The present invention relates to azaindazole and diazaindazole fused bicyclic derivatives, as well as to the therapeutic use of same, notably in the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease, as well as to methods for synthesizing same.
Protein kinases are enzymes that play a key role in cell signal transduction. They are involved in physiological processes such as cell proliferation, mitosis, differentiation, cell invasion and mobility, and apoptosis, for example.

Deregulation of the physiological mechanisms controlled by protein kinases is central to the appearance and development of many pathologies, notably including cancers. It is of particular note that many oncogenes and proto-oncogenes correspond to protein kinases.

Consequently, these enzymes are seen to play an important role during the various stages of tumor development and thus they constitute important pharmaceutical targets for cancer treatments.

Tyrosine kinase receptors (TKRs) form a particular class of protein kinases among which, among others, mention may be made of ALK, EGFR, Her2, PDGFR, Kit, VEGFR, IGFR, FGFR, Trk, Axl, Mer, Met, Ron and Ret. In this subfamily, ALK is regarded as a particularly relevant target because it is genetically modified in certain tumor pathologies and thus acquires an oncogenic nature. More precisely, chromosomal translocations leading to the production of fused protein kinases (ALK-X) which are then constitutively activated cause the development of certain cancers. ALK in oncogenic form is expressed by various tumor pathologies of different histological types. These pathologies are thus ALK-dependent. ALK in oncogenic form exists only in tumor cells and is not expressed by normal cells. For this reason, this protein kinase provides the opportunity to specifically target ALK-dependent tumor tissues while saving healthy tissues from significant toxic effects (Ott G.R. et al, Anticancer Agents Med. Chem., 2010, 10(3), 236-49).

Several cases of chromosomal translocations involving ALK, related to cancer pathologies, have already been documented. For example, the fusion protein NPM-ALK

is associated with anaplastic large-cell lymphoma (ALCL) for which an optimal treatment remains to be developed. Similarly, the fusion protein EML4-ALK is associated with tumor development in a subpopulation of patients suffering from non-small cell lung cancer. Mutated forms of ALK have al so been ob served in neuroblastoma.

c-Src is also a protein kinase whose activation state proved to be negatively correlated with the survival of patients suffering from various forms of cancer, including non-small cell lung cancer (Byers L.A. et al, Clin. Cancer Res. 2009, 15(22), 6852-6861).

For this reason, and because of its involvement in many key mechanisms such as cell cycle progression, adhesion, proliferation, migration and control of apoptosis, this protein is also regarded as a target of interest in oncology.

It has been shown in particular that the inhibition of this target, by both biochemical and pharmacological means, induced effects such as a reduction in cell proliferation, a stopping of the mitotic cycle and a slowing of tumor growth in vivo. In the particular case of non-small cell lung cancer, the inhibition of c-Src by an inhibitor

(dasatinib) led to the observation, in vitro, of inhibition of the migration and the invasion of the cells concerned.

Nevertheless, in terms of the control of tumor cell proliferation, it has been proposed that c-Src inhibition alone only induces a partial and/or transitory pharmacological response.

Consequently, there continues to be a need for inhibitors with a composite mode of action that are capable of intervening at several targets, in particular at several targets of the same signaling pathway, proposed as being more effective, with an improved therapeutic index and less likely to give rise to phenomena of compensation, resistance or therapeutic escape.

The compounds of the present invention thus have the property of inhibiting or modulating the enzymatic activity of protein kinases in general and ALK and c-Src in particular. Consequently, said compounds can be used as drug in the treatment of proliferative diseases such as cancer.

Additional indications in inflammation or in affections of the central nervous system may also be pursued.

More particularly, the present invention thus has as an object a compound of following general formula (I):

or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, a stereoisomer or a mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture,

wherein:

- Yi and Y4 each represent, independently of each other, a CH group or a nitrogen atom,

- Y2 represents a nitrogen atom or a CH or C-X-Ar group,

- Y3 represents a nitrogen atom or a C-X-Ar or C-W group,

on the condition that:

■ at least one and at most two Yi, Y2, Y3, and Y4 groups represent a nitrogen atom,

■ Y2 and Y4 cannot represent a nitrogen atom at the same time,

■ when Y2=C-X-Ar, then Y3 represents a nitrogen atom or a C-W group, and ■ when Y3=C-X-Ar, then Y2 represents a nitrogen atom or a CH group,

- Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci- C6)haloalkoxy, (d-C6)halothioalkoxy, CN, N02, ORn, SRi2, R13R14, C02Ri5, CO RieRn, SO2R18, SO2 R19R20, COR21, R22COR23, R24SO2R25, and R26 R27R28 and/or optionally fused to a heterocycle,

- X represents a divalent group selected from O, S, S(O), S(0)2, R4, SCNR^, S(0)(NR4), S(0)2(NR4), R4S, R4S(0), R4S(0)2, CH2, CH2S, CH2S(0), CH2S(0)2, SCH2, S(0)CH2, S(0)2CH2, CH2CH2, CH=CH, C≡C, CH20, OCH2,

- W represents an R5, SR5, OR5 or R5R5 group,

- U represents a CH2 or H group, one or more hydrogen atoms which may be replaced by a (Ci-Ce)alkyl group,

- V represents C(O), C(S) or CH2,

n represents 0 or 1,

- Ri represents a hydrogen atom, or an OR7 or R7R8 group,

- R2 represents a hydrogen atom, an optionally substituted heterocycle, N02; OR9 or

- R3, R4, R11 to R25 and R27 to R28 each represent, independently of each other, a hydrogen atom or a (Ci-C6)alkyl group,

- R5 and R6 each represent, independently of each other, a hydrogen atom or a (Ci- C6)alkyl, optionally substituted aryl or optionally substituted benzyl group,

- R7, Rs, R9 and Rio each represent, independently of each other, a hydrogen atom or an optionally substituted (Ci-C6)alkyl or (C3-Ci2)cycloalkyl group or an optionally substituted heterocycle, and

- R26 represents (Ci-C6)alkyl.

In the preceding definitions, all the combinations of substituents or variables are possible insofar as they lead to stable compounds.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "(Ci-C6) alkyl" refers to saturated linear or branched hydrocarbon chains comprising 1 to 6 carbon atoms. It may be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl or hexyl group.

The term "(Ci-C6)alkoxy" refers to a (Ci-C6) alkyl chain linked to the rest of the molecule via an oxygen atom. As an example, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy or tert-butoxy groups.

The term "(Ci-C6)thioalkoxy" refers to a (Ci-C6) alkyl chain linked to the rest of the molecule via a sulfur atom. As an example, mention may be made of thiomethoxy, thioethoxy, thiopropoxy, thioisopropoxy, thiobutoxy or thio-tert-butoxy groups.

The term "(Ci-C6)haloalkyl" refers to a (Ci-C6) alkyl chain such as defined above wherein one or more hydrogen atoms are replaced by a halogen atom such as defined above. It may be in particular a trifluoromethyl group.

The term "(Ci-C6)haloalkoxy" refers to a (Ci-C6)alkoxy chain such as defined above wherein one or more hydrogen atoms are replaced by a halogen atom such as defined above. It may be in particular a trifluoromethoxy group.

The term "(Ci-C6)halothioalkoxy" refers to a (Ci-C6)thioalkoxy chain such as defined above wherein one or more hydrogen atoms are replaced by a halogen atom such as defined above. It may be in particular a trifluorothiomethoxy group.

The term "(C3-Ci2)cycloalkyl" refers to cyclic hydrocarbon systems comprising from 3 to 12 carbon atoms and comprising one or more rings, in particular fused rings. As an example, mention may be made of an adamantyl or cyclohexyl group.

The term "aryl" refers to an aromatic hydrocarbon group preferably comprising from 6 to 14 carbon atoms and comprising one or more fused rings, such as, for example, a phenyl or naphthyl group. Advantageously, it is a phenyl group.

The term "heteroaryl" refers to a cyclic aromatic group comprising 5 to 7 atoms included in the ring or a bicyclic aromatic group comprising 8 to 11 atoms included in the rings, wherein 1 to 4 of the atoms included in the rings are a heteroatom selected independently from sulfur, nitrogen and oxygen atoms, and wherein the other atoms included in the rings are carbon atoms. Examples of heteroaryl groups include furyl, thienyl, pyridinyl, and benzothienyl groups.

The term "heterocycle" refers either to a stable monocycle containing from 4 to

7 cyclic atoms, or to a stable bicycle containing from 8 to 11 cyclic atoms, which may be either saturated or unsaturated, wherein 1 to 4 of the cyclic atoms are a heteroatom selected independently from sulfur, nitrogen and oxygen atoms, and wherein the other cyclic atoms are carbon atoms. As an example, mention may be made of furan, pyrrole, thiophene, thiazole, isothiazole, oxadiazole, imidazole, oxazole, isoxazole, pyridine, piperidine, pyrazine, piperazine, tetrahydropyran, pyrimidine, quinazoline, quinoline, quinoxaline, benzofuran, benzothiophene, indoline, indolizine, benzothiazole,

benzothienyl, benzopyran, benzoxazole, benzo[l,3]dioxole, benzisoxazole, benzimidazole, chromane, chromene, dihydrobenzofuran, dihydrobenzothienyl, dihydroisoxazole, isoquinoline, dihydrobenzo[l,4]dioxane, imidazo[l,2-a]pyridine, furo[2,3-c]pyridine, 2.3-dihydro-lH-indene, [l,3]dioxolo[4,5-c]pyridine, pyrrolo[l,2-c]pyrimidine, pyrrolo[l,2-a]pyrimidine, tetrahydronaphthalene, benzo[b][l,4]oxazin.

In the context of the present invention, "optionally substituted" means that the group in question is optionally substituted by one or more substituents which may be selected in particular from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (d-C6)halothioalkoxy, CN, N02, ORn, SR12, R13R14, C02Ri5, CO RieRn, S02Ri8, SO2 Ri9R20, COR2i, R22COR23, R24S02R25, and R26 R27R28, wherein R to R28 are such as defined above.

In the present invention, "pharmaceutically acceptable" refers to that which is useful in the preparation of a pharmaceutical composition that is generally safe, nontoxic and neither biologically nor otherwise undesirable and that is acceptable for veterinary and human pharmaceutical use.

"Pharmaceutically acceptable salt or solvate" of a compound refers to salts and solvates which are pharmaceutically acceptable, as defined herein, and which has the desired pharmacological activity of the parent compound.

Acceptable salts for the therapeutic use of the compounds of the present invention include the conventional nontoxic salts of the compounds of the invention such as those formed from pharmaceutically acceptable organic or inorganic acids or from pharmaceutically acceptable organic or inorganic bases. As an example, mention may be made of salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and those derived from organic acids such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, glutamic acid, benzoic acid, salicylic acid, toluenesulfonic acid, methanesulfonic acid, stearic acid and lactic acid. As an example, mention may be made of salts derived from inorganic bases such as soda, potash or calcium hydroxide and salts derived from organic bases such as lysine or arginine.

These salts may be synthesized from the compounds of the invention containing a basic or acidic part and the corresponding acids or bases according to conventional chemical methods well known to the person skilled in the art.

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

In the context of the present invention, "stereoisomer" refers to a geometric isomer or an optical isomer.

Geometric isomers result from the different position of substituents on a double bond which can then have a Z or E configuration.

Optical isomers result notably from the different position in space of substituents on a carbon atom comprising four different substituents. This carbon atom thus constitutes a chiral or asymmetrical center. Optical isomers include diastereoisomers and enantiomers. Optical isomers that are mirror images of each other but are non-superimposable are enantiomers. Optical isomers that are not mirror images of each other are diastereoisomers.

In the context of the present invention, "tautomer" refers to a constitutional isomer of the compound obtained by prototropy, i.e., by migration of a hydrogen atom and a change in location of a double bond. The different tautomers of a compound are generally interconvertible and are in equilibrium in solution in proportions which may vary according to the solvent used, the temperature or the pH.

According to a first embodiment, Y4=N.

Y2=C-X-Ar and Y3 preferably represents a C-W group.

In particular:

- or N, and advantageously CH,

- Y2=C-X-Ar,

- Y3=C-W, and

- Y4=N.

According to a second embodiment, Yi and/or Y4 represent a nitrogen atom. In this case, Y2 and Y3 preferably do not represent a nitrogen atom.

In particular:

- Yi and/or Y4 = N,

- Y2=CH or C-X-Ar, and

- Y3=C-W or C-X-Ar.

Advantageously, X represents a divalent group selected from O, S, S(O), S(0)2, R4, CH2, CH2S, CH2S(0), CH2S(0)2, HS(0)2, SCH2, S(0)CH2, S(0)2CH2, S(0)2 H, CH2CH2, CH=CH, C≡C, CH20, OCH2, R4CH2, and CH2 R4.

In aprticular, X represents a divalent group selected from S, S(O), S(0)2, R4, CH2, CH2S, CH2S(0), CH2S(0)2, HS(0)2, SCH2, S(0)CH2, S(0)2CH2, S(0)2 H, CH2CH2, C≡C, CH20, OCH2, R4CH2, and CH2 R4.

More particularly, X may be selected from S, S(O), S(0)2, CH2, CH2S, CH2S(0), CH2S(0)2, HS(0)2, SCH2, S(0)CH2, S(0)2CH2, S(0)2 H, CH2CH2, CH=CH, and C≡C.

In particular, X may be selected from S, S(0)2, CH2, SCH2, S(0)2CH2, S(0)2 H, CH2S, CH2S(0)2, HS(0)2, CH2CH2, and C≡C.

X may notably be selected from S, S(O), S(0)2, R4, CH2, SCH2, S(0)CH2,

S(0)2CH2, S(0)2NH, CH2CH2, C≡C, OCH2, and R4CH2; notably from S, S(0)2, CH2,

SCH2, S(0)2CH2, S(0)2 H, CH2CH2, and C≡C, wherein the first atom of these groups is bound to atom C of the C-X-Ar chain.

X may be in particular S, S(0)2, SCH2, S(0)2CH2, S(0)2 H, CH2S, CH2S(0)2, or HS(0)2; and notably S, S(0)2, SCH2, S(0)2CH2, or S(0)2 H, wherein the first atom of these groups is bound to atom C of the C-X-Ar chain.

Advantageously, Ar represents a heteroaryl group, such as pyridine, or an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci- C6)halothioalkoxy, CN, N02, ORn, SRi2, R13R14, C02Ri5, CO RieRn, S02Ri8,

SO2 Ri9R20, COR2i, R22COR23, and R24S02R25; and/or optionally fused to a heterocycle.

More particularly, Ar may represent an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci-C6)haloalkoxy, (d-C6)halothioalkoxy, CN, N02, ORn, SRi2,

R13R14, CO2R15, CO RieRn, SO2R18, SO2 R19R20, COR21, R22COR23, and

Ar may notably represent an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, and CO Ri6Ri7, and in particular from a halogen atom such as fluorine, (Ci-C6)alkyl such as methyl, and CONRi6Ri7 such as CO H2.

Ar can also represent a pyridine group.

Ar ma notably be selected from the following groups:

notabl from the following groups:

in articular, from the following groups:

Ar may advantageously represent the group:

W may advantageously represent an R5, SR5, OR5 or R5R6 group, and preferably R5, OR5 or R5R5, with R5 and R6 representing, independently of each other, a hydrogen atom or a (Ci-Ce)alkyl group.

W may represent in particular H, OMe, Me, OH or H2, and notably H.

Advantageously, R3 represents a hydrogen atom.

U may represent more particularly a CH2 or H group.

Advantageously, n may represent 0.

V may represent more particularly a C(O) or C(S) group, and advantageously a C(O) group.

According to a particular embodiment of the invention:

- R3=H,

- U=CH2 or H,

- V=C(0) or C(S), and notably C(O), and

- n=0 or 1, and notably 0.

According to another particular embodiment of the invention:

- V=C(0) or C(S), and notably C(O), and

- n=0.

According to still another particular embodiment of the invention:

- R3=H,

- V=C(0) or C(S), and notably C(O), and

Ri may represent more particularly a hydrogen atom or an NR7R8 group, with R7 notably representing a hydrogen atom and Rs notably representing an optionally substituted (C3-Ci2)cycloalkyl group or an optionally substituted heterocycle.

The (C3-Ci2)cycloalkyl group may be in particular a cyclohexyl. It may be substituted by one or more halogen atoms. It may be in particular the group:

The heterocyclic group may be in particular a tetrahydropyran, notably unsubstituted. It may thus be the following group:

Ri may thus represent more particularly one of the following groups:

and notably H and

R2 may represent more particularly an optionally substituted heterocycle (notably substituted by (d-C6)alkyl or H2), N02 or R9R10, with notably R9=Rio=H or else R9 and Rio each represent H or an optionally substituted (Ci-C6)alkyl.

R2 may represent in particular an optionally substituted heterocycle, notably substituted by (Ci-C6)alkyl or H2. The heterocycle may be in particular a heterocycle with 5 or 6 members comprising at least one nitrogen atom, and in particular one or two. The heterocycle may thus be selected from piperazine, piperidine and pyrrolidine.

R2 may notably represent one of the following groups:

H2 H(CH2)3 Me2, Me CH2)3 Me2,

an d and notably H2, N02,

and in

; and more particularly

The compounds of the present invention may be selected from the compounds cited in the following table:

The present invention also has as an obj ect a compound according to the invention of formula (I) such as defined above, to be used as a drug, notably intended for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease, in particular cancer.

The present invention also relates to the use of a compound of formula (I) such as defined above, for the manufacture of a drug, notably intended for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease, in particular cancer.

The present invention also relates to a method for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease, in particular cancer, comprising the administration to a person in need thereof of an effective dose of a compound of formula (I) such as defined above.

The cancer may be more particularly in this case colon cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, glioblastoma, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, diffuse B-cell lymphoma or anaplastic large-cell lymphoma.

The present invention also relates to a compound according to the invention of formula (I) such as defined above, to be used as a drug intended for the treatment of a disease associated with a kinase, and in particular a tyrosine kinase such as the kinases ALK, Abl and/or c-Src, and in particular ALK. The disease may be in particular associated with ALK and at least one other kinase, for example Abl or c-Src, in particular ALK and c-Src.

The present invention also has as an obj ect a compound according to the invention of formula (I) such as defined above, to be used as a kinase inhibitor, and in particular an inhibitor of tyrosine kinases such as ALK, Abl and/or c-Src, and in

particular ALK. The compounds according to the invention may notably be used as an inhibitor of ALK and at least one other kinase, for example Abl or c-Src. Preferentially, the compounds according to the invention are inhibitors of ALK and c-Src.

In the context of the present invention, "disease associated with a kinase" or "kinase-associated disease" refers to any diseases, and in particular diseases related to deregulation of cell proliferation, in particular cancers, due to deregulation of the expression or activity of said kinase compared to its normal state of expression or activity. Deregulation of the expression of said kinase may be modification of the sequence expressed or modification of the quantity of protein expressed. These deregulations may lead to changes in cells which may, in particular, result in proliferative disorders including cancers. Preferentially, according to the invention, kinase-associated diseases may be cancers related to deregulation of ALK and/or c-Src activity such as, for example, colon cancer, breast cancer, kidney cancer, liver cancer, pancreatic cancer, prostate cancer, glioblastoma, non-small cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumors, diffuse B-cell lymphoma and anaplastic large-cell lymphoma.

According to the invention, the expression "inhibitor of kinases" or "kinase inhibitor" refers to molecules that are able to interact with the kinase and to reduce its activity. Preferentially, the use of a kinase inhibitor according to the invention makes it possible to suppress the activity of said kinase.

The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) such as defined above, and at least one pharmaceutically acceptable excipient.

The pharmaceutical compositions according to the invention may be formulated notably for oral administration or for injection, wherein said compositions are intended for mammals, including humans.

The active ingredient may be admini stered in unit dosage forms of administration, in mixture with standard pharmaceutical carriers, to animals or to humans. The compounds of the invention as active ingredients may be used in doses ranging between 0.01 mg and 1000 mg per day, given in a single dose once per day or administered in several doses throughout the day, for example twice a day in equal

doses. The dose administered per day advantageously is between 5 mg and 500 mg, even more advantageously between 10 mg and 200 mg. It may be necessary to use doses outside these ranges as determined by the person skilled in the art.

The pharmaceutical compositions according to the invention may further comprise at least one other active ingredient, such as an anticancer agent.

The present invention also has as an obj ect a pharmaceutical composition comprising:

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

(ii) at least one other active ingredient, such as an anticancer agent,

as a combination product for simultaneous, separate or sequential use.

The present invention also relates to a pharmaceutical composition such as defined above to be used as a drug, notably intended for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease, in particular cancer.

The present invention also has as an object method for the preparation of the compounds of formula (I) according to the invention.

According to a first embodiment, the present invention relates to a method for the preparation of a compound of formula (I) according to the invention wherein V=C(0) or C(S), preferably C(O), and notably U=CH2, comprising the following successive steps:

(al) coupling between a compound of following formula (A):

wherein Yi, Y2, Y3 and Y4 are such as defined above, and R29 represents hydrogen atom or an N-protecting group,

with a compound of following formula (B):

wherein Ri, R2, U and n are such as defined above, V=C(0) or C(S), and
or a leaving group such as CI,

to yield a compound of following formula (C):

wherein Yi, Y2, Y3, Y4, Ri, R2, R29, U and n are such as defined above and V=C(0) or C(S),

(bl) optionally substitution of the nitrogen atom bound to V of the compound of formula (C) obtained in the preceding step with an R3 group other than H and/or deprotection of the nitrogen atom carrying an R29 group representing an N- protecting group to yield a compound of formula (I) with V=C(0) or C(S), and

(cl) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same.

In the context of the present invention, "N-protecting group" refers to any substituent that protects the NH or NH2 group against undesirable reactions such as the N-protecting groups described in Greene, "Protective Groups in Organic Synthesis" (John Wiley & Sons, New York (1981)) and Harrison et al., "Compendium of Synthetic Organic Methods", Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996). N-protecting groups include carbamates, amides, N-alkylated derivatives, amino acetal derivatives, N- benzylated derivatives, imine derivatives, enamine derivatives and N-heteroatom derivatives. In particular, the N-protecting group consists of formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, trityl (triphenylmethyl), tert-butyl, benzyl (Bn), t-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, p-nitrobenzyl-oxycarbonyl, trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), trifluoro-acetyl, benzyl carbamates (substituted or not) and the like. It may be in particular a trityl, tert-butyl or BOC group.

In the context of the present invention, "leaving group" refers to a chemical group which may be easily displaced by a nucleophile during a nucleophilic substitution reaction, wherein the nucleophile is more particularly an amine, and notably a primary or secondary amine. Such a leaving group may be more particularly a halogen atom such as a chlorine atom, a mesylate (CH3-S(02)0-), a triflate (CF3-S(0)20-) or a tosylate (p-Me-C6H4-S(0)20-).

Step (al):

Coupling between (A) and (B) may be carried out by techniques well known to the person skilled in the art.

When R3o=OH, the coupling may be carried out under peptide coupling conditions. It may thus be carried out in the presence of a coupling agent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), 2-(lH-benzotriazole-l-yl)-l, 1,3,3 -tetramethyluronium hexafluorophosphate (HBTU), 2-(lH-benzotriazole-l-yl)-l, 1,3, 3 -tetramethyluronium tetrafluorob orate (TBTU) or 0-(7-azobenzotriazol-l-yl)- 1, 1, 3, 3 -tetramethyluronium hexafluorophosphate (HATU); optionally combined with a secondary coupling agent such as N-hydroxysuccinimide (NHS), N-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy-4-oxo-l,2,3-benzotriazole (HOOBt), l-hydroxy-7-azabenzotriazole (HAt) or N-hydroxysulfosuccinimide (sulfo NHS). Peptide coupling may moreover be carried out in an aprotic solvent such as tetrahydrofuran, dioxane and dichloromethane.

When R3o is a leaving group such as CI, coupling may be carried out in the presence of a base such as pyridine, triethylamine or diisopropylethylamine (DIPEA). The reaction may be carried out in an aprotic solvent such as tetrahydrofuran, toluene or dichloromethane, or in a base solvent such as pyridine.

The compounds of formula (A) and (B) can be prepared by the methods described in further detail below.

Step fbl):

In the context of the present invention, "deprotection" refers to the process by which a protecting group is eliminated once the selective reaction is completed. Certain protecting groups may be preferred over others due to their convenience or their relative ease of elimination.

The deprotection step may be carried out under conditions well known to the person skilled in the art.

The substitution step may also be carried out by techniques well known to the person skilled in the art. If necessary, functionalities that may be sensitive to the reaction conditions of the substitution step may be protected beforehand and then deprotected once substitution is carried out.

Thus, if a step of deprotection of the nitrogen atom carrying an R29 group representing an N-protecting group and a step of substitution of the nitrogen atom bound to V with an R3 group must be carried out, the order in which these two steps are carried out will depend on the reaction conditions of each of these steps.

Moreover, it may al so be neces sary to carry out additi onal step s of functionalization of the molecule by techniques known to the person skilled in the art.

Step (cl):

This step may be carried out in the presence of a pharmaceutically acceptable organic or inorganic acid or a pharmaceutically acceptable organic or inorganic base such as defined above.

According to a second embodiment, the present invention relates to a method for the preparation of a compound of formula (I) according to the invention wherein V=CH2, and notably U=CH2, comprising the following successive steps:

(a2) reducing amination reaction between a compound of formula (A) such as defined above and an aldehyde of following formula (D):

wherein Ri, R2, U and n are such as defined above,

to yield a compound of following formula (E):

(E)

wherein Yi, Y2, Y3, Y4, Ri, R2, R29, U and n are such as defined above,

(b2) optionally deprotection of the nitrogen atom carrying an R29 group representing an N-protecting group and/or substitution of the nitrogen atom bound to V with an R3 group other than H of the compound of formula (E) obtained in the preceding step to yield a compound of formula (I) with V=CH2, and

(c2) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same.

Step (a2):

This step is carried out in the presence of a reducing agent such as a borohydride and in particular NaBH4, NaBH(OAc)3 or NaBH3CN.

This reaction is more particularly carried out at room temperature, i.e., at a temperature ranging between 15°C and 40°C, in particular between 20°C and 30°C.

The reaction may be typically carried out in a solvent such as dichloroethane (DCE), tetrahydrofuran (THF) or acetonitrile, optionally in the presence of water, acetic acid or trifluoroacetic acid.

The compounds of formula (A) and (D) can be prepared by the methods described in further detail below.

Step b2): see step (bl)

Step (c2): see step (cl)

According to a third embodiment, the present invention relates to a method for the preparation of a compound of formula (I) according to the invention wherein V=C(0) or C(S), n=l and U= H, comprising the following successive steps:

(a3) coupling between a compound of formula (A) such as defined above and a compound of following formul F):

wherein Ri and R2 are such as defined above and Z=0 or S,

to yield a compound of following formula (G):

wherein Yi, Y2, Y3, Y4, Ri, R2, R29, and Z are such as defined above,

(b3) optionally deprotection of the nitrogen atom carrying an R29 group representing an N-protecting group and/or substitution of the nitrogen atom bound to V with an R3 group other than H of the compound of formula (G) obtained in the preceding step to yield a compound of formula (I) with V=C(0) or C(S), n=l and U= H, and

(c3) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same.

Step (a3):

This step may be carried out under conditions well known to the person skilled in the art.

A polar or non-polar protic solvent may be more particularly used such as dichloromethane, acetone, acetonitrile, tetrahydrofuran or dioxane.

The compounds of formula (A) and (F) can be prepared by the methods described in further detail below.

Step (b3): see step (bl)

Step (c3): see step (cl)

Once the compound of formula (I) is obtained by any one of the preceding methods, it may be separated from the reaction medium by techniques well known to the person skilled in the art, and notably by evaporation of the solvent, crystallization and filtration, etc.

The compound obtained may be purified if necessary by techniques well known to the person skilled in the art, and notably by high-performance liquid chromatography (HPLC), silica gel chromatography, recrystallization when the compound is crystalline, etc.

Thus, the compounds of formula (I) according to the present invention can be prepared by the various methods summarized in diagrams la and lb below.

Diagram la

Ri = N02, halogen, OH, OMe, SMe, S(0)Me, SOzMe, OMs, OTf or OTs Rj = H or N-protecting group

Rn = Hal, OMs, OTs or OTf

(Tf represents an -SO2CF3 group and Ts represents a tosyl group)

Diagram lb

Method A:

According to method A, compounds of formula (I) are obtained by the preliminary synthesis of compounds of general formula (V) characterized by a halogenated heterobicyclic ring having an exocyclic primary amine. These compounds are obtained via the synthesis of intermediates of general formula (II) or (III).

Method Al:

Method Al, presented in diagram 2 (iodized compounds) or 3 (brominated compounds) below, describes the general process giving access to compounds of general formula (V) with W defined as in the description of general formula (I), and notably H, (Ci-Ce)alkyl or aryl, and Rj=H or N-protecting group.

Diagram 2

In the context of diagram 2, the optionally substituted 2-chloro-5-iodonicotinonitrile (Ila) is obtained from the corresponding hydroxynicotinonitrile by the successive use of an iodination agent such as N-iodosuccinimide (NIS), or molecular iodine with an inorganic base such as, for example, K2C03 or Na2C03, notably in a polar solvent such as hot DMF, followed by treatment with phosphorus oxychloride, pure or diluted in a high boiling-point non-polar solvent, or any other equivalent chlorination agent well known to the person skilled in the art. Reaction temperatures are between -20°C and 200°C. The compound (Ila) thus obtained is then transformed into optionally substituted 5-iodo-pyrazolo[3,4-b]pyridine-3-amine (Va) by its reaction, preferably under heat, in the presence of a hydrazine optionally carrying an N-protecting group such as trityl, tert-butyl or BOC.

The brominated analogues of general formula (V) as described in diagram la may be obtained by the use of the method described in the following references: Witherington et al, Bioorg. Med. Chem. Lett., 2003, 13, 1577-1580 and Lijuan Chen et al., Bioorg. Med. Chem. Lett., 2010, 20, 4273-4278. For reasons of convenience, these molecules were obtained by the use of the reaction sequence presented in following diagram 3.

The optionally functionalized 2-methoxy-nicotinotrile is obtained, for example, by reaction of sodium methanolate in methanol at a temperature between -20°C and the boiling point of the mixture. Alternatively, this compound may be obtained by methylation of 2-hydroxynicotinonitrile or other methods described above. Bromination of 2-methoxy-nicotinonitrile is typically carried out with dibromine in acetic acid at a temperature varying between 20°C and 110°C. Formation of the pyrazole is typically carried out by reaction of an excess of hydrazine, functionalized or not, at a temperature varying between 20°C and 100°C in the presence of a polar solvent such as water, ethanol, tetrahydrofuran (THF) or any other solvent with comparable properties. Alternatively, the use of hydrazine in a saline or hydrated form, without solvent, is also possible.

Method A2:

Method A2 relates to the synthesis of the functionalized pyrazolopyrazines presented in diagram 4 below with Rj=H or N-protecting group, Hal=halogen and in rticular W=H, (Ci-C6)alkyl or aryl.

Diagram 4

The optionally functionalized 3-amino-6-iodopyrazine-2-carboxamides are typically obtained in two steps from the corresponding methyl 3-aminopyrazine-2-

carboxylates by iodination in the presence of N-iodosuccinimide or molecular iodine optionally in the presence of a cofactor such as KIO3, AgC02CF3, Ag2S04, AICI3, CuCl2 or HgO, followed by a conversion reaction of the methyl ester function into carboxamide, notably by the use of ammonia in a polar solvent such as water, methanol or THF at temperatures varying between 0°C and 100°C. The carboxamide function of the optionally functionalized 3-amino-6-iodopyrazine-2-carboxamide is then converted into nitrile by the use of dehydration agents such as, in particular, CCI4/PPI13, SOCl2, PhS02Cl, P205, TsCl, COCl2, DCC/py (Ν,Ν'-dicyclohexylcarbodiimide/pyridine) or (COCl)2 used as the case may be in the presence of an organic base such as pyridine. The preferred m ethod i nvolve s the u se of pho sph oru s oxy chl ori de i n dimethylformamide (DMF). Deprotection of the dimethylformimidamide function is carried out by treatment with acid such as aqueous hydrochloric acid or any other reagent with equivalent properties. Formation of the pyrazole ring is carried out by a Sandmeyer reaction, well known to the person skilled in the art, followed by a reaction in the presence of a hydrazine, functionalized or not, under conditions as described in the methods above. Alternatively, the diazonium salt, an intermediate of the Sandmeyer reaction, may be reduced by the use, for example, of tin chloride in an acid medium or any other equivalent agent, in order to form a hydrazine function that can undergo intramolecular cyclization under the effect of heat.

Method A3:

Method A3 aims at obtaining derivatives of general formula (V) featuring a variable function in position 6 of the pyrazolopyridine bicycle. It is detailed in diagram 5 below.

* mArAsfcfe ——*■ W NASMe—

W = OH, OAlk, NHj_ HHMk, Alk, AJ. CHjAr

Rj=H or N-protecting group

(Alk=(Ci-C6)alkyl, Ar=aryl, CH2Ar=benzyl, H=halogen)

Diagram 5

Reaction of the cyanothioacetamide with ethyl 3-ethoxyacrilates variously substituted according to methods described notably by Litrivnor et al. in Russ. Chem. Bull., 1999, 48(1), 195-196 and Tsann-Long Su et al. in J. Med. Chem., 1988, 31, 1209-1215 make it possible to yield access, in two steps, to ethyl 5-cyano-6-(methylthio)nicotinates carrying a variable functionality in position 2. These syntheses are typically carried out, for the first step, in an anhydrous polar solvent such as, for example, ethanol at a temperature ranging between 0°C and 70°C in the presence of an organic base such as methylmorpholine, triethylamine, DIPEA (N,N-diisopropylethylamine) or DBU (l,8-diazabicyclo[5,4,0]undec-7-ene). The second step of intramolecular cyclization and of alkylation is typically carried out by the heating to a temperature ranging between 20°C and 100°C of a solution of the intermediate thioamidate in a polar solvent, for example ethanol in the presence of a suitable alkylating agent such as alkyl halide or dialkyl sulfate.

The 5-cyano-6-(methylthio)nicotinic acids substituted in position 2 are typically obtained by saponification of the corresponding ethyl esters according to methods well known to the person skilled in the art, notably by the use of hot lithium hydroxide. Decarboxylation of these compounds is carried out by heat treatment in a high boiling-point solvent such as diphenylether at a temperature ranging between 150°C and 250°C.

Halogenation reactions principally aim at obtaining iodinated, brominated or chlorinated derivatives, more particularly iodinated derivatives. The latter are typically obtained by a molecular iodine treatment in the presence of a silver salt such as, for example, Ag2S04 in a polar solvent such as ethanol at a temperature ranging between 0°C and 70°C. Alternative methods, notably those based on other salts such as KIO3, AgC02CF3, AICI3, CuCl2 or HgO, or other iodination agents such as N-iodosuccinimide, are also considered. The conceivable bromination methods typically rely on agents such as N-bromosuccinimide or dibromine according to methods well known to the person skilled in the art.

In the case in which W=OH (typically resulting from the use of diethyl 2-(ethoxymethylene)malonate), the corresponding compounds are protected by an alkylation reaction. This reaction is notably carried out by the use of methyl iodide or bromomethane, and silver carbonate in dioxane, THF, acetonitrile or acetone, or any other equivalent agent such as dimethyl sulfate. The 5-halo-2-(methylthio)

nicotinonitriles obtained are subjected to oxidation of their thiomethoxy function, typically by the use of m-CPBA (m-chloroperbenzoic acid), oxone or any other equivalent agent, to lead to the formation of the corresponding sulfoxide. These compounds, which may contain variable quantities of the corresponding sulfone, are engaged in a reaction in the presence of an optionally substituted hydrazine to form the corresponding 5-halogeno-pyrazolo[3,4-b]pyridin-3-am i ne carryi ng a vari ab l e functionality in position 6.

Method A4:

Method A4 aims at obtaining derivatives of general formula (V) from the compounds of general formula (III) via intermediate formation of compounds of formula (IV). These compounds are typically obtained by the pathway presented in diagram 6. The following references illustrate the method used: Gueiffier et al. Heterocycles, 1999, 51(7), 1661-1667; Gui-Dong Zhu et al. Bioorg. Med. Chem., 2007, 15, 2441-2452.

(IVb) (Ve)

Diagram 6

The compounds of general formula (Ilia), acetylated beforehand by one or another of the methods well known to the person skilled in the art, are subjected to the action of isoamyl nitrite, sodium nitrite or any other equivalent organic or inorganic nitrite, in water or acetic acid, for periods typically varying from 1 to 3 days at temperatures varying between 0°C and 40°C. The compounds of general formula (IVa) thus obtained are deprotected in acidic conditions, for example by the use of hydrochloric acid, before being subj ected to the action of nitration agents such as concentrated nitric acid or potassium nitrate in sulfuric acid at temperatures varying between 0°C and 25°C.

It should be noted that the direct conversion of compounds of general formula (Ilia) into deprotected compounds (IVb) is possible in general.

The nitropyrazoles thus obtained are typically reduced into aminopyrazoles of general formula (Ve) by the use of SnCl2 in hydrochloric acid. Alternative methods include the use of iron, zinc or tin in acidic conditions and methods of catalytic hydrogenation in the presence of complexes of platinum, nickel or Pd/C under an atmosphere of hydrogen or in the presence of equivalent agents such as cyclohexadiene, cyclohexene, sodium borohydride or hydrazine.

Method B:

According to method B, the compounds of formula (I) are obtained by the preliminary synthesis of compounds of general formula (VI) characterized by a functionalized heterobicyclic ring possessing an exocyclic amine. These compounds are obtained via the synthesis of intermediates of general formula (VI).

Method Bl:

Method B 1 is represented in diagram 7 below, with W notably representing H, (Ci-C6)alkyl, aryl or benzyl.

Diagram 7

The 3-nitro-6-thioxo-l,6-dihydropyridin-2-carbonitrile and 3-nitro-6-thioxo-l,6-dihydropyrazine-2-carbonitrile derivatives, optionally functionalized in position 5, are typically obtained from the corresponding 2,6-dichloro-3-nitropyridines or 2,6-dichloro- 3-nitropyrazines by the successive reactions of a cyanide salt, such as copper cyanide, in a high boiling-point polar solvent such as N-methylpyrrolidone at temperatures ranging between 100°C and 200°C; followed by the reaction of aqueous sodium hydrosulfite in a polar solvent. These compounds are then alkylated, for example by the use of a substituted benzyl bromide, in basic medium, according to methods well known to the person skilled in the art. The preferred protocol includes the use of an aprotic and anhydrous polar solvent such as acetone carrid at its boiling point and an organic base such as pyridine, triethylamine or DIPEA, or an inorganic base such as sodium, potassium or calcium carbonate. Reactions for reducing the nitro function in amine are preferentially carried out by the use of SnCl2 in hydrochloric acid. Alternative methods include the use of iron, zinc or tin in acidic conditions and methods of catalytic hydrogenation in the presence of complexes of platinum, nickel or Pd/C under an atmosphere of hydrogen or in the presence of equivalent agents such as cyclohexadiene, cyclohexene, sodium borohydride or hydrazine.

In certain cases, the product of the reduction reaction, in addition to having a primary amine, has a carboxamide function resulting from hydrolysis of the nitrile function. In this case, isolation of the corresponding 3-aminopicolinonitriles or 3-aminopyrazine-2-carbonitriles may be carried out by dehydration of the carboxamide into nitrile via the use of phosphorus oxychloride in the presence of DMF or any other method well known to the person skilled in the art. Lastly, formation of the aminopyrazole ring is carried out preferentially by the formation of a diazonium, obtained by the successive reaction at low temperature of isoamyl nitrite, sodium nitrite or any other equivalent organic or inorganic nitrite, in water, hydrochloric acid, acetic acid or sulfuric acid, at temperatures varying between 0°C and 20°C, followed by its reduction into hydrazine and intramolecular cyclization activated by heating of the reaction medium. The reduction reaction is preferentially carried out with tin chloride in acidic conditions but may also be carried out by catalytic hydrogenation or any other method well known to the person skilled in the art. In an alternative to this last step, it is conceivable that the intermediate diazonium undergoes a Sandmeyer reaction during which this functional group is substituted by a halogen atom, such as iodine, by the reaction of an adequate salt, such as NaT If this option is preferred, formation of the

aminopyrazole ring is carried out by the use of a hydrazine, functionalized or not, in a polar solvent such as ethanol at temperatures varying between 25°C and 150°C.

Method B2:

Alternatively, it is possible to take advantage of an aromatic nucleophilic substitution reaction to functionalize the pyridine or pyrazine ring in position 6. In this case the nucleophiles used are phenols, thiophenols, benzyl alcohols or thiobenzyl alcohols as well as anilines or benzylamines, functionalized or not. The general reaction diagram 8a is presented below, notably with W=H, (Ci-C6)alkyl, aryl or benzyl.

Diagram 8a

In the case in which X=0 or S, the 6-chloro-3-nitropicolinonitriles and 6-chloro-3-nitropyrazine-2-carbonitriles, optionally substituted in position 5, are reacted in the presence of the suitable nucleophile, alcohol or thiol, in a polar solvent such as acetonitrile in the presence of an inorganic base such as potassium or sodium carbonate. Solvents such as DMSO (dimethylsulfoxide), DMF (dimethylformamide), acetone, THF (tetrahydrofuran) or pyridine may also be considered. If necessary, these reactions may be catalyzed by the action of copper and may also be carried out without solvent. Typically, the preferred protocol involves temperatures ranging between 20°C and 150°C.

Alternatively, the use of bases such as pyridine, DIPEA, diisopropylamine, triethylamine, DBU, potassium tert-butylate, Et3 or NaH is also possible.

In the case in which X=N, toluene is a preferred solvent and triethylamine (NEt3) the base of choice.

The following steps, up to the compounds of general formula (Vllb), are identical to those documented in method Bl above.

Method B3:

Method B3, presented in diagram 8b below, i s a variant of method B2 characterized by a first step resulting from a catalytic coupling reaction between a benzyl boronate, in acid or ester form, and a 6-chloro-3-nitropicolinonitrile or 6-chloro-3-nitropyrazine-2-carbonitrile derivative. It is also well known to the person skilled in the art that catalytic coupling reactions using alternative catalysts and benzyl derivatives are also possible. Among these, the Stille reaction, based on tin complexes, or those based on organozinc compounds may be considered.

(Vlg) (VI lc)

Diagram 8b

An optionally substituted 2-benzyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane is obtained beforehand, for example from the corresponding benzyl chloride and octamethyl-bi-dioxaborolane in dioxane in the presence of potassium acetate and Pt(dppf)Cl2 (dppf=l, -bis(diphenylphosphino)ferrocene). This compound is brought together with a 6-chloro-3-nitropicolinonitrile, a 6-chloro-3-nitropyrazine-2-carbonitrile optionally substituted in position 5 or a 5-chloro-2-nitronicotinonitrile optionally substituted in position 6 and a palladium catalyst such as Pd(dppf)Cl2 or Pd(PPh3)4, an organic base such as triethylamine or an alcoholate, or an inorganic base such as sodium, potassium or cesium carbonate in a solvent such as toluene, benzene, THF or dioxane. The preferred reaction temperatures are between 20°C and 100°C. The products of these reactions correspond to substituted 6-benzyl-3-nitropicolinonitrile, 6- benzyl-3-nitropyrazine-2-carbonitrile or 5-benzyl-2-nitronicotinonitrile derivatives for which the following transformation steps are reproduced from method Bl above.

Method B4:

Method B4, presented in diagram 9 below, gives access to pyrazolopyridine and pyrazolopyrazines bicycles featuring optionally functionalized aryl sulfonamide functions, with Ri=(Ci-C6)alkyl and notably W=H, (Ci-C6)alkyl, aryl or benzyl.

Diagram 9

The ethyl 2-chloro-5-(chlorosulfonyl)nicotinate derivatives required for this reaction sequence may be obtained according to the methods described by Levett P.C. et al, Org. Proc. Res. Dev., 2002, 6(6), 767-772; WO 01/98284 and WO 2008/010964.

The formation of sulfonamides is typically carried out by mixing the 2-chloro-5-(chlorosulfonyl)nicotinate of interest with a primary or secondary aniline, optionally functionalized, in an aprotic solvent such as dichloromethane, THF, acetone or acetonitrile in the presence of an organic base such as triethylamine (NEt3), pyridine or DIPEA. The use of an inorganic base such as sodium or potassium carbonate may also be considered. The optimal reaction temperatures are between 0°C and 70°C.

The saponification reaction of the product thus obtained, notably by the use of lithium hydroxide in a THF/water mixture, gives access to the corresponding 2-chloro-5-(N-phenylsulfamoyl)nicotinic acids.

The corresponding acid chlorides are prepared by treatment with thionyl chloride in toluene under reflux or by any other dehydrochlorination method well known to the person skilled in the art. The reaction of these intermediates with aqueous ammonia makes it possible to form optionally functionalized 2-chloro-5-(N-

phenylsulfamoyl)nicotinamides which are then engaged in a dehydration reaction, notably by the use of POCI3, at a temperature ranging between 75°C and 150°C. The alternative use of agents such as P2O5 or trifluoroacetic anhydride and pyridine may also be considered.

Lastly, these derivatives of general formula (Vlh) are reacted in the presence of a hydrazine, functionalized or not, in a polar solvent such as ethanol at temperatures varying between 25°C and 150°C to form the corresponding derivatives of general formula (Vlld).

Method B5:

Method B5, presented in diagram 10 below, gives access to pyrazolopyridine bicycles featuring optionally functionalized benzyl ether functions, notably with W=H, (Ci-Ce)alkyl, aryl or benzyl.

The method described below is inspired by the work of J. Baldwin et al, J. Heterocyclic. Chem., 1980, 17(3), 445-448. The 5-hydroxynicotinonitrile derivatives, optionally functionalized in position 6, are alkylated, typically by the use of an optionally functionalized benzyl halide in the presence of a base. The preferred method requires the use of an aprotic polar solvent such as DMF and a base such as NaH. The optimal reaction temperatures are between 20°C and 100°C. Alternatively, the solvents which may be used include, for example, THF, DMSO, dioxane, acetonitrile, dichloromethane or acetone and bases such as *BuOK, DIPEA, pyridine, triethylamine, DBU or sodium, potassium or cesium carbonate.

Oxidation of the pyridine ring into pyridine-N-oxide is typically carried out by use of m-CPBA in dichloromethane at room temperature. Nevertheless, many

alternative methods are conceivable, notably those based on the use of sodium percarbonate in the presence of a rhenium catalyst, sodium perborate in the presence of acetic acid or the urea-hydrogen peroxide complex.

Treatment of these pyridine-N-oxide derivatives with phosphorus oxychloride leads to the formation of the corresponding 2-chloronicotinonitriles (VI).

Their reaction under heat with a hydrazine, functionalized or not, in a polar solvent such as isopropanol or ethanol leads to the formation of the pyrazolopyridine bicycles (Vile) sought.

Method B6:

Method B6, presented in diagram 10a below, gives access to optionally functionalized pyrazolopyridine and pyrazolopyrazine bicycles featuring with reversed sulfonamide functions notably with W=H, (Ci-Ce)alkyl, aryl or benzyl.

Diagram 10a

Le method described below consists in forming a sulfonamide function from an aromatic amine and an arylsulfonyl halide, or any other equivalent reagent, in the presence of a base, which can optionally be introduced as solvent or co-solvent. Alternatively, the arylsulfonyl halide or its equivalent can be generated in situ.

Their reaction under heat with a hydrazine, functionalized or not, in a polar solvent such as isopropanol or ethanol leads to the formation the desired pyrazolopyridine and pyrazolopyrazine bicycles (Vllf).

Method C:

Method C aims at the preparation of compounds of general formula (XI) as described in diagram 1.

Method CI:

Method CI, presented in diagram 11 below, is intended for the preparation of pyrazolopyridines and pyrazolopyrazines functionalized at position 6 with Rn=halogen, mesylate, tosylate or triflate, X=0, S, NH, N-(Ci-C.)alkyl, and optionally CH2 for (Xc) and (Xd), and Rj=H or N-protecting group.

This method can also be used to carry out the synthesis of molecules comprising a diatomic X group corresponding notably to an ArX group representing: -ArCH2NH-, -ArCH2N(R4)-, -ArCH20-, -ArCH2S-, -ArCH2CH2-, -ArCHCH-, or -ArCC-.

Diagram 11

The 6-hydroxy-2-(methylthio)nicotinonitriles or 5-hydroxy-3-(methylthio) pyrazine-2-carbonitriles are subjected to a dehydrochlorination reaction, typically in the presence of phosphorus oxychloride, with or without solvent, at temperatures varying between 70°C and 180°C. If a solvent is used, a high boiling-point non-polar solvent such as toluene or xylene will be preferred. Alternatively, it is possible to activate the 6-hydroxy-2-(methylthio)nicotinonitriles and 5-hydroxy-3-(methylthio)pyrazine-2-carbonitriles by their derivation into sulfonic esters via the formation of the corresponding tosylates, mesylates or triflates. If this option is preferred, the use of tosyl, mesyl or triflyl chlorides in a solvent such as toluene, dichloromethane, THF, acetonitrile, acetone or dioxane in the presence of an organic or inorganic base gives access to these derivatives.

The 6-chloro-2(methylthio)nicotinonitriles and 5-chloro-3-(methylthio)pyrazine-2-carbonitriles respectively obtained, or their sulfonic ester analogues if this option is preferred, are then reacted with a nucleophile such as a phenol, an aniline or a

thiophenol in the context of aromatic nucleophilic substitution. In this case, the reaction is carried out in a polar solvent such as DMSO, DMF, acetone, THF or acetonitrile, in the presence of a base such as potassium tert-butylate or NaH. If necessary, these reactions may be catalyzed by the action of copper and may also be carried out without solvent. Typically, the preferred protocol involves temperatures ranging between 20°C and 150°C.

Alternatively, the use of organic bases such as pyridine, diisopropylamine, triethylamine or DBU, or inorganic bases such as sodium or potassium carbonate is also possible.

Alternatively, the compounds of formula (IXb) may give rise to a catalytic coupling reaction such as a Suzuki reaction. In this case, these compounds are brought together with an optionally substituted 2-benzyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane already described in preceding method B3, a palladium catalyst such as Pd(dppf)Cl2 or Pd(PPh3)4, an organic base such as triethylamine or an alcoholate, or an inorganic base such as sodium, potassium or cesium carbonate in a solvent such as toluene, benzene, THF or dioxane. The preferred reaction temperatures are between 20°C and 100°C.

The derivatives obtained by one or another of these methods are then oxidized, typically by the use of m-CPBA or oxone to form the corresponding methyl sulfoxides or methyl sulfones. These compounds, sometimes obtained as mixtures, are used as-is in the aminopyrazole ring formation reaction by use of an optionally substituted hydrazine in a polar solvent such as ethanol at temperatures varying between 25°C and 150°C.

Alternatively, it is possible to modify the reaction sequence, notably by reversing the synthesis steps.

Method C2:

Method C2, presented in diagram 12 below, is intended for the preparation of pyrazolopyridines and pyrazolopyridazines functionalized at position 6 with X=0, S, H, N-(Ci-C.)alkyl, or CH2 and Rj=H or N-protecting group.

Diagram 12

The 6-hydroxy-4-(methylthio)nicotinonitrile or 6-hydroxy-4-(methylthio) pyridazin-3-carbonitrile derivatives are oxidized, typically by the use of m-CPBA or oxone to form the corresponding methyl sulfoxides or methyl sulfones. These compounds, sometimes obtained as mixtures, are used as-is in the aminopyrazole ring formation reaction by use of an optionally substituted hydrazine in a polar solvent such as ethanol at temperatures varying between 25°C and 150°C.

The pyrazolopyridines and pyrazolopyridazines thus obtained are subjected to a dehydrochlorination reaction, typically in the presence of phosphorus oxychloride, with or without solvent, at temperatures varying between 70°C and 180°C. If a solvent is used, a high boiling-point non-polar solvent such as toluene or xylene will be preferred. The optionally substituted 6-chloro-pyrazolo[4,3-c]pyridin-3-amine and 6-chloro-pyrazolo[4,3-c]pyridazin-3-amine respectively obtained are then reacted with a nucleophile such as a phenol, an aniline or a thiophenol in the context of aromatic nucleophilic substitution. In this case, the reaction is carried out in a polar solvent such as DMSO, DMF, acetone, THF or acetonitrile, in the presence of a base such as potassium tert-butylate or NaH. If necessary, these reactions may be catalyzed by the action of copper and may also be carried out without solvent. Typically, the preferred protocol involves temperatures ranging between 20°C and 150°C.

Alternatively, the use of organic bases such as pyridine, diisopropylamine, triethylamine or DBU, or inorganic bases such as sodium or potassium carbonate is also possible.

Alternatively, the compounds of formula (XlVa) may give rise to a catalytic coupling reaction such as a Suzuki reaction. In this case, these compounds are brought together with an optionally substituted 2-benzyl-4,4,5,5-tetramethyl-l,3,2-

dioxaborolane described above in preceding method B3, a palladium catalyst such as Pd(dppf)Cl2 or Pd(PPh3)4, an organic base such as triethylamine or an alcoholate, or an inorganic base such as sodium, potassium or cesium carbonate in a solvent such as toluene, benzene, THF or dioxane. The preferred reaction temperatures are between 20°C and 100°C.

Method C3:

Method C3, presented in diagram 12a below, is a variant of method CI based on the regioselective functionalization of 2,6-dichloronicotinonitrile either by an anionic nucleophile such as a phenate or a thiophenate, or by an organo metallic such as a benzylzinc chloride. In the latter case, the reaction is catalyzed for example with a palladium(II) complex. The transformation of the chloronicotinonitrile thus obtained in the corresponding pyrazolopyridine, in the case where Yi = CH, is carried out as previousl described in method Al .

Diagram 12a

Method D:

These methods have as an obj ect the synthesis of compounds of general formula (I) or (VII) by the use of various catalytic coupling methods.

Method Dl:

Method Dl, presented in diagram 13 below, makes use of the coupling reaction as described in J.A.C. S., 1984, 106, 158 between an organozinc compound prepared in situ and an aryl bromide catalyzed by palladium complexes.

Diagram 13

The optionally substituted 3-amino-diazaindazoles or 3-amino-azaindazoles are brought together with a zinc benzyl chloride, optionally substituted, in an aprotic polar solvent such as THF or dioxane, in the presence of a catalytic quantity of a palladium complex such as (dppf)2PdCl2 CH2Cl2. The coupling reaction i s carried out at temperatures ranging between 25°C and 100°C.

Method D2:

Method D2, presented in diagram 14 below, makes use of the coupling reaction as described by Gueiffier A. et al, Tetrahedron, 2006, 62, 6042-6049, between a thiol, in particular a thiophenol or a benzylthiol, and an aryl iodide catalyzed by copper complexes.

Diagram 14

This reaction is typically carried out in a high boiling-point polar solvent such as 2-propanol in the presence of a catalytic quantity of polyethylene glycol, a metal salt such as copper iodide (Cul) and an excess of an inorganic base such as potassium carbonate, calcium carbonate or sodium carbonate. The reaction temperatures typically vary between 50°C and 100°C.

Method D3:

Method D3, presented in diagram 15 below, makes use of the coupling reaction as described by Sonogashira, K. et al. in Tetrahedron Lett., 1975, 16, 4467-4470 between an acetylene derivative and an aryl halide catalyzed by copper and palladium complexes.

group

Diagram 15

Such a reaction is typically carried out by the reaction under an inert atmosphere of a heteroaryl halide with a stoichiometric quantity of an optionally substituted ethynylbenzene in the presence of a catalytic quantity of a palladium complex, for example PdCl2(PPh3)2 or Pd(PPh3)4, a catalytic quantity of a copper salt, for example Cul, and an organic base such as triethylamine or DIPEA, or an inorganic base such as potassium or cesium carbonate. The protocol generally involves reaction temperatures ranging between 20°C and 45°C in solvents including DMF, THF, dioxane or diethyl ether.

Method E:

The protocols of method E aim at functionalizing the exocyclic amine of aminopyrazole rings by their reaction with an intermediate featuring an electrophile function, optionally generated in situ, such as acid chloride, an isocyanate, a isothiocyanate or an aldehyde.

Method El:

Method El, presented in diagram 16 below, aims at the transformation of the primary exocyclic amine function of aminopyrazole compounds into an amide function.

j=H or N-protecting group

Diagram 16

These compounds are synthesized via the corresponding 3 -aminopyrazole by the addition of adequate acid chloride prepared beforehand by the use of oxalyl chloride and a catalytic quantity of DMF in a solvent such as tetrahydrofiiran. These acid chlorides may be obtained by the use of alternative methods, such as those based on the use of thionyl chloride or phosphorus oxychloride, well known to the person skilled in the art. The condensation of acid chlorides on aminopyrazoles is typically carried out in an aprotic solvent such as tetrahydrofiiran, toluene or dichloromethane in the presence of a base such as DIPEA, pyridine or triethylamine.

Alternatively, the use of a base as a solvent, in particular pyridine, i s a possibility.

Alternatively, this type of reaction may be conducted in a biphasic system according to the well-known Schotten-Baumann method.

Alternatively, formation of the amide bond may be carried out from the corresponding 3 -aminopyrazole and the acid of interest by the use of peptide coupling conditions using reagents such as HOBt (hydroxybenzotriazole), TBTU (O-(benzotriazol-l-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate), HATU (2-(lH-7-azabenzotriazol-l-yl)-l, l,3,3-tetramethyluronium hexafluorophosphate), EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide) or carbonyldiimidazole at a temperature ranging between -20°C and 100°C in an aprotic solvent such as tetrahydrofuran, dioxane, dichloromethane or any solvent with similar properties.

CLAIMS
1. A compound of following general formula (I):

or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture,

wherein:

- Yi and Y4 each represent, independently of each other, a CH group or a nitrogen atom,

- Y2 represents a nitrogen atom or a CH or C-X-Ar group,

- Y3 represents a nitrogen atom or a C-X-Ar or C-W group,

on the condition that:

■ at least one and at most two Yi, Y2, Y3, and Y4 groups represent a nitrogen atom,

■ Y2 and Y4 cannot represent a nitrogen atom at the same time,

■ when Y2=C-X-Ar, then Y3 represents a nitrogen atom or a C-W group, and ■ when Y3=C-X-Ar, then Y2 represents a nitrogen atom or a CH group,

- Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-C6)haloalkyl, (Ci- C6)haloalkoxy, (d-C6)halothioalkoxy, CN, N02, ORn, SRi2, R13R14, C02Ri5, CO RieRn, SO2R18, SO2 R19R20, COR21, R22COR23, R24SO2R25, and R26 R27R28 and/or optionally fused to a heterocycle,

- X represents a divalent group selected from O, S, S(O), S(0)2, NR4, SCNR^, S(0)(NR4), S(0)2(NR4), R4S, R4S(0), R4S(0)2, CH2, CH2S, CH2S(0), CH2S(0)2, SCH2, S(0)CH2, S(0)2CH2, CH2CH2, CH=CH, C≡C, CH20, OCH2,

- W represents an R5, SR5, OR5 or R5R5 group,

- U represents a CH2 or H group, one or more hydrogen atoms which may be replaced by a (Ci-Ce)alkyl group,

- V represents C(O), C(S) or CH2,

n represents 0 or 1,

- Ri represents a hydrogen atom, or an OR7 or R7R8 group,

- R2 represents a hydrogen atom, an optionally substituted heterocycle, N02; OR9 or

- R3, R4, R11 to R25 and R27 to R28 each represent, independently of each other, a hydrogen atom or a (Ci-C6)alkyl group,

- R5 and R6 each represent, independently of each other, a hydrogen atom or a (Ci- C6)alkyl, optionally substituted aryl or optionally substituted benzyl group,

- R7, Rs, R9 and Rio each represent, independently of each other, a hydrogen atom or an optionally substituted (Ci-Ce)alkyl or (C3-Ci2)cycloalkyl group or an optionally substituted heterocycle, and

- R26 represents a (Ci-C6)alkyl group.

The compound according to claim 1, characterized

Yi and/or Y4 = N,

Y2=CH or C-X-Ar, and

Y.=C-W or C-X-Ar.

3. The compound according to either claim 1 or claim 2, characterized in that X represents a divalent group selected from S, S(O), S(0)2, R4, CH2, CH2S, CH2S(0), CH2S(0)2, CH20, CH2 R4, HS(0)2, SCH2, S(0)CH2, S(0)2CH2, S(0)2 H, OCH2, R4CH2, CH2CH2, CH=CH, and C≡C; notably from S, S(O), S(0)2, R4, CH2, SCH2, S(0)CH2, S(0)2CH2, S(0)2 H, CH2CH2, C≡C, OCH2, and NR4CH2; in particular from

S, S(0)2, CH2, SCH2, S(0)2CH2, S(0)2 H, CH2CH2, and C≡C, wherein the first atom of these groups is bound to atom C of chain C-X-Ar.

4. The compound according to any one of claims 1 to 3, characterized in that Ar represents an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-C6)alkyl, (Ci-Ce)haloalkyl, (Ci-Ce)haloalkoxy, (Ci-C6)halothioalkoxy, CN, N02, ORn, SR12, R13R14, C02Ri5, and CO RieRn, S02Ri8, SO2 Ri9R20, COR2i, R22COR23 or R24S02R25; or a pyridine group.

5. The compound according to claim 4, characterized in that Ar represents a group selected from the followin groups:

6. The compound according to any one of claims 1 to 5, characterized in that W represents an R5, SR5, OR5 or R5R5 group, with R5 and ¾ representing, independently of each other, a hydrogen atom or a (Ci-C6)alkyl group.

7. Compound according to any one of claims 1 to 6, characterized in that:

- R3=H,

- U=CH2 or H,

- V=C(0) or C(S), and notably C(O), and

- n=0 or 1, and notably 0.

8. The compound according to any one of claims 1 to 7, characterized in that Ri represents a hydrogen atom or an R7R8 group, with R7 representing a hydrogen atom and Rs representing an optionally substituted (C3-Ci2)cycloalkyl group or an optionally substituted heterocycle.

9. The compound according to claim 8, characterized in that Ri represents the following groups:

10. The compound according to any one of claims 1 to 9, characterized in that R2 represents N02, R9R10 or a heterocycle optionally substituted by (Ci-C6)alkyl or H2.

11. The compound according to claim 10, characterized in that R2 represents one of the following groups:

H2, H(CH2)3 Me2, Me(CH2)3 Me2, N02,

12. The compound according to any one of claims 1 to 11, characterized in that it is selected from the following compounds:

13. A compound according to any one of claims 1 to 12, for use as a drug.

14. A compound according to any one of claims 1 to 12, for use as a drug intended for the treatment of cancer, inflammation and neurodegenerative diseases such as

Alzheimer's disease, in particular cancer.

15. A compound according to any one of claims 1 to 12, for use as an inhibitor of kinases such as ALK, Abl and/or c-Src.

16. A compound according to any one of claims 1 to 12, for use as a drug intended for the treatment of a disease associated with a kinase such as ALK, Abl and/or c-Src.

17. A pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 12, and at least one pharmaceutically acceptable excipient.

18. The pharmaceutical composition according to claim 17, further comprising at least one other active ingredient such as an anticancer agent.

19. A pharmaceutical composition comprising:

(i) at least one compound of formula (I) according to any one of claims 1 to 12, and

(ii) at least one other active ingredient, such as an anticancer agent,

as a combination product for simultaneous, separate or sequential use.

20. A method for the preparation of a compound of formula (I) according to any one of claims 1 to 12, wherein V=C(0) or C(S), preferably C(O), and notably U=CH2, comprising the following successive steps:

(al) coupling between a compound of following formula (A):

wherein Yi, Y2, Y3 and Y4 are as defined in claim 1, and R29 represents a hydrogen atom or an N-protecting group,

with a compound of following formula (B):

wherein Ri, R2, U and n are as defined in claim 1, V=C(0) or C(S), and
or a leaving group such as CI,

to yield a compound of following formula (C):

Y, N

(C)

wherein Yi, Y2, Y3, Y4, i, R2, U and n are as defined in claim 1, R29 is such as defined above and V=C(0) or C(S),

(bl) optionally substitution of the nitrogen atom bound to V of the compound of formula (C) obtained in the preceding step with an R3 group other than H and/or deprotection of the nitrogen atom carrying an R29 group representing an N- protecting group to yield a compound of formula (I) with V=C(0) or C(S),

(cl) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same.

21. A method for the preparation of a compound of formula (I) according to any one of claims 1 to 12, wherein V=CH2, and notably U=CH2, comprising the following successive steps:

(a2) reducing amination reaction between a compound of formula (A) such as defined in claim 20 and an aldehyde of following formula (D):

wherein Ri, R2, U and n are as defined in claim 1,

to yield a compound of following formula (E):

wherein Yi, Y2, Y3, Y4, i, R2, U and n are as defined in claim 1 and R29 is such as defined in claim 20,

(b2) optionally deprotection of the nitrogen atom carrying an R29 group representing an N-protecting group and/or substitution of the nitrogen atom bound to V with an R3 group other than H of the compound of formula (E) obtained in the preceding step to yield a compound of formula (I) with V=CH2, and

(c2) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same.

22. A method for the preparation of a compound of formula (I) according to any one ms 1 to 12 wherein V=C(0) or C(S), n=l and U= H, comprising the following successive steps:

coupling between a compound of formula (A) such as defined in claim 1 and a compound of following formula (F):

wherein Yi, Y2, Y3, Y4, Ri and R2 are as defined in claim 1, R29 is such as defined in claim 20 and Z is such as defined above,

(b3) optionally deprotection of the nitrogen atom carrying an R29 group representing an N-protecting group and/or substitution of the nitrogen atom bound to V with an R3 group other than H of the compound of formula (G) obtained in the preceding step to yield a compound of formula (I) with V=C(0) or C(S), n=l and U= H, and

(c3) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same.