WO2022243649A1

WO2022243649A1 - Novel azaindole derivatives as anticancer agents

Info

Publication number: WO2022243649A1
Application number: PCT/FR2022/050978
Authority: WO
Inventors: Laurence Briant; Eric Bernard
Original assignee: Centre National De La Recherche Scientifique (Cnrs)
Priority date: 2021-05-21
Filing date: 2022-05-23
Publication date: 2022-11-24

Abstract

The present invention relates to compounds of formula (I): for use in the prevention and/or treatment of cancer, autoimmune and inflammatory diseases, graft rejection and fibroses.

Description

DESCRIPTION

TITLE: NEW AZAINDOLE DERIVATIVES AS ANTICANCER AGENTS

FIELD OF THE INVENTION

The present invention relates to compounds derived from 7-azaindole useful as inhibitors of AXL and/or FLT3 kinases, in particular for the treatment of cancer. The present invention also relates to their method of preparation.

TECHNOLOGICAL BACKGROUND

AXL is a Receptor Tyrosine Kinase (RTK) belonging to the TAM family composed of TYRO-3, AXL and MER. Initially discovered and demonstrated in patients with chronic myeloid leukemia (CML), the involvement of the AXL receptor in a large number of other liquid and solid cancers (breast, leukaemia, lung, prostate, gastrointestinal, ovary, melanoma, pancreas, liver, thyroid, etc. is now well detailed and validated (Paccez et al., Int. J. Cancer (2014), 134: 1024-1033). More specifically, AXL is a key regulator of the mesenchymal phenotype of cancer cells; mesenchymal cancer cells are more aggressive cells (increase in their ability to invade and migrate, their ability to survive and adapt in stressful situations and their ability to resist targeted therapies and traditional chemotherapy). Consequently, the overexpression of AXL and of its ligand GAS6 (Growth Arrest-Specific 6) has been correlated with tumor progression (invasion, metastasis), with poor vital prognosis, but also with phenomena of resistance to treatment. Thus, the strong oncogenic potential of AXL has been demonstrated and this protein is considered as a new therapeutic target in the treatment of cancer (Wu et al., Oncotarget (2014), 5(20): 9546-9563).

In addition, several studies have also demonstrated the overexpression or inhibition of AXL in many pathologies other than cancer, such as: autoimmune diseases (Yanagita et al. Am. J. Pathol. (2001) , 158, 1423-1432), inflammation (Fiebeler et al. Am. J. Kidney Dis. (2004), 43: 286-295, Weinger et al. J. Neuroinflammation (2011) 8: 49), rejection grafts, sclerosis (Weinger et al. Am. J. Pathol. (2009) 175: 283-293), vascular anomalies (Ekman et al. Clin. Biochem. (2010) 43: 110-114), obesity (Hsiao et al. J. Clin. Endocrinol. Metab. (2013) 98: E267-274), infectious diseases (Shibata et al. J. Immunol. (2014) 192(8): 3569-81), and including viral entry into cells, neurodegenerative diseases (Fourgeaud, et al., Nature (2016), 532: 240-244), endometriosis, kidney disease and failure. FLT3 (Fms-Like Tyrosine kinase 3, also known as CD135 or STK-1 for Cluster of Differentiation antigen 135 and Stem cell tyrosine kinase 1 respectively) is an RTK playing an essential role in survival, proliferation and differentiation hematopoietic stem cells. For several years, many teams have demonstrated the overexpression of this receptor in leukemic cells. For example, activation of the FLT3 receptor by its ligand stimulates the proliferation of acute myeloblastic leukemia (AML) cells while also inhibiting apoptosis. Moreover, the mutation of the FLT3 gene is the most frequently observed genetic alteration in AML and is recognized as a mutation responsible for the development of myeloblastic pathologies by causing constitutive activation of the protein. In the same way, the genetic alteration of FLT3 is a very poor prognostic factor for patient survival. The two most frequent classes of somatic mutation are duplications of certain parts of the gene causing the expression of a protein called FLT3-ITD (Internai Tandem Duplication), in about 23% of AML cases, and the appearance of mutations puncta in the kinase domain (aspartic acid D835 mutation) leading to the expression of FLT3-KDM. Accordingly, the World Health Organization recommends identifying FLT3 mutations in patients with AML in order to establish an initial diagnosis and define treatment.

RTK FLT3 is thus at the center of research for the treatment of acute leukemias such as AML or ALL (acute lymphoblastic leukemia) or myeloproliferative syndromes such as myelofibrosis for example. Several first and second generation FLT3 inhibitors have been developed and tested in the clinical phase but, to date, none have been approved or marketed. Indeed, many problems were encountered during the clinical phases with these compounds such as significant side effects or the appearance of resistance. The development of new FLT3 inhibitors should more particularly resolve the problems of bone marrow depression and cardiotoxicity (prolongation of QTc) observed with current inhibitors.

Recent publications have also raised the interest of inhibiting AXL alone or simultaneously with FLT3 in the treatment of patients with AML and carriers of the FLT3-ITD mutation [Park et al., Blood (2013), 121 (11 ): 2064-2073, Park et al., Leukemia (2015), 29(12): 2382-2389],

To date, there are several kinase inhibitors active on AXL (Myers et al., J. Med. Chem. (2015), 59(8): 3593-3608) but none are really selective or specific for this kinase . In a large majority of cases, the activity on AXL is secondary to the main activity sought on MET or MER due to the sequence similarity between these RTKs. This is particularly the case for Bosutinib or Cabozantinib, which are kinase inhibitors multi-targets or MTKI (MultiTargeted Kinase Inhibitors) already on the market, or BMS777607 (currently in clinical phase 2). This is also the case of the 7-azindole derivative NPS-1034, which exhibits a relatively broad inhibition profile, inhibiting a large panel of kinases such as AXL/DDR1/FLT3/KIT/MEK/MET/ROS1 and TIE1.

BMS-777607

NPS-1034

Another AXL kinase inhibitor is R428 (also called BGB324), currently in the clinical phase. This compound - with a very different structure from the kinase inhibitors currently on the market - has also been shown to be active on other kinases such as

ABL/KIT/JAK2-3/LCK/PDGFRB/TI E2...

R428/BGB324 There is therefore a need for new, more selective compounds which inhibit AXL and/or FLT3 (preferably AXL and FLT3).

The present invention thus provides novel 7-azaindole derivatives which strongly inhibit AXL kinase mainly, as well as FLT3 and/or its mutants, for application in the treatment of diseases mediated by AXL kinase and/or FLT3 and/or its mutants , especially cancer.

Due to this very specific and unique inhibition profile to date for this type of structure, these compounds can be used in therapy in the treatment of pathologies associated with deregulation of protein kinases, in particular AXL and/or FLT3 (and/or its mutants). In the case of cancers, by affecting AXL and/or FLT3, these compounds will act aggressively by simultaneously attacking the tumor, its microenvironment and metastases while preventing the appearance of resistance. The inhibitors of the present invention can thus be used for the treatment of numerous liquid cancers (such as chronic or acute leukemia, lymphomas, myeloproliferative syndromes) as well as solid cancers, such as cancers of the skin, breast, lung, pleura, bladder, prostate, gastrointestinal, ovaries, pancreas, liver, kidney, thyroid, salivary glands, head and neck, colorectal, cervix, endometrium, vulva, skin, brain, sarcomas and melanoma. In addition, these compounds may help resensitize patients who are resistant to other anti-cancer treatments. These inhibitors could also be useful in the treatment of non-cancerous diseases in which AXL and/or FLT3 are implicated, such as autoimmune, inflammatory diseases, transplant rejection and fibrosis.

SUMMARY OF THE INVENTION

The subject of the present invention is thus a compound of formula (I):

X represents a hydrogen atom or a halogen atom,

Y is chosen from a hydrogen atom, a -CN group, -CH ₂ OH, -CH=NOH, -CO ₂ H, an optionally mono or polysubstituted aryl, an optionally mono or polysubstituted heteroaryl, and -L-(CH ₂ )pW,

- L represents -C(O)NH-, -CH ₂ NH-, -NHC(O)-, -CH ₂ N=CH-, -CH=N-, -NHC(O)NH- or - CH ₂ NHC (O)-,

- p is an integer from 0 to 2,

- when L represents -CH ₂ NH-, -NHC(O)-, -CH ₂ N=CH-, -CH=N-, -NHC(O)NH- or - CH ₂ NHC(O)-, W is chosen from:

• a hydrogen atom,

• a C ₁ -C ₆ alkyl, preferably a methyl,

• a C ₆ -C ₁₀ aryl optionally mono- or polysubstituted, advantageously by 1 to 3 groups independently chosen from a halogen atom, a hydroxyl, a C ₁ -C ₆ alkyl or a C ₁ -C ₆ alkoxyl , and • a 5-10 membered heteroaryl containing from 1 to 3 heteroatoms independently chosen from N, O and S, said heteroaryl being optionally mono- or polysubstituted, advantageously it is optionally substituted by 1 to 4 groups independently chosen from: o an atom of o halogen, o hydroxyl, o oxo group, o C ₁ -C ₆ alkoxyl, o C ₁ -C ₆ alkyl, in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and o a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom and/or a C ₁ -C ₆ alkyl;

- when L represents -C(O)NH-, W is chosen from:

• an optionally mono- or polysubstituted phenyl, advantageously it is optionally substituted by a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl, or a C ₁ -C ₆ alkoxyl group, and

• a 5-10 membered heteroaryl comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heteroaryl being optionally mono- or polysubstituted, advantageously it is optionally substituted by 1 to 4 substituents independently chosen from: o an atom of halogen, o a hydroxyl, o an oxo group, o a C ₁ -C ₆ alkoxyl group, o a C ₁ -C ₆ alkyl in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and o a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom and/or a C ₁ -C ₆ alkyl;

Z represents -CH ₂ Q or -0(CH ₂ ) _m T,

- Q represents -OH, -SO2R1, -NR2R3, or -R4

• Ri represents a C ₁ -C ₆ alkyl,

• R ₂ and R ₃ each independently represent a C ₁ -C ₆ alkyl, and

• R ₄ represents a 5-7 membered heterocycloalkyl, comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heterocycloalkyl being optionally substituted with 1 to 3 substituents independently selected from C ₁ -C ₆ alkyl, C(O)-C ₁ -C ₆ alkyl and C(O)O-C ₁ -C ₆ alkyl,

- m is equal to 1 or 2,

- T is -0(CH ₂ ) _n CH3 or -Rs

• n is equal to 0 or 1

• R ₅ is a 5 to 7 membered heterocycloalkyl comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heterocycloalkyl being optionally substituted by 1 to 3 substituents independently chosen from a C ₁ -C ₆ alkyl, a C (O)-C ₁ -C ₆ alkyl and a C(O)O-C 1 -O 0 _-alkyl ; a pharmaceutically acceptable salt thereof or a mixture thereof, for its use in the prevention and/or treatment of cancer, autoimmune, inflammatory diseases, transplant rejection and fibrosis.

A subject of the present invention is also a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof as active principle, and a pharmaceutically acceptable excipient, for its use in the prevention and/or treatment of cancer, autoimmune and inflammatory diseases, transplant rejection and fibrosis.

DETAILED DESCRIPTION

As a general rule, the following terms and definitions are used.

The expression “peptide coupling” in the present invention denotes the reaction making it possible to form an amide bond —NH—C(O)—. The techniques used in this reaction are common to peptide syntheses, that is to say proceed by activation of a carboxylic acid to react with an amine. The peptide coupling reactions used in the present invention are thus derived from peptide syntheses, and directly applicable to the subject of the present invention.

Peptide coupling reactions are well known to those skilled in the art, and can in particular be carried out using a coupling agent such as N,N'-dicyclohexylcarbodiimide (DCC) or 1-ethyl-3-( 3'-dimethylaminopropylcarbodiimide (EDO), or N-hydroxy-5-norbornene-2,3-dicarbodiimide), or a benzotriazole (such as 0-(1 H-benzotriazol-1-yl)-N,N tetrafluoroborate ,N',N'-tetramethyluronium (TBTU), benzotriazol-1-yl-oxytris(dimethylamino)phosphonium (BOP) hexafluorophosphate, 0-(7-azabenzotriazol-1-yl)-1,2,3-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-benzotriazol-1-yl-tetramethyl tetrafluoroborate (TBTU)), or an N-hydroxybenzotriazole (HOBT)/EDCI mixture, in a solvent such as chloroform, dichloromethane, dichloroethane, ethyl acetate, dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), N-methyl pyrrolidinone (NMP), preferably at a temperature between 20°C and 150°C.

Alternatively, a peptide coupling takes place by first activation of the carboxylic acid by transformation into the acyl chloride (in particular in the presence of thionyl chloride or acetyl chloride) or a corresponding anhydride (for example in the presence of acetic or isopropyl anhydride), then reaction with the desired amine, preferably in the presence of a base to neutralize the acid released during the reaction (in particular HCl in the case of an acyl chloride).

The term C(O) is equivalent to “C=0”.

The expression “alkyl” or “alkyl group” in the present invention denotes a linear or branched saturated aliphatic group containing 1 to 6 carbon atoms, if this is not explained. Examples of alkyl groups covered by the object of the present invention are methyl, ethyl, propyl, butyl, tert-butyl, isopropyl groups.

In certain embodiments, it is specified that one or more hydrogen atoms of the alkyl group are optionally replaced by a fluorine atom. In this case, preferably, 1 to 3 hydrogen atoms at most are concerned. An example is the CH ₂ CF ₃ group.

The term "aryl group" or "aryl" in the present invention means an aromatic cyclic group (mono- or polycyclic) containing between 6 and 10 carbon atoms. Examples of aryl groups covered by the object of the present invention are phenyl, napthyl, preferably phenyl.

The term "heteroaryl group" or "heteroaryl" in the present invention means a 5- to 10-membered aromatic (mono- or polycyclic) cyclic group containing between 2 and 9 carbon atoms and between 1 and 3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Examples of heteroaryl groups are furan, pyrrole, thiophene, thiazole, isothiazole, imidazole, oxazole, isoxazole, pyrazole, pyridine, pyridone, pyrazine, pyridazine, pyrimidine, pyrimidinedione, quinoline, indole, quinoxaline, benzofuran, dihydrobenzofuran, benzodioxole, benzotriazole, benzimidazole, 3-oxo-2,3-dihydro-1 H-pyrazole, preferably chosen from pyrrole, imidazole, 3-oxo-2,3-dihydro-1 H-pyrazole, thiophene, pyridine, 2(1 H )-pyridinone, 4(1H)-pyridinone, pyrimidine, pyrimidine-2,4-dione, benzofuran, benzodioxole, indole and benzimidazole. The term "heterocycloalkyl" or "heterocycloalkyl group" in the present invention means a 5-7 membered aliphatic ring group, comprising one or more (preferably 1 to 2) heteroatoms independently selected from nitrogen, oxygen or sulfur, such as morpholin, piperidine, piperazine, pyrrolidine, homopiperazine (1,4-diazacycloheptane). Preferably, it is morpholine or piperazine.

The term "halogen atom" in the present invention means a fluorine, chlorine, bromine or iodine atom. Preferably, it is chlorine or fluorine, in particular fluorine.

The term "alkoxyl group" or "alkoxyl" in the present invention means an alkyl group bonded to an oxygen. Examples of alkoxyl groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy. Preferably it is a methoxy or ethoxy group.

The term "aryloxy group" in the present invention means an aryl group bonded to an oxygen atom. Examples of aryloxy groups are phenyloxy groups.

The expression “hydroxyl group” or “hydroxyl” in the present invention denotes: OH.

The term "oxo group" refers to the substituent: =O.

The expression "optionally substituted aryl or heteroaryl group" in the present invention denotes an aryl or heteroaryl optionally substituted by one or more (preferably 1 to 3, more preferably 1 or 2) substituents independently chosen from: an atom of halogen, a nitro -(NO ₂ ) group, a cyano (CN) group, a C ₁ -C ₆ alkoxyl group, a C ₅ -C ₁₀ aryloxy group, a C ₁ -C ₆ alkyl group in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, a heteroaryl group, a hydroxyl group, an oxo group, a -CONH-C ₁ -C ₆ -alkyl group, a -NHCO-C ₁ -C ₆ -alkyl group, and an NR2R3 group in which R2 and R3 independently represent a C ₁ -C ₆ alkyl group, or a C ₆ -C ₁₀ aryl group optionally substituted by a halogen atom and/or a C ₁ -C ₆ alkyl group .

Preferably, the substituents in the expression "optionally substituted aryl or heteroaryl group" are independently chosen from: o a halogen atom, in particular a fluorine or a chlorine, o a hydroxyl, o an oxo group, o a C alkoxyl ₁ -C ₆ , in particular a methoxy, o a C ₁ -C ₆ alkyl, in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, preferably a methyl or CH ₂ CF ₃ group, and o a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom (in particular a fluorine or a chlorine) and/or a C ₁ -C ₆ alkyl, for example a fluorophenyl (preferably 4-fluorophenyl) or a methylfluorophenyl (for example 4-fluoro- 2-methylphenyl);

The term "7-azaindole" in the present invention refers to the 1 H-pyrrolo[2,3-b]pyridine unit:

In the present invention, the term "pharmaceutically acceptable" is intended to denote that which is useful in the preparation of a pharmaceutical composition which is generally safe, non-toxic and neither biologically nor otherwise undesirable and which is acceptable for veterinary use as well as human pharmaceutical.

In the present invention, the expression “pharmaceutical composition” denotes any composition consisting of an effective dose of at least one compound of the invention and at least one pharmaceutically acceptable excipient. Such excipients are selected, depending on the pharmaceutical form and the desired method of administration, from the excipients usually known to those skilled in the art.

The term "pharmaceutically acceptable salts" of a compound is intended to denote salts which are pharmaceutically acceptable, as defined herein, and which possess the desired pharmacological activity of the parent compound. Such salts include:

(1) hydrates and solvates,

(2) pharmaceutically acceptable acid addition salts formed with pharmaceutically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with pharmaceutically acceptable organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2- hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, l methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid and the like, or

(3) pharmaceutically acceptable base addition salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or a d aluminum; is coordinated with a pharmaceutically acceptable organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The expression "mixtures of enantiomers" in the present invention denotes any mixture of enantiomers. The mixture can be racemic, that is to say 50/50 of each enantiomer by weight (w/w), or non-racemic, that is to say enriched in one or the other of the enantiomers, for example so as to obtain an enantiomeric excess greater than or equal to 95%, preferably greater than or equal to 98%, more preferably greater than 99%.

The expression “mixtures of diastereomers” in the present invention designates any mixture of diastereomers whatever the proportion.

The expression “treatment” applies to all types of animals, preferably to mammals and more preferably to humans. In the case of the treatment of a non-human animal, the expression will refer to veterinary treatment.

The present invention relates to compounds of formula (I):

in which

X represents a hydrogen atom or a halogen atom, Y is chosen from a hydrogen atom, a -CN group, -CH ₂ OH, -CH=NOH, -CO ₂ H, an optionally mono or polysubstituted aryl, an optionally mono or polysubstituted heteroaryl, and -L-(CH ₂ )pW,

- p is an integer from 0 to 2,

• a hydrogen atom,

• a C ₁ -C ₆ alkyl, preferably a methyl,

• a C ₆ -C ₁₀ aryl optionally mono- or polysubstituted, advantageously by 1 to 3 groups independently chosen from a halogen atom, a hydroxyl, a C ₁ -C ₆ alkyl or a C ₁ -C ₆ alkoxyl , and

• a 5-10 membered heteroaryl containing from 1 to 3 heteroatoms independently chosen from N, O and S, said heteroaryl being optionally mono- or polysubstituted, advantageously it is optionally substituted by 1 to 4 groups independently chosen from: o an atom of o halogen, o hydroxyl, o oxo group, o C ₁ -C ₆ alkoxyl, o C ₁ -C ₆ alkyl, in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and o a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom and/or a C ₁ -C ₆ alkyl;

- when L represents -C(O)NH-, W is chosen from:

• a 5-10 membered heteroaryl comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heteroaryl being optionally mono- or polysubstituted, advantageously it is optionally substituted by 1 to 4 substituents independently chosen from: o an atom of 'halogen, o a hydroxyl, o an oxo group, o a C ₁ -C ₆ alkoxyl group, o a C ₁ -C ₆ alkyl in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and o a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom and/or a C ₁ -C ₆ alkyl;

Z represents -CH ₂ Q or -0(CH ₂ ) _m T,

- Q represents -OH, -SO2R1, -NR2R3, or -R4

• Ri represents a C ₁ -C ₆ alkyl,

• R ₂ and R ₃ each independently represent a C ₁ -C ₆ alkyl, and

• R ₄ represents a 5-7 membered heterocycloalkyl, comprising 1 to 2 heteroatoms independently chosen from N, O and S, said heterocycloalkyl being optionally substituted by 1 to 3 substituents independently chosen from a C ₁ -C ₆ alkyl, a C(O)-C ₁ -C ₆ alkyl and a C(O)0-C ₁ -C ₆ alkyl,

- m is equal to 1 or 2,

- T is -0(CH ₂ ) _n CH3 or -R5

• n is equal to 0 or 1

• R ₅ is a 5 to 7 membered heterocycloalkyl comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heterocycloalkyl being optionally substituted by 1 to 3 substituents independently chosen from a C ₁ -C ₆ alkyl, a C (O)-C ₁ -C ₆ alkyl and a C(O)O-C ₁ -C ₆ alkyl; a pharmaceutically acceptable salt thereof or a mixture thereof, for their use in the prevention and/or treatment of cancer, autoimmune, inflammatory diseases, transplant rejection and fibrosis.

The compound of formula (I) according to the invention can be in the form of a stereoisomer or of a mixture of stereoisomers, such as tautomers, enantiomers or diastereoisomers.

In a first embodiment, the compounds of the invention are of formula (Ia):

In a second embodiment, the compounds of the invention are of formula (Ib):

In a third embodiment, the compounds of the invention are of formula (le):

In a fourth embodiment, the compounds of the invention are of formula (Id):

In formulas (Ia), (Ib), (Ic) and (Id), the substituents X, Y and Z are as defined above and below. In a particular embodiment, in the compounds of the invention, Z represents -CH ₂ R ₄ or -0(CH ₂ ) _m R ₅ . Preferably, in this embodiment, R ₄ and R ₅ independently represent a piperazine, morpholine or homopiperazine group, optionally substituted by a C ₁ -C ₆ alkyl or a C(O)O(C ₁ -C ₆ ) group. -alkyl. In this embodiment, m preferably represents 2. In a particular embodiment, Z represents -CH ₂ OH, -CH ₂ SO ₂ CH ₃ ,

-OCH ₂ OCH ₂ CH3, -OCH ₂ CH ₂ OCH ₃ , -N(CH ₂ CH ₃ ) ₂ ,

In a preferred embodiment, Z represents -CH ₂ R4 in which R4 represents a piperazine group, optionally substituted by a C ₁ -C _{6 alkyl,} in particular a methyl.

In a particular embodiment, X represents a halogen, in particular fluorine.

In a particular embodiment, X represents hydrogen.

In a particular embodiment, Y represents -H, -CN, -CH ₂ OH, -CH=NOH, optionally mono or polysubstituted aryl or heteroaryl, or -L-(CH ₂ )pW.

In an advantageous embodiment, Y represents an optionally mono or polysubstituted aryl or heteroaryl, or -L-(CH ₂ )pW.

In the case where Y represents an optionally mono- or polysubstituted aryl or heteroaryl, it is preferably an optionally mono- or polysubstituted aryl, in particular a phenyl, in particular unsubstituted.

In an even more advantageous embodiment, Y represents L-(CH ₂ )pW. In the case where Y represents -L-(CH ₂ )pW, preferably, p is then equal to 0, 1 or 2.

Advantageously, when Y represents L-(CH ₂ )pW, L represents -C(O)NH-, -CH ₂ NH-, - NHC(O)-, -NHC(O)NH- or -CH ₂ NHC(O )-, preferably -CH ₂ NH-, -NHC(O)- or -NHC(O)NH-

In the embodiment where Y represents -L-(CH ₂ )pW, W advantageously represents a 6-10 membered aryl or 5-10 membered heteroaryl containing from 1 to 2 heteroatoms independently chosen from N, S and O, said aryl or heteroaryl being optionally mono- or polysubstituted. In a preferred embodiment, W represents a 6-10 membered aryl, in particular a phenyl, unsubstituted or monosubstituted, preferably by a hydroxyl.

In another preferred embodiment, W represents a 5- or 6-membered heteroaryl, containing 1 to 2 heteroatoms independently chosen from N, S and O, in particular N, such as pyrazole, pyridine or imidazole. Advantageously, said heteroaryl is optionally substituted by 1 to 4, preferably 1 or 2 groups independently chosen from: o a halogen atom, in particular a fluorine, o an oxo group, o a C ₁ -C ₆ alkyl, in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, in particular a methyl, and o a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom (in particular a fluorine) and/or a C ₁ alkyl -C ₆ , for example a methyl, a fluorophenyl (preferably 4-fluorophenyl) or a methylfluorophenyl (for example 4-fluoro-2-methylphenyl).

Preferably, W represents pyrazole, 3-oxo-2,3-dihydro-1 H-pyrazole, pyridine, 2(1 H)-pyridinone, 4(1 H)-pyridinone or imidazole, in particular 2(1H)-pyridinone or imidazole, optionally substituted by 1 to 4, preferably 1 or 2 groups independently chosen from: o a C ₁ -C ₆ alkyl, in particular a methyl, and o a C 1 -C 6 aryl, and C ₆ -C ₁₀ optionally substituted by a C ₁ -C ₆ alkyl, for example a methyl.

In particular, W is then chosen from:

, preferably

In an advantageous embodiment, Y represents an aryl, heteroaryl or L-(CH ₂ ) _P -W, L representing -CH ₂ NH or -NHC(O)NH-, in particular -CH ₂ NH, p being an integer of 0 to 2, and W being chosen from:

• a phenyl optionally substituted by a hydroxyl, or a C ₁ -C ₆ alkyl, preferably a hydroxyl,

• a 5-10 membered heteroaryl comprising from 1 to 2 heteroatoms independently chosen from N, O or S, in particular N, preferably chosen from the group consisting of: pyrrole, imidazole, thiophene, pyridine, pyrimidine, benzofuran, benzodioxole, indole and benzimidazole, more preferably imidazole.

For example, when Y represents L-(CH ₂ ) _P -W, L representing -CH ₂ NH or -NHC(O)NH-, in particular -CH ₂ NH, p being an integer from 0 to 2, W is chosen from :

• a phenyl group optionally substituted by a hydroxyl group, or a C ₁ -C ₆ alkyl group, preferably a hydroxyl, and

• a pyrrole, imidazole, 3-oxo-2,3-dihydro-1 H-pyrazole, thiophene, pyridine, 2(1 H)-pyridinone, 4(1 H)-pyridinone, pyrimidine, pyrimidine-2,4-dione , benzofuran, benzodioxole, indole and benzimidazole, more preferably imidazole. In this embodiment, Z preferably represents -CH ₂ R4 OR -O(CH ₂ ) _m R and preferably -CH ₂ R4. Preferably, in this embodiment, R4 and R5 independently represent a piperazine or morpholine group, optionally substituted by a C ₁ -C ₆ alkyl or a C(O)O(C ₁ -C ₆ ) _-alkyl group. More preferably, Z represents -CH ₂ R4 in which R4 represents a piperazine group, substituted by methyl. Furthermore, in this embodiment, X advantageously represents a halogen, in particular fluorine.

Preferably, when Y represents L-(CH ₂ ) _P -W, L representing -CH ₂ NH or - NHC(O)NH-, p being an integer from 0 to 2, and W is a phenyl optionally substituted by a hydroxyl group, or a C ₁ -C ₆ alkyl group, preferably a hydroxyl.

In another advantageous embodiment, Y represents -NHC(O)-W, with W representing a heteroaryl of 5 to 10 members, comprising from 1 to 2 heteroatoms chosen independently from N, O and S, in particular N, said heteroaryl being optionally substituted with 1 to 4 substituents independently selected from:

• an oxo group,

• a C ₁ -C ₆ alkyl in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, in particular a methyl, and

• a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom (in particular a fluorine) and/or a C ₁ -C ₆ alkyl, for example a methyl, a fluorophenyl (preferably 4-fluorophenyl) or a methylfluorophenyl (for example 4-fluoro-2-methylphenyl).

Preferably, in this embodiment, W is selected from the group consisting of: pyrazole, pyrrole, imidazole, 3-oxo-2,3-dihydro-1H-pyrazole, thiophene, pyridine, 2(1H)-pyridinone , 4(1H)-pyridinone, pyrimidine, pyrimidine-2,4-dione, benzofuran, benzodioxole, indole and benzimidazole, and even more preferably it is 2(1H)-pyridinone.

Even more preferably, in this embodiment, W is 2(1H)-pyridinone optionally substituted with 1 to 4, especially 1 to 2, substituents independently chosen from:

• a C ₁ -C ₆ alkyl, in particular a methyl, and

• a C ₆ -C ₁₀ aryl, in particular a phenyl optionally substituted by a halogen atom, in particular a fluorine.

In this embodiment, Z preferably represents CH ₂ R ₄ or O(CH ₂ ) _m R ₅ , preferably —CH ₂ R ₄ . Preferably, in this embodiment, R ₄ and R ₅ represent independently a piperazine or morpholine group, optionally substituted by a C ₁ -C ₆ alkyl or a C(O)0(C ₁ -C ₆ )-alkyl group. More preferably, Z represents -CH ₂ R ₄ in which R4 represents a piperazine group, substituted by methyl.

Preferably, the compound of the invention is chosen from:

Compositions and Therapeutic Applications

The compounds of the present invention inhibit AXL and/or FLT3 receptors (and/or mutants thereof). Preferably, the compounds of the invention inhibit both AXL and FLT3 receptors (and/or mutants thereof).

More particularly, the compounds of the invention are used as inhibitors of the proliferation of cancer cell lines U20S, HepG2, A549, HCT116 and/or HeLa.

The compounds of the present invention and their pharmaceutically acceptable salts, or the compositions of the invention are therefore useful as inhibitors of AXL and/or FLT3 (and/or its mutants), in particular for the inhibition of cell proliferation and/or angiogenesis involved in animal or human diseases.

A subject of the present invention is the compounds of formula (I) as defined above for their use in the prevention and/or treatment of cancer, autoimmune and inflammatory diseases, transplant rejection and fibrosis. More particularly, the compounds can be used to prepare pharmaceutical compositions comprising, as active principle, at least one compound of formula (I) described above or a pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable excipient. Thus, the present invention relates to a pharmaceutical composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof as active principle, and a pharmaceutically acceptable excipient, for its use in the prevention and/or treatment of cancer , autoimmune and inflammatory diseases, rejection grafts and fibrosis. Said excipients are chosen according to the pharmaceutical form and the mode of administration desired from the usual excipients which are known to those skilled in the art.

An object of the invention therefore relates to the use of the compounds of formula (I) as defined above or of a pharmaceutical composition as defined above in the prevention and/or treatment of cancer, autoimmune diseases -immune, inflammatory, graft rejection and fibrosis.

In other words, the invention relates to the use of a compound of formula (I) as defined above or of a pharmaceutical composition as defined above for the preparation of a medicament for the prevention and/or treatment of cancer, autoimmune and inflammatory diseases, transplant rejection and fibrosis.

As AXL and FLT3 are involved in numerous biological processes and therapeutically validated targets, the compounds of the present invention and their pharmaceutically acceptable salts, or the compositions of the invention, are useful as medicaments, in particular in the treatment of associated pathologies to dysregulation of protein kinases, in particular AXL and/or FLT3 (and/or its mutants). They may in particular be intended for the treatment or prevention of a disease mediated by AXL and/or FLT3, such as tumorigenesis, human immune disorders, inflammatory diseases, thrombotic diseases, cardiovascular diseases, viral infections , bacterial or parasitic, transplant rejection, fibrosis, sclerosis, neurodegenerative diseases, endometriosis, kidney disease and insufficiency, neurofibromatosis, malignant hematological tumors and cancers such as leukemia, lymphoma, syndromes myeloproliferative diseases, skin cancer, lung cancer, cancer of the pleura, gastrointestinal cancer, pancreatic cancer, brain tumors, cervical cancer, ovarian cancer , liver cancer, bladder cancer, breast cancer, melanoma, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, head and neck cancer u neck, prostate cancer, vulvar cancer, thyroid cancer or sarcomas.

In particular, the compound of formula (I) as defined above or the pharmaceutical composition as defined above is useful in the prevention and/or treatment of cancers chosen from tumorigenesis, leukaemias, lymphomas, myeloproliferative syndromes, skin cancer, lung cancer, cancer of the pleura, gastrointestinal cancer, cancer of the pancreas, brain tumors, cancer of the neck of the uterus, cancer of the ovary, liver cancer, bladder cancer, breast cancer, melanoma, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, head and neck cancer, prostate cancer, vulvar cancer, thyroid cancer and sarcomas.

The compounds of the present invention and their pharmaceutically acceptable salts, or the compositions of the invention are particularly useful for use in the treatment or prevention of liquid or solid cancers. Liquid cancers are in particular malignant hemopathies chosen from non-Hodgkin's lymphoma, Hodgkin's lymphoma, myeloma, myeloid sarcoma and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML). Solid cancers are typically cancers of the liver, pancreas, lung, breast, prostate, kidney, head and neck, thyroid, colorectal, melanoma or chemoresistant cancers.

The compounds of the present invention may be used alone or in combination with an additional therapeutic agent, particularly useful in the treatment of cancer, typically selected from the group consisting of a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, a immunomodulator or immunosuppressant, an agent for treating a neurological disorder, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an for treating blood disorders, an agent for the treatment of diabetes, an agent for the treatment of immunodeficiency disorders and an agent for the treatment of pain. Preferably, the additional therapeutic agent is a chemotherapeutic agent such as etoposide.

The present invention also relates to a kit comprising: a) a first composition comprising a compound according to the invention or a pharmaceutically acceptable salt thereof as active principle, and a pharmaceutically acceptable excipient, and b) a second composition comprising a additional therapeutic agent, in particular useful in a treatment against cancer, typically chosen from the group consisting of a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, an agent for the treatment of a neurological disorder, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, a agent for the treatment of immunodeficiency disorders and an agent for the treatment of pain, as a combination product for separate, concomitant or spread out use. Said kit is useful in the prevention and/or treatment of cancer.

The pharmaceutical compositions according to the invention can be administered parenterally, such as intravenously or intradermally, or topically, orally or nasally.

Parenteral forms include aqueous suspensions, isotonic saline solutions or sterile, injectable solutions which may contain pharmacologically compatible dispersing agents and/or wetting agents. Oral forms include tablets, soft or hard capsules, powders, granules, oral solutions and suspensions. Nasal forms include aerosols. Forms that can be administered topically include patches, gels, creams, ointments, lotions, sprays, eye drops.

Preferably, the compounds or compositions of the invention are administered orally or parenterally (in particular intravenously).

The effective dose of a compound of the invention varies according to many parameters such as, for example, the route of administration chosen, weight, age, sex, state of progress of the pathology at treat and the susceptibility of the individual to be treated.

The present invention, according to another of its aspects, also relates to a method for treating the pathologies indicated above which comprises the administration, to a patient in need thereof, of an effective dose of a compound according to the invention, or one of its pharmaceutically acceptable salts or of a composition according to the invention, preferably parenterally (in particular intravenously) or orally.

The present invention also relates to the methods for preparing the compounds described above, in particular from 5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine.

According to the first embodiment, the method relating to the invention is shown in Scheme 1.

Scheme 1 where X and Z are as defined previously and Y represents a hydrogen atom, CHO, CN, CH ₂ OH, CO ₂ H, NH ₂ , or a phenyl group. The method then comprises at least the steps of: a) tosylation of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (II), for example with toluene-4-sulfonyl chloride in the presence of a base such as sodium hydride, to obtain intermediate (III), b) Suzuki-Miyaura type coupling reaction in the presence of a palladium catalyst such as palladium dichloro [1,1'-Bis( diphenylphosphino)ferrocene] (Pd(dppf)Cl2), with the intermediate of formula (IV) in which U represents a boronic acid or its pinacole ester, to obtain the compound of formula (V), c) coupling reaction of Suzuki-Miyaura type in the presence of a palladium catalyst such as palladium dichloro [1,1'-Bis(diphenylphosphino)ferrocene] (Pd(dppf)Cl2), with the intermediate of formula (VI) in which U' represents a boronic acid or its pinacole ester, to obtain the intermediate of formula (VII), and d) hydrolysis of the tosyl group with a base, preferably sodium hydroxide or carbonate d e cesium, to obtain a compound of formula (I). The synthesis of the amino intermediate compounds (VIII) (ie the compounds of formula (I) for which X and Z are as defined above and Y represents a group (CH ₂ ) _n NH ₂ where n is equal to 1 is represented in Diagram 2.

Diagram 2 where X and Z are as previously defined.

In this embodiment, the method for preparing the amine intermediates of formula (VIII) can comprise at least the steps of: e) condensation of the hydroxylamine on a compound of formula (I) in which Y is CHO to form the oxime of formula (IX), f) reduction of the oxime (IX), in particular in the presence of zinc under ultrasound to obtain the methylamine intermediate of formula (VIII)

Those skilled in the art will naturally apply all the other well-described and known synthetic techniques to synthesize these types of compounds. The compounds of formula (I) in which Y represents an L-(CH ₂ ) _P -W group with L representing an amide group -NHC(O)- or -CH ₂ NHC(O)-, are for example obtained by a method of synthesis from amino-7-azaindoles derivatives shown in Scheme 3:

Diagram 3 where W, X, Z and p are as previously defined and n equal to 0 or 1.

The method of Scheme 3 comprises at least one peptide coupling reaction step between an acid of formula W-(CH ₂ ) _P -C(O)OH and the amino intermediate of formula (VIII) as defined previously, in particular in presence of at least one activating agent such as 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N-tetramethyluronium hexafluorophosphate (HATU) and a base such as diisopropylethylamine (DIEA).

Those skilled in the art will naturally apply all the other well-known synthetic techniques to obtain these types of amide compounds. The compounds of formula (I) in which Y represents an L-(CH ₂ ) _P -W group with L representing a -CONH- group, are for example obtained by a method of synthesis from 7-azaindole carboxylic derivatives of formula (X) represented in Scheme 4 according to two methods among others:

Diagram 4 where W, Z and p are as previously defined.

Advantageously, the methods of Scheme 4 comprise at least one peptide coupling reaction step between an acid of formula (X) and an amine of formula W-(CH ₂ ) _P -NH ₂ , either by coupling or by generation in situ acyl chlorides by prior action of thionyl chloride.

The urea compounds of the present invention, ie the compounds of formula (I) in which Y represents an L-(CH ₂ ) _P -W group with L representing a urea -NHCONH- group, are for example prepared according to the method represented in Figure 5:

Diagram 5 where W, X and Z are as previously defined.

Advantageously, the methods of Scheme 5 comprise at least one reaction of a compound of formula (VIII) in which n is equal to 0, with an isocyanate of formula W-NCO, W being as defined above. Said isocyanates are either commercially available or obtained according to synthetic methods known to those skilled in the art. In addition, those skilled in the art will naturally apply all the other well-known synthetic techniques to obtain these types of urea compounds. According to another embodiment, concerning the method of synthesis of the secondary amine compounds of the present invention, ie the compounds of formula (I) in which Y represents a group L-(CH ₂ ) _P -W with L representing a group - CH ₂ NH-, two methods among others are represented in Scheme 6:

Diagram 6 where W, X, Z and p are as previously defined.

Advantageously, the methods of Scheme 6 comprise at least one step of reductive amination between either a compound of formula (VIII) in which n is equal to 1, with aldehydes of formula W-CHO, or between the 7- azaindole aldehydes of formula (XI) and an amine of formula W(CH ₂ ) _P -NH ₂ .

The aldehydes of formula W-CHO and the amines of formula W(CH ₂ ) _P -NH ₂ are in particular commercially available, or easily obtained according to preparation methods known to those skilled in the art.

Those skilled in the art will naturally apply all the other well-known synthetic techniques to obtain these types of amide compounds.

Another embodiment relates to the method of synthesis of secondary amine derivatives of formula (XII) obtained by deprotection of the compound of formula (XIII) according to Scheme 7 below:

Diagram 7 where X and Y are as previously defined.

Advantageously, the method comprises at least one stage of hydrolysis of the carbamate compound of formula (XIII) in an acid medium to form the desired secondary amine of formula (XII).

Those skilled in the art will naturally apply all the other well-known synthetic techniques to deprotect the expected secondary amine.

DESCRIPTION OF THE FIGURES Figure 1: Inhibition of the phosphorylation of Axi in cellulo by compounds 1, 2 and 3 in comparison with R428/Bemcentinib. The A549 cells were preincubated for 1 hour with 2.5 mM of compound targeting Axl. They were then stimulated for 5 min with 1 mM pervanadate. The evaluation of the inhibition of the phosphorylation of the residue Y779 of the intracytoplasmic domain of the kinase Axl is done by immunoblot using the antibody R&D Systems (AF2228) and measurement of the intensity of the signals by densitometry (Image J ) (P-Axl/Axl ratio).

Figure 2: Determination of the IC50s of compounds 1, 2 and 3 with respect to the inhibition of Axl kinase and of FLT3 kinase. 10 concentrations of the compound were prepared by serial dilutions. Compounds are screened in 1% final DMSO. The kinases were diluted to a twice concentrated concentration in kinase buffer. All ATP solutions were diluted to a 4-fold working concentration (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA). Each compound was incubated at 10 concentrations between 100 nM and 0.00495 nM in order to calculate the IC ₅₀ . The ICso's are indicated: a) results of compound 1; b) results of compound 2; c) results of compound 3.

Figure 3: Evaluation of the anticancer activity of compounds 1, 2, 3 and 10 on HepG2 cells. Values are means of triplicates + standard deviation.

Figure 4: Evaluation of the anti-cancer activity of compounds 1, 2 and 3 on U20S cells. Values are means of triplicates + standard deviation.

Figure 5: Evaluation of the anti-cancer activity of compound 1 on HeLa cells. Values are means of triplicates + standard deviation. Figure 6: Evaluation of the anti-cancer activity of compounds 1, 2 and 3 on HCT116 cells. Values are means of triplicates + standard deviation.

Figure 7: Combined anticancer action of compound 1 and Etoposide on the A549 line (a) and on the HeLa line (b).

Figure 8: Combined anticancer action of compounds 2, 3 and 10 and Etoposide on the HepG2 and HCT116 lines. The proliferation index scale is indicated. The figures indicate the mean values of duplicates.

EXAMPLES

The invention will be better understood on reading the following examples, which are given purely by way of illustration and should not be interpreted as limiting the scope of the present invention.

Example 1. Hardware Synthesis

The syntheses and analyzes were carried out under the following conditions.

Nuclear Magnetic Resonance ¹ H and ¹³ C:

Device: Bruker Avance 400 (400 MHz); Bruker Advance 300 (300 MHz)

Conditions of use: Room temperature, chemical shifts expressed in parts per million (ppm), multiplicity of signals indicated by lowercase letters (singlet s, doublet d, triplet t, quadruplet q, multiplet m), dimethyl sulphoxide d ₆ , methanol d4, chloroform di as deuterated solvents.

High Pressure Liquid Chromatography (HPLC):

Device: Agilent Technology 1260 Infinity

Conditions of use: Zorbax SB-C18 or Eclipse plus column (2.1 x 50 mm), 1.8 µm; temperature: 30°C, flow rate: 0.5 mL/min for methods X and Y and 0.4 mL/min for method Z, elution gradient Water (A) / Acetonitrile (B) / 0.1% formic acid (Time (min )/%B):

• Method X: 0/10, 0.3/10, 5.7/100, 6.0/100

• Y method: 0/10, 1/50, 6/100, 8/100

• Z method: 0/10, 11/100, 15/100

Mass Spectrometry (MS):

Device: Quadripole Agilent Technologies 6120 Conditions of use: ElectroSpray (ESI) in positive and/or negative mode.

Weights:

Device: Denver Instrument TP214 (accuracy 0.1 mg)

Conditions of use: Weighing carried out to the nearest milligram. Reactions under pressure:

Apparatus: 300 mL Parr autoclave.

Conditions of use: Hydrogenation under 20 bars of hydrogen.

Reaction under microwave irradiation:

Device: CEM Discover SP® Conditions of use: Power of 200 Watts, Medium stirring speed

In the following, the following abbreviations are used:

General synthesis of 3,5-diaryl-1H-Dyrrolo[2,3-b]Dyridines intermediates (I) ^1st step, synthesis of 5-bromo-3-iodo-1-(toluene-4-sulfonyl)-1H -pyrrolo[2,3-b]pyridine(III)

3 g of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (II) are diluted in 60 mL of anhydrous THF under argon and cooled in an ice bath. 558 mg (1.5 eq) of sodium hydride (60%) are added slowly and the medium is stirred at 0° C. for 20 minutes. Then tosyl chloride (2.11 g, 1.2 eq) is added, and the medium is stirred at AT for 5 hours. The solvent is evaporated. The residue obtained is suspended in a minimum of petroleum ethers and filtered. The precipitate is washed twice with a 2M sodium hydroxide solution, then dried under vacuum overnight.

¹ H NMR (400 MHz, DMSO-d6) δ (ppm) 8.52 (d, J = 1.9, 1 H), 8.22 (s, 1 H), 8.01 (m, 3H), 7.44 (d, J = 8.2, 2H), 2.51 (s, 3H). Yield: 97%; HPLC: 99%; MS [M+1]: 476.9-478.9

^2nd step, general synthesis of 3-5-bis-aryl-1H-pyrrolo[2,3-b]pyridines (I) (in which Y

= CHO, NH? or phenyl substituted by phenyl) 5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (III) (100 mg), the first boronic acid to couple (IV) (1 eq ) and potassium carbonate (3 eq) are suspended in a 3/1 water (3 mL) dioxane mixture, and the mixture is degassed under Argon for 20 minutes. Pd(dppf)Cl2 (2%) is added and the mixture is stirred at 80° C. under microwave irradiation for 1 to 3 times 20 minutes until the starting reagent is completely consumed. The reaction medium is washed with a saturated aqueous NaHCO3 solution and extracted with ethyl acetate. The solvents are evaporated off, the residue is taken up in ethyl acetate, washed with saturated aqueous NaHCO3 solution, dried over anhydrous Na2SO4, filtered and evaporated to dryness, then purified on a silica column. The compound is then dissolved in a dioxane/water mixture (3/1.4 mL), in the presence of the second boronic acid or its pinacol(VI) ester (1.2 eq) and potassium carbonate (3 eq). The medium is degassed again under Argon for 20 minutes, Pd(dppf)Cl2 (0.025 eq) is then added and the mixture is stirred at 120° C. for 45 minutes under microwave irradiation. 500 μL of 1 M sodium hydroxide (3 eq) are then added to the reaction medium and stirred at 100° C. for 45 minutes under microwave irradiation. The reaction medium is then washed with a saturated aqueous NaHCO3 solution, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered and evaporated to dryness, then purified on a normal phase silica column (dichloromethane/methanol-ammonia).

Synthesis of amines

Method 1: Synthesis of 4-Fluoro-3-(5-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-

Pyrrolo[2,3-b]pyridin-3-yl)-phenylamine

Step 1: Synthesis of 5-Bromo-3-(2-fluoro-5-nitro-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine

5-Bromo-3-iodo-1-(toluene-4-sulfonyl)-pyrrolo[2,3-b]pyridine (460mg), 2-(2-Fluoro-5-nitro-phenyl)-4, 4,5,5-tetramethyl-[1,3,2]dioxaborolane (1 eq) and potassium carbonate (3 eq) are suspended in a dioxane/water mixture (9/1, 20 mL), and degassed under Argon for 20 minutes. Pd(dppf)Cl2 (18 mg, 0.025 eq) is added and the mixture is stirred for 2 to 4 times for 20 minutes at 50° C. under microwave irradiation until total consumption of the reagent, measured by LC/MS. The solvents are evaporated off, the residue is taken up in ethyl acetate, washed with a saturated aqueous solution of NaHC03, dried over anhydrous Na2S04, filtered and evaporated to dryness, then purified on a normal phase silica column (petroleum ether/ dichloromethane).

Yield: 66%; HPLC: 90%; MS [M+1]: 490.0-492.0

Step 2: Synthesis of 3-[5-Bromo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-blpyridin-3-yl-4-fluoro-phenylamine 5-Bromo-3-(2-fluoro-5-nitro-phenyl)-1-(toluene-4-sulfonyl)-1/-/-pyrrolo[2,3-b]pyridine (100 mg) is suspended in 3 mL of ethyl acetate with 232 mg of tin chloride dihydrate (5 eq) and stirred at reflux for 4 hours. The reaction medium is taken up in ethyl acetate and washed with a saturated aqueous NaHCO3 solution. The precipitate is filtered off and rinsed with water, then with ethyl acetate. The aqueous phase is extracted with ethyl acetate. The organic phases are dried over anhydrous Na2SO4, filtered and evaporated to dryness, then purified on a normal phase silica column (petroleum ether/ethyl acetate).

Yield: 76%; HPLC: 97%; MS [M+1]: 460.0-462.0

Step 3: Synthesis of 4-Fluoro-3-{5-[3-(4-methyl-piperazin-1-methyl)-phenyl]-1H-

PVrrolo[2,3-b]pyridin-3-yl}-phenylamine

3-[5-Bromo-1-(toluene-4-sulfonyl)-1/-/-pyrrolo[2,3-b]pyridin-3-yl]-4-fluoro-phenylamine (475 mg), the 1 -methyl-4-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-piperazine (1,2 eq) and potassium carbonate (3 eq) are suspended in a dioxane/water mixture (9/1, 20 mL) and degassed under Argon for 20 minutes. Pd(dppf)Cl2 (19 mg, 0.025 eq) is then added and the mixture is stirred at 120° C. for 45 minutes under microwave irradiation. 3 mL of 1 M sodium hydroxide is then added to the reaction medium and stirred at 100° C. for 45 minutes under microwave irradiation. The reaction medium is then washed with a saturated aqueous NaHCO3 solution, extracted with ethyl acetate, dried over anhydrous Na2SO4, filtered and evaporated to dryness, then purified on a normal phase silica column (dichloromethane/ammoniacal methanol).

Yield: 91%; HPLC: 98%; MS [M+1]: 416.3

Synthesis of the different non-commercial carboxylic acids:

1-(4-Fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (HPLC: 97%; MS [M+1]: 243.1) was obtained according to the procedure described [Traoré et al. European Journal of Medicinal Chemistry (2013), 70, 789-801].

1-(4-Fluoro-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (HPLC: 97%; MS [M+1]: 248.2) was obtained according to the procedure described [Flynn et al. Organic Process Research & Development (2014), 18(4), 501-510]. 1-(4-Fluoro-phenyl)-4-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (HPLC: 100%; MS [M+1]: 248.2) was obtained as a by-product during the synthesis of 1-(4-Fluoro-phenyl)-6-methyl-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid described above.

General synthesis of amide compounds from amino-7-azaindole compounds and carboxylic acids.

The carboxylic acid (1eq) is dissolved in anhydrous DMF and placed in a dried Schlenck, under an Argon atmosphere. N,N′-dicyclohexylcarbodiimide (1eq), then the amino-7-azindole derivative (1eq) are added. The medium is then stirred at 70° C. overnight. The solvent is evaporated. The residue obtained is then dissolved in ethyl acetate, washed twice with a saturated aqueous solution of NaHC03, once with a saturated aqueous solution of sodium chloride, dried over anhydrous Na2S04, filtered on cotton, evaporated to dryness , and purified on a reverse phase silica column (water/acetonitrile) with 1% trifluoroacetic acid to give the desired amide derivative.

General synthesis of ureas

The amine derivative (1 eq), the phenyl isocyanate (1.05 eq) and the triethylamine (2 eq) are dissolved in anhydrous THF and stirred, under argon, at room temperature overnight. The reaction medium is quenched with a saturated solution of NaHCO3. Oa aqueous phase is extracted with ethyl acetate and dried over sodium sulfate. The organic phases are combined, evaporated to dryness, and purified on a normal phase silica column (dichloromethane/methanol-ammonia) to give the desired urea derivative.

Synthesis of amine compounds from formyl-azaindoles

The aldehyde derivative (1 eq) and the amine derivative (1 eq) are dissolved in a methanol/acetic acid mixture (9/1). The mixture is stirred for 3 hours at room temperature then sodium cyanoborohydride (2 eq) is added and the medium is stirred at room temperature overnight. The solvent is evaporated, the residue is taken up in ethyl acetate, washed twice with a saturated aqueous solution of NaHC03, once with a saturated aqueous solution of sodium chloride, dried over anhydrous Na2S04, filtered on cotton and evaporated to dryness . The residue obtained is purified on a silica column with a gradient from 100% dichloromethane to 90/10 dichloromethane/methanol-ammoniacal.

Deprotection of amino derivatives.

The protected amine derivative (1 eq) is dissolved in dioxane and concentrated hydrochloric acid (4 eq). The mixture is stirred for 2 hours at room temperature. The solvent is evaporated off, the residue is taken up in an ethyl acetate/water mixture. The aqueous phase is neutralized by adding powdered NaHCO3. The precipitate is filtered, then washed with water and dried.

Example 2. BIOLOGICAL TESTS

A- Selectivity of the compounds of the invention with respect to the AxL kinase

The compounds of the invention were evaluated for their Axl kinase inhibitory activity, in a selective manner.

1- Inhibition of Axl kinase phosphorylation in cellulo

The A549 cells were preincubated for 1 hour with 2.5 mM of compound 1, 2 or 3. They were then stimulated for 5 min with 1 mM pervanadate, a compound known to activate the Axl kinase by phosphorylation.

The inhibition of the phosphorylation of the Y779 residue of the intracytoplasmic domain of AxI is visualized by immunoblot using the R&D Systems antibody (AF2228).

The results are illustrated in FIG. 1. They show a much weaker or even zero activation of the Y779 residue of AxL in the presence of compounds 1, 2 and 3 in comparison with the control in DMSO.

2- Selective inhibition of Axl kinase

The inhibitory activity of the compounds on a panel of kinases including among others AXL and FLT3 was evaluated by Thermo Fisher Scientific using Z'- ^LYTE and ADAPTA Select Screen technology.

The fluorescence-based biochemical assay uses coupled enzymes and is based on the difference in sensitivity of phosphorylated and non-phosphorylated peptides to proteolytic cleavage. The peptide substrate is labeled with 2 fluorophores - one at each end - allowing fluorescence transfer (FRET).

Compounds 1, 2 and 3 are tested in wells at the final concentration of 1% in DMSO. The results are presented in the following table:

Percentage of kinase inhibition by the compounds of the invention. Columns from left to right: the kinases tested compound 1- compound 2- compound 3.

The results show that each of the compounds of the invention shows excellent activity (95%, 95% and 94% inhibition) on the Axl kinase when, vis-à-vis other kinases, the results are disparate from one composed to another.

To calculate the IC _50s of inhibition of Axi and of FLT3 by the compounds of the invention, 10 concentrations of each compound 1, 2 and 3 were prepared by serial dilutions to one-third from the starting concentration. Axl or FLT3 kinases were diluted to a 2X concentration in kinase buffer. All ATP solutions are diluted in a 4X working concentration (50 mM HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl2, 1 mM EGTA).

Each compound is incubated at 10 concentrations between 100 nM and 0.00495 nM in order to calculate the IC ₅₀ .

The results are illustrated in figure 2 and summarized in the table below

Compounds 1, 2 and 3 show excellent activity against the two kinases Ax1 and FLT3. Compound 3 even shows selectivity for Axi over FLT3, with Axl playing a critical role in FLT3 activation.

B- Anti-cancer evaluation

The evaluation of anti-cancer activities was carried out on the following human cancer cell lines:

a- Anti-tumor activity of the compounds

The cancer cell lines (1× ^{10 4} cells per well) are distributed in 96-well plates and incubated with increasing concentrations of compound for 36 hours. Cell proliferation is determined by measuring the reduction of MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] in the presence of phenazine ethosulfate (PES), using the Cell Titer 96 Aqueous One Solution kit (Promega). The values are normalized with respect to those of the control wells treated with DSMO (0), solvent for diluting the compounds, in volumes comparable to the test conditions. The results are illustrated in Figures 3 to 6 and in the following table:

EC50 of anti-tumor activities of compounds 1, 2, 3 and 10 on U20S, HeLa, HCT116 and HepG2 cells. EC50 values were calculated from sigmoidal dose-response curves using Prism 5.0 Graph-Pad software (GraphPad Software, La Jolla, CA, USA), normalizing the values to those of control wells treated with DSMO (0 %) and the control wells containing no cells (100%). The EC50 of R428/Bemcentininb is indicated in parallel for the U20S line.

Compounds 1, 2, 3 and 10 are therefore strongly inhibitors of cell proliferation in at least one cell type, indicating that these molecules are capable of blocking tumor growth (proliferation of epithelial cells). b- Antitumor activity in combination with conventional anticancer agents

The anticancer activity of the compounds was evaluated in combination with conventional anticancer agents, in particular Etoposide (topoisomerase inhibitor).

The cancer cell lines (1× ^{10 4} cells per well) are distributed in 96-well plates and incubated for 36 hours with combinations of concentrations of Etoposide (0-200 mM) and of compound according to the invention (0-50 mM). Cell proliferation is determined by measuring the reduction of MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] in the presence of phenazine ethosulfate (PES), using the Cell Titer 96 Aqueous One Solution kit (Promega). The control conditions (OmM) correspond to cells maintained in the presence of equivalent volumes of dilution solvent (DMSO).

The results are illustrated in Figures 7 and 8. The inhibitor combination tests indicate that the addition of a concentration of compound according to the invention less than or equal to 2.5 mM potentiates the anti-cancer activity of Etoposide. These compounds are therefore likely to potentiate conventional anti-cancer treatments. This effect was observed for compounds 1, 2, 3 and 10.

Claims

1. Compound of formula (I):

in which

X represents a hydrogen atom or a halogen atom,

- p is an integer from 0 to 2,

• a hydrogen atom,

• a C ₁ -C ₆ alkyl, preferably a methyl,

• a 5-10 membered heteroaryl containing from 1 to 3 heteroatoms independently chosen from N, O and S, said heteroaryl being optionally mono- or polysubstituted, advantageously it is optionally substituted by 1 to 4 groups independently chosen from o an atom of halogen, o hydroxyl, o oxo group, o C ₁ -C ₆ alkoxyl, o C ₁ -C ₆ alkyl in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and o a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom and/or a C ₁ -C ₆ alkyl;

- when L represents -C(O)NH-, W is chosen from:

• a 5-10 membered heteroaryl comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heteroaryl being optionally mono- or polysubstituted, advantageously it is optionally substituted by 1 to 4 substituents independently chosen from o an atom of halogen, o hydroxyl, o oxo group, o C ₁ -C ₆ alkoxyl group, o C ₁ -C ₆ alkyl in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and o a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom and/or a C ₁ -C ₆ alkyl;

Z represents -CH ₂ Q or -0(CH ₂ ) _m T,

- Q represents -OH, -SO2R1, -NR2R3, or -R4

• Ri represents a C ₁ -C ₆ alkyl,

• R ₂ and R ₃ each independently represent a C ₁ -C ₆ alkyl, and

- m is equal to 1 or 2,

- T is -0(CH ₂ ) _n CH3 or -R5

• n is equal to 0 or 1

• R ₅ is a 5 to 7 membered heterocycloalkyl comprising from 1 to 2 heteroatoms independently chosen from N, O and S, said heterocycloalkyl being optionally substituted by 1 to 3 substituents independently chosen from a C ₁ -C ₆ alkyl, a C (O)-C ₁ -C ₆ alkyl and a C(O)O-C ₁ -C ₆ alkyl; or a pharmaceutically acceptable salt thereof or a mixture thereof, for its use in the prevention and/or treatment of cancer, autoimmune, inflammatory diseases, transplant rejection and fibrosis.

2. Compound for use according to claim 1, of formula (Id):

wherein X, Y and Z are as defined in claim 1.

3. Compound for its use according to claim 1 or 2, characterized in that Z represents - CH ₂ R ₄ in which R4 represents a piperazine group, optionally substituted by a C ₁ -C _{6 alkyl,} in particular a methyl.

4. Compound for its use according to any one of claims 1 to 3, characterized in that X represents a halogen, in particular fluorine.

5. Compound for its use according to any one of claims 1 to 4, characterized in that Y represents an aryl, heteroaryl or L- (CH ₂ ) _P -W, L representing -CH ₂ NH or - NHC (O) NH-, p being an integer from 0 to 2, and W being chosen from:

- a phenyl optionally substituted by a hydroxyl group, or a C ₁ -C ₆ alkyl group, and

- a 5-10 membered heteroaryl comprising from 1 to 2 heteroatoms independently chosen from N, O or S.

6. Compound for its use according to claim 5, characterized in that Y represents L-(CH ₂ ) _P -W, L representing -CH ₂ NH or -NHC(O)NH-, p being an integer from 0 to 2 , and W being chosen from:

- a phenyl optionally substituted by a hydroxyl group, and

- an imidazole.

7. Compound for its use according to any one of claims 1 to 4, characterized in that Y represents -NHC(O)-W, with W representing a heteroaryl of 5 to 10 members, comprising from 1 to 2 heteroatoms independently chosen from N, O or S, said heteroaryl being optionally substituted by 1 to 3 substituents independently chosen from:

- an oxo group,

- a C ₁ -C ₆ alkyl in which 1 or more hydrogen atoms is optionally replaced by a fluorine atom, and - a C ₆ -C ₁₀ aryl optionally substituted by a halogen atom and/or a C ₁ -C ₆ alkyl.

8. Compound for its use according to claim 7, characterized in that said heteroaryl is a 2 (1 H)-pyridinone, optionally substituted by 1 to 3 substituents independently chosen from:

- a methyl, and

- a phenyl optionally substituted by a fluorine atom.

9. Compound for its use according to claim 1 chosen from:

10. Pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof as active ingredient, and a pharmaceutically acceptable excipient for its use in the prevention and / or treatment of cancer , autoimmune and inflammatory diseases, transplant rejection and fibrosis.

11. A composition for its use according to claim 10, further comprising an additional therapeutic agent selected from the group consisting of a chemotherapeutic or antiproliferative agent, an anti-inflammatory agent, an immunomodulating agent or immunosuppressant, an agent for treating a neurological disorder, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for the treatment of diabetes, an agent for the treatment of immunodeficiency disorders and an agent for the treatment of pain.

12. Compound for its use according to any one of claims 1 to 9 or composition for its use according to claim 10 or 11, for preventing or treating tumorigenesis, leukemias, lymphomas, myeloproiiferative syndromes, skin cancer , lung cancer, pleural cancer, gastrointestinal cancer, pancreatic cancer, brain tumors, cervical cancer, ovarian cancer, liver cancer, ie bladder cancer, breast cancer, melanoma, colorectal cancer, endometrial carcinoma, salivary gland carcinoma, kidney cancer, head and neck cancer, prostate cancer, vulvar cancer, thyroid cancer or sarcomas.

13. Compound for its use according to any one of claims 1 to 9 or composition for its use according to claim 10 or 11, for preventing or treating a hematological malignancy chosen from ie non-Hodgkin's lymphoma, ie Hodgkin's lymphoma, myeloma, ie myeloid sarcoma and leukemias such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphoid leukemia (CLL), or chronic myeloid leukemia (CML).

14. Compound for its use according to any one of claims 1 to 9 or composition for its use according to claim 10 or 11, for preventing or treating a solid cancer chosen from cancers of the liver, pancreas, lungs, breast , prostate, kidney, head and neck, thyroid, colorectal, ie melanoma or chemoresistant cancers.