, DMSO, 1,2-dimethoxy ethane, EtOH or DMF, other catalysts, such as palladium chloride or tris(dibenzylideneacetone)dipalladium, or other bases, such as NaOH or CS2CO3.

[0198] Compounds of formula (XII) can be then deprotected to give the azaindole derivatives of formula (XIII) by using NaOH in DMSO at room temperature or Na2COs solution at 110°C (Step ii). This step could also be performed with other conditions like TBAF in THF at 66°C, or MeONa in MeOH at room temperature. Compounds of formula (I) can be finally obtained by chiral separation of the racemate of formula (XIII) (Step iii), typically using a Daicel chiralflash IG. (-,A)- enantiomers are first eluted, followed by the (+,5)-enantiomers.

[0199] According to an embodiment, compounds of general formula (I) may be prepared by a process wherein the following steps are carried out in that order, starting from synthetic intermediates of formula (V) and (XI): i. a Suzuki coupling reaction performed at a temperature comprised between 60°C and 110°C, to give compounds of formula (XII), ii. a deprotection of the protecting groups to give azaindoles of formula (XIII), iii. a separation of the racemates by chiral chromatography.

[0200] Thus, another subject of the invention concerns compounds of formula (V), (XI) and (XII) wherein:

[0201] - Cy is a 5- or 6-membered (hetero)cycloalkyl group, optionally substituted by one or more radicals selected from halogen atoms, (Ci-Ce)alkyl group, trifluoromethyl group, cyano group, (C3-Ce)cycloalkyl group and (Cs-Cejheterocycloalkyl group, wherein said (Ci- Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group;

[0202] - Ri represents a (Ci-Ce)alkyl group;

[0203] - R-2 represents a (Ci-Ce)alkyl group, a (Cs-Cejcycloalkyl group, or a (Ci-Ce)alkyl group substituted by one or more radicals selected from halogen atoms, cyano group, (Ci- Ce)alkoxy group and (Cs-Cejcycloalkyl group; or Ri and R2 form together with the nitrogen atom a 3- to 6-membered heterocyclic group;

[0204] - Re, R7, Rs and R9 represent, independently of each other, a hydrogen atom, a halogen atom, a (Ci-Ce)alkyl group, a trifluoromethyl group or a cyano group, wherein said (Ci-Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group; and

[0205] - PG is a protecting group chosen from -Tosyl, -Mesyl, -Brosyl, -Nosyl, -Triflyl, -tertbutyloxycarbonyl, -trimethylsilylethoxymethyl, -Trimethylsilyl, -Triisopropyl silyl, preferably a group -Tosyl.

[0206] The present invention will be better understood by referring to the following examples which are provided for illustrative purpose only and should not be interpreted as limiting in any manner the instant invention. EXAMPLES

[0207] Example 1: Preparation of compounds according to the invention Compounds N°1 to N°6 can be prepared according to the methods described above.

[0208] The following table illustrates the chemical structures of compounds N°1 to N°6 according to the invention:

[0209] Table 1: Chemical structure of compounds of the invention

[0210]

[0211] Example 2: ERK2 (MAPK1) Enzymatic assay

[0212] To assess the capacity of compounds to inhibit ERK2 enzymatic activity, Z’-Lyte biochemical assay from Life technologies can be used according to manufacturer’s instructions. Briefly, black 384-well plates containing 100 nl of 100X compound solution in 100% DMSO, 2.4 pl kinase buffer, 5 pl 2X MAPK1 (ERK2) / Ser / Thr 03 mixture and 2.5 pl 4X ATP solution can be used. Plates can be shaken for 30 seconds and incubated for 60 minutes at room temperature. Then, 5 pl of a 1 : 1024 dilution of Development Reagent A can be added. Plates can be shaken for 30 seconds and incubated for 60 minutes at room temperature. A plate reader can be used to read fluorescence. In this assay, ERK2 enzyme can be used at a concentration of 0.4 pg / ml (5.74 nM) at ATP Km (100 pM). Kinase buffer consisted of 50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCh, 1 mM EGTA. Compounds IC50 can be determined with a 3 -fold serial dilution (10 point titrations in duplicate).

[0213] Example 3: Cell line proliferation assay

[0214] A cell line assay can be used to determine the capacity of compounds to inhibit cell proliferation. A375 cells (malignant melanoma) can be grown to near 80% confluence and seeded at 3000 cells per 100 pl per well in DMEM with 10% FBS in 96-well flat bottom plates. Cells can be incubated for 24 hours at 37°C under 5% CO2. 100 pl compound solutions can be added to cells and incubated for 72 hours at 37°C. Total volume of media can be 200 pl per well. Compounds can be screened in 0.15% DMSO (final) using 10 titration points in duplicate. Negative control wells consisted of vehicle only (0.15% DMSO in 10% FBS DMEM). After 72 hours of compound treatment, SDS 1% (final) can be added to positive control wells for 15 minutes at 37°C. Then, medium can be discarded and replaced by 100 pl per well of a MTT solution (3-[4.5-dimethylthiazol-2-yl]-2.5- diphenyltetrazolium bromide) (Sigma, Cat#M5655) at 0.5mg / ml in 10% FBS DMEM. Cells can be incubated for 4 hours at 37°C. MTT reaction can be stopped and homogenized by the addition of lOOpl per well of SDS 10% 0.01M HC1. After 16 hours at 37°C, absorbance can be measured at 570 nm in a Bio-Tek plate reader (PowerWave HT). Percent of proliferation inhibition can be calculated using negative controls (0.15% DMSO) as 0% growth inhibition and positive controls (1% SDS) as 100% growth inhibition. IC50 values (concentration inducing a half-maximal growth inhibition) can be determined by non-linear regression analysis of the inhibition curve generated by mean replicate values (using a sigmoid doseresponse with variable Hill Slope and constraining the top to a constant value of 100 and the bottom to a value between 0 and 50). Analysis can be performed using GraphPad Prism software.

Claims

CLAIMS1. Compound of formula (I):wherein:- Cy is a 5- or 6-membered (hetero)cycloalkyl group, optionally substituted by one or more radicals selected from halogen atoms, (Ci-Ce)alkyl group, trifluoromethyl group, cyano group, (C3-Ce)cycloalkyl group and (C3-C6)heterocycloalkyl group, wherein said (Ci- Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group;- Ri represents a (Ci-Ce)alkyl group;- R2 represents a (Ci-Ce)alkyl group, a (C3-Ce)cycloalkyl group, or a (Ci-Ce)alkyl group substituted by one or more radicals selected from halogen atoms, cyano group, (Ci-Ce)alkoxy group and (C3-Ce)cycloalkyl group; or Ri and R2 form together with the nitrogen atom a 3- to 6-membered heterocyclic group;- Re, R7, Rs and R9 represent, independently of each other, a hydrogen atom, a halogen atom, a (Ci-Ce)alkyl group, a trifluoromethyl group or a cyano group, wherein said (Ci-Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group; or one of its pharmaceutically acceptable salts.

2. Compound according to claim 1, wherein Cy is a 6-membered (hetero)cycloalkyl group, in particular substituted in meta position by a radical selected from halogen atoms, trifluoromethyl group and (C3-C6)heterocycloalkyl group.

3. Compound according to anyone of the preceding claims, wherein Cy is a 6- membered (hetero)cycloalkyl group selected from a cyclohexyl group and a tetrahydropyran group.

4. Compound according to claim 1, wherein Cy is a 5-membered (hetero)cycloalkyl group, in particular substituted in 3-position by one or more radicalsselected from halogen atoms, (Ci-Ce)alkyl group, trifluoromethyl group, cyano group, (C3- Ce)cycloalkyl group and (C3-C6)heterocycloalkyl group, wherein said (Ci-Ce)alkyl is itself optionally substituted with a (Ci-Ce)alkoxy group.

5. Compound according to anyone of the preceding claims, wherein Ri represents a methyl group.

6. Compound according to anyone of the preceding claims, wherein R2 represents a (Ci-Ce)alkyl group, and preferably R2 represents a methyl group.

7. Compound according to anyone of the preceding claims, wherein both Ri and R2 represent a methyl group.

8. Compound according to anyone of the preceding claims, wherein the asymmetric carbon bearing the group -CH2NRiR2 is of R configuration.

9. Compound according to anyone of the preceding claims, wherein Re represents a hydrogen atom or a (Ci-Ce)alkyl group, and preferably Re represents a hydrogen atom.

10. Compound according to anyone of the preceding claims, wherein R7 represents a hydrogen atom or a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom, and preferably R7 represents a hydrogen atom.

11. Compound according to anyone of the preceding claims, wherein Rs represents a hydrogen atom or a halogen atom, in particular a chlorine atom, a fluorine atom, a bromine atom, or an iodine atom, and preferably Rs represents a hydrogen atom.

12. Compound according to anyone of the preceding claims, wherein R9 represents a hydrogen atom, a halogen atom or a trifluoromethyl group, and preferably R9 represents a hydrogen atom.

13. Compound according to claim 1, chosen among:or one of their pharmaceutically acceptable salts.

14. Compound according to anyone of the preceding claims, for use for preventing and / or inhibiting and / or treating a disease or a condition mediated by ERK kinases activity, in particular by ERK2 kinase activity.

15. Compound for use according to claim 14, wherein the disease or the condition is chosen among cancers and metastases.

16. Compound for use according to claim 14 or 15, wherein the disease or the condition is chosen among glioblastomas, multiple myelomas, carcinomas, leukemia, in particular myeloid (AML), lymphocytic, myelocytic, myelogenous (CML) or lymphoblastic leukemias, myelodysplastic syndromes, Kaposi’s sarcomas, cutaneous angiosarcomas, solid tumours, lymphomas, in particular non-hodgkin’s lymphomas, melanomas, in particular malignant melanomas, bladder cancers, breast cancers, gastric cancers, colon cancers, colorectal cancers, endometrial cancers, lung cancers, including non-small-cell cancers, pancreatic cancers, prostate cancers, rectal cancers, kidney cancers, head and neck cancers, liver cancers, ovarian cancers, in particular serous ovarian cancers, seminoma cancers, cancers of the respiratory tract and chest, thyroid cancers, in particular papillary or follicular thyroid cancers, and other tumours expressing ERK.

17. Compound for use according to claim 14, wherein the disease or the condition is chosen among a neoplastic disorder, an allergy disorder, an inflammatorydisorder, an autoimmune disorder, a Plasmodium related disease, a mast cell associated disease, a graft- versus -host disease, a metabolic syndrome, a CNS related disorder, a neurodegenerative disorder, a pain condition, a substance abuse disorder, a prion disease, a heart disease, a fibrotic disease, idiopathic arterial hypertension (IP AH), and primary pulmonary hypertension (PPH).

18. Compound for use according to claim 14, for use for preventing and / or inhibiting and / or treating the Human Immunodeficiency Virus (HIV).

19. Use of a compound according to any one of claims 1 to 13, for preventing and / or inhibiting and / or treating a disease or a condition mediated by ERK kinases activity, preferably ERK2 kinases activity.

20. Medicament comprising at least one compound according to anyone of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising at least one compound according to anyone of claims 1 to 13, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

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