NZ614432B2 - Derivatives of azaindazole or diazaindazole type as medicament - Google Patents

Abstract

The disclosure relates to an azaindazole or diazaindazole derivative compound of formula (I), 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; as well as to the use of same as a drug; to the use of same as a kinase inhibitor; to the pharmaceutical compositions comprising same; and to methods for the preparation of same. These compounds are intended for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease. re; as well as to the use of same as a drug; to the use of same as a kinase inhibitor; to the pharmaceutical compositions comprising same; and to methods for the preparation of same. These compounds are intended for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease.

Description

/051283 TIVES OF AZAINDAZOLE OR DIAZAINDAZOLE TYPE AS MEDICAMENT The present invention s 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. n kinases are enzymes that play a key role in cell signal transduction. They are involved in physiological processes such as cell eration, mitosis, differentiation, cell invasion and mobility, and apoptosis, for e.

Deregulation of the physiological mechanisms lled by protein kinases is central to the appearance and development of many ogies, notably including cancers. It is of particular note that many oncogenes and 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 ceutical targets for cancer treatments.

Tyrosine kinase receptors (TKRs) form a particular class of protein kinases among which, among , 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 . More precisely, chromosomal translocations leading to the production of fiised 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 3O saving healthy tissues from signif1cant toxic effects (Ott GR. el 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 filSlOI‘l protein NPM-ALK is associated with stic large-cell lymphoma (ALCL) for which an optimal treatment remains to be developed. rly, 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 also been observed 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 nonsmall cell lung cancer (Byers L.A. et al., Clin. Cancer Res. 2009, , 861).

For this , 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 , 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 s a partial and/or transitory pharmacological 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 eutic index and less likely to give rise to phenomena of compensation, resistance or therapeutic escape.

The discussion of nts, acts, materials, devices, articles and the like is ed in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general dge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

Where the terms "comprise", "comprises", "comprised" or "comprising" are used in this specification (including the claims) they are to be interpreted as specifying the presence of the stated features, integers, steps or components, but not precluding the presence of one or more other features, integers, steps or components, or group thereof.

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. uently, said compounds can be used as drug in the treatment of erative diseases such as cancer.

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

In one , the present invention es a compound of following general formula (I): or a pharmaceutically acceptable salt or solvate of same, a er 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: - Y1 and Y4 each represent, independently of each other, a CH group or a nitrogen atom, - Y2 ents a C-X-Ar group and Y3 represents a nitrogen atom or a C-W group, or - Y2 ents a nitrogen atom or a CH group and Y3 represents a C-X-Ar group, on the condition that: at least one and at most two Y1, Y2, Y3, and Y4 groups represent a nitrogen atom, Y2 and Y4 cannot represent a nitrogen atom at the same time, - Ar ents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1- C6)halothioalkoxy, CN, NO2, OR11 , SR12 , NR13 R14 , CO2R15, CONR 16 RI7 , SO2R18 , SO 2NR 19 R20 , COR21 , NR22 COR 23 , NR24 SO 2R25 , and R26 NR 27 R28 and/or optionally fused to a heterocycle, - X represents a divalent group selected from O, S, S(O), S(O)2, NR4, S(NR4), R4), S(O) 2(NR 4), NR4S(O), NR4S(O) 2, CH2, CH2S, CH2S(O), CH2S(O) 2, SCH2, S(O)CH2, S(O) 2CH 2, CH2CH 2, CH=CH, CºC, CH2O, OCH2, NR4CH 2, and CH2NR 4, - W ents an R5, SR5, OR5 or NR5R6 group, - U represents a CH2 or NH group, one or more hydrogen atoms which may be ed by a (C1-C6)alkyl group, - V represents C(O), C(S) or CH2, - n represents 0 or 1, - R1 represents a hydrogen atom, or an OR7 or NR7R8 group, - R2 represents a hydrogen atom, an optionally substituted heterocycle, NO2, OR9 or NR 9R10 , - R3, R4, R11 to R25 and R27 to R28 each represent, independently of each other, a hydrogen atom or a )alkyl group, - R5 and R6 each represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl, optionally substituted aryl or optionally substituted benzyl group, - R7, R8, R9 and R10 each represent, independently of each other, a hydrogen atom or an optionally substituted (C1-C6)alkyl or (C3-C12 )cycloalkyl group or an optionally substituted heterocycle, and - R26 represents a (C1-C6)alkyl group.

More particularly, the present invention thus has as an aspect 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, n: - Y1 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 Y1, 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 ents 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 ents an aryl or heteroaryl group ally substituted by one or more groups selected from a halogen atom, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1- C6)halothioalkoxy, CN, NO2, OR11 , SR12 , NR13 R14 , CO2R15 , CONR16 R17 , SO2R18 , SO 2NR 19 R20 , COR21 , NR22 COR 23 , NR24 SO2R25 , and R26 NR 27 R28 and/or optionally fused to a heterocycle, - X represents a divalent group selected from O, S, S(O), S(O)2, NR4, S(NR4), S(O)(NR4), S(O)2(NR4), NR48, NR4$(O), NR4$(O)2, CH2, CH2S, CH2S(O), CH2S(O)2, SCH2, S(O)CH2, S(O)2CH2, CH2CH2, CH=CH, CzC, CH2O, OCH2, NR4CH2, and CH2NR4, - W represents an R5, SR5, 0R5 or NR5R6 group, - U represents a CH2 or NH group, one or more hydrogen atoms which may be replaced by a (C1-C6)alkyl group, - V represents C(O), C(S) or CH2, - n represents 0 or 1, - R1 ents a hydrogen atom, or an 0R7 or NR7Rg group, - R2 represents a hydrogen atom, an optionally substituted heterocycle, N02, 0R9 or NR9R10, - R3, R4, R11 to R25 and R27 to R23 each represent, independently of each other, a hydrogen atom or a (C1-C6)alkyl group, - R5 and R5 each represent, independently of each other, a hydrogen atom or a (C1- C6)alkyl, ally substituted aryl or optionally tuted benzyl group, - R7, R3, R9 and R10 each represent, independently of each other, a hydrogen atom or an optionally substituted (C1-C6)alkyl or (Cg-C12)cycloalkyl group or an ally substituted heterocycle, and - R26 represents (C1-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 “(C1-C6) alkyl” refers to ted linear or branched hydrocarbon chains comprising 1 to 6 carbon atoms. It may be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, lerl—butyl, pentyl or hexyl group.

The term 6)alkoxy” refers to a (C1-C6) alkyl chain linked to the rest of the 3O molecule Via an oxygen atom. As an example, mention may be made of methoxy, ethoxy, y, isopropoxy, butoxy or utoxy groups.

The term “(C1-C6)thioalkoxy” refers to a (C1-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 erZ-butoxy groups.

The term “(C1-C6)haloalkyl” refers to a ) alkyl chain such as defined above wherein one or more hydrogen atoms are replaced by a n atom such as defined above. It may be in particular a trifluoromethyl group.

The term “(C1-C6)haloalkoxy” refers to a (C1-C6)alkoxy chain such as defined above wherein one or more en atoms are replaced by a halogen atom such as defined above. It may be in particular a trifluoromethoxy group.

The term “(C1-C6)halothioalkoxy” refers to a (C1-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-C12)cycloalkyl” refers to cyclic arbon systems comprising from 3 to 12 carbon atoms and comprising one or more rings, in particular fiised rings.

As an e, 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 fiised 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, n l 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 e containing from 8 to 11 cyclic atoms, which may be either saturated or unsaturated, wherein l to 4 of the cyclic atoms are a heteroatom selected independently from sulfur, nitrogen and oxygen atoms, and n the other cyclic atoms are carbon atoms. As an example, mention may be made of fiiran, pyrrole, thiophene, thiazole, isothiazole, oxadiazole, imidazole, oxazole, isoxazole, pyridine, piperidine, pyrazine, piperazine, tetrahydropyran, pyrimidine, quinazoline, quinoline, quinoxaline, uran, benzothiophene, indoline, indolizine, benzothiazole, benzothienyl, benzopyran, benzoxazole, benzo[l,3]dioxole, benzisoxazole, benzimidazole, ne, chromene, dihydrobenzofuran, dihydrobenzothienyl, dihydroisoxazole, isoquinoline, dihydrobenzo[1,4]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, nally 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, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1- C6)haloalkoxy, (C1-C6)halothioalkoxy, CN, N02, OR11, SR12, NR13R14, C02R15, CONR16R17, SOzRis, SOzNRszo, CORzi, NR22COR23, NR24502R25, and R26NR27R28, wherein R11 to R23 are such as defined above.

In the present invention, “pharmaceutically able” refers to that which is useful in the preparation of a pharmaceutical composition that is generally safe, ic 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 , and which has the desired pharmacological activity of the parent compound.

Acceptable salts for the therapeutic use of the nds of the present invention include the conventional ic 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, esulfonic acid, stearic acid and lactic acid. As an example, mention may be made of salts derived from inorganic bases such as soda, potash or m ide and salts derived from organic bases such as 3O 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 es 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 ts. As an example, mention may be made of solvates due to the presence of water or ethanol.

In the context of the present ion, oisomer” refers to a geometric isomer or an optical isomer.

Geometric isomers result from the different position of sub stituents 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 sing four different substituents. This carbon atom thus constitutes a chiral or asymmetrical center. Optical isomers e 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 nd obtained by prototropy, 1'. 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: .

-Ar and Y3 preferably represents a C-W group.

In ular: — Y1=CH or N, and ageously CH, — Y2=C-X-Ar, — Y3=C-W, and — Y4: .

According to a second embodiment, Y1 and/or Y4 represent a nitrogen atom.

In this case, Y2 and Y3 preferably do not represent a nitrogen atom.

WO 01239 In particular: — Y1 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(O)2, NR4, CH2, CH2S, CH2S(O), CH2S(O)2, NHS(O)2, SCH2, S(O)CH2, S(O)2CH2, S(O)2NH, , CH=CH, CzC, CH2O, OCH2, NR4CH2, and .

In aprticular, X represents a divalent group selected from S, S(O), S(O)2, NR4 CH2, CH2S, CH2S(O), )2, NHS(O)2, SCH2, S(O)CH2, S(O)2CH2, S(O)2NH, CH2CH2, CzC, CH2O, OCH2, NR4CH2, and CH2NR4.

More ularly, X may be selected from S, S(O), S(O)2, CH2, CH2S, CH2S(O), CH2S(O)2, NHS(O)2, SCH2, 2, S(O)2CH2, H, CH2CH2, CH=CH, and CzC.

In particular, X may be selected from S, S(O)2, CH2, SCH2, S(O)2CH2, S(O)2NH, CH2S, CH2S(O)2, NHS(O)2, CH2CH2, and CzC.

X may notably be selected from S, S(O), S(O)2, NR4, CH2, SCH2, S(O)CH2, S(O)2CH2, S(O)2NH, CH2CH2, CzC, OCH2, and , notably from S, S(O)2, CH2, SCH2, S(O)2CH2, S(O)2NH, CH2CH2, and CzC, wherein the first atom of these groups is bound to atom Q of the Q—X-Ar chain.

X may be in particular S, S(O)2, SCH2, S(O)2CH2, S(O)2NH, CH2S, CH2S(O)2, or NHS(O)2; and notably S, S(O)2, SCH2, S(O)2CH2, or S(O)2NH, wherein the first atom of these groups is bound to atom Q of the Q—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, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C1- C6)halothioalkoxy, CN, NO2, OR11, SR12, NR13R14, CO2R15, CONR16R17, , SO2NR19R20, COR21, NR22COR23, and NR24SO2R25, and/or optionally fused to a heterocycle.

More ularly, Ar may represent an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)halothioalkoxy, CN, NO2, OR11, SR12, NR13R14, COzRis, CONR16R17, SOzRis, SOzNRszo, CORzi, NR22COR23, and NRMSOszs.

Ar may notably represent an aryl group, such as , optionally substituted by one or more groups selected from a halogen atom, (C1-C6)alkyl, (C1-C6)haloalkyl, and CONR16R17, and in particular from a n atom such as fluorine, (C1-C6)alkyl such as methyl, and CONR16R17 such as CONHZ.

Ar can also represent a pyridine group.

Ar may notably be ed from the following groups: F F Cl C? F é— O? G?- F F 7 f0;— 7 7C| 7 g— >>7=O Q; CF3 GE_ N I—\ CI g_ :— and notably from the following groups: F CI CI @2—7Q HZN ,_ Q? 60 @2— F 7CI 7 g_7C| 76% IN \ g- in particular, from the following groups: F C' O? g}- Q? H2N F and , ,C' , .

Ar may advantageously represent the group: 2012/051283 W may advantageously ent an R5, SR5, 0R5 or NR5R6 group, and preferably R5, 0R5 or NR5R6, with R5 and R6 representing, independently of each other, a hydrogen atom or a (C1-C6)alkyl group.

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

Advantageously, R3 represents a hydrogen atom.

U may represent more particularly a CH2 or NH group.

Advantageously, 11 may ent 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 NH, — V=C(O) 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(O) or C(S), and notably C(O), and — n=0.

According to still another particular embodiment of the invention: — R3=H, — V=C(O) or C(S), and notably C(O), and — n=0.

R1 may ent more ularly a hydrogen atom or an NR7R8 group, with R7 notably representing a hydrogen atom and R3 notably representing an optionally substituted (Cg-C12)cycloalkyl group or an optionally substituted cycle.

The (Cg-C12)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 ing group: _§ 0 R1 may thus represent more particularly one of the following groups: I-lN O I-lN H, W711» and V17!” F; and notably H and I-lN O I-lN O VII/11' VII/11' ; and advantageously R2 may represent more particularly an optionally tuted heterocycle lO ly substituted by (C1-C6)alkyl or NH2), N02 or NR9R10, with notably R9=R10=H or else R9 and R10 each represent H or an optionally substituted (C1-C6)alkyl.

R2 may represent in particular an optionally substituted heterocycle, notably substituted by (C1-C6)alkyl or NH2. 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 idine.

R2 may notably represent one of the following groups: NHL NH(CH2)3NM62, NM6(CH2)3NM62, N02, \—/ ; and notably NH2, N02, and in _g-N©N_ _g N— particular and ; and more ularly _§_N N— The compounds of the present invention may be selected from the compounds cited in the following table: WO 01239 WO 01239 WO 01239 WO 01239 WO 01239 WO 01239 WO 01239 The present invention also has as an aspect a compound according to the invention of a (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 t 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 ent 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 , kidney cancer, liver cancer, pancreatic cancer, prostate , glioblastoma, nonsmall cell lung cancer, neuroblastoma, inflammatory myofibroblastic tumor, diffuse B- cell lymphoma or anaplastic large-cell lymphoma.

The t 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 s ALK, Abl and/or c-Src, and in particular ALK. The e 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 aspect 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 t 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 ty of n 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 , 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 ct with the kinase and to reduce its ty. 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 nd of formula (I) such as defined above, and at least one ceutically acceptable excipient.

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

The active ient may be stered in unit dosage forms of administration, in mixture with rd 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 n 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 aspect a pharmaceutical composition comprising: ??? at least one compound of formula (I) such as d above, and ???? 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 , inflammation and neurodegenerative es such as Alzheimer's disease, in particular cancer.

The present invention also provides a 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 n V=C(O) or C(S), preferably C(O), and notably U=CH 2, sing the following successive steps: (a1) coupling between a compound of following formula (A): wherein Y1, Y2, Y3 and Y4 are such as defined above, and R29 represents a hydrogen atom or an N-protecting group, with a compound of ing formula (B): KU)n wherein R1, R2, U and n are such as defined above, V=C(O) or C(S), and R30=OH or a g group such as C1, to yield a compound of following formula (C): (C) wherein Y1, Y2, Y3, Y4, R1, R2, R29, U and n are such as defined above and V=C(O) 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 ng an R29 group representing an N- protecting group to yield a compound of formula (I) with V=C(O) or C(S), and (c1) optionally forming of a salt of the compound of a (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, ctive Groups in Organic Synthesis” (John Wiley & Sons, New York (1981)) and Harrison el al., “Compendium of Synthetic Organic Methods”, Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996). N—protecting groups include ates, amides, N—alkylated derivatives, amino acetal derivatives, N- benzylated derivatives, imine tives, enamine derivatives and N—heteroatom derivatives. In particular, the N—protecting group consists of formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, trityl (triphenylmethyl), Zerl-butyl, benzyl (Bn), t- butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), p-methoxybenzyloxycarbonyl, p- nitrobenzyl-oxycarbonyl, oroethoxycarbonyl (TROC), xycarbonyl (Alloc), 9- fluorenylmethyloxycarbonyl (Fmoc), trifluoro-acetyl, benzyl carbamates ituted or not) and the like. It may be in ular a trityl, Zerl-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 ularly a halogen atom such as a chlorine atom, a mesylate (CH3-S(Oz)O-), a triflate (CF3-S(O)zO-) or a tosylate (p-Me-C6H4-S(O)gO-).

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

When R30=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)ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CD1), benzotriazole- l -yl)- l, 1,3,3-tetramethyluronium orophosphate (HBTU), 2-( l H—benzotriazole- l -yl)- 1, 1,3,3 -tetramethyluronium tetrafluoroborate (TBTU) or O-(7-azobenzotriazol-l-yl)-l,1,3,3-tetramethyluronium hexafluorophosphate (HATU), optionally combined with a secondary coupling agent such as N- hydroxysuccinimide (NHS), N—hydroxybenzotriazole (HOBt), 3,4-dihydrohydroxy- 4-oxo-1,2,3-benzotriazole (HOOBt), l-hydroxyazabenzotriazole (HAt) or N- ysulfosuccinimide (sulfo NHS). Peptide coupling may moreover be d out in an aprotic solvent such as tetrahydrofuran, dioxane and dichloromethane.

When R30 is a leaving group such as Cl, coupling may be carried out in the 3O ce of a base such as pyridine, triethylamine or diisopropylethylamine (DIPEA).

The reaction may be carried out in an aprotic t 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 gbl 1: In the context of the present invention, “deprotection” refers to the process by which a ting 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 d in the art. If necessary, functionalities that may be sensitive to the on conditions of the substitution step may be ted 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 tution 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 also be necessary to carry out additional steps of functionalization of the le by techniques known to the person skilled in the art.

Ste 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. ing to a second ment, the present ion relates to a method for the preparation of a compound of formula (1) 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): ( U) n O (D) wherein R1, R2, U and n are such as defined above, to yield a nd of following formula (E): wherein Y1, Y2, Y3, Y4, R1, 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) ed 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.

Ste a2 : This step is carried out in the ce of a reducing agent such as a borohydride and in particular NaBH4, NaBH(OAc)3 or N.

This reaction is more ularly carried out at room temperature, 1'. 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 2O 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 (CZ): see step (cl) According to a third embodiment, the present invention relates to a method for the preparation of a compound of a (1) according to the invention wherein V=C(O) or C(S), n=1 and U=NH, comprising the following successive steps: (a3) coupling between a compound of formula (A) such as defined above and a compound of following a (F): C\\Z n R1 and R2 are such as defined above and Z=O or S, to yield a compound of ing formula (G): Y2IY1‘ \ n N Y3 Y4/ N" wherein Y1, Y2, Y3, Y4, R1, 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 a (G) obtained in the preceding step to yield a compound of formula (I) with V=C(O) or C(S), n=l and U=NH, 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.

Ste 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, ydrofuran or dioxane.

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

Step gb3 1: see step (bl) Step (C3 1: see step (cl) Once the nd 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 ion, etc.

The compound obtained may be d 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 a (1) according to the present invention can be prepared by the various methods summarized in diagrams la and lb below.

Method 3 Hal . , ; precursors —- : NA 3 3 (.E'flfi : I V4 ,. : Nears iHaIY: H3 3, HaL Ir, f“ w...

E , E/KEN .. {MY NH'2 (My Method E “r“3 , _ , (WU , : ; I32] ' L' h ' P R]:H orN- protecting group Method B Rm _-Ha“I om sowE” E" R?' I Method o _ IQI Methodfi E: v}, I NH? NflRfl E wry} AF Are. cm W 5; Method g m3} KY‘I‘IK 3 J3 It“: —* ‘ precursors M-- 2» I13 x- 2 H1 Mt : Y4 MI {VII IIIRI I” RI Ri = NOZ, halogen, OH, OMe, SMe, S(O)Me, SOzMe, OMs, OTf or OTs Method F Rj = H or N-protecting group Iyfln \N—Ffia MKY‘I’y x J 3 N :3 f" Y N I H Diagram 1a ‘ acychc Method Q | precursors 3’ ..N \\ V}! :p f recursors —-WAY! “—' I im mt}_ \ W EFII'ECUI'SEIFS _"‘ .335}H may21::31' 32W} #4, .-.-_ __.,I-.,- .,_.,,. we“. ,,- .__.___.._.I-_.,____- .I-5_w.,___..- _.~__,_.,_,,.,._.___-_____m-__-.u_ -mgr Ri = NOZ, halogen, OH, OMe, SMe, S(O)Me, SOzMe, OMs, OTf or OTs Rj = H or N-protecting group Rn = Hal, OMs, OTs or OTf (Tf represents an —SOZCF3 group and Ts represents a tosyl group) Diagram 1b 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).

MethodA1.' Method Al, presented in diagram 2 (iodized compounds) or 3 (brominated compounds) below, describes the l process giving access to compounds of general formula (V) with W defined as in the description of general formula (I), and notably H, (C1-C6)alkyl or aryl, and RiZH or ecting group.

ON | ON | CN I |\ \ \ Z \ —’ —’ | \ —’ N , | , , | W N OH OH W N CI W N N.

(Ila) (Va) DiagramZ In the context of diagram 2, the optionally substituted 2-chloro iodonicotinonitrile (11a) is obtained from the ponding hydroxynicotinonitrile by the successive use of an iodination agent such as N—iodosuccinimide (N18), or molecular iodine with an inorganic base such as, for example, K2C03 or Na2C03, notably in a polar solvent such as hot DMF, ed by treatment with phosphorus 2O oxychloride, pure or diluted in a high boiling-point non-polar t, 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 (IIa) thus obtained is then transformed into optionally substituted 5-iodo-pyrazolo[3,4-b]pyridineamine (Va) by its reaction, ably under heat, in the presence of a hydrazine ally carrying an N—protecting group such as trityl, Zerl-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 el al., Bioorg. Med. Chem. Lett., 2003, 13, 1577-1580 and Lijuan Chen el 3O al., Bioorg. Med. Chem. Lett., 2010, 20, 4273-4278. For reasons of convenience, these molecules were ed by the use of the reaction sequence presented in following diagram 3.

NaOMe CN Br CN \ [Br+] \ RJ-NHNH2 Br l _’ | _> N I / | OMe W N OMe W N N (Ilb) (Vb) m3 The optionally functionalized 2-methoxy-nicotinotrile is obtained, for example, by on of sodium olate 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. ation of 2-methoxy-nicotinonitrile is lly 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 t with comparable properties.

Alternatively, the use of hydrazine in a saline or hydrated form, without solvent, is also possible.

MethodA2: Method A2 relates to the synthesis of the functionalized pyrazolopyrazines presented in diagram 4 below with RiZH or N-protecting group, Hal=halogen and in particular W=H, (C1-C6)alkyl or aryl.

OMe OMe NH2 WINII‘) —* WIZf° —* WIN56° —> WI:I:NH2 NH2 NH2 —>WI:I: —’WIWTNII (INIc) (Vc) Rj Diagram 4 The optionally functionalized 3-aminoiodopyrazinecarboxamides are typically obtained in two steps from the corresponding methyl 3-aminopyrazine carboxylates by iodination in the presence of N—iodosuccinimide or molecular iodine optionally in the presence of a cofactor such as K103, AgCOgCFg, AgZSO4, AlCl3, CuClz or HgO, followed by a sion reaction of the methyl ester filnction into carboxamide, y 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 oiodopyrazinecarboxamide is then converted into nitrile by the use of dehydration agents such as, in particular, Ph3, SOClz, PhSOzCl, P205, TsCl, COClz, DCC/py (N,N’-dicyclohexylcarbodiimide/pyridine) or (COCl)2 used as the case may be in the presence of an organic base such as pyridine.

The preferred method involves the use of phosphorus oride in ylformamide (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, ed by a reaction in the presence of a hydrazine, functionalized or not, under conditions as described in the s 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.

MethodA3: Method A3 aims at obtaining derivatives of general formula (V) featuring a variable function in position 6 of the pyrazolopyridine bicycle. It is ed in diagram 5 below. a NM? wkgmaa a? am EndElMSQ ‘ H L NE “E W ‘ SE}. Maw? WE] W ”4 Wk, Em CHEW m3, c0351 .CN am:W39 E L am W H, rrEéME GE? HEN 5 LN CM .. Basal-*9 w 3 EH: MHE‘ NE W. CHEM Eggs, £0ng W E + E L.Efimchkga H2“ 55 EEC]:E {3N "€353: EEEEJ“Ea Mfififi "E. y I ,-——-—y_- w M” WTQ‘AIQN mm (a) 1 Dr 2 w = {M am. NHE NHEEE. Mk. Ar. CHQN Rj=H Dr N-pmtecting group C1-C6)alkyl, Ar=aryl, CHgAr=benzyL H=halogen) Diagram 5 2012/051283 Reaction of the cyanothioacetamide with ethyl 3-ethoxyacrilates variously substituted according to methods described notably by Litrivnor el al. in Russ. Chem.

Bull., 1999, 48(1), 195-196 and Long Su el al. in J. Med. Chem., 1988, 31, 1209- 1215 make it le to yield access, in two steps, to ethyl 5-cyano (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]undecene). The second step of intramolecular cyclization and of alkylation is typically carried out by the heating to a ature 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 ting agent such as alkyl halide or dialkyl sulfate.

The 5-cyano(methylthio)nicotinic acids substituted in position 2 are typically obtained by saponification of the corresponding ethyl esters according to s 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 boilingpoint solvent such as diphenylether at a ature ranging between 150°C and 250°C.

Halogenation reactions principally aim at obtaining iodinated, brominated or chlorinated derivatives, more particularly iodinated tives. The latter are typically ed by a molecular iodine treatment in the presence of a silver salt such as, for example, AgZSO4 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 K103, AgCOZCF3, AlCl3, CuClg or HgO, or other tion agents such as N- iodosuccinimide, are also considered. The conceivable ation methods lly 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 e, THF, acetonitrile or acetone, or any other equivalent agent such as dimethylsulfate. The 5-halo(methylthio) nicotinonitriles obtained are subjected to oxidation of their thiomethoxy filnction, 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 e, are d in a on in the presence of an ally substituted hydrazine to form the corresponding 5-halogeno-pyrazolo[3,4-b]pyridinamine carrying a variable functionality in position 6.

MethodA4: Method A4 aims at obtaining derivatives of general formula (V) from the compounds of l formula (111) 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: Gueiff1er el al.

Heterocycles, 1999, 51(7), 1661-1667, Gui-Dong Zhu el al. Bioorg. Med. Chem., 2007, , 452.

Hal Y1 CH3 Hal Y1 CH3 Hal Y1 Y ‘ Y I [NO+] YYEN N. / —> N. x —> N Y4 NH2 Y4 All" [Base] (Illa) \ 0 CH3 ()lVa 0% CH3 No2 NH2 HaIY Hal Y1 Hal Y1 \ \ ~ \ —> tj‘r rn r n (IVb)H .Y4 N —> .Y N H 4 H (Ve) Diagram6 The compounds of general formula (IIIa), acetylated hand 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 atures 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 subjected to the action of nitration agents such as trated nitric acid or potassium nitrate in sulfuric acid at atures varying between 0°C and 25°C.

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

The nitropyrazoles thus ed are typically reduced into aminopyrazoles of l formula (Ve) by the use of SHC12 in hydrochloric acid. ative methods include the use of iron, zinc or tin in acidic conditions and s of catalytic enation 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 B]: Method B1 is ented in diagram 7 below, with W notably representing H, (C1-C6)alkyl, aryl or benzyl.

'ININ—»'INICN—»IllI N—LVNININ w Y4 No2 w Y4 No2 w Y4 No2 w Y4 No2 (Vla) ArVs N CN Ar 3 N [Red] \ V | 1-[ONO'] \ _> | \N / / w Y4 NH2 2. [Red] w Y4 N. 1[ONO\ RJNHNV R.

(VII a) 2. [3]HI' ArVS N\ ON (Vlb) w Y4 Hal Diagram7 The 3-nitrothioxo-l,6-dihydropyridincarbonitrile and 3-nitrothioxo-l,6- dihydropyrazinecarbonitrile derivatives, optionally functionalized in position 5, are typically obtained from the corresponding 2,6-dichloronitropyridines or 2,6-dichloro- WO 01239 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 s sodium hydrosulf1te 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 ate. Reactions for reducing the nitro function in amine are preferentially carried out by the use of SnClz in hydrochloric acid. ative methods include the use of iron, zinc or tin in acidic conditions and methods of catalytic enation in the presence of complexes of platinum, nickel or Pd/C under an atmosphere of en 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 ponding 3-aminopicolinonitriles or 3- aminopyrazinecarbonitriles may be carried out by dehydration of the carboxamide into nitrile via the use of phosphorus oxychloride in the ce 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 ion of a diazonium, obtained by the successive reaction at low ature of isoamyl nitrite, sodium nitrite or any other equivalent organic or nic nitrite, in water, hydrochloric acid, acetic acid or sulfilric 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 on is preferentially carried out with tin chloride in acidic ions 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 tuted by a halogen atom, such as iodine, by the reaction of an adequate salt, such as NaI. 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 32: 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 s, thiophenols, benzyl alcohols or thiobenzyl alcohols as well as anilines or benzylamines, functionalized or not. The general on diagram 8a is ted below, notably with W=H, (C1-C6)alkyl, aryl or benzyl.

WININ:”NININ:2—»[—»Red] ANXNININNZ2 [base] (VIC) (Vld) AXINICN 1' [ONO-1 w Y4 NH2 2. [Red] AWIYEJiN ()VIIb (Vld) ‘l. [ONNI'_ 2. HNHZJ [Hal'] ArXINION V(|e) w Y4 Hal Diagram 8a In the case in which X=O or S, the 6-chloronitropicolinonitriles and 6-chloro- 3-nitropyrazinecarbonitriles, optionally substituted in on 5, are reacted in the presence of the suitable nucleophile, alcohol or thiol, in a polar solvent such as acetonitrile in the ce of an inorganic base such as potassium or sodium carbonate. ts 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 ol es temperatures ranging between 20°C and 150°C.

Alternatively, the use of bases such as pyridine, DIPEA, diisopropylamine, triethylamine, DBU, potassium Zerl-butylate, NEt3 or NaH is also possible. 2012/051283 In the case in which X=N, toluene is a preferred t and triethylamine (NEt3) the base of choice.

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

Method B3: Method B3, presented in diagram 8b below, is 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-chloronitropicolinonitrile or 6-chloro- 3-nitropyrazinecarbonitrile derivative. It is also well known to the person skilled in the art that catalytic coupling reactions using alternative sts and benzyl derivatives are also le. Among these, the Stille reaction, based on tin complexes, or those based on organozinc compounds may be considered.

CI Y CN /\ .0 Y ON 1~ Ar 6 | [Pd°] Ar 1 + —’ | , o / w Y4 N02 w Y4 No2 (Vlf) [Red] Ar/TYL 1.[ONO'] Ar/Iflng W Y: NH2 2- [Red] w Y4’ H (Vlg) (Vllc) m 8b An optionally substituted 2-benzyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane is obtained beforehand, for example from the ponding benzyl chloride and octamethyl-bi-dioxaborolane in dioxane in the presence of potassium acetate and Pt(dppf)C12 (dppf=l,l’-bis(diphenylphosphino)ferrocene). This compound is brought together with a 6-chloronitropicolinonitrile, a 6-chloronitropyrazinecarbonitrile optionally substituted in position 5 or a 5-chloronitronicotinonitrile optionally substituted in position 6 and a palladium catalyst such as Pd(dppf)C12 or 3)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, e, THF or dioxane. The preferred reaction temperatures are between 20°C and 100°C. The products of these ons correspond to substituted 6-benzylnitropicolinonitrile, 6- 2012/051283 nitropyrazinecarbonitrile or 5-benzylnitronicotinonitrile derivatives for which the following transformation steps are uced 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 -C6)alkyl and notably W=H, (C1-C6)alkyl, aryl or benzyl.

CIOZS “I:L\—>1. ArNHR|/[base] NO\\S// WIN YleHO NO\\S// 2. LiOH R1 Rl WIN R1 RI VSVI:r RZQQVSV\VO |Y1 \\/;D NH2 CN RJNHNHZ ©§S”I: (Vlh) (VIId)R Diagram 9 The ethyl 2-chloro(chlorosulfonyl)nicotinate derivatives required for this reaction sequence may be obtained according to the methods described by Levett P.C. el al., Org. Proc. Res. Dev., 2002, 6(6), 2, WO 01/98284 and .

The formation of sulfonamides is typically carried out by mixing the 2-chloro (chlorosulfonyl)nicotinate of interest with a primary or secondary e, optionally functionalized, in an aprotic solvent such as dichloromethane, THF, acetone or acetonitrile in the presence of an c base such as ylamine (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. 2O The saponif1cation 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- -(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 s ammonia makes it possible to form optionally functionalized 2-chloro(N- phenylsulfamoyl)nicotinamides which are then engaged in a dehydration on, notably by the use of POC13, at a temperature ranging between 75°C and 150°C. The alternative use of agents such as P205 or roacetic anhydride and pyridine may also be considered.

Lastly, these derivatives of general formula (VIh) 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 .

Method B5.' Method B5, ted in diagram 10 below, gives access to pyrazolopyridine bicycles featuring optionally functionalized benzyl ether functions, notably with W=H, (C1-C6)alkyl, aryl or benzyl.

HO CN ArVO CN |\ ArAHaI ArVO CN [OX] \ —> |\ —> | / / @/ w N [base] w N w N Ar 0 CN Ar 0 V \ V R-NHNH2 \ \ _. | J—. | N / / w N CI w N N (VII) (Vlle) Diagram 10 The method described below is inspired by the work of J. Baldwin el al., J.

Heterocyclic. Chem., 1980, 17(3), 445-448. The 5-hydroxynicotinonitrile derivatives, ally functionalized in position 6, are alkylated, lly by the use of an optionally functionalized benzyl halide in the presence of a base. The preferred method requires the use of an c 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 e, for example, THF, DMSO, dioxane, acetonitrile, dichloromethane or e and bases such as tBuOK, 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 tives with phosphorus oxychloride leads to the formation of the corresponding 2-chloronicotinonitriles (VI).

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

Method B6: Method B6, presented in diagram lOa below, gives access to optionally functionalized pyrazolopyridine and pyrazolopyrazine bicycles ing with ed sulfonamide ons, notably with W=H, (C1-C6)alkyl, aryl or benzyl. 4” 4” o=s=o o: s: o NHz ”YINI1:N“—»111”W [base] HNYNINIffi HENINIf (Vlj) V(||f) Diagram 1021 Le method described below consists in forming a amide 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 ted 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 (VIIf).

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

Method C1: Method Cl, presented in diagram 11 below, is intended for the preparation of pyrazolopyridines and pyrazolopyrazines fiinctionalized at position 6 with Rn=halogen, mesylate, tosylate or triflate, X=O, S, NH, N-(Cl-C-)alkyl, and optionally CH2 for (Xc) and (Xd), and RiZH or N—protecting group.

This method can also be used to carry out the synthesis of molecules comprising a diatomic X group corresponding y to an ArX group representing: -ArCH2NH-, - ArCH2N(R4)-, -ATCH20-, -ArCHZS-, -ArCH2CH2-, -ArCHCH-, or -ArCC-.

Y1 ON ON 1 1 —> ”X“ I Ar\ HO N SMe Rn1:1: [Base] 1N1SMe (|)Xa (X3) 131‘ —> O NJ 1N SMe (IXb) AXIN111—»[Ox] RNHNH2 £Y1I$N AuxJENI:N_> Ar‘x N’ N (Xc) (Xd) (685 )1ou2 (Xla) Diagram 11 The 6-hydroxy(methylthio)nicotinonitriles or 5-hydroxy(methylthio) pyrazinecarbonitriles are subjected to a dehydrochlorination on, typically in the presence of phosphorus oxychloride, with or without solvent, at temperatures varying n 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 te the 6- hydroxy(methylthio)nicotinonitriles and 5-hydroxy(methylthio)pyrazine carbonitriles by their derivation into sulfonic esters via the formation of the corresponding tosylates, mesylates or es. If this option is preferred, the use of tosyl, mesyl or triflyl chlorides in a solvent such as toluene, dichloromethane, THF, itrile, 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(methylthio)pyrazine- 2-carbonitriles respectively obtained, or their sulfonic ester analogues if this option is preferred, are then reacted with a phile such as a phenol, an aniline or a thiophenol in the context of aromatic philic 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 lerl—butylate or NaH. If necessary, these reactions may be zed 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 nic 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 t together with an optionally substituted 2-benzyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane already described in preceding method B3, a palladium catalyst such as Pd(dppf)C12 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 e. The preferred reaction temperatures are between °C and 100°C.

The derivatives obtained by one or another of these s are then oxidized, typically by the use of m-CPBA or oxone to form the ponding 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 g between 25°C and 150°C. atively, it is possible to modify the reaction sequence, notably by reversing the synthesis steps.

Method C2: Method C2, ted in diagram 12 below, is intended for the ation of pyrazolopyridines and pyrazolopyridazines functionalized at position 6 with X=O, S, NH, N—(Cl-C-)alkyl, or CH2 and RiZH or N—protecting group.

WO 01239 2012/051283 mus; ”O—>“ @wa—>2. R-NHNH2 fr _ _ (Xlla) (X)|||a RI (X)|VaR N,Y1‘ —> I \N AKX / N (le) RJ Diagram 12 The 6-hydroxy(methylthio)nicotinonitrile or 6-hydroxy(methylthio) pyridazincarbonitrile 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 yrazole 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 tuted 6-chloro-pyrazolo[4,3-c]pyridinamine and 6-chloro- pyrazolo[4,3-c]pyridazinamine 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 ZerZ-butylate or NaH. If necessary, these reactions may be catalyzed by the action of copper and may also be carried out t solvent. Typically, the preferred protocol involves atures ranging n 20°C and 150°C.

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

Alternatively, the compounds of a (XIVa) may give rise to a catalytic coupling reaction such as a Suzuki on. In this case, these compounds are brought together with an optionally substituted 2-benzyl-4,4,5,5-tetramethyl-1,3,2- dioxaborolane described above in ing method B3, a ium catalyst such as Pd(dppf)Clg 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 t such as toluene, benzene, THF or dioxane. The preferred reaction temperatures are between °C and 100°C.

Method C3: Method C3, presented in diagram 12a below, is a variant of method C1 based on the regioselective functionalization of 2,6-dichloronicotinonitrile either by an anionic nucleophile such as a phenate or a thiophenate, or by an organometallic 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 ed in the corresponding pyrazolopyridine, in the case where Y1 = CH, is carried out as previously described in method A1.

IYICN Y1 CN Y1 ~ ‘ | ~ \ ArXH base 1 R-NHNH2 N r I J: J1 N/ —,’ Ax / CI CI X N CI _> AKX N’ N Y1 CN Y1 CN I l Y1 ~ ~ ~ \ ArCsznC', NJ 1 RJNHNH; NJ , CI N CI N CI NN PdCI2 N Diagram 1221 Method D: These methods have as an object the synthesis of compounds of general formula (I) or (VII) by the use of various catalytic coupling s.

Method D1: Method D1, presented in diagram 13 below, makes use of the coupling reaction as bed in J.A.C.S., 1984, 106, 158 between an organozinc compound prepared in silu and an aryl e catalyzed by palladium complexes.

[W] , , Y; + nm ————-h- At 1~ g xN _ Ri Rj=H Dr N-prntecting grnup ‘ is, ! Rh 3H Dr (‘4 ill Diagram 13 The optionally substituted 3-amino-diazaindazoles or 3-amino-azaindazoles are brought together with a zinc benzyl chloride, ally substituted, in an aprotic polar solvent such as THF or dioxane, in the presence of a catalytic quantity of a palladium complex such as (dpngPdClgCHzClz. The coupling on is 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. el al., Tetrahedron, 2006, 62, 049, between a thiol, in particular a thiophenol or a benzylthiol, and an aryl iodide catalyzed by copper complexes.

HRMwmzi Eight] A? V-SYY1W "y n I w ”at:3 N, 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 (CuI) and an excess of an inorganic base such as potassium carbonate, calcium ate or sodium carbonate. The on 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. el al. in Tetrahedron Lett., 1975, 16, 4467-4470 between an acetylene tive and an aryl halide catalyzed by copper and palladium complexes.

Ry; Ric , N did"; A? W“, __ N — R3 He; “in ; AME; [W] ”1”: . 3 Ya, N Y3 V1,; VN R1 F31 Rj=H Dr I‘d-protecting group Diagram 15 Such a on 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 ty of a palladium complex, for example PdC12(PPh3)2 or Pd(PPh3)4, a catalytic quantity of a copper salt, for example CuI, and an organic base such as triethylamine or DIPEA, or an inorganic base such as potassium or cesium ate. 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 ophile function, optionally generated in situ, such as acid chloride, an isocyanate, a isothiocyanate or an aldehyde.

Method E1: Method El, presented in diagram 16 below, aims at the transformation of the primary exocyclic amine function of aminopyrazole compounds into an amide fiinction. 1 in R2 0 NH: R1 NH with \ “(ERR x “1'93 + N x 'L ln— ‘ri'l r ”Y4 N 3W4 N R] '3 OH R] Rj=H Dr N-prutecting group m 16 These compounds are sized via the corresponding 3-aminopyrazole by the on of adequate acid chloride prepared beforehand by the use of oxalyl chloride and a catalytic quantity of DMF in a solvent such as tetrahydrofuran. These acid chlorides may be obtained by the use of alternative methods, such as those based on the use of l chloride or phosphorus oxychloride, well known to the person d in the art. The condensation of acid chlorides on aminopyrazoles is typically carried out in an aprotic solvent such as tetrahydrofuran, 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, is a possibility.

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

WO 01239 atively, 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- triazol-l-yl)-N,N,N’,N’-tetramethyluronium uoroborate), HATU (2-(lH azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate), EDCI (lethyl ethylaminopropyl)carbodiimide) or carbonyldiimidazole at a temperature ranging between -20°C and 100°C in an aprotic solvent such as tetrahydrofuran, dioxane, romethane or any solvent with similar properties.

Method E2: Derivatives characterized by the presence of a secondary amine in position 3 of the aminopyrazole ring are synthesized by a reducing amination reaction according to diagram 17 below.

NH? NH yg‘yin‘ 3 mk. {Red} . x “YE“; 9*» J- N "P H‘F’é}, ‘ H Y Y X R6 R, Rj=H Dr N-prntecting group [WY R4 3, 3.

RR ~— H Elf h «M Diagram 17 Reducing amination reactions are typically carried out by miXing adequate stoichiometric quantities of aminopyrazole and aldehyde in a solvent such as DCE (dichloroethane), THF or acetonitrile, optionally in the presence of a quantity of water, TFA oroacetic acid) or acetic acid, by adding successive fractions of a reducing agent such as NaBH4, NaBH(OAc)3 or NaBHgCN. These reactions are typically carried out at room temperature.

Method E3: Derivatives carrying a 3-ureido or 3-thioureido function are obtained by the reaction, presented in diagram 18 below, of an aminopyrazole with an isocyanate or isothiocyanate obtained according to methods well known to the person skilled in the art.

E CF NH2 [1;] E 44H Ygfiflr‘g NH R 1 '1T - N + 4 :12 flx - Hj 3V4 N.

R: Hj Rj=H Dr N-prntecting group E = CI Dr 3 Diagram 18 In a typical reaction, the reaction mixture is prepared in a polar or non-polar aprotic solvent such as dichloromethane, acetone, DMF, DMA, acetonitrile, THF or dioxane d at atures varying between 20°C and the boiling point of the chosen solvent. If necessary, recourse to a weakly nucleophilic organic or inorganic base may prove to be necessary. In this case, sodium hydride is a le option.

Method F: post-synthetic deprotections and modifications Method F1: ections The trifluoroacetate protecting groups are removed by the action of an organic base such as triethylamine or ne in a polar solvent such as methanol, ethanol or THF at the reflux temperatures of the solvents used.

The lerl—butyl or trityl protecting groups carried by the pyrazole rings are displaced by the action of a strong acid, typically TFA, in a non-polar solvent such as dichloromethane or DCE.

Method F2: alkyne reductions R H \I:k~MRa kwMR3 H]: H or N-Rprutecting group Fagzl'i UrR:\/Z’kU3n Diagram 19 Reactions for ng diaryl alkynes into diaryl alkanes are typically carried out by catalytic enation, under hydrogen re, in the presence of catalysts such as PtOg, Pt, Pd/C, Ni or Rh. Alternatively, the use of DIBAL-H (diisobutylaluminum hydride) in the presence or the absence of a catalyst such as szTlClz is conceivable.

Method F3: oxidation ofsulfides into sulfones and sulfoxides Mia?“ Ramdfia RI“, 3 ’3’ C}: Mafia E334 g: A: (“mi N ._ V» » r v,1 , Ar-if‘; __ _ 3‘11, H WV: andfnr N ‘r’gV; N W R, R, Rj=H or N-prntecting group ,W_ R; a if.

F! =Hnr , . Iv: , V411?” Diagram 20 Oxidation reactions of sulfides into ides are typically carried out Via the use of oxone in a mixture of polar ts such as THF/MeOH or DMF/water. The optimal reaction temperatures are typically between 25°C and 50°C.

Many alternative methods are available, and some give the possibility of producing semi-oxidized derivatives, namely sulfoxides. Such alternative methods include the use of m-CPBA, KMnO4/Mn02 in dichloromethane, H202 (30%) in a biphasic medium and the presence of a phase transfer catalyst or a catalyst in the form of a urea complex (UHP).

The combined use of H202 and metal complexes such as Sc(OTf)3 promotes partial oxidation derivatives.

Other known methods e, for example, the use of CAN/NaBr03 (CAN=ceric ammonium nitrate).

The examples which follow illustrate the ion without limiting its scope in any way.

The following abbreviations are used: DMSO Dimethylsulfoxide EI Electron impact ES Electrospray LCMS Liquid chromatography — mass spectrometry mg milligram mL milliliter NMR r magnetic resonance 1. S nthesis of the com ounds in to the ion Examples of method A1 Example 1: 5-i0d0-1H-pyrazolo[3,4-b]pyridine—3-amine | N N N Example 121: 2-hydr0xyi0donicotinonitrile 9 g (0.5 eq) of N—iodosuccinimide at room temperature is added to a solution of 10 g (83 mmol) of 2-hydroxynicotinonitrile in 150 ml of anhydrous dimethylformamide. The reaction mixture is d at 60°C. After 30 minutes of stirring, 9 g (0.5 eq) of N- iodosuccinimide is added and then the reaction mixture is stirred at 60°C for 5 hours.

The solvent is evaporated and the precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 18.5 g (90%) of 2-hydroxy cotinonitrile in the form of a beige powder.

LCMS (E1, m/z): (M+1) 246.93 1H NMR: 6H ppm (400 MHz, DMSO): 12.79 (1H, s, OH), 8.36 (1H, d, CHamm), 8.04 (1H, d, CHamm).

Example 1b: 2-chl01‘0-S-iodonicotinonitrile .7 ml (329 mmol) of phosphorus oxychloride at 0°C and 6 drops of sulfuric acid are added to 9 g (6.6 mmol) of 2-hydroxyiodonicotinonitrile. The reaction mixture is heated at 110°C for 5 hours and then at room temperature overnight. The reaction mixture is poured in a beaker containing ice and a little water, and a precipitate is . The mixture is allowed to gradually return to room ature and then is filtered and rinsed with water. The solid is dried to yield 6.8 g (70%) of 2-chloro iodonicotinonitrile.

LCMS (E1, m/z): (M+1) 265.45 1H NMR: 6H ppm (400 MHz, DMSO): 9.61 (1H, d, CHamm), 9.14 (1H, d, CHarom).

Example 1: S-iodo-lH-pyrazolo[3,4-b]pyridine—3-amine Hydrazine (3.86 ml, 79 mmol) is added at room temperature to 7 g (26.5 mmol) of a solution of roiodonicotinonitrile in 25 ml of propanol. The reaction mixture is heated at 85°C for 7 hours and then at room temperature overnight. The suspended solid is filtered, rinsed with isopropanol and then with ether and dried in an oven at 50°C to give 6 g (87%) of -1H—pyrazolo[3,4-b]pyridineamine.

LCMS (E1, m/z): (M+1) 260.95 1H NMR: 6H ppm (400 MHz, DMSO): 12.12 (1H, bs, NH), 8.51(1H, d, , 8.45 (1H, d, CHamm), 5.64 (2H, bs, NHz).

The following compounds were obtained according to the same method. l/ N w N N l--_ 1):;e11rlli-I‘1t):tyl1odo- 1H-pyrazolo[3,4-b]pyr1d1n- 317.05 .I-:I-Illpldg-Gmethyl-1H-pyrazolo[3,4-b]pyr1d1n 275.02 ** HNMR, DMSO-d6, Ex. 12 8.55 (1H, bs, CHamm), 8.42 (1H, bs, CHamm), 6.33 (1H, bs, CHamm), 1.57 (9H, s, CH)., 13 11.92 (1H, s, NH), 8.55 (1H, s, CHamm), 5.59 (2H, bs, NHZ), 2.66 (3H, s, CH3).

Example 2: S-bromo-lH-pyrazolo[3,4-b]pyridine—3-amine |,NNN Example 2a: 0xy-nicotinonitrile 4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room temperature for 10 minutes and then 10 g (72.2 mmol) of 2- chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25°C for 16 hours. The reaction is hydrolyzed by slowly adding water at 0°C. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 7.85 g (81%) of oxy-nicotinonitrile in the form of a yellow solid.

LCMS (E1, m/z): (M+1) 135.04 1H NMR: 6H ppm (400 MHz, DMSO): 8.46-8.48 (1H, dd, CHamm), 8.25-8.27 (1H, dd, CHarom), 7.17—7.20 (1H, dd, CHamm), 3.99 (3H, s, CH3).

Example 2b: 0meth0xy-nicotinonitrile 12.23 g (149 mmol) of sodium acetate and then 7.66 ml (149 mmol) of bromine at 0°C are added to 10 g (74.6 mmol) of a solution of 2-methoxy-nicotinonitrile in 29 ml of acetic acid. The on e is heated at 70°C overnight. After returning to room temperature, the reaction medium is added to an ice bath and the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 11.6 g (73%) of 5-bromo methoxy-nicotinonitrile in the form of a white solid.

LCMS (E1, m/z): (M+1) 214.95 1H NMR: 6H ppm (400 MHz, DMSO): 8.61 (1H, d, CHamm), 8.60 (1H, d, CHamm), 3.98 (3H, s, CH3) Example 2: o-lH-pyrazolo[3,4-b]pyridine—3-amine ml (23.47 mmol) of hydrazine is added at room temperature to 5 g (23.47 mmol) of -bromomethoxynicotinonitrile. The reaction medium is carried at 100°C for 3 hours. After returning to room temperature, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 3.6 g (72%) of 5-bromo-1H-pyrazolo[3,4- b]pyridineamine in the form of a yellow solid.

LCMS (E1, m/z): (M+1) 214.05 1H NMR: 6H ppm (400 MHz, DMSO): 12.18 (1H, s, NH), 8.38 (1H, d, CHamm), 8.37 (1H, d, CHamm), 5.66 (2H, s, NH).

Examples of method A2 Example 3: S-iodo-lH-pyrazolo[3,4-b]pyrazine—3-amine I N N H Example 321: methyl oiod0pyrazine—Z-carboxylate 1.5 equivalents ofN—iodosuccinimide are added at room ature to 5 g (32.7 mmol) of a methyl 3-aminopyrazinecarboxylate solution in 25 ml of dimethylformamide.

The reaction medium is heated at 65°C for 1 hour, added together with 0.5 equivalents of N—iodosuccinimide and maintained at 65°C for 24 hours. After returning to room temperature, the solvent is evaporated and then the product is extracted several times with dichloromethane. The organic phases are combined, washed with 10% sodium bisulf1te solution, dried on ium sulfate and concentrated to yield 8 g (88%) of methyl 3-aminoiodopyrazinecarboxylate in the form of a yellow solid.

LCMS (E1, m/z): (M+1) 280 1H NMR: 6H ppm (400 MHz, DMSO): 8.50 (1H, s, CHamm), 7.50 (2H, bs, NHz), 3.20 (3H, s, CH3). 2012/051283 Example 3b: 3-aminoiodopyrazine—Z-carboxamide ml of ammonia in water is added under magnetic stirring to 15 g (53.8 mmol) of a solution of methyl 3-aminoiodopyrazinecarboxylate in 150 ml of methanol. The reaction medium is stirred at 25°C for 48 hours. After evaporation of the ts, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 12.50 g of 3-aminoiodopyrazinecarboxamide (88%) in the form of a beige solid.

LCMS (E1, m/z): (M+1) 265.02 1H NMR: 6H ppm (400 MHz, DMSO): 8.35 (1H, s, CHamm), 7.85 (1H, bs, NH), 7.60 (3H, bs, NH), 3.25 (3H, s, CH3) Example 3c: N’-(3—cyan0i0d0pyrazine—Z-yl)—N,N-dimethylformimidamide 13.59 ml (146 mmol) of phosphorus oxychloride is added drop by drop at 0°C to 11 g (41.7 mmol) of a solution of 3-aminoiodopyrazinecarboxamide in 80 ml of dimethylformamide. The reaction mixture is stirred at room temperature overnight and then poured in a beaker containing ice and a little water. The pH is ed to 8 with 1 N soda solution, a precipitate is formed. The mixture is allowed to gradually return to room temperature and then the solid formed is filtered, rinsed with water and dried at 50°C to yield 10.50 g of N’-(3-cyanoiodopyrazineyl)-N,N-dimethyl formimidamide (84%) in the form of a beige solid.

LCMS (E1, m/z): (M+1) 302.07 1H NMR: 6H ppm (400 MHz, DMSO): 8.69 (1H, s, CHamm), 8.67 (1H, s, CHethyl), 3.20 (3H, s, CH3), 3.11 (3H, s, CH3).

Example 3d: 3-amin0i0d0pyrazine-Z-carbonitrile 77 ml (77 mmol) of 1 M hydrochloric acid solution is added to 7.7 g (25.6 mmol) ofN’- (3-cyanoiodopyrazinyl)-N,N-dimethylformimidamide. The reaction medium is heated at 50°C for 4 hours and then stirred at room temperature ght. The precipitate formed is filtered, rinsed with water and dried at 50°C to yield 6 g (95%) of 3-aminoiodopyrazinecarbonitrile in the form of a beige solid.

LCMS (E1, m/z): (M+1) 247.0 1H NMR: 6H ppm (400 MHz, DMSO): 8.49 (1H, s, CHamm), 7.53 (2H, bs, NHZ).

Example 3e: 3-chl0r0i0d0pyrazine—2-carbonitrile 64.3 ml of hloric acid is added at -5°C to 7.7 g (31.3 mmol) of 3-amino iodopyrazinecarbonitrile. At this temperature, a sodium e solution (4.32 g, 62.6 mmol) dissolved in 9 ml of water is added to the reaction mixture and is stirred for 4 hours at -50°C and then at room temperature overnight. Another equivalent of sodium nitrite is added to the reaction mixture and the precipitate formed is filtered, rinsed with water and dried at 50°C to yield 3.65 g (44%) of 3-chloroiodopyrazinecarbonitrile in the form of a beige solid.

LCMS (E1, m/z): (M+1) 266.49 1H NMR: 5H ppm (400 MHz, DMSO): 9.13 (1H, s, CHamm) Example 3: S-iodo-lH-pyrazolo[3,4-b]pyrazineamine 0.74 ml (9.8 mmol) of hydrazine is added to 2.6 g (9.80 mmol) of a solution of 3- chloroiodopyrazinecarbonitrile in 15 ml of butanol. The reaction mixture is heated at 110°C for 5 hours and then left at room temperature overnight. The ded solid is d, rinsed with butanol and then dried in an oven at 50°C to yield 2.2 g (86%) of -iodo-1H-pyrazolo[3,4-b]pyrazineamine in the form of a brown solid.

LCMS (E1, m/z): (M+1) 262.02 1H NMR: 6H ppm (400 MHz, DMSO): 12.59 (1H, bs, NH), 8.60 (1H, d, CHamm), 5.83 (2H, bs, NHZ).

Examples of method A3 Example 4: 5-i0d0—6-meth0xy-1H-pyrazolo[3,4-b]pyridinamine MeON N Example 4a: ethyl S-cyano-2—hydroxy(methylthi0)nic0tinate Ethyl 5-cyanohydroxy(methylthio)nicotinate is ed by following the procedure of Ya. Yu. Yakunin el 61]., Russian Chemical Bulletin, 1999, 48(1), 195-6 with a total yield of 34%.

LCMS (E1, m/z): (M-l) 237.22 1H NMR: 6H ppm (400 MHz, DMSO): 12.72 (1H, bs, OH), 8.40 (1H, s, CHamm), 4.29 (2H, q, CH2), 2.64 (3H, s, CH3), 1.30 (3H, t, CH3).

Example 4b: 5-cyano-2—hydroxy(methylthio)nic0tinic acid 4.16 g (2 eq) of lithium hydroxide monohydrate is added at room temperature to a solution of 11.8 g (49.5 mmol) of ethyl 5-cyanohydroxy(methylthio)nicotinate in 100 ml of ethanol and 100 ml of water. The reaction e is stirred at 60°C for 2 hours. The ethanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen chloride (pH=1). The precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 9.9 g (95%) of 5-cyanohydroxy (methylthio)nicotinic acid in the form of a brown powder.

LCMS (E1, m/z): (M-1) 209.09 1H NMR: 6H ppm (400 MHz, DMSO): 8.32 (1H, s, CHamm), 2.61 (3H, s, CH3).

Example 4c: oxy-Z-(methylthi0)nic0tin0nitrile A on of 6 g (28.5 mmol) of 5-cyanohydroxy(methylthio)nicotinic acid in ml of diphenyl ether is stirred at 250°C for 4 hours. After returning to room temperature, 100 ml of cyclohexane is added and the reaction medium is triturated for minutes. The solid formed is filtered, rinsed thoroughly with cyclohexane and then dried under vacuum to yield 2.87 g (60%) of oxy(methylthio)nicotinonitrile in the form of a brown powder.

LCMS (E1, m/z): (M+1) 167.12 1H NMR: 6H ppm (400 MHz, DMSO): 12.16 (1H, bs, OH), 7.92 (1H, d, CHamm), 6.46 (1H, d, CHarom), 2.59 (3H, s, CH3).

Example 4d: 6-hydr0xyi0d0(methylthio)nicotinonitrile 6 g (1.6 eq) of silver sulfate and 4.58 g (1.5 eq) ofiodine are added successively to a solution of 2 g (12 mmol) of 6-hydroxy(methylthio)nicotinonitrile in 200 ml of ethanol. The reaction medium is stirred at room ature for 2 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and then taken up in ethyl acetate. The organic phase is washed with water three times, dried on magnesium sulfate and evaporated to yield 3.18 g (90%) of oxyiodo (methylthio)nicotinonitrile in the form of a yellow powder.

LCMS (E1, m/z): (M+1) 292.93 1H NMR: 6H ppm (400 MHz, DMSO): 12.96 (1H, bs, OH), 8.38 (1H, s, CHamm), 2.62 (3H, s, CH3).

Example 4e: 5-i0d0methoxy-Z-(methylthi0)nicotinonitrile 905 pl (2 eq) of methyl iodide and 2.1 g (1.05 eq) of silver carbonate are added successively to a solution of 2.12 g (7.26 mmol) of 6-hydroxyiodo (methylthio)nicotinonitrile in 20 ml of 1,4-dioxane. The reaction medium is d at 60°C for 5 hours. The solid is filtered and the e rinsed thoroughly with methanol.

The filtrate is evaporated and the residue purified by silica column chromatography (4:6 dichloromethane/cyclohexane as eluent) to yield 1.52 g (68%) of methoxy lthio)nicotinonitrile in the form of a white powder.

LCMS (E1, m/z): (M+1) 306.95 1H NMR: 6H ppm (400MHz, DMSO): 8.50 (1H, s, CHamm), 4.04 (3H, s, CH3), 2.63 (3H, s, CH3).

Example 4f: S-iod0meth0xy(methylsulfinyl)nic0tin0nitrile 1.42 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.6 g (5.23 mmol) of methoxy(methylthio)nicotinonitrile in 20 ml 0 f dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnesium sulfate, filtered and ated to yield 1.63 g (97%) of -iodomethoxy(methylsulfinyl)nicotinonitrile in the form of a white powder which may also contain 5-iodomethoxy(methylsulfonyl)nicotinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.

LCMS (E1, m/z): (M+1) 322.95 1H NMR: 6H ppm (400MHz, DMSO): 8.86 (1H, s, CHamm), 4.05 (3H, s, CH3), 2.95 (3H, s, CH3).

Example 4: 5-i0d0—6-meth0xy-1H-pyrazolo[3,4-b]pyridinamine 294 pl (1.2 eq) of hydrazine monohydrate is added to a solution of 1.63 g (5.05 mmol) of 5-iodomethoxy(methylsulfinyl)nicotinonitrile in 30 ml of 2-propanol. The reaction medium is stirred at 80°C for 9 hours. After returning to room temperature, the solid formed is filtered and rinsed with 2-propanol to yield 1.14 g (78%) of 5-iodo methoxy-1H—pyrazolo[3,4-b]pyridinamine in the form of a white .

LCMS (E1, m/z): (M+1) 291.00 1H NMR: 6H ppm (400MHz, DMSO): 11.87 (1H, s, NH), 8.49 (1H, s, CHamm), 5.49 (2H, bs, NHZ), 3.90 (3H, s, CH3).

Example 5: S-iodo-lH-pyrazolo[3,4-b]pyridine-3,6-diamine |,NN H2N N Example 5a: 4-methylm0rpholinium (2,4)-ethyl-S-amino-Z,4—dicyan0-5— topenta-2,4-dienoate 4-methylmorpholinium (2,4)—ethylamino-2,4-dicyanomercaptopenta-2,4-dienoate is prepared according to the ure described by VD. Dyachenko el 61]., try of Heterocyclic Compounds, 2005, 41(4), 503-10 with a yield of 50%. 1H NMR: 6H ppm (400 MHz, DMSO): 9.60 (1H, bs, NH), 8.66 (1H, s, CH), 8.33 (1H, bs, NH), 7.43 (1H, bs, NH), 4.08 (2H, q, CH2), .02 (2H, m, CH2), 3.55-3.78 (2H, m, CH2), 3.24—3.42 (2H, m, CH2), 3.98-3.17 (2H, m, CH2), 2.81 (3H, s, CH3), 1.19 (3H, t, CH3).

Example 5b: ethyl 2-aminocyano(methylthi0)nic0tinate 2.73 ml (1 eq) of methyl iodide is added to a solution of 14.2 g (43.8 mmol) of 4- methylmorpholinium (2,4)—ethylamino-2,4-dicyanomercaptopenta-2,4-dienoate in 78 ml of N,N-dimethylformamide. The reaction mixture is stirred at room temperature for 1 hour and then at 75°C for 20 hours. After returning to room temperature, water is added and the solid formed is filtered and dried under vacuum to yield 10.31 g (100%) of ethyl 2-aminocyano(methylthio)nicotinate in the form of a beige powder.

LCMS (E1, m/z): (M+1) 238.20 1H NMR: 6H ppm (400 MHz, DMSO): 8.25 (1H, s, CHamm), 8.19 (1H, bs, NH), 7.99 (1H, bs, NH), 4.27 (2H, q, CH2), 2.58 (3H, s, CH3), 1.31 (3H, t, CH3).

Example 5c: 2-amin0cyano(methylthio)nicotinic acid 3.08 g (2 eq) of lithium hydroxide monohydrate is added at room temperature to a solution of 8.7 g (36.7 mmol) of ethyl ocyano(methylthio)nicotinate in 87 ml of ethanol and 87 ml of water. The reaction e is stirred at 60°C for 2 hours.

The ethanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed with ethyl acetate and then re-acidified by adding 1 N aqueous hydrogen chloride (pH=1). The precipitate formed is filtered, rinsed with water and with diethyl ether and then dried under vacuum to yield 7.67 g (quantitative) of 2-aminocyano (methylthio)nicotinic acid in the form of a brown powder.

LCMS (E1, m/z): (M+1) 210.16 1H NMR: 6H ppm (400 MHz, DMSO): 13.28 (1H, bs, COZH), 8.21 (1H, s, CHamm), 8.13 (2H, bs, NHZ), 2.57 (3H, s, CH3).

Example 5d: 6-amin0(methylthi0)nic0tin0nitrile A solution of 3 g (14.3 mmol) of ocyano(methylthio)nicotinic acid in 30 ml of diphenyl ether is stirred at 255°C for 60 hours. After returning to room temperature, 60 ml of cyclohexane is added and the reaction medium is triturated for 30 minutes. The solid formed is filtered and then rinsed thoroughly with cyclohexane. The solid is redissolved in ethyl acetate and then the organic phase is washed with water, dried on magnesium sulfate, d and then evaporated to yield 1.32 g (55%) of 6-amino (methylthio)nicotinonitrile in the form of a brown powder.

LCMS (E1, m/z): (M+1) 166.13 1H NMR: 6H ppm (400 MHz, DMSO): 7.58 (1H, d, CHamm), 7.12 (2H, bs, NHZ), 6.20 (1H, d, CHarom), 2.51 (3H, s, CH3).

Example 5e: 6-amino-S-iodo—Z-(methylthio)nicotinonitrile 3.75 g (1.5 eq) of silver sulfate and 2.85 g (1.4 eq) of iodine are added successively to a solution of 1.32 g (8.02 mmol) of 6-amino(methylthio)nicotinonitrile in 65 ml of ethanol. The reaction medium is stirred at room temperature for 3 hours. The solid is filtered and the residue rinsed ghly with methanol. The filtrate is evaporated and 2O redissolved in ethyl acetate. The organic phase is washed with water three times, dried on magnesium sulfate and evaporated to yield 1.89 g (81%) of 6-aminoiodo (methylthio)nicotinonitrile in the form of a brown powder.

LCMS (E1, m/z): (M+1) 291.99 1H NMR: 6H ppm (400 MHz, DMSO): 8.13 (1H, s, , 7.19 (1H, broad flat singlet, NHZ), 2.51 (3H, s, CH3).

Example 5f: 6-amin0i0d0-2—(methylsulfinyl)nic0tin0nitrile 1.77 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.89 g (6.51 mmol) of 6-aminoiodo(methylthio)nicotinonitrile in 60 m l o f dichloromethane. The reaction medium is stirred at room temperature for 1 hour. Ethyl 3O acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnesium sulfate, d and evaporated to yield 1.5 g (75%) of 6- aminoiodo(methylsulf1nyl)nicotinonitrile in the form of a white powder which may also contain oiodo(methylsulfonyl)nicotinonitrile in small tions (<20%). If necessary, the mixture is used as-is in the ing steps.

LCMS (EI, m/z): (M+1) 307.98 1H NMR: 5H ppm (400 MHz, DMSO): 8.45 (1H, s, CHamm), 7.70 (2H, broad fiat singlet, NHZ), 2.84 (3H, s, CH3).

Example 5: S-iodo-lH-pyrazolo[3,4-b]pyridine-3,6-diamine 275 pl (2 eq) of hydrazine monohydrate is added to a on of 872 mg (2.84 mmol) of 6-aminoiodo(methylsulfinyl)nicotinonitrile in 11 ml of 2-propanol. The reaction medium is stirred at 80°C for 3 hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on magnesium sulfate, filtered and evaporated.

The residue is triturated in a minimum of diisopropyl ether. The solid is filtered to yield 523 mg (67%) of 5-iodo-1H-pyrazolo[3,4-b]pyridin-3,6-diamine in the form of a brown powder.

LCMS (EI, m/z): (M+1) 276.00 1H NMR: 5H ppm (400 MHz, DMSO): 11.23 (1H, s, NH), 8.26 (1H, s, CHarom), 6.11 (2H, bs, NHZ), 5.25 (2H, bs, NHz).

Examples of method B1 Example 6: 5-(3,5-diflu0r0benzylthi0)—1H-pyrazolo[4,3-b]pyridinamine Example 6a: 6-chlor0nitropicolinonitrile 2,6-Dichloronitropyridine (5.18 mmol, 1 g) is mixed with 5 ml of N—methyl pyrrolidinone in a microwave reactor. The reaction mixture is heated at 180°C for 15 minutes (6 bars). The crude reaction product is dissolved in ethyl acetate, filtered and washed several times using an aqueous phase. The organic phase is collected, dried on magnesium sulfate and dry trated. The crude product thus obtained is d by silica gel chromatography (heptane/AcOEt) to yield, after concentration, 0.62g (65%) of a brown oil. 1H NMR: 6H ppm (400 MHz, DMSO): 8.81 (1H, d, CHamm), 8.18 (1H, d, ).

Example 6b: 3-nitr0thi0x0-1,6-dihydropyridinecarb0nitrile One equivalent of NaSHzHgO is added to a on of 6-chloronitropicolinonitri1e (5.45 mmol, 1 g) in 20 m1 of EtOH. The color turns orange. The reaction medium is d at room temperature for 30 s. The crude on product is then concentrated, redissolved in ethyl acetate and extracted several times using an acidic aqueous phase (1 N HC1) and then a neutral phase. The organic phase is concentrated and the crude reaction product recrystallized in acetone to yield 0.64 g (79%) of yellow crystals. 1H NMR: 6H ppm (400 MHz, DMSO): 8.71 (1H, d, CHamm), 8.27 (1H, d, CHarom).

Example 6c: 6-(3,S-diflu0r0benzylthi0)—3-nitr0picolinonitrile A mixture of 3-nitrothioxo-1,6-dihydropyridincarbonitri1e (4.42 mmol, 1.34g), 3,5-difiurobenzy1benzylbromide (8.83 mmol, 1.828 g), and K2C03 (11.04 mmol, 1.525 g) in 5 m1 of acetone is heated at 70°C for 10 hours and then ated under reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane) to yield 1.33 g (98%) of the expected product.

LCMS (ES-): m/z 306 . 1H NMR: 6H ppm (400 MHz, DMSO): 8.53 (1H, d, CHamm), 7.91 (1H, d, CHamm), 7.21 (2H, m), 7.17 (1H, m), 4.55 (2H, CH2).

Example 6d: 3-amin0(3,5-difluorobenzylthi0)picolinamide A mixture of 6-(3,5-difiuorobenzy1thio)nitropicolinonitri1e (0.05 g, 0.163 mmol) and PtOz (0.739 mg, 3.25 umol) in 10 m1 of MeOH is placed under stirring at atmospheric pressure of hydrogen for 2 hours. The catalyst is filtered, the solution is concentrated and the residue thus obtained is purified by silica gel chromatography (AcOEt/heptane) to yield, after concentration, 0.04 g (83%) of white crystals.

LCMS (ES+) m/z: 296 (MH+). 1H NMR: 5H ppm (400 MHz, DMSO): 7.84 (1H, broad s, NH), 7.40 (1H, broad s, NH), 7.14 (1H, d, CHamm), 7.08 (4H, m, CHamm), 6.80 (2H, broad s, NHZ), 4.43 (2H, s, CH2).

Example 6e: 3-amin0(3,5-difluorobenzylthi0)picolinonitrile A mixture of 3-amino(3,5-difiuorobenzylthio)picolinoamide (2.37 mmol, 0.7 g) and P2C15 (9.48 mmol, 1.346 g), 20 m1 of toluene and 1 m1 of ionic solvent (1-buty1 methylimidazolium uoroborate) are placed in a microwave reactor and then heated WO 01239 at 140°C for 30 minutes. The crude reaction product is then concentrated under reduced pressure and the orange crystals thus obtained are redissolved in ethyl acetate and washed using saturated aqueous NaHC03 solution. The organic phase is dried on magnesium e and then concentrated to yield 0.7 g of a brown oil. This crude reaction product is d by silica gel chromatography (AcOEt/heptane + 0.1% of NEt3) to yield, after concentration, 0.15 g (23%) of orange crystals. 1H NMR: 5H ppm (400 MHz, DMSO): 7.73 (1H, d, CHamm), 7.25 (2H, m, CHarom), 7.18 (1H, m), 6.85 (1H, d), 5.43 (2H, CH2).

Example 6: -diflu0r0benzylthi0)—1H-pyrazolo[4,3-b]pyridinamine A solution cooled to 0°C ofNaNOz in 3 ml of water is added drop by drop to a solution at 0°C of 3-amino(3,5-difluorobenzylthio)picolinonitrile (1.587 mmol, 0.44g) in ml of 6 N HCl solution. After 15 minutes, a solution cooled to 0°C of SnClz~2H20 diluted in 4 ml of 12 N HCl is added drop by drop. The reaction medium is then stirred at 25°C for 1 hour. The solution is extracted with ethyl acetate and then washed using ted NaHC03 solution and then saturated NaCl solution. The organic phase is collected, dried on ium sulfate and then concentrated under reduced pressure.

The residue is purified by silica gel chromatography (AcOEt/heptane) to yield, after concentration of the organic phases, 0.07 g (15%) of black crystals. 1H NMR: 6H ppm (400 MHz, DMSO): 11.64 (1H, s, NH), 7.63 (1H, d, CHamm), 7.21 (2H, m, CHamm), 7.13 (1H, d, CHarom), 7.04 (1H, m, CHamm), 5.38 (2H, s, NHZ), 4.51 (2H, s, CH2).

The following compounds are obtained by a similar : A’13$\\ WY4N. ——ll—-—m -(2,5-difluorobenzy1thio)-1H- 5% H CH H 293.0 pyrazolo[4,3-b]pyr1d1n—3 -am1ne. . . 4 steps CI 5 -(2, 5 -dich10robenzy1thio)-1H- 3% 6-3 H CH H 324.9 pyrazolo[4,3-b]pyr1d1n—3 -am1ne. . . 4 steps ** 1H NMR: 5H ppm (400 MHz, DMSO): 6-2: 11.65 (1H, s, NH), 7.64 (1H, dd, CHarom, J=8.8Hz), 7.42-7.51 (1H, m, CHarom), 7.20-7.25 (1H, m, ), 7.14 (1H, dd, CHarom, z), 7.01-7.11 (1H, m, CHarom), 5.37-5.41 (2H, m, NH2), 4.49 (2H, s). 6-3: 11.65 (1H, s, NH), 7.83 (1H, m, CHarom), 7.61 (1H, dd, CHarom, J=8.8Hz), 7.50 (1H, m, CHarom), 7.28-7.32 (1H, m, CHarom), 7.10 (1H, dd, CHarom, z), 7.01-7.11 (1H, m, CHarom), 5.42 (2H, s, NH2), 4.47 (2H, s).

Examples of method B2 Example 7: 5-(3,5-dichlorophenylthi0)-1H-pyrazolo[4,3-b]pyridinamine CIOU“/5 N\ Example 7a: 6-(3,5-dichl0rophenylthi0)nitr0picolinonitrile A mixture of 6-chloronitropicolinonitri1e (3.70g, 0.02 mol), 3,5-dichlorobenzenethiol (3.60 g, 0.02 mol) and K2C03 (5.6 g, 0.04 mol) in 100 m1 of acetonitrile is carried at 70°C for 16 hours. The crude on product is diluted in an ethyl acetate fraction and washed using an aqueous phase. The organic phase is dried with sodium sulfate and the e is purified by silica gel chromatography (AcOEt/petroleum ether) to yield 5.4 g (80%) of a yellow solid.

Example 7b: 3-amin0(3,5—dichlorophenylthi0)picolinonitrile 10 m1 of concentrated HCl is added to a solution of -dichloropheny1thio) nitropicolinonitrile (3.4 g, 0.01 mol) in 50 m1 of methanol under stirring. The reaction medium is refluxed, added together with 1.68 g (0.03 mol) of iron and stirred for 10 minutes. After returning to room temperature, the reaction mixture is added together with 100 ml of ethyl acetate and 50 ml of water. The pH is adjusted to 10 using 30% soda solution and the organic phase is ted and then dried on anhydrous sodium sulfate before being concentrated. The residue is purified by silica gel chromatography (ethyl acetate/petroleum ether) to yield, after concentration of the fractions, 2.82 g (91%) of a yellow solid.

LCMS (m/e): 296(M+H+). %.

Example 7: 5-(3,5-dichlorophenylthi0)-1H-pyrazolo[4,3-b]pyridinamine A solution of 350 mg of NaNOz (5.07 mmol) in water (2 ml) is added to a stirring solution of 1.5 g of 3-amino(3,5-dichlorophenylthio)picolinonitrile (5.07 mmol) in 100 ml of 50% sulfuric acid at 0°C. The mixture is stirred for 20 minutes at 0-5°C. A on of 2.9 g of SHC12’2H20 (12.7 mmol, 2.5 eq) in hloric acid (12 N solution, 10 ml) is then added and the solution is stirred for 1 hour at room temperature.

The solid formed is d and then washed twice with 20 ml of water. The solid is suspended in 100 ml and the pH is adjusted to 10 by adding 30% soda solution. The organic phase is separated and then dried on anhydrous sodium sulfate before being concentrated under vacuum. A light yellow solid is obtained after recrystallization in ethyl acetate (470 mg, 34%).

LCMS m/z 311 (M+H+). 1H NMR: 6H ppm (400 MHz, DMSO): 11.91 (1H, bs, NH), 7.79 (1H, d, , 7.55 (1H, s, CHamm), 7.36 (2H, s, CHamm), 7.33 (1H, m, CHamm), 5.42 (2H, s, NHZ).

The following compounds are obtained by a similar method: x N Ar’ 1 EN\ \ W Y4 N Mass MH+ II 5-(3,5-difluorobenzyloxy)-1H- pyrazolo [4, 3 -b]pyridin—3 -amine -(3 ,5 -difluoropheny1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -amine II 5-(2,4-difluoropheny1thio)-1H- pyrazolo [4, 3 -b]pyridin—3 -amine II 5 -(2,4-dichloropheny1thio)- 1H- 24% pyrazolo[4,3-b]pyridin—3 -amine 3 steps -(2-(tn'fluoromethy1)phenylthio)-lH- 17% pyrazolo[4,3-b]pyridin—3 -amine 3 steps -(3,5-difluoropheny1thio)-1H- 6% pyrazolo[3,4-b]pyrazin-3 -amine 7 steps -(2,4-dichloropheny1thio)-1H- lo [3 ,4-b]pyrazin-3 -amine -(2-(tn'fluoromethy1)phenylthio)-1H- pyrazolo [3 yrazin-3 -amine IInunnmnnn 5-(3,5-difluorobenzyloxy)-1H- pyrazolo [4, 3 -b]pyridin—3 -amine -(2, 5 -difluorobenzyloxy)- 1H- pyrazolo [4, 3 -b]pyridin—3 -amine -(2, 5 -dichlorobenzyloxy)-1H- pyrazolo [4, 3 -b]pyridin—3 -amine -(5-chloro(tn'fluoromethyl)benzyloxy)- 1H-pyrazolo [4, 3 -b]pyridin—3 -amine -(pyridiny1methoxy)-1H-pyrazolo[4,3- b]pyridin-3 -amine ** 1H NMR: 5H ppm (400 MHz, DMSO): 7-1: 11,61 (1H, 3 large, NH), 7,73 (1H, d, CHarom), 7,24 (2H; m, CHarom), 7,18 (1H, m, CHarom), 6,86 (1H, d, CHarom). 7-2: 11.95 (1H, sl, NH), 7.78 (1H, d, CHarom, Hz), 7.33 (1H, d, , J=11.6Hz), 7.19 (1H, t, CHarom), 7.04 (2H, 2d, CHarom, J=8.8Hz), 5.51 (2H, s, NHZ). 7-3: 11.80 (1H, sl, NH), 7.70 (1H, d, CHarom, J=8.8Hz), 7.60 (1H, t, CHarom), 7.49 (1H, q, CHarom), 7.27-7.33 (1H, m, CHarom), 7.11 (1H, d, CHarom, J=8.8Hz), 5.41 (2H, s, NHz). 7-4: 11.93 (1H, sl, NH), 7.80 (1H, d, CHarom, J=11.6Hz), 7.62 (1H, d, CHarom, J=11.6Hz), 7.40 (1H, dd, CHarom, J=11.2Hz), 7.29 (1H, d, , J=11.6Hz), 7.1 (1H, s, ), 5.51 (2H, s, NHZ). 7-5: 11.86 (1H, 31, NH), 7.87 (1H, d, CHarom, J=9.6Hz), 7.73 (1H, d, , J=11.6), 7.50-7.68 (2H, m, CHarom), 7.44 (1H, d, CHarom, J=10.4Hz), 7.11 (1H, d, CHarom, J=11.6Hz), 5.46 (2H, s, NHz). 7-6: 12.66 (1H, sl, NH), 8.52 (1H, s, CHarom), .20 (1H, m, CHarom), 7.02-7.10 (2H, m, CHarom), 5.90 (2H, 3, NH;). 7-7: 12.70 (1H, 3, NH), 8.52 (1H, s, ), 7.60 (1H, d, CHarom, J=8.8Hz), 7.38 (1H, dd, CHarom, J=8.4Hz), 7.12 (1H, s, CHarom), 5.92 (2H, s, NHZ). 7-8: 12.66 (1H, 3, NH), 8.39 (1H, s, CHarom), 7.84 (1H, d, CHarom, J=7.6Hz), 7.58 (1H, t, CHarom), 7.50 (1H, t, CHarom), 7.34 (1H, d, CHarom, J=7.6Hz), .87 (2H, s, NHZ). 7-9: 11,57 (1H, 3, NH), 7,74 (1H, d, Charom, J=9Hz), 7,25 (3H, m, CHarom), 6,88 (1H, d, Charom, J=9Hz), 5,44 (2H, 3), 5,08 (2H, 3). 7-10: 11.58 (1H, s, NH), 7.73 (1H, d, CHarom, J=12.0Hz), 7.48-7.58 (1H, m, CHarom), 7.21-7.37 (2H, m, CHarom), 6.85 (1H, d, CHarom, J=12.0Hz), 5.44 (2H, s, CH), 5.10 (2H, sl, NH2). 7-11: 11.60 (1H, sl, NH), 7.70-7.77 (2H, m, CHarom), 7.57 (1H, d, CHarom, J=11.2Hz), 7.40-7.50 (1H, m, CHarom), 6.89 (1H, d, CHarom, J=12.0Hz), 5.48 (2H, s, CH), 5.06 (2H, sl, NH2). 7-12: 11.60 (1H, sl, NH), 7.91 (1H, s, CHarom), 7.83 (1H, d, CHarom, J=11.2Hz), 7.75 (1H, d, , J=12.0Hz), 7.66 (1H, d, CHarom, J=9.6Hz), 6.88 (1H, d, CHarom, J=12.0Hz), 5.58 (2H, s, CH), 5.01 (2H, sl, NH2). 7-13: 11.56 (1H, sl, NH), 8.77 (1H, s, ), 8.55 (1H, s, CHarom), 7.96 (1H, d, CHarom, J=10.4Hz), 7.72 (1H, d, CHarom, J=12.0Hz), 7.42 (1H, dd, , J=10.0Hz), 6.83 (1H, d, CHarom, J=11.6Hz), 5.45 (2H, s, CH), 5.15 (2H, sl, NH2).

Example 8: N5-(3,5-diflu0r0phenyl)—1H-pyrazolo[4,3-b]pyridine-3,5-diamine H NH2 Fr;mN N\ Example 821: 6-(3,5-diflu0r0phenylamino)—3-nitr0picolinonitrile A mixture of 6.5 g of 6-chloronitropicolinonitrile (0.065 mol) and 6.2 g of 3,5- difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70°C for 5 hours. The crude reaction product is d in an ethyl acetate on and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.

Example 8b: 0(3,5—diflu0r0phenylamin0)picolin0nitrile ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenylthio) icolinonitrile (3.9 g, 0.0141 mol) in 150 ml of ethanol under stirring. The reaction medium is refluxed, added together with 2.4 g of iron (0.0423 mol) and stirred at 80°C for 1 hour. After returning to 0°C the pH is adjusted to 8 using 1 N soda solution and the reaction medium is filtered on Celite. The on mixture is added er with 100 ml of ethyl acetate and 50 ml of methanol. The organic phase is extracted and the aqueous phase is extracted several times by ethyl acetate fractions. The organic phases are combined and then dried on anhydrous sodium sulfate before being concentrated to yield, after concentration, 2.3 g (66%) of a brown solid.

Example 8: 5-(3,5-diflu0r0phenylamin0)—1H-pyrazolo[4,3-b]pyridinamine A solution of 713 mg of NaNOz (10.3 mmol) in water (5 ml) is added, drop by drop, to a stirring solution of 2.3 g of 3-amino(3,5-difluorophenylamino)picolinonitrile (9.4 mmol) in 100 ml of 6 N hydrochloric acid at 0°C. The mixture is stirred for 20 minutes at 0-5°C. A solution of 5.3 g of SnC12-2H20 (23.5 mmol, 2.5 eq) in hloric acid (12 N on, 30 ml) is then added drop by drop and the solution is stirred for 1 hour at room temperature. The reaction medium is then cooled at 0°C and basif1ed to pH 8 using 30% soda solution. The e is extracted with ethyl acetate and washed using saturated NaCl solution and the organic phase is dried on anhydrous sodium sulfate before being concentrated under vacuum. The residue is purified by silica column chromatography (AcOEt). A light yellow solid is obtained (530 mg, 22%).

LCMS: m/z 262 (M+H+). 1H NMR: 6H ppm (400 MHz, DMSO): 11.47 (s, 1H), 9.45 (s, 1H), 7.65 (m, 3H), 6.87 (d, 1H, J=7.8 Hz), 6.60 (m, 1H), 5.09 (s, 2H).

The ing compounds are ed by a similar method: A’ r113XN\\ WY4N_ --ll—--E F N-(2,5 -difluorophenyl)- 1H- 4% 8-1 CH H H 262.0 pyrazolo [4,3 -b]pyridine-3 ,5 -diamine 4 Steps CI N-(2,5-dichlorophenyl)-1H- 9% 8-2 CH H H 294.0 pyrazolo[4,3-b]pyr1d1ne-3,5-diam1ne. . . . 4 steps ** 1H NMR: 5H ppm (400 MHz, DMSO): 8-1: 11.46 (1H, s, NH), 8.75-8.82 (2H, m, CHarom), 7.65 (1H, dd, CHarom, J=9.2Hz), 7.19-7.31 (2H, m, ), 6.67-6.63 (1H, sl, CHarom), 5.06 (2H, s, NHZ). 8-2: 11.58 (1H, sl, NH), 8.65 (1H, s, CHarom), 8.35 (1H, s, CHarom), 7.69 (1H, d, CHarom, J=12.0Hz), 7.45 (1H, d, CHarom, Hz), 7.24 (1H, d, CHarom, J=12.0Hz), 6.96 (1H, dd, CHarom, J=11.2Hz), 5.03 (2H, Sl, NHz).

Example of method B3 Example 9: 5-(3,5-diflu0r0benzyl)—1H-pyrazolo[4,3-b]pyridinamine FW“N\ This compound can be prepared from the following intermediates, according to method Example 9a: -difluorobenzyl)—4,4,5,5—tetramethyl-1,3,2-di0xab0rolane Example 9b: 6-(3,5-dilluorobenzyl)nitr0picolinonitrile Example 9c: 3-amin0(3,5-diflu0r0benzyl)picolin0nitrile Example of method B4 Example 10: 3-amino-N-(3,5-difluorophenyl)—1H-pyrazolo[3,4-b]pyridine amide Example 10a: 5-(N-(3,5-difluorophenyl)sulfamoyl)nic0tinic acid 2.74 g (9.64 mmol) of ethyl 2-chloro(chlorosulfonyl)nicotinate in solution in 20 ml of anhydrous dichloromethane is added, drop by drop at 0°C, to a mixture of 623 mg (4.82 mmol) of 3,5-difluoroaniline and 1.68 ml (12.05 mmol) of triethylamine diluted in ml of anhydrous dichloromethane. The solution is stirred at room temperature for 3 hours. The solvent is evaporated to yield a light brown solid. The solid is triturated in 20 ml of methanol, filtered and then rinsed with 3 ml of methanol to yield 2.85 g of a white solid.

This solid is redissolved in 25 ml of tetrahydrofuran and is added together with a on of 0.421 g (10.04 mmol) of m monohydrate hydroxide in 10 ml of water.

The reaction e is left under stirring for 3 hours at 35°C and then diluted in water, acidified with 1 N hloric acid and extracted with ethyl acetate. The organic phase is collected, dried on sodium sulfate, filtered and concentrated to yield 1.12 g of 5-(N- (3,5-difluorophenyl)sulfamoyl)nicotinic acid in the form of an orange solid (yield=67%). 1H NMR: 5H ppm (400 MHz, DMSO): 8.91 (1H, S, CHamm), 8.51 (1H, s, CHarom), 7.02 (1H, dd, CHamm), 6.83 (2H, d, ).

Example 10b: ro-S-(N-(3,5—diflu0r0phenyl)sulfamoyl)nic0tinamide 0.288 ml (3.87 mmol) of thionyl chloride and a drop of DMF are added successively to 0.450 g (1.29 mmol) of 2-chloro(N-(3,5-difluorophenyl)sulfamoyl)nicotinic acid in ml of anhydrous toluene. The mixture is placed under stirring, at reflux of toluene, for 2 hours. The acid de reaction mixture is then added drop by drop to an iced solution, under stirring, of 4.5 ml of 25% ammonium hydroxide. A release of gas is observed. The reaction medium is left under stirring at room temperature for 30 minutes. The reaction medium is extracted several times with ethyl e. The combined organic phases are dried on anhydrous sodium sulfate and then concentrated. 0.315 g of 2-chloro(N-(3,5-difluorophenyl)sulfamoyl)nicotinamide in the form of a light brown solid is obtained (yield=72%). 1H NMR: 8H ppm (400 MHz, DMSO): 11.18 (1H, bs, NH), 8.86 (1H, s, CHamm), 8.22 (1H, s, CHarom), 8.21 (1H, bs, NH), 7.98 (1H, bs, NH), 6.96 (1H, dd, CHarom), 6.79 (2H, d, CHarom).

Example 10c: 6-chloro-S-cyano-N-(3,5-difluor0phenyl)pyridine—3-sulf0namide 3.4 ml (36.2 mmol) of phosphoryl chloride and a drop of concentrated sulfuric acid are added to 0.315 g (0.906 mmol) of 2-chloro(N-(3,5-difluorophenyl) oyl)nicotinamide. The reaction mixture is stirred for 2 hours at 90°C and then added drop by drop to ice. The brown solid is filtered, rinsed with water and then dried under vacuum. 0.217 g of 6-chlorocyano-N-(3,5-difluorophenyl)pyridine sulfonamide is ed in the form of a light brown solid (yield=72%). 1H NMR: 8H ppm (400 MHz, DMSO): 11.34 (1H, bs, NH), 9.04 (1H, s, CHamm), 8.92 (1H, s, CHamm), 7.03 (1H, dd, CHamm), 6.85 (2H, d, CHarom).

Example 10: 3-amino-N-(3,5-difluorophenyl)—1H-pyrazolo[3,4-b]pyridine—5- sulfonamide 0.377 ml (2.63 mmol) of 35% hydrazine is added to 0.217 g (0.658 mmol) of ro- -cyano-N-(3,5-difluorophenyl)pyridinesulfonamide diluted in 6 ml of isopropanol.

The solution is heated at 75°C for 2 hours. The t is evaporated to yield 0.214 g of 3-amino-N-(3,5-difluorophenyl)-1H-pyrazolo[3,4-b]pyridinesulfonamide in the form of a yellow solid (yield=100%). 1H NMR: 5H ppm (400 MHz, DMSO): 8.74 (1H, d, CHarom), 8.68 (1H, d, CHarom), 6.88 (1H, dd, CHarom), 6.80 (2H, d, CHarom), 6.04 (2H, bs, NH).

Examples of method B5 Example 11: 5-(3,5-diflu0r0benzyloxy)—1H-pyrazolo[3,4-b]pyridinamine Q» NH2 F WM/\ N IZ/ This compound can be ed from the following intermediates, according to method e 11a: 5-hydr0xynic0tin0nitrile A mixture of 1g of oxynicotinonitrile (7.46 mmol) and 8.62 g of pyridine hydrochloride is heated at 200°C for 2 hours. The crude reaction product is diluted in a water fraction several times with diethyl ether. The aqueous phase is basif1ed by adding sodium bicarbonate and then extracted again with diethyl ether. The organic phase is dried and then concentrated to yield 850 mg of 5-hydroxynicotinonitrile (95%) in the form of a beige solid.

LCMS: m/z 120,94 (M+H+). 1H NMR: 5H ppm (400 MHz, DMSO): 10,79 (s, 1H), 8,46 (s, 1H, CHarom.), 8,42 (s, 1H, CHarom.), 7,60 (s, 1H, CHarom.).

Example 11b: 5-(3,5-difluorobenzyloxy)nic0tin0nitrile 876 mg (2 eq) of sodium hydride is added gradually at 0°C under nitrogen to a solution of 865 mg of 5-hydroxynicotinonitrile (7.2 mmol) in 15 mL of dimethylacetamide. The mixture is stirred 10 min at 0°C before adding 2.24 g (1.5 aq) of 3,5-difluorobenzyl e. The mixture is placed under stirring for 2.5 additional hours before being diluted in an ethyl acetate fraction and being washed with aqueous fractions. The WO 01239 organic phases are isolated, dried and trated. The solid residue obtained is recrystallized in methanol to yield 1.1 g (68 % of 5-(3,5-difiuorobenzyloxy) nonitrile in the form of a beige powder.

LCMS: m/z 247.11 (M+H+). 1H NMR: 6H ppm (400 MHz, DMSO): 8,69 (s, 1H, CH), 8,65 (s, 1H, CH), 8,08 (s, 1H, CH), 7,26 (m, 3H, CH), 5,28 (d, 2H, CH2).

Example 11c: 3-cyan0(3,S-diflu0r0benzyloxy)pyridine 1-0xide 224 mg of m-CPBA is added at 0°c to a solution in acetonitrile of 250 mg of 5-(3,5- difiuorobenzyloxy)nicotinonitrile. The reaction medium is stirred for 20 hours while a precipitate is formed progressivelt. this solid is then filtered and washed to yield 200 mg (75%) of 3-cyano(3,5-difiuorobenzyloxy)pyridine 1-oxide in the form of a white powder.

LCMS: m/z 263,06 (M+H+).

Example 11d: 2-chl0r0(3,5-diflu0r0benzyloxy)nic0tin0nitrile A mixture of 650 mg of 3-cyano(3,5-difluorobenzyloxy)pyridine 1-oxide in 2.3 mL of POC13 added with few drops of H2804 is heated at 110°C for 1h30. The crude reaction medium is then poured in ice and the precipitate thus formed is isolated by filtration and dried under vacuum to yield 600 mg of a beige solid in the form of a mixture of regioisomers comprising mainly the desired 2-chloro(3,5- difiuorobenzyloxy)nicotinonitrile which is used without r purification.

LCMS: m/z 281,02 (M+H+).

Example 11: 5-(3,5-diflu0r0benzyloxy)—1H-pyrazolo[3,4-b]pyridinamine 313 mg of hydrazine hydrate (5 eq) is added to a solution of 1.6 g of 2-chloro(3,5- obenzyloxy)nicotinonitrile (450 umol) in 10 mL of propanol. The reaction mixture is heated at 100°C for 6 hours. After return to room temperature leading to a precipitation, the crude reaction medium is filtered, the solid is removed and the e is dry ated. It is then purified by chromatography on a silica column eluted with a gradient of ethyl acetate and methanol, whereas the more polar fraction is isolated, concentrated and suspended again in a small fraction of methanol under stirring. The solid thus obtained is isolated and dried to yield 221 mg of -difiuorobenzyloxy)— 1H-pyrazolo[3,4-b]pyridinamine in the form of a beige solid wich is used without further purification.

LCMS: m/z 277,07 (M+H+). e of method B6 Example 11bis: N-(3-amin0-1H-pyrazolo[3,4-b]pyridin-S-yl)—3,S-difluorobenzene sulfonamide <1 H N F ,8; \ Ono I N ;N Exam Q l e 1 1 b i s-a: N-(6-chlor0-S-cyanopyridinyl)-3,5-diflu0r0benzene- sulfonamide 1.132 g (5.32 mmol) of fiuorobenzenesulfonyle chloride is added under argon to a solution of 545 mg (3.55 mmol) of 5-aminochloronicotinotrile in 20 mL of an anhydrous 1:1 mixture of THF and pyridine. The reaction medium is heated to 70°C for 3 hours and let 12 additional hours under stirring at room temperature. The solvent is dry evaporated and the crude reaction product is redissolved in ethyl acetate and washed with several aqueous ons. The organic phase is dried on magnesium sulfate, filtered, concentrated and then purified by silica gel chromatography to yield 784 mg (67%) ofN—(6-chlorocyanopyridinyl)-3,5-difiuorobenzene-sulfonamide. 1H NMR: 5H ppm (400 MHz, DMSO) : 11,39 (1H, sl, NH), 8. 34 (1H, m, CHarom), 8,10 (1H, m, CHarom), 7,67 (1H, m, CHarom), 7,59 (2H, m, CHarom).

Example 11bis: N-(3-amin0-1H-pyrazolo[3,4-b]pyridin-S-yl)—3,5—diflu0robenzene- sulfonamide 1.786 g (35.7 mmol) of hydrazine hydrate is added under argon to a solution of 784 mg (2.38 mmol) of N—(6-chlorocyanopyridinyl)-3,5-difiuorobenzene-sulfonamide in 6 mL of ethanol. The on is heated to 100°C for 20 hours and then cooled to room ature. The solvent is evaporated to yield 810 mg ofN—(3-amino-1H-pyrazolo[3,4- b]pyridinyl)-3,5-difiuorobenzene-sulfonamide (100%) which is used without further purification in the ing steps.

LCMS: m/z 326,07 (M+H+).

Example of method C1 Example 12: N6-(2,4-diflu0r0phenyl)—1H-pyrazolo[3,4-b]pyridine-3,6—diamine F F\\ |,NN This compound can be prepared from the following intermediates, according to method Example 12-a: 5-cyano(methylthio)pyridin-2—yl trifluoromethanesulfonate .26 mL (1.2 eq) of potassium 2-methy1propanolate and then 9.03 g (1.2 eq) of 1,1,1-trifluoro-N-pheny1-N—(trifluoromethylsu1fony1)methanesu1fonamide a r e a d d e d dropwise to a solution of 3.5 g (21.06 mmol) of 6-hydroxy(methylthio)nicotinonitrile in 180 mL of ydrofurane under nitrogen. The reaction mixture is d at room temperature for 2h45. Water is added and the product is extracted with ethyl acetate.

The organic phase is dried on anhydrous magnesium sulfate, filtered and evaporated to yield an orange solid. The product is purified on a silica gel column (eluent: eXane/dichloromethane 5:5) to yield 5.31 g (85%) of 5-cyano (methylthio)pyridiny1trifluoromethanesulfonate in the form of a yellow solid. 1H NMR: 6H ppm (400 MHz, DMSO): 8,57 (1H, d, CH), 7,52 (1H, d, CH), 2.59 (3H, s, CH3).

Example 12-b: 6-(2,4-diflu0r0phenylamin0)(methylthi0)nicotinonitrile 0.81 mL (1.2 eq) of ,4-difluoroani1ine and 1.53 g (1.4 eq) of cesium(I) carbonate are added under nitrogen to a solution of 2 g (6.71 mmol) of 5-cyano (methylthio)pyridiny1 romethanesulfonate in 30 mL of 1,4-dioxane. The medium is d for 5 minutes under argon before adding 0.25 g (0.06 eq) of de 2,2’- bis(dipheny1phosphino)-1,1’-binaphthy1 and 0.08 g (0.04 eq) of (1E,4E)-1,5- diphenylpenta-1,4-dienone, ium(II) complex. The reaction medium is stirred at 100°C for 2 hours. After return to room temperature, ethyl e and brine are added.

The organic phase is dried on anhydrous magnesium sulfate, f1tered and evaporated.

The residue obtained is purified on silica gel chromatography (eluent: cyclohexane/ethyl acetate 8:2 then 7:3) to yield 1.52 g (82%) of 6-(2,4-difluoropheny1amino) (methylthio)nicotinonitrile in the form of a white solid.

WO 01239 2012/051283 LCMS (IE, m/z): (M+1) 278,06. 1H NMR: 6H ppm (400 MHz, DMSO): 9,57 (1H, s, NH), ,86 (2H, m, CH), 7,28- 7,44 (1H, m, CH), 7,02-7,18 (1H, m, CH), 6,60 (1H, d, CH), 2.41 (3H, s, CH3).

Example 12: N6-(2,4-diflu0r0phenyl)—1H-pyrazolo[3,4-b]pyridine-3,6—diamine 769 mg (3.12 mmol) of m-chloroperbenzoic acid (mCPBA) is added under argon to a stiring solution of 786 mg (2.83 mmol) of 6-(2,4-difluorophenylamino) (methylthio)nicotinonitrile in 25 mL of dichloromethane. The reaction medium is stirred 1 hour at room temperature before adding a fraction of ethyl acetate and washed this organic phase with a NaHC03 saturated solution. The combined organic phases are dried on magnesium sulfate and dry evaporated. The crude reaction product is dissolved again in 10 mL of propanol and 2 equivalents of hydrazine hydrochloride in water are added. The mixture is heated at 90°C for 6 hours before being d in water and extracted with ethyl acetate. The organic phase is dried on magnesium e and dry evaporated before being purified by silica gel chromatography to yield 495 mg of N6- (2,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow- orange solid (67%).

LCMS (IE, m/z): (M+1) 262,14. 1H NMR: 6H ppm (400 MHz, DMSO): 11,40 (1H, s, NH), 8,76 (1H, s, NH), 8,15 (1H, m, CH), 7,81 (1H, d, CH), 7,28 (1H, m, CH), 7,06 (1H, m, CH), 6,55 (1H, d, CH), 5,24 2O (2H, s, NHZ).

The following compound is obtained by a similar method: N6--(3,5--difluorobenzyl)- 1H- pyrazolo[3,4-b]pyridine-3,6- 70% 276,15 diamine ** H NMR, dmso-d6, EX.: 121; 11,17 (1H, s, NH), 7,66 (1H, d, CH), 7,37 (1H, s, NH), 7,04 (3H, m, CH), 6,24 (1H, d, CH), 5,11 (2H, s, NHZ), 4,52 (2H, s, CH2).

Example 12bis: N6-(2,4—diflu0r0phenyl)—N6-methyl-1H-pyrazolo[3,4-b]pyridine— 3,6-diamine F F\\ |,NN Example 12bis-a: 6-((3,5-diflu0r0phenyl)(methyl)amin0)(methylthi0) nicotinonitrile 3.05 mL (5.04 mmol) of potassium 2-methylpropanolate and then 286 uL (1.8 eq) of iodomethane are added se under nitrogen to a solution of 700 mg (2.52 mmol) of 6-(2,4-difluorophenylamino)(methylthio)nicotinonitrile in 20 mL of N,N—dimethyl formamide. The reaction medium is d at room temperature for 24 hours and then 126 uL (0.8 eq, 2.02 mmol) of iodomethane is added. The reaction medium is stirred at room temperature for 2 additional hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on ous magnesium sulfate, filtered, and evaporated to yield 660 mg (90%) of 6-((2,4-difluorophenyl)(methyl)amino)—2- (methylthio)nicotinonitrile in the form of a brown solid.

LCMS (IE, m/z): (M+1) 292,09. 1H NMR: 6H ppm (400 MHz, DMSO): 7,74-7,80 (1H, m, CH), 7,55-7,63 (1H, m, CH), 7,43—7,52 (1H, m, CH), 7,18-7,27 (1H, m, CH), 6,16-6,30 (1H, m, CH), 3,43 (3H, s, CH3), 2.42 (3H, s, CH3).

Example 12bis: N6-(2,4—diflu0r0phenyl)—N6-methyl-1H-pyrazolo[3,4-b]pyridine— 3,6-diamine 452 mg (1.84 mmol) of mCPBA is added under argon to a ng solution of 486 mg (1.67 mmol) of 6-((2,4-difluorophenyl)(methyl)amino)(methylthio)nicotinonitrile in mL of dichloromethane. The reaction medium is stirred 30 min at room temperature before adding an ethyl e fraction. The organic phase is washed with a NaHC03 saturated solution, dried on ium sulfate and dry evaporated. The crude reaction product is dissolved again in 6 mL of propanol and 164 uL (3.38 mmol) of ine hydrochloride in water is added. The mixture is heated at 90°C for 6 hours before being diluted in water and extracted with ethyl acetate. the organic phase is dried on magnesium sulfate and dry evaporated before being purified by silica gel chromatography to yield 328 mg of N6-(2,4-difluorophenyl)-N6-methyl-1H- pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (70%).

LCMS (IE, m/z): (M+1) 276,15. 1H NMR: 6H ppm (400 MHz, DMSO): 11,41 (1H, s, NH), 7,75 (1H, d, CH), 7,51—7,55 (1H, m, CH), 7,40—7,43 (1H, m, CH), 7,17—7,22 (1H, m, CH), 6,03 (1H, d, CH), 5,23 (2H, s, NHZ), 3,28 (3H, s, CH3).

Example of method C3 Example 12ter: 6-(2,4-diflu0r0phenylthi0)—1H-pyrazolo[3,4-b]pyridinamine e 12ter—a: 2-chlor0(2,4-diflu0r0phenylthi0)nic0tin0nitrile A on of 362 mg (1.05 eq) of potassium hydroxide in 10 mL of ethanol is added, under nitrogen, to a solution of 698 uL (6.16 mmol) of 2,4-difluorobenzenethiol in 30 mL of ethanol. The reaction medium is d at room temperature for 15 minutes and then cooled in ice before adding a solution of 1.015 g (0.95 eq) of 2,6- dichloronicotinonitrile in 30 mL of ethanol. The reaction medium is stirred for 2 hours at 0-5°C. 63 mL of a 0.1N HCl solution is added to stop the reaction. Water is added and the producted is extracted with ethyl acetate. The organic phase is dried on anhydrous ium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography t: cyclohexane/ethyl acetate 94:6) to yield 1.09 g (66%) of 2- chloro(2,4-difluorophenylthio)-nicotinonitrile in the form of a White solid.

LCMS (IE, m/z): (M+1) 282,98. 1H NMR: 6H ppm (400 MHz, DMSO): 8,24 (1H, d, CH), 7,77-7,85 (1H, m, CH), 7,52— 7,63 (1H, m, CH), 7,25—7,35 (2H, m, CH), 2,41 (3H, s, CH3).

Example 12ter: 6-(2,4-diflu0r0phenylthi0)—1H-pyrazolo[3,4-b]pyridinamine 0.561 mL (11.57 mmol) of ine monohydrate is added under nitrogen to a stirring solution of 1.09 g (3.86 mmol) of ro(2,4-difluorophenylthio)nicotinonitrile in mL of propanol. The reaction medium is heated at 80°C for 4 hours. A precipitate is obtained when the reaction medium is returned to room temperature. This precipitate is WO 01239 filtered and rinced with ethanol. The solid is dissolved in an ethyl acetate fraction and washed with a 1N HCl solution. The organic phase is dried on magnesium sulfate and dry evaporated to yield 420 mg (39%) of -difluorophenylthio)-1H-pyrazolo[3,4- b]pyridinamine in the form of a yellow solid. 1H NMR: 6H ppm (400 MHz, DMSO): 12,10 (1H, s, NH), 8,11 (1H, d, CH), 7,82- 7,89(1H, m, CH), 7,58-7,63 (1H, m, CH), 7,32-7,36 (1H, m, CH), 6,86 (1H, d, CH), 4,59 (2H, s, NHZ).

The following compound is ed by a similar method: I /YL \ ArX N N. m—I— F 6- 2,4-difluoro henox( p y)-1H- CH H lo[3,4-b]pyridinamine Example 129uater: -diflu0r0benzyl)—1H-pyraz010[3,4-b]pyridinamine F NH2 F N NN 17.35 mL of a 0.5M solution in THF of (3,5-difluorobenzyl)zinc chloride (8.58 mmol) is added under argon to a solution of 416 mg of palladium(II) chloride (510 mmol) and 883 mg of 2,6-dichloronicotinonitrile (5.1 mmol) in 2 mL of anhydrous THF. The on is refluxed for 7 hours, then cooled to room temperature. A IN soda aqueous solution is added and the product is extracted with several successive ethyl acetate fractions. The organic phases are dried on magnesium sulfate and dry evaporated before being purified by silica gel chromatography to yield 680 mg of a mixture of 2-chloro (3,5-difluorobenzyl)—nicotinonitrile and by-products wich is used without further purification in the following step.

The previous mixture is dissolved in 10 mL of isopropanol under stirring and 750 uL of % hydrazine hydrate is added. The solution is heated at 80°C for 4 hours. The solvent is dry evaporated and the product is purified by silica gel chromatography (dichloromethane/methanol 9:1) to yield 290 mg of -difluorobenzyl)—1H- pyrazolo[3,4-b]pyridinamine (64%).

LCMS (IE, m/z): (M+1) 261.16. 1H NMR: 6H ppm (400 MHz, DMSO): 11,82 (1H, s, NH), 8,01 (1H, d, CH), 6,99-7,04 (3H, m, CH), 6,91 (1H, d, CH), 5,49 (2H, s, NHZ), 4,12 (2H, s, CH2).

Example of method D1: Example 13: 5-(3,5-diflu0r0benzyl)—1H-pyrazolo[3,4-b]pyridine—3-amine | N N N 0.575 g (0.704 mmol) of (dppf)2PdClg~CH2C12 and 28 ml (l4.08 mmol) of 3,5- difluorobenzyl zinc (II) chloride are added to 1.5 g (7.04 mmol) of a solution of 5- bromo-lH-pyrazolo[3,4-b]pyridinamine in 10 ml of tetrahydrofuran. The reaction medium is heated at 90°C for 18 hours. After returning to room temperature, the reaction is hydrolyzed by slowly adding water at 0°C. After filtration of the precipitate formed, the solid is rinsed with tetrahydrofuran and the aqueous te is extracted l times with ethyl acetate. The organic phases are combined, dried on magnesium sulfate and concentrated. The residue is purified by silica chromatography (95:45:05 and then 95:4:1 romethane/methanol/ammonium as eluent) to yield 1.7 g (93%) of 5-(3,5-difluorobenzyl)-lH-pyrazolo[3,4-b]pyridineamine in the form of a beige solid.

LCMS (E1, m/z): (M+1) 261.41. 1H NMR: 6H ppm z, DMSO): 11.87 (1H, s, NH), 8.31 (1H, d, CHamm), 7.92 (1H, d, CHamm), 6.98-7.08 (3H, m, , 5.47 (2H, s, NH), 4.04 (2H, s, CH2).

The following compounds are obtained by a similar method: A’rIrN\\ WY4N.

I-II_-- -(3,5-difluorobenzyl)-1H- 8% 13-1 CH H H 261.1 lo[4,3-b]pyr1d1nam1ne. ~ . 4 steps F F -(3 ,5 -difluorobenzy1)-1H- 21% 13-2 N H H 262. 1 pyrazolo[3,4-b]pyrazm-3 -am1ne. ~ 3 steps F F ** 1H NMR: 5H ppm (400 MHz, DMSO): 13-1: 11.61 (1H, s1, NH), 7.65 (1H, d, CHarom, J=11.6Hz), 7.20 (1H, d, CHarom, Hz), 6.95-7.10 (3H, m, CHarom), .32 (2H, s1, NH2), 4.18 (2H, s, CH2). 13-2: 12.31 (1H, s1, NH), 8.44 (1H, s, CHarom), .08 (3H, m, CHarom), 5.61 (2H, s1, NH2), 4.25 (2H, s, CH2).

Examples of method D2 Example 14: 5-(3,5-diflu0r0phenylthi0)—1H-pyrazolo[3,4-b]pyrazinamine FomSN F 0.7 g (2.68 mmol) of 5-iodo-1H-pyrazolo[3,4-b]pyridineamine, 0.74 g (5.36 mmol) of anhydrous potassium carbonate and 0.10 g of copper iodide (0.536 mmol) are mixed in a 50 m1 round-bottom flask. 15 m1 of propanol, 0.01 g (0.2 mmol) of polyethylene glycol and 0.43 g (2.95 mmol) of f1uorothiophenol are then added. The reaction mixture is heated at 80°C for 2 hours. The solvent is evaporated and the solid formed is filtered, rinsed with water and then with pentane and dried in an oven at 50°C to yield 0.75 g (100%) of 5-(3,5-difluropheny1thio)-1H-pyrazolo[3,4-b]pyrazinamine in the form of a brown solid.

LCMS (E1, m/z): (M+1) 280.03. 1H NMR: 6H ppm (400 MHz, DMSO): 12.65 (1H, bs, NH), 8.52 (1H, s, CHarom), 7.18 (1H, t, CHarom), 7.05-7.18 (2H, m, CHarom), 5.89 (2H, s, NH).

WO 01239 The following derivatives were obtained according to the same method: N'Rs Ar 3 T’mr f‘hY1 Y / 3Y4 N 2-1 [SE I_-- 2-(3-amino-1H- CH, CH, N H H pyrazolo[3,4-b]pyridin ylthio)benzamide E -QQ4> N—(5-(3,5- dimethylphenylthio)-1H- pyrazolo[3 ,4-b]pyridin-3 - CH, CH,N H H yl)(4-methy1piperazin- H 1-y1)(tetrahydro-2H- pyran ylamino)benzamide “Q“ 5-(3 , 5- CH, CH, N H H difluorophenylthio)- 1H- pyrazolo[3 ,4-b]pyridin-3 - amine Q III 5-(2. 5- CH, C- dichlorophenylthio) OMe, N methoxy- 1H-pyrazolo[3,4- Q b]pyridin-3 -amine III 5-(2. 5- CH, C-NHZ, I{I H dichlorophenylthio)-1H- pyrazolo[3 ,4-b]pyridine- 3 ,6-diamine 1 -ZerZ-buty1(3 5- CH, CH, N H tBu difluorobenzylthio)- 1H- pyrazolo[3 ,4-b]pyridin-3 - amine IIIN 5-(3 , 5- CH, CMe, difluorophenylthio) -1H-pyrazolo[3 ,4- din-3 -amine I” 5-(3 , 5- difluorophenylthio) methoxy- 1H-pyrazolo[3 ,4- b]pyridin-3 -amine -flfl--Illflfllflfl F 1-ZerZ-buty1-5 -(3 , 5 - 14_9 D] H CH, CH, N H tBu difluorophenylthio)-1H- F pyrazolo[3,4-b]pyridin amme N-(5-(2.5- CI dichlorophenylthio)-1H- pyrazolo[3,4-b]pyridin ”'10 $1 CH: CH: N H H yl)(4-methy1piperazin- CI 1-y1)(tetrahydro-2H- pyran y1amino)benzamide N-(6-amino(3,5- ophenylthio)- 1H- CH, C-NHg, pyrazolo[3,4-b]pyridin 14'” D] H H yl)(4-methy1piperazin- F 1-y1)(tetrahydro-2H- pyran y1amino)benzamide ** 1H NMR, DMSO-d6, EX.: 14.3; 12.65 (1H, bs, NH), 8.52 (1H, s, , 7.18 (1H, t, CHarom), 7.05-7.18 (2H, m, , 5.89 (2H, s, NH). 14-6: 8.21 (2H, bs, CHamm), 7.07 (1H, m, CHamm), 6.90 (2H, m, CHamm), 6.27 (2H, bs, NH), 4.03 (2H, s, CH), 1.63 (9H, s, CH). 147 12.16 (1H, bs, NH), 8.39 (1H, s, CHamm), 7.00-7.08 (1H, m, CHamm), 6.64- 6.72 (2H, m, CHamm), 5.73 (2H, bs, NHZ), 2.54 (3H, s, CH3). 14-9: 8.51 (1H, bs, CHarom), 8.35 (1H, bs, CHamm), 7.02 (1H, m, CHamm), 6.72 (2H, bs, CHamm), 6.52 (2H, bs, NH), 1.67 (9H, s, CH). (ND: not determined).

Example 14bis: N-(5-(3,5—diflu0r0phenylamin0)-1H-pyrazolo[3,4-b]pyridinyl)—4- (4-methylpiperazinyl)—2-(tetrahydr0-2H-pyranylamin0)benzamide.

H HN F N | N N/ N F N’» A solution of 225 mg of N-(5-iodotrity1—1H-pyrazolo[3,4-b]pyridiny1)- 4-(4-methy1piperaziny1)(tetrahydro-2H-pyrany1amino)benzamide (0.25 mmol), 36 mg of difluoroaniline (0.275 mmol), 19 mg of R-(+)-2,2’-bis(dipheny1phosphino)- inaphty1e (0.030 mmol), 11 mg (0.013 mmol) of tris(dibenzylideneacetone) dipalladium(0) and 75 mg (0.75 mmol) of sodium tert-butoxide in 10 mL of THF is refluxed under argon ght. The crude reaction medium is cooled, extracted with ethyl acetate and washed with water. The organic phase is dried on magnesium sulfate and purified by silica gel chromatography to yield N—(S-(3,5-difluorophenylamino)-l- trityl- lH-pyrazolo [3 yridin-3 -yl)(4-methylpiperazin- l -yl)(tetrahydro-2H- pyranylamino)benzamide which is used in the following step without further purification.

The product thus obtained is dissolved in 10 mL of dichloromethane at 0°C and 56 mg (0.5 mmol) of TFA is added. The reaction medium is stirred for 4 hours. Water is added and the pH of the reaction medium is adjusted to 7 with a NaHC03 solution. The aqueous phase is collected, basif1ed (pH 9-10) with a concentrated K2C03 solution and extracted with dichloromethane. The organic phase is collected, dried on magnesium sulfate and dry ccentrated to yield 40 mg of N—(S-(3,5-difluorophenylamino)-lH- pyrazolo [3 ,4-b]pyridin-3 -yl)(4-methylpiperazin- l -yl)(tetrahydro-2H-pyran ylamino)benzamide.

LCMS (IE, m/z): (M+1) 562.12. 1H NMR: 6H ppm (400 MHz, DMSO): 13,45 (1H, sl, NH), 10,47 (1H, sl, NH), 8,65 (1H, s, CHamm), 8,55 (1H, s, CHamm), 8,14 (1H, d, NH), 7,77 (1H, d, CHamm), 7,26 (2H, m, , 7,05 (1H, m, CHamm), 6,25 (1H, d, CHamm), 6,14 (1H, s, NH), 6,77 (1H, s, NH), 3,82-3,84 (2H, dt, CH), 3,72 (1H, m, CH), 3,47—3,52 (2H, m, CH), 3,28-3,34 (4H, m, CH), 2,43 (4H, m, CH), 2,23 (3H, s, CH3), 1,94 —1,97 (2H, m, CH), ,39 (2H, m, CH).

Examples of method D3: Example 15: N-(S-((3,5-difluorophenyl)ethynyl)—1H-pyrazolo[3,4-b]pyridinyl)—4- (4-methylpiperazinyl)—2-(tetrahydr0-2H-pyranylamin0)benzamide 0.94 mg (0.926 mmol) of triethylamine is added to 400 mg (0.712 mmol) of N—(5-iodo- 1H-pyrazolo [3 ,4-b]pyridin-3 -yl)(4-methylpiperazinyl)(tetrahydro-2H-pyran ylamino)benzamide, 67.8 mg (0.356 mmol) of CuI, and 50 mg (0.071 mmol) of 3)2C12 under argon in 12 ml of anhydrous dioxane under stirring. The reaction is heated for 3.5 hours at 100°C. The reaction mixture is diluted with 30 ml of water and extracted with ethyl e. The organic phase is dried on sodium sulfate, filtered and concentrated. The residue obtained is purified by silica gel chromatography (dichloromethane/methanol) to yield 152 mg of N-(5-((3,5-difluorophenyl)ethynyl)-1H- pyrazolo [3 ,4-b]pyridin-3 -yl)(4-methylpiperazinyl)(tetrahydro-2H-pyran ylamino)benzamide in the form of a yellow solid (yield=3 7%).

LCMS (E1, m/z): (M+1) 572.17. 1H NMR: 6prm (400MHz, DMSO): 13.57 (1H, bs, NH), 10.56 (1H, bs, NH), 8.68 (1H, s, CHarom), 8.43 (1H, s, CHarom), 8.13 (1H, d, NH), 7.80 (1H, d, ), 7.38 (2H, m, CHarom), 6.27 (1H, d, CHarom), 6.15 (1H, d, CHarom), 3.84-3.82 (2H, dt, CH), 3.70 (1H, m, CH), 3.45—3.50 (2H, m, CH), 3.21—3.33 (4H, m, CH), 2.42-2.46 (4H, m, CH), 2.28 (3H, s, CH3), 1.94—1.97 (2H, m, CH), 1.37—1.39 (2H, m, CH).

The ing derivative was ed according to the same method: -((3 5 -difluorophenyl)ethynyl)- 1H- pyrazolo[3,4-b]pyrazin-3 -amine ** HNMR, dmsod6, EX.: 15.1: 12.71 (1H, sl, NH), 8.66 (1H, s,CHarom), 7.407.47 (3H, m, CHarom), 6.01 (2H, sl, NHg).

Examples of method E The protocols comprising method E aim at functionalizing the exocyclic amine of the aminopyrazole rings by their reaction with an intermediate featuring an electrophilic function, optionally generated in situ, such as acid chloride, isocyanate, isothiocyanate or aldehyde. ation of the reaction intermediates Example 16: 2-(N-(4,4-diflu0r0cyclohexyl)—2,2,2—triflu0roacetamid0)(4-methyl piperazin-l-yl)benz0ic acid o 037 r} a.FN Example 16a: tert-butyl 4-(4-methylpiperazinyl)—2-nitr0benz0ate This compound was usly described in WC 2008/74749. 5.28 ml (47.6 mmol) of 1-methylpiperazine is added to 4.1 g (17 mmol) of ZerZ-butyl 4- 2-nitrobenzoate. The reaction mixture is stirred without solvent for 5 hours. 150 ml of water is added to the reaction mixture and it is stirred for 24 hours. The precipitate formed is filtered, rinsed with water and dried under vacuum to yield 4.9 g (90%) of lerl—butyl 4-(4-methylpiperazinyl)nitrobenzoate in the form of a yellow solid.

LCMS (E1, m/z): (M+1) 322.37. 1H NMR: 5H ppm (400 MHz, DMSO): 7.69 (1H, d, CHamm), 7.30 (1H, d, CHarom), 7.20 (1H, dd, ), 3.38 (4H, m, CH), 2.40 (4H, m, CH), 2.22 (3H, s, CH3), 1.45 (9H, s, CH3).

Example 16b: tert-butyl 0(4-methylpiperazinyl)benz0ate This compound was previously described in WC 2008/74749. 0.160g (1.500 mmol) of ium on carbon (10%) and 15.19 ml (150 mmol) of cyclohexene are added to a solution of 4.82g (15 mmol) of lerl—butyl 4-(4- WO 01239 methylpiperazinyl)nitrobenzoate in 100 ml of ethanol. The reaction mixture is heated at a ature of 80°C for 8 hours. The reaction mixture is filtered and then rinsed with ethanol to yield 4.2 g (yield=96%) of lerl—butyl 2-amino(4- methylpiperazinyl)benzoate in the form of a yellow solid.

LCMS (E1, m/z): (M+1) 292.39. 1H NMR: 6H ppm (400 MHz, DMSO): 7.44 (1H, d, CHamm), 6.40 (2H, bs, NHZ), 6.19 (1H, dd, CHamm), 6.12 (1H, d, CHamm), 3.17 (4H, m, CH), 2.40 (4H, m, CH), 2.22 (3H, s, CH3), 1.49 (9H, s, CH3).

Example 16c: tert-butyl 2-(4,4-diflu0r0cyclohexylamin0)(4—methylpiperazin yl)benz0ate 1.045 ml (13 .5 7 mmol) of trifluoroacetic acid, 1 g (7.46 mmol) of 4,4- difiuorocyclohexanone and 2.158 g (8.20 mmol) of ethylammonium triacetoxyborohydride are added to 1.521 g (5.22 mmol) of lerl—butyl 2-amino(4- methylpiperazinyl)benzoate dissolved in 60 ml of dichloromethane. The reaction is left under stirring at room temperature for 24 hours. The solvent is evaporated and then the crude reaction product is redissolved in 30 ml of ethyl acetate. The solution is successively washed with 0.5 M HCl on, 0.5 M soda solution and finally with saturated NaHC03 on. The organic phase is dried on sodium sulfate, d and concentrated to obtain 2.2 g of ZerZ-butyl 2-(4,4-difiuorocyclohexylamino)(4- methylpiperazinyl)benzoate in the form of a light brown gum (yield=72%).

LCMS (E1, m/z): (M+1) 410.3. 1H NMR: 6H ppm (400 MHz, DMSO): 7.73 (1H, bs, NH), 7.58 (1H, m, CHamm), 7.77 (1H, m, CHamm), 6.09 (1H, bs, CHamm), 3.37 (4H, m, CH), 3.27 (4H, m, CH), 2.47 (4H, m, CH), 2.25 (3H, s, CH), 1.99 (4H, s, CH), 1.40 (9H, s, CH). e 16d: tert-butyl 2-(N-(4,4-difluorocyclohexyl)—2,2,2-trifluoroacetamid0) (4-methylpiperazinyl)benz0ate 0.99 ml (6.98 mmol) of trifluoroacetic ide and 1.12 ml (8.06 mmol) of triethylamine are added to 2.2 g (5.3 mmo l ) o f lerl—butyl 2-(4,4- difiuorocyclohexylamino)(4-methylpiperazinyl)benzoate dissolved in 40 ml of dichloromethane. The reaction is left under stirring at room temperature for 3 hours.

The solvent is evaporated and then the crude reaction product is taken up in 30 ml of ethyl acetate. The solution is washed with saturated NaHC03 solution. The organic WO 01239 phase is dried on sodium sulfate, filtered and concentrated to obtain 2.5 g of lerl—butyl 2-(N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamido)(4-methylpiperazinyl) benzoate in the form of a light brown gum (yield=92%).

LCMS (E1, m/z): (M+1) 506.26. 1H NMR: 5H ppm (400 MHz, DMSO): 7.84 (1H, In, CHamm), 7.09(lH, m, CHarom), 6.89 (1H, bs, CHamm), 3.45-3.39 (8H, m, CH), 2.83 (4H, m, CH), 2.20 (4H, m, CH), 2.05 (3H, s, CH), 1.46 (9H, s, CH).

Example 16: 2-(N-(4,4-diflu0r0cyclohexyl)—2,2,2—triflu0roacetamid0)(4-methyl zin-l-yl)benz0ic acid 7.62 ml (99 mmol) of trifluoroacetic acid is added to 2.5 g (4.95 mmol) of ZerZ-butyl 2- (N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamido)(4-methylpiperazinyl) benzoate dissolved in 30 ml of dichloromethane. The reaction is left under stirring at room temperature overnight. The solvent is evaporated and then the crude reaction t is redissolved in 30 ml of ethyl acetate. The solvents are evaporated, the solid formed is redissolved in ethyl ether and the solvent is evaporated again. This operation is repeated three times until a light brown solid is obtained. 2.2 g of 2-(N-(4,4- ocyclohexyl)-2,2,2-trifluoroacetamido)(4-methylpiperazinyl)b enzoi c acid in the form of a trifluoroacetic salt is obtained (yield=79%).

LCMS (E1, m/z): (M+1) 450.1. 1H NMR: 6H ppm (400 MHz, DMSO): 10.01 (1H, bs, OH), 7.92 (1H, m, CHamm), 7.13 (1H, m, CHamm), 7.01 (1H, bs, CHamm), 4.39 (1H, m, CH), 3.12—3.52 (8H, m, CH), 2.86 (3H, s, CH), 17520 (8H, m, CH).

The following compounds are also obtained by this method: 4-(4-methylpiperazinyl)—2-(2,2,2—triflu0ro-N-(tetrahydr0-2H-pyranyl) id0)benz0ic acid.

This compound was previously described in , and WO 2010/69966.

LCMS (EI, m/z): (M+1) 416.40. 1H NMR: 6H ppm (400 MHz, DMSO): 12.60 (1H, bs, OH), 10.08 (1H, bs, OH), 7.90 (1H, d, CHarom), 7.13 (1H, dd, CHarom), 6.90 (1H, d, CHarom), 4.40 (1H, m, CH), 4.10 (2H, m, CH), 3.70-3.90 (2H, m, CH), 3.59-3.62 (4H, m, CH), 3.30-3.32 (4H, m, CH), 2.87 (3H, s, CH3), 1.87-1.98 (1H, m, CH), 1.59-1.60 (1H, m, CH), 1.00-1.54 (2H, m, CH). 4-((3-(dimethylamin0)pr0pyl)(methyl)amino)—2-(2,2,2—triflu0ro-N-(tetrahydro-ZH- pyranyl)acetamid0)benz0ic acid.

This nd was previously described in and . e 17: (S)—2-(2,2,2—trifluoro-N-(tetrahydro-2H-pyranyl)acetamid0)—4-(3— (2,2,2—trifluoroacetamido)pyrrolidinyl)benz0ic acid (3;ng F F Example 17a: tert-butyl (S)(3-(tert-butoxycarb0nylamin0)pyrrolidinyl)—2- hydro-ZH-pyran-4ylamin0)benz0ate This compound was obtained by reproducing example 16d using lerl—butyl (S)- pyrrolidinylcarbamate.

Example 17b: (S)—4-(3-aminopyrrolidinyl)—2-(tetrahydr0-2H-pyranylamin0) benzoic acid 19.7 ml (25 eq) of trifluoroacetic acid is added to a solution of 4.72 g (10.23 mmol) of lerl—butyl (S)(3 -(ZerZ-butoxycarbonylamino)pyrrolidinyl)(tetrahydro-2H-pyran- ino)benzoate in 100 ml of dichloromethane. The reaction medium is stirred at room temperature for 30 hours. The solvents are evaporated and the residue is redissolved in diethyl ether and triturated until a solid is obtained. The solid formed is filtered and dried under vacuum to yield 4.3 g (100%) of a yellow powder of (S)—4-(3- aminopyrrolidinyl)(tetrahydro-2H-pyranylamino)benzoic acid in the form of a trifluoroacetic acid salt.

LCMS (E1, m/z): (M+1) 306.22.

Example 17 : (2,2,2—trifluoro-N-(tetrahydro-2H-pyranyl)acetamid0)—4-(3— (2,2,2—trifluoroacetamido)pyrrolidinyl)benz0ic acid 1.74 ml (3.5 eq) of ylamine and 1.6 ml (2.1 eq) of trifluoroacetic anhydride are added to a solution of 1.5 g (3.58 mmol) of (S)(3-aminopyrrolidinyl) (tetrahydro-2H-pyranylamino)benzoic acid in the form of a trifluoroacetic acid salt in 40 ml of dichloromethane at 0°C. The on medium is stirred at room temperature for 24 hours. Water (10 ml) is added drop by drop and then the organic phase is washed with ted sodium chloride solution, dried on magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (96:4 dichloromethane/methanol as eluent) to yield 250 mg (14%) of (S)(2,2,2-trifluoro-N— (tetrahydro-2H-pyranyl)acetamido)(3 -(2,2,2-trifluoroacetamido)pyrrolidinyl) benzoic acid in the form of a yellow powder.

LCMS (E1, m/z): (M+1) 498.07.

Example 18: u0r0eth0xy)—4-(4-methylpiperazinyl)benz0ic acid This compound can be prepared from the following intermediates. e 18a: tert-butyl 4-fluoro(2-flu0r0ethoxy)benz0ate Example 18b: tert-butyl 2-(2-flu0r0eth0xy)—4-(4-methylpiperazinyl)benz0ate The following compound was also obtained by this method: 2-(2-flu0r0ethoxy)—4-(4-(1-methylpiperidinyl)piperazinyl)benz0ic acid. 2O Example 19: 4-(4-methylpiperazinyl)(2,2,2—triflu0r0-N-(2-flu0r0ethyl)— acetamido)—benz0ic acid This compound can be prepared from the following intermediates.

Example 19a: tert-butyl 4-fluoro(2-flu0r0ethylamin0)benz0ate Example 19b: tert-butyl 4-fluoro(2,2,2-trifluoro-N-(Z-fluoroethyl)acetamid0) benzoate Example 19c: tert-butyl 4-(4—methylpiperazinyl)(2,2,2-triflu0r0-N-(2- fluor0ethyl)-acetamido)—benz0ate The following compound was also obtained by this : 3O 4-((3-(dimethylamin0)pr0pyl)(methyl)amino)—2-(2,2,2—triflu0ro-N-(Z-fluoroethyl) acetamid0)benz0ic acid.

Example 20: 4-(1-methylpiperidinyl)—2-(2,2,2—trifluoro-N-(tetrahydro-ZH- pyranyl)acetamid0)benz0ic acid rifloroacetate FFgLN N CF3COOH This compound can be prepared from the following intermediates.

Example 20a: tert-butyl 2-nitr0(pyridinyl)benz0ate 1.67 g of bis(triphenylphosphine)palladium(II)chloride (2.38 mmol) and 15.8 g of sodium carbonate (149 mmol) are added to a solution of 18 g of tert-butyl 4-bromo nitrobenzoate (59.6 mmol) and 10.98 g of neylboronic acid (89 mmol) in a mixture of 200 ml of dimethoxyethane and 100 mL of water. The reaction medium is heated at 100°C for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CH2Clz/ACOEtI 100:0 to 70:30, 30 min).

The product is isolated in the form of an oil which crystallizes to yield 14.64 g (82%) of crystals.

MS (m/z): (M+1) 301.0. 1H NMR: 6H ppm (400 MHz, DMSO): 8.73 (2H, d, CHarom, J=6.0Hz), 8.44 (1H, s, CHarom), 8.24 (1H, dd, CHarom, J=8.0Hz), 7.97 (1H, d, CHarom, J=8.0Hz), 7.85 (2H, dd, CHarom, z), 1.54 (9H, s).

Example 20b: 4-(4-(tert-butoxycarb0nyl)nitr0phenyl)—1-methylpyridinium iodide 7.55 mL od iodomethane (121 mmol) is added to a on of 16.2 g of tert-butyl 2- nitro(pyridinyl)benzoate (60.6 mmol) in 20 mL of acetone. The reaction medium is heated at 60°C for 4 hours and then at room temperature ght. After dry concentration, 27 g of orange crystals are isolated (100%).

MS (m/z): (M+1) 315.0. 1H NMR: 6H ppm (400 MHz, DMSO): 9.14 (2H, d, CHarom, J=6.4Hz), 8.71 (1H, s, CHarom), 8.63 (2H, d, CHarom, J=6.4Hz), 8.47 (1H, dd, CHarom, J=8.0Hz), 8.08 (1H, d, CHarom, J=8.0Hz), 4.37 (3H, s, CH), 1.54 (9H, s).

WO 01239 Example 20c: tert-butyl 2-amin0(1-methylpiperidinyl)benz0ate 0.48 g of platine (IV) oxide (2.12 mmol) is added to a solution of 26.8 g of 4-(4-(tert- butoxycarbonyl)nitrophenyl)methylpyridinium iodide (60.6 mmol) in 200 mL of methanol placed in a reactor made in stainless steel. The reaction medium is brought under 5 bar of hydrogen for 24h. The catalyst is filtered and the filtrate is concentrated under reduced pressure to yield 24.8 g (98%) of white crystals.

MS (m/z): (M+1) 291.1. 1H NMR: 5H ppm (400 MHz, DMSO): 9.18 (1H, s, HI), 7.60 (1H, d, CHarom, J=8.4Hz), 6.54-6.40 (3H, m, CHarom), 6.39 (1H, d, CHarom, J=8.0Hz), .53 (2H, m, CH), 3.06 (2H, t, CH), 2.81 (3H, s, CH), 2.60-2.70 (1H, m, CH), 1.89-1.97 (2H, m, CH), 1.70-1.80 (2H, m, CH), 1.52 (9H, s).

Example 20d: tert-butyl 4-(1-methylpiperidinyl)—2-(tetrahydro-ZH-pyran ylamino)benz0ate 7.18 mL of 2,2,2-trifluoroacetic acid (93 mmol), 4.11 mg of dihydro-2H-pyran-4(3H)- one (44.5 mmol) and then 14.5 g of tetramethylammonium triacetoxyborohydride (53.8 mmol) are successively added to a solution of 15 g of tert-butyl 2-amino(1- methylpiperidinyl)benzoate in 200 mL of dichloromethane under stirring. The reaction medium is d at room temperature for 2 h and then taklen up with a 1N soda solution. The organic phase is isolated, dried on magnesium sulfate and then dried 2O trated. The residue contained always HI. It is thus taken up in dichloromethane and washed with 100 mL of a 1H soda solution. The organic phase is decanted, dried on magnesium sulfate and dry trated to yield 14.6 g of a yellow solid (quantitative yield).

MS (m/z): (M+1) 375.2. 1H NMR: 6H ppm (400 MHz, DMSO): 7.69 (1H, d, CHarom, J=8.4Hz), 7.63 (1H, d, CHarom, J=7.6Hz), 6.65 (1H, s, CHarom), 6.44 (1H, dd, CHarom, z), 3.74-3.86 (2H, m, CH), .71 (1H, m, CH), 3.51 (2H, t, CH), 3.05-3.12(2H, m, CH), 2.6-2.5 (1H, m, CH), 2.42 (3H, s, CH), 2.30—2.40 (2H, m, CH), 1.89-1.97 (2H, m, CH), 1.64- 1.77 (4H, m, CH), 1.52 (9H, s), 1.33—1.45 (2H, m, CH). 3O Example 20c: utyl 4-(1-methylpiperidinyl)—2-(2,2,2-triflu0ro-N- (tetrahydr0-2H-pyranyl)acetamid0)benz0ate 6.35 mL of triethylamine and 5.50 mL of 2,2,2-trifluoroacetic ide (39.6 mmol) are added at 0°C to a solution of 11.4 g of tert-butyl 4-(1-methylpiperidinyl) (tetrahydro-2H-pyranylamino)benzoate (30.4 mmol) in 240 mL of dichloromethane under stirring. The reaction medium is stirred at room temperature for 1h and then 100 mL of water is added dropwise. The c phase is decanted, dried on magnesium sulfate and dry concentrated. The residue is taken up in a mixture of ethanol/diethyl ether to yield a solid which is filtered on a fritted disc and 12.06 g of white crystals is isolated. The filtrate is concentrated (4.5g) and then purified by flach tography on silica (CHgClg/meOH: 95:5 to 90: 10, 20 min). The product obtained is recrysltallized in diethyl ether to yield 1.04 g of additional white ls (global yield = 74%).

MS (m/z): (M+1) 471.1. 1H NMR: 5H ppm (400 MHz, DMSO): 9.45 (1H, sl, NH+), 7. 96 (1H, d, CHarom, J=8Hz), 7.51 (1H, d, CHarom, J=8Hz), 7.31 (1H, s, CHarom), 5 (1H, m, CH), 3. 90—375 (2H, m, CH), 353.35 (4H, m, CH), 3.1-2.85 (3H, m, CH), 2.79 (3H, s, CH3), 2.11% (3H, 3, CH), 191.75 (2H, m, CH), 1.55—1.40 (11H, m), 1.0-0.85 (1H, m, CH).

Example 20: 4-(1-methylpiperidinyl)—2-(2,2,2—trifluoro-N-(tetrahydro-ZH- pyranyl)acetamid0)benz0ic acid hydrotrifluoroacetate. 6.33 mL of 2,2,2-trifluoroacetic acid (82 mmol) is added under stirring to a solution of 3.2 g of tert-butyl 4-(1-methylpiperidinyl)(2,2,2-trifluoro-N—(tetrahydro-2H- pyranyl)acetamido)benzoate (5.47 mmol) (in the form of a salt of trifiuoroacetic acid) in 30 mL of dichloromethane. The reaction medium is stirred at room temperature for 16h, and then evaporated under reduced pressure. The e is taken up in ethanol, and the white solid formed is filtered on a fritted disc to yield 1.61 g (53%) of white crystals.

MS (m/z): (M+1) 415.1. 1H NMR: 6H ppm (400 MHz, DMSO): 13.39 (1H, sl, COOH), 9.46 (1H, sl, COOH du TFA), 7.99 (1H, d, CHarom, z), 7.49 (1H, d, CHarom, J=8.4Hz), 7.30 (1H, s, CHarom), 4.53 (1H, m, CH), 3.74-3.86 (2H, m, CH), 3.35—3.45 (5H, m, CH), 2.90—3.01 (3H, m, CH), 2.76 (3H, s, CH), 1.65-2.04 (5H, m, CH), .54 (2H, m, CH).

Example 21: 1-(4—is0thi0cyanatophenyl)methylpiperazine This compound was prepared by adapting the method described in EP1215208.

The following compound was also ed by this : utyl 2-isothi0cyanato—5-(4-methylpiperazinyl)phenylcarbamate.

Example 22: tert-butyl 2-isocyanato—S-(4—methylpiperazinyl)phenylcarbamate This compound can be prepared from the following intermediates.

Example 22a: tert-butyl 5-(4-methylpiperazinyl)—2-nitr0phenylcarbamate Example 22b: tert-butyl 2-amin0(4-methylpiperazinyl)phenylcarbamate Example 22: tert-butyl 2-isocyanato—S-(4—methylpiperazinyl)phenylcarbamate Example 23: 4-(4—methylpiperazinyl)—2-(tetrahydr0-2H-pyranylamin0) benzaldehyde o H (5 OHN Example 23a: methylpiperazinyl)—2-(tetrahydr0-2H-pyranylamino) phenyl)methanol 500 mg (1.060 mmol) of 4-(4-methylpiperazineyl)(2,2,2-trifluoro-N—(tetrahydro- 2H-pyranyl)acetamido)benzoic acid dissolved in 5 ml of tetrahydrofuran is added at 0°C to a suspension of 201 mg (5.30 mmol) of LiAlH4 in 9 ml of tetrahydrofuran. The reaction mixture is stirred at 0°C for 1 hour and then at room temperature for 3 hours.

The reaction mixture is cooled at 0°C and then, drop by drop, 200 pl water, then 200 pl of soda solution (15% by weight) and finally 1 ml of water are added. The reaction mixture is stirred at room ature for 2 hours and then filtered and rinsed with tetrahydrofuran. The filtrate is concentrated to yield 250 mg (yield=77%) of (4-(4- methylpiperazineyl)(tetrahydro-2H-pyranylamino)phenyl)methanol in the form of a white solid.

LCMS (E1, m/z): (M+1) 306.14. 1H NMR: 6prm (400 MHz, DMSO): 6.85 (1H, d, CHamm), 6.20 (1H, d, CHamm), 6.10 (1H, d, CHamm), 4.95 (1H, bs, OH), 4.87 (1H, d, NH), 4.37 (2H, d, CH2), 3.83-3.86 (2H, m, CH), 3.56 (1H, m, CH), 3.46-3.56 (3H, m, CH), 3.45 (1H, m, CH), 3.05—3.07 (4H, m, CH), 2.41—2.44 (4H, m, CH), 2.21 (3H, s, CH3), 1.89-1.92 (2H, m, CH). e 23: 4-(4—methylpiperazinyl)—2-(tetrahydr0-2H-pyranylamin0) benzaldehyde 85 mg (0.982 mmol) of manganese dioxide is added at room ature to a solution of (4-(4-methylpiperazine- l -yl)(tetrahydro-2H-pyranylamino)phenyl)methanol (100 mg, 0.327 mmol) in a mixture of ethyl acetate (10 ml) and dichloromethane (9 ml).

The reaction mixture is placed in an ultrasonic bath for 5 hours. The reaction mixture is filtered, the solvents are evaporated and the crude product is purified by chromatography to yield 50.0 mg (yield=50.3%) of (4-(4-methylpiperazineyl)—2- (tetrahydro-2H-pyranylamino)benzaldehyde in the form of a white solid.

LCMS (E1, m/z): (M+1) 304.19. 1H NMR: sprm (400 MHz, DMSO): 9.43 (1H, d, CH), 7.32 (1H, d, CHamm), 6.36 (1H, d, CHamm), 6.08 (1H, d, CHamm), 3.94-3.99 (2H, m, CH), 3.77 (1H, m, CH), .63 (2H, m, CH), 3.42—3.45 (4H, m, CH), 2.57-2.60 (4H, m, CH), 2.36 (3H, s, CH3), 2.04— 2.08 (2H, m, CH), 1.51-1.60 (2H, m, CH).

Example 24: 2-(4—(4-methylpiperazinyl)phenyl)acetic acid COOH '1“ Example 24a: 2,2,2-trichlor0(4-(4-methylpiperazinyl)phenyl)ethanol 1.0 ml (10.00 mmol) of trichloroacetic acid and, in small ns, 1.854 g (10 mmol) of sodium 2,2,2-trichloroacetate are added at room temperature to a solution of 1.362 g (6.67 mmol) of 4-(4-methylpiperazine-l-yl)benzaldehyde in 13.5 m l o f dimethylformamide. The reaction mixture is stirred for 3 hours at room temperature.

The solvent is concentrated and the crude reaction product extracted with ethyl e.

The organic phase is washed using saturated sodium bicarbonate on. The organic phases are combined, dried on magnesium sulfate and then concentrated to yield 2012/051283 1.760 g (yield=82%) of 2,2,2-trichloro(4-(4-methylpiperazineyl)phenyl)ethanol in the form of a white solid.

LCMS (E1, m/z): (M+1) 324.04. 1H NMR: 5H 7.41 (2H, d, CHamm), 7.02 (1H, bs, OH), 6.90 (2H, ppm (400 MHz, DMSO): d, CHarom), 5.08 (1H, bs, CH), 3.14-3.16 (4H, m, CH), 2.42-2.47 (4H, m, CH), 2.21 (3H, s, CH3).

Example 24: 2-(4-(4-methylpiperazinyl)phenyl)acetic acid 0.559 g (14.77 mmol) of sodium borohydride is added y to 2.294 g (7.35 mmol) of dibenzyl diselenide in 28 ml of ethanol. The reaction e is stirred at room temperature for 1 hour. 2.266 g (7 mmol) of 2,2,2-trichloro(4-(4-methylpiperazine yl)phenyl)ethanol and 1.680 g (42.0 mmol) of sodium hydroxide are then added. The reaction mixture is stirred at 35°C for 24 hours. The solvent is concentrated and the crude product extracted with ethyl acetate after adding a pH 5 aqueous phase. The organic phases are combined, dried on magnesium sulfate and then concentrated to yield 2-(4-(4-methylpiperazineyl)phenyl)acetic acid which is used without additional purification.

LCMS (E1, m/z): (M+1) 235.294.

Example 25: 2-(4-(4-methylpiperazinyl)—2-nitrophenyl) acetic acid This compound can be ed from the ing intermediates.

Example 25a: diethyl 2-(4-fluoro-Z-nitrophenyl)malonate Example 25b: diethyl 2-(4-(4-methylpiperazinyl)—2-nitr0phenyl)malonate Example of method E1: Example 26: N-(S-(3,5—diflu0r0phenylthi0)-1H-pyrazolo[3,4-b]pyridinyl)—4-(4- methylpiperazinyl)—2-(2,2,2—triflu0ro-N-(tetrahydro-ZH-pyranyl) acetamid0)benzamide ONJS< F F F O|,N N F Q 0.95 ml (11.21 mmol) of oxalyl de and 2 drops of anhydrous dimethylformamide are added to 2.97 g (5.61 mmol) of a solution of 4-(4-methylpiperazinyl)(2,2,2- trifluoro-N—(tetrahydro-2H-pyranyl)acetamido)benzoic acid in 95 m l o f dichloromethane. The reaction mixture is stirred for 2 hours at room temperature. The solvents are evaporated, the solid formed is taken up in toluene and the t evaporated. This operation is repeated three times until a white solid is obtained. The acid chloride is dissolved in 35 ml of anhydrous tetrahydrofuran at -20°C and then the solution formed is added to a solution containing 1.56 g (5.61 mmol) of 5-(3,5- difluorophenylthio)-1H-pyrazolo[3,4-b]pyridinamine and 3.71 ml (21.30 mmol) of N—ethyl-N—isopropylpropanamine in 30 ml of anhydrous tetrahydrofuran. The reaction mixture is d for 3 hours at -20°C and then overnight at room temperature.

The precipitate obtained is filtered and rinsed with tetrahydrofuran and water and then dried to yield 2 g (53%) of N—(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin (4-methylpiperazinyl)(2,2,2-trifluoro-N—(tetrahydro-2H-pyran yl)acetamido)benzamide.

LCMS (E1, m/z): (M+1) 676.20. 1H NMR: 6H ppm (400 MHz, DMSO): 13.66 (1H, bs, NH), 11.08 (1H, bs, NH), 8.61 (1H, S,CHa1‘om), 8.46 (1H, s, CHamm), 7.83 (1H, d, CHarom), 7.05—7.10 (2H, m, CHamm), 2O 6.83-6.89 (3H, m, CHamm), 4.39-4.44 (1H, m, CH), .85 (1H, m, CH), 3.69-3.72 (1H, m, CH), 3.59-3.62 (1H, m, CH), 3.30—3.32 (4H, m, CH2), 2.30—2.44 (4H, m, CH2), 2.27 (3H, s, CH3), 1.87-1.90 (1H, m, CH), 1.59-1.60 (1H, m, CH), 1.49—1.50 (1H, m, CH), 1.20—1.40 (1H, m, CH).

The following derivatives were obtained according to the same method: <<-<I—\/L E 5 Z Mass MH+ N-(5-(2-carbamoy1phenylthio)- 1H- pyrazolo [3 ,4-b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 rophenylsulfonyl)- lH-pyrazolo [3 ,4-b]pyridin—3 -y1) (4-methy1piperaziny1) (tetrahydro-ZH-pyran—4- o)benzamide N-(5-iodo- lH-pyrazolo [3 ,4- b]pyridin-3 -y1)(4-methy1piperazin- 1-y1)(2,2,2-trifluoro-N— (tetrahydro-ZH-pyran—4- y1)acetamido)benzamide N-(5-(3,5-difluorophenylthio)-1H- pyrazolo[3,4-b]pyridin—3 -y1)(4- nitrophenyDacetamide N-(5 -(3 ,5 -difluorobenzylsulfonyl)- lH-pyrazolo [3 ,4-b]pyridin—3 -y1) (4-methy1piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide 2-(N-(4,4-difluorocyclohexyl)-2,2,2- roacetamido)-N-(5 -(3 , 5 - difluorophenylsulfonyl)- 1H- pyrazolo [3 ,4-b]pyridin—3 -y1)(4- piperaziny1)benzamide N-(5 -(3 ,5 -difluorobenzy1)-1H- pyrazolo [3 ,4-b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide [L N-(5-(3,5-difluorophenylthio)-1H- H E j 1 H H CH, N lo[3,4-b]pyr1d1n-.3-y1)(4-(4- methylplperazm-l- [ yl)pheny1)acetamide N-(5-iodomethoxy-1H- lo [3 ,4-b]pyridin—3 -y1)(4- piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide minoiodo- lH-pyrazolo [3 ,4- b]pyridin-3 -y1)(4-methy1piperazin- 1-y1)(2,2,2-trifluoro-N— (tetrahydro-ZH-pyran—4- y1)acetamido)benzamide (S)-N-(5 -(3 , 5 -difluorophenylthio)- lH-pyrazolo [3 yridin—3 -y1) (2,2,Z-uifluoro-N-(tetrahydro-ZH- pyrany1)acetamido)(3 -(2,2,2— trifluoroacetamido)pyrrolidin— 1 - y1)benzamide N-(5 -(3 ,5 -difluorophenylthio)- 1H- pyrazolo [3 ,4-b]pyridin—3 -y1)(4- methylpiperaziny1)benzamide N-(5 -(3 ,5 -difluorobenzyl)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorobenzyloxy)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorobenzyloxy)- 1H- lo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorobenzyloxy)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperazin-l-y1)(2,2,2- 62% 674.2 trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorobenzyloxy)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- piperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide 2,5-dichlorobenzyloxy)-1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-dichlorobenzyloxy)-1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(5 -chloro (trifluoromethyl)benzyloxy)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- 55% 740.2 piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(5 -chloro (trifluoromethyl)benzyloxy)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide 4-(4-methy1piperaziny1)-N-(5 - jn-3 -y1methoxy)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1) (2,2,Z-uifluoro-N-(tetrahydro-ZH- pyrany1)acetamido)benzamide 4-(1-methy1piperidin—4-y1)-N-(5 - jn-3 -y1methoxy)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1) (2,2,Z-uifluoro-N-(tetrahydro-ZH- pyrany1)acetamido)benzamide N-(5 -(3 ,5 -difluorophenylthio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorophenylthio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorophenylthio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperazin(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorophenylthio)- 1H- pyrazolo [4, 3 idin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -dichloropheny1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- ro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -dichloropheny1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- piperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5 -dichloropheny1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5 -dichloropheny1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide 4-(4-methy1piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran yl)acetamido)-N-(5 -(2- oromethyl)phenylthio)- 1H- pyrazolo [4, 3 -b]pyridin—3 - y1)benzamide 4-(1-methy1piperidin—4-y1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran yl)acetamido)-N-(5 -(2- (trifluoromethyl)phenylthio)- 1H- pyrazolo [4, 3 -b]pyridin—3 - y1)benzamide N-(5 -(3 ,5 -difluorobenzy1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperazin(2,2,2- trifluoro-N-(tetrahydro-2H-pyran tamido)benzamide N-(5 -(3 ,5 -difluorobenzy1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorobenzy1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorobenzy1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5 -dichlorobenzy1thio)- 1H- lo [4, 3 -b]pyridin—3 -(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide 2,5 -dichlorobenzy1thio)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorophenylamino)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorophenylamino)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran tamido)benzamide N-(5-(2,5-difluorophenylamino)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperazin(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 rophenylamino)- 1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-dichlorophenylamino)-1H- pyrazolo [4, 3 -b]pyridin—3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide 1()7 N-(5-(2,5-dichlorophenylamino)-1H- pyrazolo [4, 3 idin—3 -y1)(1- methylpiperidjny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorobenzyl)- 1H- pyrazolo [3 ,4-b]pyrazin-3 -(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 robenzyl)- 1H- pyrazolo [3 ,4-b]pyrazin-3 -y1)(1- methylpiperidinyl)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran yl)acetamido)benzamide N-(5 -((3 ,5 -difluorophenyl)ethynyl)- 1H-pyrazolo[3,4-b]pyrazin-3 -y1) ((3- (dimethylamino)propy1)(methy1)amin o)(2,2,2-t1ifluoro-N—(tetrahydro- 2H-pyrany1)acetamido)benzamide N-(5 -((3 ,5 -difluorophenyl)ethynyl)- lH-pyrazolo [3 ,4-b]pyrazin-3 -y1) ( 1 -methy1piperidiny1)(2,2,2- ro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorophenylthio)- 1H- pyrazolo [3 ,4-b]pyrazin-3 -y1)((3 - N, N (dimethylamino)propy1)(methyDamin 43% 693 .2 o)(2,2,2—t1ifluoro-N—(tetrahydro- 2H-pyrany1)acetamido)benzamide N-(5-(2,5 -dichloropheny1thio)- 1H- pyrazolo [3 ,4-b]pyrazin-3 -y1)(4- methylpiperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide 4-(4-methy1piperazin(2,2,2- trifluoro-N-(tetrahydro-2H-pyran yl)acetamido)-N-(5 -(2- (trifluoromethyl)phenylthio)- 1H- pyrazolo [3 ,4-b]pyrazin-3 - y1)benzamide N-(5 -(3 ,5 -difluorophenylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) (4-methy1piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 rophenylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 - ( 1 1piperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorophenylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) (4-methy1piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorophenylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) ( 1 -methy1piperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -dichlorophenylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) (4-methy1piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -dichlorophenylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 - ( 1 1piperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-dichlorophenylsulfonyl)- lH-pyrazolo [4, 3 idin—3 -y1) (4-methy1piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-dichlorophenylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) ( 1 -methy1piperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorobenzylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) hy1piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5 -(3 ,5 -difluorobenzylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) ( 1 -methy1piperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorobenzylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) (4-methy1piperaziny1)(2,2,2- ro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide 2,5-difluorobenzylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) (1-methylpiperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-difluorobenzylsulfinyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) hylpiperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-dichlorobenzylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) (4-methy1piperaziny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-dichlorobenzylsulfonyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) (1-methylpiperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-(2,5-dichlorobenzylsulfinyl)- lH-pyrazolo [4, 3 -b]pyridin—3 -y1) (1-methylpiperidiny1)(2,2,2- trifluoro-N-(tetrahydro-2H-pyran y1)acetamido)benzamide N-(5-iodotrity1- 1H-pyrazolo [3 ,4- b]pyridin-3 -y1)(4-methy1piperaziny1)(tetrahydro-2H-pyran ylamino)benzamide N-(5-(3,5- difluorophenylsulfonamido)-1H- yrazolo[3,4-b]pyridin—3-y1)(4- methylpiperazin-l-y1)(2,2,2- ro-N-(tetrahydro-2H-pyran yl)acetamido)benzamide ** HNMR, dmso-d6, EX.: 26-4: 13,64 (1H, sl, NH), 11,26 (1H, sl, NH), 8,68 (1H, d, CHarom), 8,58 (1H, d, CHarom), 8,20 (2H, d, CHarom), 7,64 (2H, d, CHarom), 7,03 (1H, m, CHarom), 6,78 (2H, In, CHarom), 3,95 (2H, m, CH2). 26-8: 13,59 (1H, sl, NH), 11,05 (1H, sl, NH), 8,68 (1H, d, CHarom), 8,57 (1H, d, CHarom), 7,19 (2H, d, ), ,08 (1H, m, ), 6,88 (2H, d, ), 6,75-6,79 (2H, m, CHarom), 3,61 (2H, m, CH2), 3,07- 3,09 (4H, m, CH), 2,41-2,44 (4H, m, CH), 2,20 (3H, s, CH3). 26-9: 13,17 (1H, sl, NH), ,90 (1H, sl, NH), 8,55 (1H, s, CHarom), 7,79 (1H, d, CHarom), 7,07 (1H, dd, CHarom), 6,90 (1H, d, CHarom), 4,40-4,50 (1H, m, CH), 3,96 (3H, s, CH3), 3,82-3,89 (1H, m, CH), 3,74-3,80 (1H, m, CH), 3,34-3,41 (2H, m, CH), 3,28-3,33 (4H, m, , 2,43-2,47 (4H, m, 2*CH2), 2,23 (3H, s, CH3), 1,85-1,92 (1H, m, CH), 1,58- 1,63 (1H, m, CH), 1,45-1,53 (1H, m, CH), 1,22-1,33 (1H, m, CH). 26-10: 12,48 (1H, sl, NH), 10,72 (1H, sl, NH), 8,30 (1H, s, CHarom), 7,77 (1H, d, CHarom), 7,06 (1H, dd, CHarom), 6,88 (1H, d, ), 6,40 (2H, sl, NHZ), 4,40-4,50 (1H, m, CH), 3,82-3,89 (1H, m, CH), 3,74-3,80 (1H, m, CH), 3,34-3,41 (2H, m, CH), 3,28-3,33 (4H, m, 2*CH2), 2,43-2,47 (4H, m, 2*CH2), 2,23 (3H, s, CH3), 1,85-1,92 (1H, m, CH), 1,58- 1,65 (1H, m, CH), 1,45-1,55 (1H, m, CH), 1,22-1,34 (1H, m, CH). (ND: not determined). 26-14: 12.99 (1H, sl, NH), 10.25 (1H, 3, NH), 7.96 (1H, d, CHarom, J=9.2Hz), 7.90-7.80 (1H, m, CHarom), 7.23-7.16 (3H, m, CHarom), 7.12-7.08 (1H, m, CHarom), 6.96 (1H, d, CHarom, J=8.8Hz), 6.87 (1H, s, CHarom), 5.31 (2H, s), 4.49- 4.42 (1H ,m), 3.86-3.75 (2H, m), 3.45 (1H, m), 3.37 (1H,m), 3.35 (4H, s), 2.42 (4H, s), 2.22 (3H, s), 1.90-1.75 (2H, m), .49 (1H, m), 1.31-1.25 (1H, 111). 26-16: 13.00 (1H, 3, NH), 10.27 (1H, 3, NH), 7.95 (1H, d, CHarom, J=8.8Hz), 7.89-7.84 (1H, m, CHarom), 7.50-7.40 (1H, m, CHarom), 7.35-7.20 (2H, m, CHarom), 7.12-7.09 (1H, m, CHarom), 6.94 (1H, d, , J=8.8Hz), 6.87 (1H, s, CHarom), 5.30 (2H, s), 4.52- 4.43 (1H, m), 3.85-3.75 (2H, m), 3.46-3.43 (1H, m), 3.36 (5H, s), 2.45 (4H, s), 2.22 (3H, s), 1.92-1.82 (2H, m), .52 (1H, m), 1.33-1.26 (1H, m). 26-20: 13.01 (1H, s, NH), 10.22 (1H, s, NH), 7.97 (1H, d, CHarom, J=8.8Hz), 7.90-7.78 (3H, m, CHarom), 7.68-7.64 (1H, m, ), 7.12-7.08 (1H, m, CHarom), 6.97 (1H, d, CHarom, J=8.8Hz), 6.85 (1H, s, CHarom), 5.43 (2H, s), 4.45-4.40 (1H, m), 3.86-3.70 (2H, m), 3.46-3.42 (1H, m), 3.30-3.28 (5H, m), 2.46 (4H, s), 2.23 (3H, s), 1.90 (1H, d, J=11.2Hz), 1.77 (1H, d, J=11.2Hz), 1.58-1.50 (1H, m), 1.30-1.20 (1H, m).

In certain cases, the major product of these reactions corresponds to the disubstituted product characterized by the onal functionalization of the pyrazole ring. In these cases, this product is isolated and transformed into a monosubstituted product by treatment with a base as described below.

Example 27: N-(S-(3,5—diflu0r0phenylthi0)—1-H-pyraz010[3,4-b]pyrazine—3-yl)—4-(4- methylpiperazine—1-yl)—2-(tetrahydro-ZH-pyranylamin0)benzamide 013.3% e 27a: N-(S-(3,5—diflu0r0phenylthi0)—1-(4-(4-methylpiperazine—1-yl)—2- (2,2,2—triflu0ro-N-(tetrahydr0-2H-pyranyl)acetamid0)benz0yl)—1H-pyraz010[3,4- b]pyrazine—3-yl)—4-(4-methylpiperazine—1-yl)—2-(2,2,2-triflu0ro-N-(tetrahydro-ZH- pyranyl)acetamid0)benzamide 1.51 ml (17.90 mmol) of oxalyl de and 2 drops of anhydrous dimethylformamide are added to 4.74 g (8.95 mmol) of a solution of 4-(4-methylpiperazineyl)(2,2,2- trifluoro-N—(tetrahydro-2H-pyranyl)acetamido)benzoic acid in 60 m l o f dichloromethane. The reaction mixture is d for 2 hours at room temperature. The solvents are evaporated, the solid formed is taken up in toluene and the solvent is evaporated, this ion is repeated three times until a white solid is obtained.

The acid chloride is added at 0°C in small fractions to 1 g (3.58 mmol) of 5-(3,5- difluorophenylthio)-1H-pyrazolo[3,4-b]pyrazine-3 -amine dissolved in 15 ml 0 f pyridine. The reaction mixture is stirred at 25°C ght at room temperature. After evaporation of the solvent, the residue is purified by silica gel chromatography (90: 10 dichloromethane/methanol and then 90:9:1 and then 90:5:5 dichloromethane/ ol/ammonium as eluent) to yield N-(5-(3,5-difluorophenylthio)(4-(4- methylpiperazineyl)(2,2,2-trifluoro-N-(tetrahydro-2H-pyranyl)acetamido) benzoyl)-1H-pyrazolo[3,4-b]pyrazineyl)(4-methylpiperazineyl)(2,2,2- trifluoro-N-(tetrahydro-2H-pyranyl)acetamido)benzamide.

LCMS (E1, m/z): (M+1) 1074.64.

Example 27: N-(S-(3, 5-diflu0r0phenylthi0)—1-H-pyrazolo[3,4-b]pyrazine—3-yl)—4- (4-methylpiperazine—1-yl)—2-(tetrahydr0-2H-pyranylamin0)benzamide. 0.27 ml (1.95 mmol) of triethylamine is added to 0.21 g (0.19 mmol) of a solution ofN- (5-(3, 5-difluorophenylthio)(4-(4-methylpiperazineyl)(2,2,2-trifluoro-N- (tetrahydro-2H-pyranyl)acetamido)benzoyl)—1H-pyrazolo[3,4-b]pyrazineyl)(4- methylpiperazineyl)(2,2,2-trifluoro-N-(tetrahydro-2H-pyranyl)acetamido) benzamide in 5 ml of methanol. The reaction medium is heated at 65°C for 4 hours, and then overnight at room temperature. After evaporation of the solvent, the product is ted several times with ethyl acetate. The c phases are ed, washed with saturated sodium bicarbonate on, dried on magnesium sulfate and trated. The residue is purified by silica gel chromatography 1 dichloromethane/methanol/ammonium as eluent) to yield 0.065 g (57%) of N-(5-(3,5- difluorophenylthio)H-pyrazolo [3 ,4-b]pyrazine-3 -yl)(4-methylpiperazineyl) (tetrahydro-2H-pyranylamino)benzamide in the form of a yellow solid.

LCMS (E1, m/z): (M-l) 579.21. 1H NMR: 6H ppm (400MHz, DMSO): 13.95 (1H, bs, NH), 10.25 (1H, bs, NH), 8.62 (1H, s, CHamm), 8.27 (1H, d, NH), 7.80 (1H, d, CHamm), 7.17—7.27 (3H, m, CHamm), 6.27 (1H, d, CHamm), 6.12 (1H, d, CHamm), 3.79-3.82 (2H, m, CH), 3.67 (1H, m, CH), 3.45— 3.50 (2H, m, CH), 3.26-3.29 (4H, m, CH), 2.42—2.44 (4H, m, CH), 2.22 (3H, s, CH3), 1.90—1.93 (2H, m, CH), 1.31-1.36 (2H, m, CH).

WO 01239 The following nds were obtained by the same method: I/~\ N WN N [:2]- n----_-Mass N—(5 -(3 ,5 - O I Q difluorophenylsulfonyl)-1H- E 1 pyrazolo [3 ,4-b]pyridin-3 - CH H yl)(4-methylp1perazm-l- NH N ! [ (tctrahydro-2H-pyran- 4-ylamino)benzamide N—(5 -(3 ,5 - O l Q difluorophenylsulfinyl)-1H- E j pyrazolo [3 ,4-b]pyrazin-3 - N H yl)(4-methylpiperazin-l- ; yl)(tctrahydro-2H-pyran- 4-ylamino)benzamide N—(5 -(3 ,5 - difluorophenylsulfonyl)- 1H- pyrazolo [3 yrazin-3 - yl)(4-methylpiperazin- l - yl)(tctrahydro-2H-pyran- 4-ylamino)benzamide N—(6-(3,5-difluorobenzyl)- lH-pyrazolo[3,4-b]pyridin— 3-yl)(4-methylpiperazin- 1-yl)(tetrahydro-2H- pyranylamino)benzamide N—(6-(3 ,5 - difluorobenzylamino)- 1H- pyrazolo [3 ,4-b]pyridin-3 - yl)(4-methylpiperazin- l - yl)(tctrahydro-2H-pyran- 4-ylamino)benzamide Reactions carried out in pyridine often make it possible to modify the regioisomer distribution of the products. The following example is characteristic of a reaction of this type.

Example 27-bis: N-(S-(N-(3,5-diflu0r0phenyl)sulfam0yl)—1H-pyrazolo[3,4- b] pyridinyl)—4-(4-methylpiperazinyl)—2-(2,2,2-triflu0ro-N-(tetrahydro-ZH- pyranyl)acetamid0)benzamide 2012/051283 0.224 ml (2.63 mmol) of oxalyl chloride and 2 drops of anhydrous dimethylformamide are added to 0.697 g (1.316 mmol) of a solution of 4-(4-methylpiperazin-l-yl)(2,2,2- trifluoro-N—(tetrahydro-2H-pyranyl)acetamido)benzoic acid in 20 m l o f dichloromethane. The on mixture is stirred for 2 hours at room temperature. The solvents are evaporated, the solid formed is redissolved in toluene and the solvent is evaporated. This operation is repeated three times until a white solid is obtained.

The acid chloride is dissolved in 5 ml of anhydrous pyridine and then the solution formed is added to a solution of 0.214 g (0.658 mmol) of 3-amino-N-(3,5- difluorophenyl)-1H-pyrazolo[3,4-b]pyridinesulfonamide in 5 ml of pyridine at 0°C.

The reaction mixture is stirred for 3 hours at 0°C, and then overnight at room ature. The pyridine is evaporated and the crude reaction t is redissolved in toluene and then dry concentrated. The reaction mixture is d with saturated NaHC03 solution and extracted with ethyl acetate. The organic phase is dried on MgSO4, filtered and concentrated and the crude product is used directly in the deprotection reaction with no purification or characterization.

The following compounds were obtained by the same method: -I--lI-_-Mass -(-6(24--d1fluorophenylth10)- 1H- pyrazolo[3,4-b]pyr1d1n---yl)-(4- 1 H ]CH H methylpiperazin-l -yl)--(2,22- trifluoro-N—-(tetrahydro-2H-pyran- 4-yl)acetam1do)benzam1de N-(6-(2,4-d1fluorophenylam1no)- jCH H1H-pyrazolo[3,4-b]pyr1d1n-3 -yl) - H(2,2,2-tr1fluoro-N-(tetrahydro-2H(4-methylp1perazinyl) pyranyl)acetam1do)benzamide \ , N—(6-((2,4- Ii] N difluorophenyl)(methyl)am1no)- . 1H-pyrazolo[3 ,4-b]pyr1d1n-3 -yl)- 27bls-3 H E 1 CH Q H N 4-(4-methylp1perazinyl) F (2,2,2-tr1fluoro-N-(tetrahydro-2H- pyranyl)acetamido)benzam1de Example of method E2: Example 28: 5-(3,S-difluorophenylthi0)—N-(4-(4-methylpiperazinyl)benzyl)—1H- pyrazolo [3,4-b] pyridinamine 41.5 ul of trifluoroacetic acid (0.539 mmol) and, in small fractions, 129 mg (0.611 mmol) of sodium triacetoxyborohydride are added to a solution of 100 mg (0.35 mmol) of 5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridinamine and 81 mg (0.395 mmol) of 4-(4-methylpiperazinyl)benzaldehyde in 20 ml of a 1:1 mixture of dichloromethane and tetrahydrofuran. The reaction medium is stirred for 16 hours at room ature. An additional fraction of 125 pl of roacetic acid and 388 mg of sodium triacetoxyborohydride are added and the reaction medium is stirred for an additional 24 hours. The t is then concentrated and the reaction medium extracted with ethyl acetate and washed using saturated sodium bicarbonate solution. The organic phases are ed, dried on magnesium sulfate and then concentrated to yield a yellow oil. A trituration of this oil in methanol leads to the isolation of 135 mg of a yellow solid.

LCMS (E1, m/z): (M+1) . 1H NMR: 6H ppm (400 MHz, DMSO): 12.43 (1H, bs, NH), 8.49 (1H, d, CHamm), 8.47 (1H, d, CHamm), 7.25 (2H, d, CHamm), 7.03-7.08 (1H, m, CHamm), 6.89 (2H, d, CHamm), 6.76-6.77 (3H, m, NH and CHamm), 4.34 (2H, d, CH), 3.08 (4H, m, CH), 2.44 (4H, m, CH), 2.21 (3H, s, CH3).

The following derivative was obtained according to the same method: 1 in \r’ \ \ l/ N w N N I-I-m -(3 , 5-difluorophenylthio)-N-(4- hy p pl i erazin- l -y )l 91% 5 12. 16 n1trobenzyl)- lH-pyrazolo [3 ,4- b]pyridin-3 -amine **1H NMR, DMSO-d6, EX.: 28-1: 12.43 (1H, bs, NH), 8.49 (1H, d, CHamm), 8.47 (1H, d, CHarom), 7.51 (1H, d, CHarom), 7.45 (1H, m, CHarom), 7.27 (1H, m, CHarom), 7.03-7.08 (1H, m, CHamm), 7.00 (1H, t, NH), 6.77-6.80 (2H, m, CHamm), 4.63 (2H, d, CH), 3.19— 3.21 (4H, m, CH), 2.42—2.45 (4H, m, CH), 2.21 (3H, s, CH3).

Example of method E3 e 29: 1-(5-(3,5—diflu0r0phenylthi0)—1H-pyrazolo[3,4-b]pyridinyl)—3-(4—(4- methylpiperazinyl)phenyl)thi0urea s K‘N, F S N \ \ H | N N N 0.507 g (2.17 mmol) of l-(4-isothiocyanatophenyl)methylpiperazine is added at 25°C to 0.540 g (2.17 mmol) of 3,5-difluorophenylthio-lH—pyrazolo[3,4-b]pyridinamine dissolved in 12 ml of anhydrous dimethylacetamide. The mixture is left under stirring for 15 hours at 85°C. The reaction is treated by adding 20 ml of water and then is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The product is purified by silica tography (15:1 romethane/methanol as eluent) to yield 0.156 g (yield=15%) of 1-(1-lerl—butyl (3 , 5-difluorophenylthio)-1H-pyrazolo[3 ,4-b]pyridin-3 -yl)-3 -(4-(4-methylpiperazin yl)phenyl)thiourea in the form of a light brown solid.

LCMS (E1, m/z): (M+1) 512.08. 1H NMR: 6H ppm (400 MHz, DMSO): 13.69 (1H, bs, NH), 11.50 (1H, bs, NH), 11.19 (1H, bs, NH), 8.96 (1H, d, CHamm), 8.66 (1H, d, CHamm), 7.41 (2H, d, CHamm), 7.10 (1H, ddd, CHamm), 6.95 (2H, d, CHamm), 6.89 (2H, bd, CHamm), 3.13-3.16 (4H, m, CH), 2.45—2.47 (4H, m, CH), 2.23 (3H, s, CH).

Example 29-bis: 1-(5-(3,5-diflu0r0phenylthi0)—1H-pyrazolo[3,4-b]pyridin-3—yl)—3- (4-(4-methylpiperazinyl)phenyl)urea J1 Nb“ HNN \J F S\\H 0.048 g (1.19 mmol) of sodium hydride is added at 0°C to 0.200 g (0.598 mmol) of 1- ZerZ-butyl(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridinamine dissolved in ml of anhydrous dimethylacetamide. The reaction is left under stirring for 10 minutes. 0.130 g (0.598 mmol) of 1-(4-isocyanatophenyl)methylpiperazine is then added at 0°C. The mixture is left under stirring for 3 hours at room temperature. The reaction is d by adding 20 ml of water drop by drop at 0°C and then is extracted with ethyl acetate. The c phase is dried on sodium e, filtered and concentrated. The t is purified by silica chromatography to yield 0.150 g (yield=45%) of 1-(1-lerl—butyl(3 , 5-difluorophenylthio)-1H-pyrazolo[3 ,4-b]pyridin-3 - yl)(4-(4-methylpiperazinyl)phenyl)urea in the form of a light brown solid.

LCMS (E1, m/z): (M+1) 552.21. 1H NMR: 6H ppm (400 MHz, DMSO): 8.92 (1H, bs, NH), 8.58 (1H, bs, NH), 8.51 (1H, bs, CHarom), 8.30 (1H, bs, CHarom), 7.31 (2H, d, CHarom), 7.05 (1H, m, ), 6.83-6.85 (2H, m, CHamm), 3.03-3.08 (4H, m, CH), 2.45-2.48 (4H, m, CH), 2.21 (3H, s, CH), 1.76 (9H, s, CH).

A solution of 0.150 g (0.272 mmol) of 1-(1-ZerZ-butyl(3,5-difluorophenylthio)-1H- lo[3,4-b]pyridinyl)(4-(4-methylpiperazinyl)phenyl)urea dissolved in ml of TFA (trifluoroacetic acid) is refluxed for 3 hours. The solvent is evaporated and the crude reaction product is diluted with saturated NaHC03 on and extracted with ethyl acetate. The organic phase is dried on MgSO4, filtered and concentrated. The solid obtained is triturated in methanol, filtered and dried. 110 mg (82%) of 1-(5-(3,5- difluorophenylthio)- 1H-pyrazolo [3 yridin-3 -yl)-3 -(4-(4-methylpiperazinyl) phenyl)urea in the form of a beige solid is obtained.

LCMS (E1, m/z): (M+1): 496.06. 1H NMR: 6H ppm (400 MHz, DMSO): 10.85 (1H, bs, NH), 9.57 (1H, bs, NH), 8.57 (1H, bs, CHamm), 8.30 (1H, bs, CHamm), 7.39 (2H, d, CHamm), 6.99 (1H, m, CHamm), 6.89 (2H, d, CHamm), 6.70 (2H, bd, CHamm), 3.03-3.08 (4H, m, CH), 2.45-2.48 (4H, m, CH), 2.21 (3H, s, CH).

Examples of method F Examples of method F1: deprotection Example 30: N-(S-(3, u0r0phenylthi0)—1-H-pyrazolo[3, 4-b]pyridineyl)—4- (4-methylpiperazineyl)—2-(tetrahydr0-2H-pyranylamin0)benzamide HNCo FO(16b I N N N N F ON 9.08 ml (65.1 mmol) of triethylamine is added to 2 g (2.96 mmol) of a solution of N—(5- (3 , 5-difluorophenylthio)-1H-pyrazolo[3 ,4-b]pyridin-3 -yl)(4-methylpiperazinyl) (2,2,2-trifluoro-N—(tetrahydro-2H-pyranyl)acetamido)benzamide in 65 m l o f methanol. The reaction medium is heated at 65°C for 2 hours, and then overnight at room ature. The precipitate formed is filtered, rinsed with pentane, with water and then with diethyl ether, and then is dried under vacuum to yield 0.73 g (43%) of (N- (5-(3, 5-difluoropheny1thio)H-pyrazolo[3 ,4-b]pyridine-3 -y1)(4-methy1piperazine (tetrahydro-2H-pyranylamino)benzamide in the form of a white solid.

LCMS (EI, m/z): (M+1) 580.23. 1H NMR: 5H ppm (400 MHz, DMSO): 13.59 (1H, bs, NH), 10.56 (1H, bs, NH), 8.61 (1H, s, CHamm), 8.50 (1H, s, CHamm), 8.17 (1H, d, NH), 7.80 (1H, d, CHamm), 7.07 (1H, m, CHarom), 6.86 (2H, In, CHarom), 6.23 (1H, d, CHarom), 6.13 (1H, d, CHarom), 3.79-3.82 (2H, dt, CH), 3.60 (1H, m, CH), 3.45-3.50 (2H, m, CH), 3.21-3.33 (4H, m, CH), 2.42- 2.46 (4H, m, CH), 2.22 (3H, s, CH3), 1.91-1.94 (2H, m, CH), 1.35-1.38 (2H, m, CH). 1 2 1 Iwas: HH a I.-a: E-E-Aoafifiiaoefiaoé2 $WEEEEiQOBNSE -m~-€3€b8YNAE-TENSQQEESQE o?§§o£ofifim3é-§§m -Efiqeaazi%§§%E-%e-e-z -oHcEbiYNAE-TENQomEEfioaévé QEENNEQGEENE- fififineoée-m"02 iéé-maeaazinsfiea -m~-€3€b8YNAE-TENSQQEESQE o?§§o£ofifim3é-§§m -m"O2-Aoaaaxfioaoeoée-$1 -wnEBONSEAAHAoEzbsameosfic -H-Egaaafioeiéé-WEEEE QUEENEDVAE wimfimim i865-ioéafifieoée-m"02 $26:33.?"22883-5 -m~-€3€b8YNAE-TENSQQEESQE o?§§o£ofifim3é-§§m -wnEBONSEAAH-wxofioaéécovaZ A?H-Egaaafioeiéé-WEEEE -¢-§§-m~-o§%§c-m QUEENEQGEENE insfieaifi-ocofiéanaéz A?H-Egaaafioeiéé-WEEEE -¢-§§-m~-o§%§c-m QUEENEQGEENE 6089: $9.? Zamonbmvmv mvmv Zamonbmvmv Zamonbmvmv n n n n 2:3 E0 EU EU EU zdzooamxonmo zdzooamxonmo znflzoéxonmo 2: > O O O O O O O 0 O 0 O Q O wEEooom = A fi II V S E E g 1: 'q E 8:650 —Z Z-> —Z 2+ —2 2+ —2 2+ —2 2+ —2 2+ —2 -> \_/ \_/ \_/ \_/ \_/ \_/ \_/ 295 03 03I I I u. I I I M Z Z 2 Z Z Z \ 0C} \ \ ”- \ 0C} \ 0C} \ 323256 wqgozom -x -ddAgendaaaieoée-waived $maeEaEinoBNeE -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m insfieadd-AENfineosdé-md-mo-z A?d-Egaaafioeiéé-WEEEE -¢-§§-d~-eafib2o-m oEdaNdonAoEEmE queoéefi02 $WEEHEEimEONaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m fiieoéefi02 -dvWEEHEEimEONaa dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd4365-ioéafiéeoée-m"02 $maeEaEinoBNeE -mm-o%Ewboc-NAE-TENSQQEESQE onAoEEmEé-§§m -miodONeEdd-AENfineosdé-md-mo-z A?d-Egaaafioeiéé-WEEEE -¢-§§-d~-eafib2o-m oEdaNdonAoEEmE -ddaxoaggeosdfin02 $maeEaemioBNeE -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -ddaxoaggeosdfin02 -WEEHEEaioBNaa dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m zdoq<xodo zdoq<xodo zdoq<xodo zdoq<xodo do do do mEOUq‘mNU do do do "odd "odd "odd "EU "2 "2 "2 nnnnnana I I Z 0 2012/051283 ddAQBfiqgeosde-md-mo-z $m-EEEE-misfiaa -mm-o%EbiV-NAE-TENSQQEESQE - fioEEmEé-dwam ddAQBfiqgeosde-md-mo-z dEla-m-EEEE-misfiaa dweafibgo-N-a-w-qisaaafioe m-EEEV- oUEEEofioEEmEé-dwam ddéxodfiqgeoEQQ-md-mo-z $m-EEEE-misfiaa -mm-o%EbiV-NAE-TENSQQEESQE oUEEEofioEEmEé-dwam ddéxodfiqgeoEQQ-md-mo-z dEla-m-EEEE-misfiaa dweafibgo-N-a-w-qisaaafioe oUEEEofioEEmEé-dwam -m-eoEo-mo-mo-z -md-ondfidoncbwoaeodfibv $m-acEaE-m-EOBNSE -mm-o%EbiV-NAE-TENSQQEESQE oUEEEofioEEmEé-dwam -m-eoEo-mo-mo-z -md-ondfidoncbwoaeodfibv m-acEaE-m-EOBNSE dweafibgo-N-a-w-qisaaafioe oUEEEofioEEmEé-dwam WEEEQS. 92»- mi afiseaafioai-w BONES-m H w-EE-dN-eafibgo- oEdaNdonAoEEmE -3268? N-a do do do do do do do do do do do do do do oxE oxE oxE n n ONE oxE oxE oxE d 2 2 n u Z z d 2 1 24 $.50 38m .xomo 38m .xbm 38m .xonN 38m .xém 38m Ax; 38m .xomw 38m N N N N N N N -WEEK?3aéaeuaaafioa-d: -WEEEE.misfieédd-axofioaa -figidweafific-we» oEdaNdonAoEEmE -dlefiafiieoéefi02 $WEEHEEaioBNaa EbiYNAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dlefiafiieoéefi02 -WEEHEEaioBNaa dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd-eéafiieoée-mdéz $WEEHEEaioBNaa -mNéoUEbiYNAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-eéafiieoée-mdéz -dvWEEHEEaioBNaa dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd-Aoafiaieodoefi02 $WEEHEEaioBNaa -mNéoUEbiYNAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m afiaieodoefi02 -dvWEEHEEaioBNaa dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd-Aoafiaieodoe-mdéz $WEEHEEaioBNaa -mNéoUEbiYNAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m do do do do do do do do do do do do do do do do "odd "odd "odd "odd "odd "odd "odd "odd "2 "2 "2 "2 "2 "2 "2 "2 —Z —Z 2+ —Z —Z Z -> —z —2 2+ —2 —Z Z-> \_/ \_/ \_/ \_/ I I I I Z 0 Z O z 0 Z O \ \ ddAoafiaieodoe-md-mo-z dEla-m-EEEE-misfiaa go-N-a-w-qisaaafioe -Banwboc- -N-N-N oUEEEofioEEmEé-dwam -mo- dd- N- 09535979»- 79»- 55539382:- mo-z-Aoaaa-w-gi-dm Aoafiaiafioeeosfia Tania m i 5&3“;onN-a-w-Ecuaaafioe-:4 mo-z-Aoaaa-w-gi-dm dd-Aoafiaiafioaeosfia WEEHES$iBONwam ddAoEoqueoée-m-mo-mo-z $m-EEEE-misfiaa -mm-o%EbiV-NAE-TENSQQEESQE oUEEEofioEEmEé-dwam ddAoEoqueoée-m-mo-mo-z dEla-m-EEEE-misfiaa dweafibgo-N-a-w-qisaaafioe oUEEEofioEEmEé-dwam ddAOEHEEQBSE?md-mo-z $m-EEEE-misfiaa -mm-o%EbiV-NAE-TENSQQEESQE Bfioomeosfib BONES oUEEEofioEEmEé-dwam EEQBSE?md-mo-z dEla-m-EEEE-misfiaa oUEEEofioEEmEé-dwam E- dweafibgo-N-a-w-qisaaafioe do do do do do do do do do do do do do do oxE oxE oxE oxE oxE n oxE oxE d 2 2 2 2 u 2 d 1 26 -dd-Aodzfiqgeodoe-mdéz $WEEHEEaioBNaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-Aodzfiqgeodoe-mdéz -dvWEEHEEaioBNaa dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd-Aoqéfiéfiaeoéefi02 $WEEHEEaioBNaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m qéfiéfiaeoéefi02 -dvWEEHEEaioBNaa dweafibgo-Nééaisaaafioe onAoEEmEé-§§m -dd-Aoqéfiéfiaeosde-mdéz $WEEHEEaioBNaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-Aoqéfiéfiaeosde-mdéz -dvWEEHEEaioBNaa dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd-Aoaaaaieodoe-mdéz $WEEHEEaioBNaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-Aoaaaaieodoe-mdéz -WEEHEEaioBNaa dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m do do do do do do do do do do do do do do do do "odd "odd "odd "odd "odd "odd "odd "odd "2 "2 "2 "2 "2 "2 "2 "2 O O O O O O O O O 0 0 O O O O fi’ o E E 'q d E E E E -> —z —2 2+ —2 —Z Z Z Z+ \_/ \_/ .— \_/ z 0 1 27 é- i - 2 AE- -N- -N- 2 @- -E 2883.5 H-ENQomeEH-oa- -E - 2883.5 N-Ecfiaaafioa- - AoEEmAEfioEV QEENNEQGEENE- aieoée- -mN-eafiboc- QEENNEQGEENE- 4&4??? -oHcEbiY oUEEEofioEEmEé-qwam AoEEmAEfioEV oUEEEofioEEmEé-qwam NV- - ocngqop-AE- N- oée- w-gaa-mN-eafific- QUEENEQGEENE w-gaa-mN-eafific- QUEENEQGEENE winning-*- éfiqoneoée- a»- N- H $4“- H a»- @- 2 oaaa-N-gi-EN WENSESé- fl m- m- oUEEEofioEEmEé-qwam N @- 9-2 TENNESS- m-ENSE N -EAaéaoaaéeoée-m9-2 m-ENaaE-wnsogé AEmoEAoqngfioEEV #:SEiN-eanwboc 9- @- 28min afiieoée-m9-2 -EAoéaaieozoe-m-NV-mV-z WENSEEé-QBONNEQ -ENSomEEfioE- Aoafiaiafioeeosfia $m-EEEE-misfiea mV-z 9-2 N-qeuoaaafioa m-ENaaE-wnsogé AEmoEAoqngfioEEV #:SEiN-eanwboc -mNéHUENbBV-NAE-TENSQQEESQE E. BONES -EAaqéaafiéeoée-m9-2 -mNéHUENbBV-NAE-TENSQQEESQE S w 2 2 2 2 2 2 2 :0 H6 H6 H6 H6 H6 H6 H6 n de de de de de de de n -z 2 -z -z -z -z -z n O O O O O O O 0 o U O O 0 E II fi’ S = 'q E E E g —2 2+ —Z Z-> \_/ z \_/ 0 Z 0 LL LL I \\ LL LL 1 2 8 -dd-aqodaafiéeoée-m"02 13-maeEaemioBNeE go-Nééaisaaafioe onAoEEmEé-§§m -dd-aqodaafiéeoée-mdéz $maeEaemioBNeE -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-aqodaafiéeoée-mdéz 13-maeEaemioBNeE dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd-Esooamaaieodoe-m"02 $WEEHEEaioBNaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-Esooamaaieodoe-m"02 -dvWEEHEEaioBNaa go-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd-Esooamaaieodoe-mdéz $WEEHEEaioBNaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-Esooamaaieodoe-mdéz $WEEHEEaioBNaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-aqodadfifineoée-m"02 $maeEaemioBNeE -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m do do do do do do do do do do do do do do do do "odd "odd "odd n n n oxE oxE "odd "odd oxE "2 "2 "2 u u "2 u z z "2 z O O O O O O O O O O O U 0 O o E E E E E d E 'q IZZ -> —Z —Z 2+ —Z —Z Z \_/ \_/ \_/ .— Z O -dd-aqodadfifineoée-m"02 13-maeEaemioBNeE dweafibgo-Nééaisaaafioe -dd-aqodadfifineoée-mdéz $maeEaemioBNeE -mm-o%Ewboc-NAE-TENSQQEESQE -dd-aqodadfifineoée-mdéz 13-maeEaemioBNeE dweafibgo-Nééaisaaafioe -dd-fiéfigfiqgeoée-mdéz 13-maeEaemioBNeE dweafibgo-Nééaisaaafioe -Nnmflm oEdaNdonAoEEmEé-§§m onAoEEmEé-§§m oEdaNdonAoEEmEé-§§m oEdaNdonAoEEmEé-§§m 83888:me -dd-aqodadfifineodoe-mdéz $maeEaemioBNeE -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-aqodadfifineodoe-mdéz maeEaemioBNeE dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dd-fiéfixfifineodoe-mdéz 13-maeEaemioBNeE dweafibgo-Nééaisaaafioe oEdaNdonAoEEmEé-§§m -dlefiafiieoéefi02 13-m-=%E&n.§EON§a EBEV oEEmNdonAoEEwE- AEmoEAodddefioEé fidwimiméébdwboc do do do do do do do Z do do do do do do do ":0 "odd n u "odd "odd n oxE oxE oxE "odd "Oomdm "2 u u z d "2 "2 z "2 ":0 O O O O O O O O O O O O o O O E E E II E E 1.: E E —Z Z+ —Z 2+ Z 2.. \_/ \_/ / / I I Z 0 Z 0 -dd-Aoqéfiéfiaeosde-$6-82 $WEEHEEimEONaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -GEEEEBEViaéeoée8-2 $26:33.?"22883-5 -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-adaéodaaqoaaeoée-m"02 $WEEHEEimEONaa Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m -dd-eéafiieoéei62 $WEEHEEimEONaa -mm-o%Ewboc-NAE-TENSQQEESQE oEdaNdonAoEEmEé-§§m 2 z Z z "oxE "oxE ":0 "oxE do do "Oomdm do do do ":0 do ** 1H NMR, DMSO-dé, Ex.: 30-3: 13.86 (1H, bs, NH), 10.70 (1H, bs, NH), 8.67 (2H, bs, CHarom), 8.10 (1H, d, NH), 7.77 (1H, d, CHarom), 7.22 (1H, m, CHarom), 6.95 (2H, d, CHarom), 6.26 (1H, d, ), 6.16 (1H, bs, CHarom), 4.85 (2H, bs, CH), 3.82-3.86 (2H, dt, CH), 3.70 (1H, m, CH), 3.47-3.53 (2H, m, CH), 3.28-3.32 (4H, m, CH), 2.42-2.46 (4H, m, CH), 2.20 (3H, s, CH3), 1.94-1.98 (2H, m, CH), 1.34-1.41 (2H, m, CH).; 30-5: 13.25 (1H, bs, NH), 10.48 (1H, bs, NH), 8.42 (1H, s, ), 8.11 (1H, d, NH), 7.76 (1H, d, CHarom), 7.00—7.10 (1H, m, CHarom), 6.79-6.87 (2H, m, CHarom), 6.23 (1H, dd, CHarom), 6.12 (1H, d, CHarom), 3.94 (3H, s, CH3), 3.75-3.83 (2H, m, CH), 3.63-3.71 (1H, m, CH), 3.42-3.52 (2H, m, CH), 3.22-3.32 (4H, m, 2*CH2), 2.36-2.48 (4H, m, 2*CH2), 2.22 (3H, s, CH3), 1.88-1.97 (2H, m, CH), 1.32-1.42 (2H, m, CH). 30-6: 13.10 (1H, bs, NH), 10.38 (1H, bs, NH), 8.56 (1H, s, CHarom), 8.12 (1H, d, NH), 7.75 (1H, d, CHarom), 6.23 (1H, dd, CHarom), 6.14 (1H, d, CHarom), 3.97 (3H, s, CH3), 3.80-3.86 (2H, m, CH), .74 (1H, m, CH), 3.40-3.55 (2H, m, CH), 3.22-3.32 (4H, m, 2*CH2), 2.36-2.48 (4H, m, 2*CH2), 2.23 (3H, s, CH3), 1.90-1.99 (2H, m, CH), 1.32-1.45 (2H, m, CH). 30- 7: 12.43 (1H, bs, NH), 10.22 (1H, bs, NH), 8.32(1H, s, CHarom), H, d, NH), 7.73 (1H, d, CHarom), 6.37 (2H, bs, NH2), 6.22 (1H, dd, CHarom), 6.13 (1H, d, CHarom), 3.78- 3.86 (2H, m, CH), 3.65-3.74 (1H, m, CH), 3.44-3.54 (2H, m, CH), 3.22-3.32 (4H, m, 2*CH2), 2.36-2.48 (4H, m, 2*CH2), 2.23 (3H, s, CH3), .99 (2H, m, CH), 1.32- 1.45 (2H, m, CH). 30-8: 13.79 (1H, bs, NH), 10.91 (1H, bs, NH), 10.69 (1H, bs, NH), 8.83 (1H, s, CHarom), 8.76 (1H, s, CHarom), 8.18 (1H, d, NH), 7.80 (1H, d, CHarom), 6.82- 6.75 (3H, m, CHarom), 6.26 (1H, d, CHarom), 6.15 (1H, d, CHarom), .82 (2H, dt, CH), 3.72 (1H, m, CH), 3.54-3.47 (2H, m, CH), 3.32-3.29 (4H, m, CH), 2.42-2.46 (4H, m, CH), 2.28 (3H, s, CH3), .95 (2H, m, CH), 1.43-1.36 (2H, m, CH). 30-13: 12.99 (1H, 3, NH), 9.92 (1H, 3, NH), 8.38 (1H, d, NH, z), 7.92 (1H, d, CHarom, J=8.4Hz), 7.84 (1H, d, CHarom, J=9.2Hz), 7.32 (1H, d, CHarom, J=8.4Hz), 7.07-7.00 (3H, m, CHarom), 6.26 (1H, d, CHarom, J=8.8Hz), 6.14 (1H, s, CHarom), 4.21 (2H, s), 3.82-3.76 (2H, m), 3.69-3.63 (1H, m), 3.48 (2H, t), 3.28 (4H, s), 2.46 (4H, s), 2.25 (3H, s), 2.00-1.90 (2H, m), 1.37-1.26 (2H, 111). 30-14: 12.96 (1H, sl, NH), 9.84 (1H, 3, NH), 8.34 (1H, d, NH, J=7.6Hz), 7.96 (1H, d, CHarom, J=9.2Hz), 7.81 (1H, d, CHarom, J=8.8Hz), 7.25 (1H, s, CHarom), 7.23 (1H, s, ), 7.17 (1H, t, CHarom), 6.96 (1H, d, CHarom, J=9.2Hz), 6.25 (1H, d, CHarom, z), 6.14 (1H, s, CHarom), 5.35 (2H, s), 3.82-3.77 (2H, m), 3.67 (1H, sl), 3.46 (2H, t), 3.29 (4H, s), 2.50 (4H, s), 2.29 2012/051283 (3H, s), 1.93-1.88 (2H, m), 1.35-1.25 (2H, 111). 30-15: 13.01 (1H, sl, NH), 10.11 (1H, sl, NH), 7.99 (1H, sl, NH), 7.97 (1H, d, CHarom, J=9.2Hz), 7.84 (1H, d, CHarom, J=8.4Hz), 7.25-7.14 (3H, m, CHarom), 6.97 (1H, d, CHarom, J=8.8Hz), 6.67 (1H, sl, CHarom), 6.51 (1H, d, CHarom, J=8.0Hz), 5.35 (2H, s, CHarom), 3.83-3.78 (2H, m), 3.68-3.63 (1H, m), 3.47 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.45-2.40 (1H, m), 2.19 (3H, s), 2.00-1.87 (4H, m), 1.75-1.65 (4H, m), 1.34-1.28 (2H, 111). 30-16: 12.95 (1H, sl, NH), 9.85 (1H, 3, NH), 8.33 (1H, d, NH, J=7.6Hz), 7.95 (1H, d, , J=8.8Hz), 7.81 (1H, d, CHarom, J=8.8Hz), 7.48 (1H, q, CHarom), 7.31-7.20 (2H, m, CHarom), 6.93 (1H, d, CHarom, J=9.2Hz), 6.25 (1H, d, CHarom, J=9.2Hz), 6.14 (1H, s, CHarom), 5.35 (2H, s), 3.81-3.76 (2H, m), 3.68 (1H, 31), 3.47 (2H, t), 3.26 (4H, s), 2.44 (4H, s), 2.29 (3H, s), 1.94-1.88 (2H, m), 1.36-1.27 (2H, 111). 30-17: 13.06 (1H, sl, NH), 10.12 (1H, sl, NH), 7.93 (1H, 31, NH), 7.86 (2H, d, CHarom, J=8.4Hz), 7.51-7.44 (1H, m, CHarom), 7.30- 7.20 (2H, m, CHarom), 6.90 (1H, 31, CHarom), 6.64 (1H, 31, ), 6.49 (1H, 31, CHarom), 5.37 (2H, s, CHarom), 3.83-3.76 (2H, m), 3.68-3.63 (1H, m), 3.46 (2H, t), 2.86 (2H, d, J=10.4Hz), 2.44-2.38 (1H, m), 2.19 (3H, s), 1.99-1.90 (4H, m), .65 (4H, m), 1.40-1.30 (2H, 111). 30-18: 12.94 (1H, sl, NH), 9.81 (1H, 3, NH), 8.32 (1H, d, CHarom, J=7.7Hz), 7.96 (1H, d, CHarom, J=9Hz), 7.81 (1H,d, , J=9Hz), 7.71 (1H, d, NH), 7.51 (1H, d, CHarom, J=8.6Hz), 7.43 (1H, dd, CHarom, J=8.6Hz), 6.97 (1H, d, CHarom, J=8.6Hz), 6.24 (1H, d, CHarom, J=8.9Hz), 6.13 (1H, s, CHarom), 5.39 (2H, s), 3.82-3.74 (2H, m), 3.72-3.62 (1H, m), 3.46 (2H, t), 3.28-3.22 (4H, m), 2.46- 2.40 (4H, m), 2.22 (3H, s), 1.95-1.87 (2H, m), 1.37-1.26 (2H, 111). 30-19: 13.01 (1H, sl, NH), 10.09 (1H, 3, NH), 7.97 (2H, d, CHarom, J=9Hz), 7.83 (1H,d, CHarom, z), 7.71 (1H, dd, NH), 7.50 (1H, d, CHarom, J=7.4Hz), 7.43 (1H, dd, CHarom, J=8.6Hz), 6.98 (1H, d, CHarom, J=9Hz), 6.67 (1H, s, CHarom), 6.51 (1H, d, CHarom, J=8.2Hz), 5.38 (2H, s), 3.84-3.75 (2H, m), 3.72-3.62 (1H, m), 3.46 (2H, t), 2.86 (2H, d), 2.43 (1H, m), 2.19 (3H, s), 1.99-1.88 (4H, m), 1.74-1.64 (4H, m), 1.38-1.26 (2H, 111). 30-20: 12.97 (1H, sl, NH), 9.82 (1H, 3, NH), 8.32 (1H, d, NH, J=8.0Hz), 7.97 (1H, d, CHarom, J=8.8Hz), 7.87 (1H, s, ), 7.80-7.76 (2H, m, ), 7.64 (1H, d, CHarom, J=8.4Hz), 6.96 (1H, d, , J=8.8Hz), 6.24 (1H, d, CHarom, J=8.8Hz), 6.13 (1H, s, CHarom), 5.47 (2H, s), 3.81-3.76 (2H, m), 3.66 (1H, sl), 3.46 (2H, t), 3.26 (4H, s), 2.43 (4H, s), 2.29 (3H, s), .88 (2H, m), .25 (2H, 111). 30-21: 13.03 (1H, 3, NH), .08 (1H, 3, NH), 8.00-7.95 (2H, m, CHarom), 7.87-7.75 (3H, m, CHarom), 7.63 (1H, 2012/051283 d, CHarom, J=8.4Hz), 6.97 (1H, d, , J=8.8Hz), 6.67 (1H, s, CHarom), 6.51 (1H, d, CHarom, J=8.0Hz), 5.47 (2H, s, CHarom), 3.83-3.76 (2H, m), 3.68-3.64 (1H, m), 3.47 (2H, t), 2.87 ( 2H, d, Hz), 2.45-2.40 (1H, m), 2.20 (3H, s), 2.00-1.87 (4H, m), 1.74-1.65 (4H, m), 1.36-1.25 (2H, 111). 30-22: 12.93 (1H, 3, NH), 9.86 (1H, 3, NH), 8.70 (1H, s, ), 8.51 (1H, dd, , J=5.2Hz), 8.38 (1H, d, NH, J=8.0Hz), 7.96-7.90 (2H, m, CHarom), 7.84 (1H, d, CHarom, J=8.8Hz), 7.73-7.33 (1H, m, CHarom), 6.91 (1H, d, CHarom, J=8.8Hz), 6.27 (1H, d, CHarom, J=8.8Hz), 6.15 (1H, s, CHarom), 5.35 (2H, s), 3.83-3.77 (2H, m), 3.70-3.64 (1H, m), 3.47 (2H, t), 3.59 (4H, s), 2.59 (4H, s), 2.34 (3H, s), 1.95-1.88 (2H, m), 1.40-1.28 (2H, 111). 30-23: 13.03 (1H, 3, NH), 10.17 (1H, 3, NH), 8.70 (1H, s, CHarom), 8.52 (1H, dd, CHarom, z), 8.06 (1H, d, NH, J=7.6Hz), 7.96 (1H, d, CHarom, J=8.8Hz), 7.94-7.88 (2H, m, CHarom), 7.37-7.34 (1H, m, CHarom), 6.93 (1H, d, CHarom, J=9.2Hz), 6.69 (1H, s, CHarom), 6.52 (1H, d, CHarom, J=8.0Hz), 5.36 (2H, s, ), 3.83-3.79 (2H, m), 3.68-3.64 (1H, m), 3.46 (2H, t), 3.25-3.15 (2H, m), 2.65-2.55 (3H, m), 2.54 (3H, s), 2.00-1.85 (6H, m), 1.41-1.28 (2H, 111). 30-24: 13.21 (1H, 3, NH), 10.00 (1H, 3, NH), 8.30 (1H, d, NH, J=7.6Hz), 8.00 (1H, d, CHarom, J=8.8Hz), 7.79 (1H, d, CHarom, J=9.2Hz), 7.33 (1H, d, CHarom, J=8.8Hz), 7.26-7.16 (3H, m, ), 6.24 (1H, d, CHarom, J=8.8Hz), 6.13 (1H, s, CHarom), 4.06-3.99 (2H, m), 3.67 (1H, sl), 3.47 (2H, t), 3.28 (4H, s), 2.47 (4H, s), 2.25 (3H, s), 1.94-1.88 (2H, m), 1.37-1.26 (2H, 111). 30-25: 13.26 (1H, 3, NH), 10.28 (1H, 3, NH), 8.02 (1H, d, , J=8.8Hz), 7.97 (1H, d, NH, J=7.6Hz), 7.83 (1H, d, CHarom, J=8.0Hz), 7.34 (1H, d, CHarom, J=8.8Hz), 7.27-7.17 (3H, m, CHarom), 6.68 (1H, s, CHarom), 6.51 (1H, d, CHarom, J=8.0Hz), 3.85-3.78 (2H, m), 3.71-3.65 (1H, m), 3.47 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.48-2.40 (1H, m), 2.19 (3H, s), 1.98-1.88 (4H, m), 1.74-1.66 (4H, m), 1.36-1.27 (2H, 111). 30-26: 13.12 (1H, 3, NH), 9.95 (1H, 3, NH), 8.32 (1H, d, NH, J=7.6Hz), 7.93 (1H, d, CHarom, J=8.8Hz), 7.79 (1H, d, CHarom, J=8.8Hz), 7.73 (1H, t, CHarom), 7.52-7.40 (2H, m, CHarom), 7.12 (1H, d, CHarom, z), 6.25 (1H, d, CHarom, J=8.8Hz), 6.13 (1H, s, CHarom), 3.83-3.77 (2H, m), 3.69 (1H, sl), 3.48 (2H, t), 3.28 (4H, s), 2.44 (4H, s), 2.27 (3H, s), 1.96-1.89 (2H, m), 1.37-1.27 (2H, 111). 30-27: 13.17 (1H, 3, NH), 10.21 (1H, 3, NH), 7.99-7.92 (2H, m, CHarom et NH), 7.81 (1H, d, CHarom, J=8.4Hz), .70 (1H, m, CHarom), 7.51-7.40 (2H, m, CHarom), 7.13 (1H, dd, , J=8.8Hz), 6.69 (1H, s, CHarom), 6.51 (1H, d, CHarom, J=8.4 Hz), 3.85-3.78 (2H, m), 3.72-3.67 (1H, m), 3.48 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.47-2.40 (1H, m), 2.20 (3H, s), 1.96-1.87 (4H, m), .65 (4H, m), 1.38-1.28 (2H, 111). 30-28: 13.31 (1H, sl, NH), 9.95 (1H, sl, NH), 8.31 (1H, (1, NH, J=7.6Hz), 7.99 (1H, d, CHarom, J=7.6Hz), 7.78 (1H, d, CHarom, J=9.2Hz), 7.58-7.49 (3H, m, CHarom), 7.31 (1H, d, CHarom, J=8.8Hz), 6.24 (1H, d, , J=8.8Hz), 6.10 (1H, s, CHarom), .76 (2H, m), 3.70-3.60 (1H, m), 3.45 (2H, t), 3.21 (4H, s), 2.43 (4H, s), 2.22 (3H, s), 1.94-1.86 (2H, m), 1.38-1.28 (2H, 111). -29: 13.26 (1H, 3, NH), 10.25 (1H, 3, NH), 8.01 (1H, d, CHarom, J=8.8Hz), 7.94 (1H, (1, NH, J=7.6Hz), 7.82 (1H, d, CHarom, J=8.4Hz), 7.59-7.54 (3H, m, CHarom), 7.32 (1H, d, CHarom, J=8.8Hz), 6.67 (1H, s, ), 6.54 (1H, d, CHarom, z), 3.84-3.78 (2H, m), 3.71-3.62 (1H, m), 3.47 (2H, t), 2.87 (2H, d, Hz), 2.45-2.41 (1H, m), 2.19 (3H, s), 1.96-1.90 (4H, m), 1.74-1.68 (4H, m), .27 (2H, 111). 30-30: 13.23 (1H, 3, NH), 9.98 (1H, 3, NH), 8.29 (1H, (1, NH, J=7.6Hz), 8.01 (1H, d, CHarom, J=8.8Hz), 7.79 (1H, d, CHarom, J=8.8Hz), 7.62 (1H, d, CHarom, J=8.4Hz), 7.52 (1H, s, CHarom), 7.44 (1H, d, CHarom, J=7.6Hz), 7.24 (1H, d, CHarom, J=8.4Hz), 6.25 (1H, d, CHarom, J=8.0Hz), 6.12 (1H, s, CHarom), 3.82-3.75 (2H, m), 3.73-3.67 (1H, m), 3.47 (2H, t), 3.27 (4H, s), 2.43 (4H, s), 2.22 (3H, s), 1.95-1.87 (2H, m), 1.35-1.28 (2H, 111). 30-31: 13.28 (1H, 3, NH), 10.25 (1H, 3, NH), 8.02 (1H, d, CHarom, J=8.8Hz), 7.95 (1H, (1, NH, J=7.6Hz), 7.81 (1H, d, CHarom, J=8.0Hz), 7.61 (1H, d, CHarom, J=8.4Hz), 7.56 (1H, s, ), 7.43 (1H, dd, CHarom, J=8.4Hz), 7.25 (1H, d, , J=8.8Hz), 6.68 (1H, s, CHarom), 6.51 (1H, d, CHarom, J=7.2 Hz), 3.84-3.78 (2H, m), 3.69-3.61 (1H, m), 3.47 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.47-2.41 (1H, m), 2.20 (3H, s), 2.00-1.90 (4H, m), 1.76-1.69 (4H, m), 1.40-1.30 (2H, 111). 30-32: 13.16 (1H, 3, NH), 9.95 (1H, 3, NH), 8.33 (1H, (1, NH, J=8.0Hz), 7.93 (1H, d, CHarom, z), 7.89 (1H, d, CHarom, J=9.2Hz), 7.79 (1H, d, CHarom, J=9.2Hz), 7.70-7.63 (2H, m, CHarom), 7.60 (1H, t, CHarom), 6.97 (1H, d, CHarom, J=8.8Hz), 6.25 (1H, d, CHarom, J=9.2Hz), 6.14 (1H, s, CHarom), 3.83-3.78 (2H, m), 3.68 (1H, sl), 3.48 (2H, t), 3.28 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.95-1.90 (2H, m), 1.38-1.28 (2H, 111). 30-33: 13.21 (1H, 3, NH), .22 (1H, 3, NH), 7.99 (1H, (1, NH, J=7.6Hz), 7.94 (1H, d, CHarom, J=9.2Hz), 7.89 (1H, d, CHarom, J=7.2Hz), 7.82 (1H, d, CHarom, J=8.4Hz), 7.71-7.57 (3H, m, CHarom), 6.98 (1H, d, CHarom, z), 6.69 (1H, s, CHarom), 6.52 (1H, d, CHarom, J=8.0 Hz), 3.85-3.79 (2H, m), 3.72-3.62 (1H, m), 3.48 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.47-2.41 (1H, m), 2.19 (3H, s), 2.00-1.90 (4H, m), 1.76-1.69 (4H, m), 1.40- 1.30 (2H, 111). 30-34: 13.07 (1H, 3, NH), 10.11 (1H, 3, NH), 8.32 (1H, d, NH, J=7.6Hz), 7.90-7.85 (2H, m, CHarom), 7.22 (1H, d, CHarom, J=8.8Hz), 7.19 (1H, s, CHarom), 7.17 (1H, s, CHarom), 7.03 (1H, t, CHarom), 6.30 (1H, d, CHarom, J=8.4Hz), 6.19 (1H, s, CHarom), 4.43 (2H, s), 4.02 (2H, 31), 3.80-3.74 (2H, m), 3.67 (1H, sl), 3.44 (2H, t), 3.10 (4H, s), 2.84 (3H, s), 1.89-1.84 (2H, m), 1.30-1.14 (4H, 111). 30-35: 13.08 (1H, 3, NH), 10.28 (1H, 3, NH), 7.96 (1H, d, NH, J=7.6Hz), 7.88 (1H, d, , J=8.8Hz), 7.86 (1H, d, CHarom, J=6.8Hz), 7.22 (1H, d, CHarom, J=8.8Hz), 7.18 (1H, s, CHarom), 7.17 (1H, s, CHarom), 7.02 (1H, t, CHarom), 6.66 (1H, s, CHarom), 6.51 (1H, d, CHarom, J=8.4Hz), 4.43 (2H, s), 3.80-3.74 (2H, m), 3.64 (1H, sl), 3.44 (2H, t), 2.89- 2.84 (2H, m), 2.43 (1H, sl), 2.20 (3H, s), 1.98-1.95 (2H, m), 1.89-1.84 (2H, m), 1.72- 1.69 (4H, m), .20 (2H, 111). 30-36: 13.10 (1H, sl, NH), 10.11 (1H, 3, NH), 9.73 (1H, 31, COOH), 8.34 (1H, 31, NH), 7.92-7.86 (2H, m, CHarom), 7.47-7.40 (1H, m, CHarom), 7.23 (1H, d, CHarom, J=8.8Hz), 7.20-7.13 ( 1H, m, ), .05 (1H, m, CHarom), 6.31 (1H, dd, CHarom, J=9.2Hz), 6.20 (1H, s, CHarom), 4.41 (2H, s), 4.04 (2H, d, J=8.8Hz), 3.81-3.75 (2H, m), 3.70-3.66 (1H, m), 3.51 (2H, d, J=11.2Hz), 3.44 (2H, t), 3.16-2.97 ( 4H, m), 2.87 (3H, s), 1.91-1.84 (2H, m), .22 (2H, m). 30- 37: 13.09 (1H, 3, NH), 10.29 (1H, 3, NH), 7.97 (1H, d, NH, J=7.6Hz), 7.90-7.86 (2H, m, CHarom), 7.47-7.41 (1H, m, CHarom), 7.23 (1H, d, CHarom, J=8.8Hz), 7.19-7.13 ( 1H, m, CHarom), .05 ( 1H, m, CHarom), 6.67 (1H, s, CHarom), 6.52 (1H, d, , J=8.0Hz), 4.41 (2H, s), 3.79-3.74 (2H, m), 3.66-3.62 (1H, m), 3.44 (2H, t), 2.86 ( 2H, d, J=11.2Hz), 2.45-2.40 (1H, m), 2.19 (3H, s), 2.00-1.85 (4H, m), .65 (4H, m), 1.33-1.23 (2H, 111). 30-38: 13.02 (1H, 3, NH), 10.04 (1H, 3, NH), 8.28 (1H, d, NH, J=8.0Hz), 7.88-7.84 (2H, m, CHarom), 7.74 (1H, s, CHarom), 7.43 (1H, d, , J=8.8Hz), 7.29 (1H, dd, CHarom, J=8.4Hz), 7.22 (1H, d, CHarom, J=8.8Hz), 6.25 (1H, dd, CHarom, J=9.2Hz), 6.12 (1H, s, CHarom), 4.50 (2H, s), 3.78-3.74 (2H, m), 3.66-3.62 (1H, m), 3.44 (2H, t), 3.26 (4H, s), 2.43 (4H, s), 2.22 (3H, s), 1.91-1.84 (2H, m), 1.35-1.23 (2H, 111). 30-39: 13.09 (1H, 3, NH), 10.32 (1H, 3, NH), 8.28 (1H, d, NH, J=8.0Hz), 7.90 (2H, D, CHarom), 7.74 (1H, s, CHarom), 7.43 (1H, d, CHarom, J=8.4Hz), 7.29 (1H, dd, CHarom, J=8.4Hz), 7.25 (1H, d, CHarom, J=8.8Hz), 6.67 (1H, s, CHarom), 6.54 (1H, dd, , J=8,4Hz), 4.51 (2H, s), 3.79-3.76 (2H, m), 3.70- 3.64 (1H, m), 3.44 (2H, t), 2.95-2.92 (2H, m), 2,52-2,51 (1H, m), 2.27 (3H, s), 2.13- 2,01 (2H, m), 1,90-1,87 (2H, m) 1.77-1.69 (4H, m), 1.32-1.24 (2H, 111). 30-40: 12.77 (1H, 3, NH), 9.86 (1H, 3, NH), 9.60 (1H, 3, NH), 8.40 (1H, d, NH, J=7.6Hz), 7.86 (1H, d, CHarom, J=8.8Hz), 7.83 (1H, d, CHarom, J=9.2Hz), 7.56 (2H, d, , J=8.8Hz), 6.93 (1H, d, CHarom, J=9.2Hz), 6.55 (1H, t, CHarom), 6.23 (1H, dd, , J=9.2Hz), 6.13 (1H, s, CHarom), 3.82-3.75 (2H, m), 3.69-3.61 (1H, m), 3.46 (2H, t), 3.27 (4H, s), 2.44 (4H, s), 2.29 (3H, s), 1.96-1.88 (2H, m), 1.38-1.26 (2H, 111). 30-41: 12.85 (1H, sl, NH), 10.13 (1H, 3, NH), 9.62 (1H, 3, NH), 8.03 (1H, d, NH, J=7.2Hz), 7.90-7.84 (2H, m, CHarom), 7.57 (2H, dd, CHarom, J=10.4Hz), 6.95 (1H, d, CHarom, J=8.8Hz), 6.68 (1H, s, CHarom), 6.60-6.50 (2H, m, CHarom), 3.83-3.78 (2H, m), 3.68- 3.63 (1H, m), 3.46 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.45-2.40 (1H, m), 2.20 (3H, s), 2.00-1.92 (4H, m), .65 (4H, m), 1.37-1.27 (2H, 111). 30-42: 12.77 (1H, 3, NH), 9.87 (1H, 3, NH), 9.02 (1H, 3, NH), 8.80-8.72 (1H, m, CHarom), 8.41(1H, d, NH, J=7.6Hz), 7.86 (1H, d, CHarom, J=8.8Hz), 7.83 (1H, d, CHarom, J=9.2Hz), 7.28 (1H, d, CHarom, J=9.2Hz), .15 (1H, m, CHarom), 6.63-6.57 (1H, m, CHarom), 6.23 (1H, d, CHarom, J=8.8Hz), 6.13 (1H, s, CHarom), 3.83-3.75 (2H, m), 3.70-3.64 (1H, m), 3.46 (2H, t), 3.27 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.95-1.88 (2H, m), 1.39-1.26 (2H, 111). 30-43: 12.84 (1H, 3, NH), 10.13 (1H, 3, NH), 9.05 (1H, 31, NH), .74 (1H, m, CHarom), 8.05 (1H, d, NH, z ), 7.89-7.84 (2H, m, CHarom), 7.30 (1H, d, CHarom, J=8.8Hz), 7.23-7.15 (1H, m, ), 6.67 (1H, s, CHarom), 6.64-6.58 (1H, m, CHarom), 6.51 (1H, d, CHarom, J=8.4Hz), 3.83-3.76 (2H, m), 3.68-3.64 (1H, m), 3.47 (2H, t), 2.89 ( 2H, d, J=10.8Hz), 2.45-2.40 (1H, m), 2.21 (3H, s), 2.01-1.91 (4H, m), 1.74-1.66 (4H, m), 1.38-1.27 (2H, 111). 30-44: 12.80 (1H, 3, NH), 10.16 (1H, 3, NH), 8.89 (1H, s, CHarom), 8.52 (1H, 3, NH), 8.34 (1H, d, NH, J=7.6Hz), 7.89 (1H, d, CHarom, J=9.2Hz), 7.81 (1H, d, CHarom, J=9.2Hz), 7.41 (1H, d, CHarom, J=8.8Hz), 7.35 (1H, d, CHarom, J=9.2Hz), 6.89 (1H, dd, , J=8.4Hz), 6.21 (1H, d, CHarom, J=9.2Hz), 6.11 (1H, s, CHarom), 3.83-3.75 (2H, m), 3.66-3.60 (1H, m), 3.46 (2H, t), 3.25 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.95-1.87 (2H, m), 1.37-1.26 (2H, 111). -45: 12.86 (1H, 3, NH), 10.10 (1H, 3, NH), 8.91 (1H, s, CHarom), 8.54 (1H, 3, NH), 8.00 (1H, d, NH, J=7.6Hz ), 7.90 (1H, d, CHarom, J=9.2Hz), 7.85 (1H, d, CHarom, J=8.0Hz), 7.41 (1H, d, CHarom, J=8.4Hz), 7.37 (1H, d, CHarom, z), 6.88 (1H, dd, CHarom, J=8.4Hz), 6.64 (1H, s, CHarom), 6.48 (1H, d, CHarom, J=8.4Hz), 3.83- 3.77 (2H, m), 3.67-3.60 (1H, m), 3.47 (2H, t), 2.88 (2H, d, J=11.2Hz), 2.45-2.38 (1H, m), 2.21 (3H, s), 2.00-1.87 (4H, m), 1.75-1.65 (4H, m), 1.37-1.26 (2H, 111). 30-46: 13.74 (1H, sl, NH), 10.14 (1H, 3, NH), 8.62 (1H, s, ), 8.33 (1H, d, NH), 7.81 (1H, d, CHarom, J=8.7Hz), 7.12-7.03 (3H, m, CHarom), 6.26 (1H, d, , J=8.8Hz), 6.13 (1H, s, CHarom), 4.31 (2H, s), 4.14-4.07 (4H, m), 3.68 (1H, sl), 3.28 (4H, s), 2.43 (4H, s), 2.23 (3H, s), 1.92 (2H, d, J=12.4Hz), 1.38-1.26 (2H, 111). 30-47: 13.80 (1H, sl, NH), .41 (1H, 3, NH), 8.64 (1H, s, ), 8.02 (1H, d, NH), 7.85 (1H, d, , J=8.1Hz), 7.12-7.03 (3H, m, CHarom), 6.69 (1H, s, CHarom), 6.52 (1H, d, CHarom, J=8.1Hz), 4.30 (2H, s), 3.81 (2H, d, J=11.1Hz), 3.68 (1H, 31), 3.48 (2H, t), 2.87 (2H, d, J=10.5Hz), 2.47-2.39 (1H, sl), 2.19 (3H, s), 2-1.88 (4H, m), 1.76-1.66 (4H, m), 1.39- 1.27 (2H, 111). 30-48: 13.99 (1H, 31, NH), 10.17 (1H, 3, NH), 8.34 (1H, s, CHarom), 8.29 (1H, d1, NH), 7.78 (1H, d, CHarom, J=8.9Hz), 7.54-7.41 (3H, m, CHarom), 6.07 (1H, d, CHarom, J=8.9Hz), 5.87 (1H, s, CHarom), 3.82 (2H, d1), 3.62 (1H, sl), 3.51-3.37 (4H, m), 2.97 (3H, s), 2.28-2.19 (2H, m), 2.15 (6H, s), 2-1.90 (2H, m), 1.71-1.61 (2H, m), 1.42-1.28 (2H, 111). 30-49: 14.06 (1H, sl, NH), 10.56 (1H, 3, NH), 8.85 (1H, s, CHarom), 7.97 (1H, 31, NH), 7.85 (1H, d, CHarom, J=8.1Hz), 7.50-7.40 (3H, m, CHarom), 6.71 (1H, s, CHarom), 6.54 (1H, d, CHarom, J=8.1Hz), .76 (2H, m), 3.70 (1H, 31), 3.48 (2H, t), 2.88 (2H, d, J=10.6Hz), 2.48-2.40 (1H, m), 2.20 (3H, s), .89 (4H, m), .66 (4H, m), 1.40-1.28 (2H, 111). 30-50: 13.94 (1H, sl, NH), 10.11 (1H, sl, NH), 8.59 (1H, s, CHarom), 8.30 (1H, 31, NH), 7.76 (1H, d, , J=9.2Hz), 7.27- 7.13 (3H, m, CHarom), 6.04 (1H, dd, CHarom, J=9.2Hz), 5.85 (1H, s, CHarom), 3.87- 3.76 (2H, m), 3.66-3.55 (1H, m), 3.49-3.26 (4H, m), 2.96 (3H, s), 2.22 (2H, t), 2.14 (6H, s), 1.97-1.89 (2H, m), 1.69-1.60 (2H, q), 1.40-1.28 (2H, 111). 30-51: 13.95 (1H, sl, NH), .17 (1H, 31, NH), 8.54 (1H, s, CHarom), 8.28 (1H, 31, NH), 7.78 (1H, d, CHarom, J=8.8Hz), 7.59 (1H, d, CHarom, J=9.2Hz), 7.42-7.38 (2H, m, CHarom), 6.23 (1H, d, CHarom, J=8.0Hz), 6.11 (1H, s, CHarom), 3.82-3.77 (2H, m), 3.66 (1H, sl), 3.46 (2H, t), 3.26 (4H, s), 2.43 (4H, s), 2.22 (3H, s), 1.92-1.88 (2H, m), 1.34-1.24 (2H, 111). 30-52: 13.97 (1H, sl, NH), 10.20 (1H, 3, NH), 8.38 (1H, s, CHarom), 8.27 (1H, d, NH), 7.88 (1H, d, CHarom, J=7.2Hz), 7.78 (1H, d, CHarom, J=9.2Hz), 7.66-7.55 (3H, m, CHarom), 6.26 (1H, dd, CHarom, J=9.2Hz), 6.13 (1H, s, CHarom), 3.85-3.76 (2H, m), 3.75-3.63 (1H, m), 3.48 (2H, t), 3.37-3.26 (4H, m), .52 (4H, m), 2.32 (3H, sl), 1.96-1.88 (2H, m), .26 (2H, 111). 30-53: 13.64 (1H, 3, NH), 10.20 (1H, 3, NH), 8.30 (1H, d, CHarom, J=8.8Hz), 8.23 (1H, d, CHarom, J=8.0Hz), 8.19 (1H, d, CHarom, J=8.8Hz), 7.81 (1H, d, CHarom, J=9.2Hz), 7.75-7.65 (3H, m, CHarom), 6.28 (1H, dd, CHarom, z), 6.14 (1H, s, CHarom), 3.83-3.77 (2H, m), 3.70-3.64 (1H, m), 3.48 (2H, t), 3.29 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.95-1.89 (2H, m), 1.38-1.26 (2H, 111). -54: 13.64 (1H, sl, NH), 10.48 (1H, sl, NH), 8.32 (1H, d, CHarom, J=8.8Hz), 8.19 (1H, d, CHarom, J=8.8Hz), 7.91 (1H, 31, NH), 7.85 (1H, d, CHarom, J=8.4Hz), 7.77- 7.65 (3H, m, CHarom), 6.71 (1H, s, CHarom), 6.54 (1H, d, CHarom, J=8.4Hz), 3.86- 3.80 (2H, m), 3.71-3.64 (1H, m), 3.48 (2H, t), 2.89 (2H, d, J=11.2Hz), 2.45-2.40 (1H, m), 2.21 (3H, s), 2.00-1.90 (4H, m), 1.75-1.65 (4H, m), 1.38-1.27 (2H, 111). 30-55: 13.64 (1H, 3, NH), 10.16 (1H, 3, NH), 8.29 (1H, d, CHarom, J=8.8Hz), 8.24 (1H, d, NH, J=7.6Hz), 8.17 (1H, d, , J=8.8Hz), 8.09 (1H, t, CHarom), 7.88-7.85 (1H, m, CHarom), 7.81 (1H, d, CHarom, J=9.2Hz), 7.67 (1H, q, CHarom), 6.28 (1H, d, CHarom, J=8.8Hz), 6.14 (1H, s, ), 3.83-3.75 (2H, m), 3.72-3.67 (1H, m), 3.48 (2H, t), 3.29 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.96-1.89 (2H, m), 1.35-1.28 (2H, 111). -56: 13.67 (1H, 3, NH), 10.43 (1H, 3, NH), 8.31 (1H, d, CHarom, J=8.8Hz), 8.18 (1H, d, CHarom, J=8.8Hz), 8.13-8.05 (1H, m, CHarom), 7.92 (1H, d, NH, J=7.6Hz), 7.90- 7.82 (2H, m, CHarom), 7.66 (1H, q, CHarom), 6.71 (1H, s, CHarom), 6.54 (1H, d, CHarom, J=8.4Hz), .80 (2H, m), .65 (1H, m), 3.49 (2H, t), 2.89 (2H, d, J=11.2Hz), 2.48-2.42 (1H, m), 2.21 (3H, s), 1.99-1.90 (4H, m), 1.76-1.68 (4H, m), 1.37- 1.27 (2H, 111). 30-57: 13.66 (1H, 3, NH), 10.17 (1H, 3, NH), 8.30 (1H, d, CHarom, J=8.8Hz), 8.24-8.16 (2H, m, CHarom et NH), 8.03-7.97 ( 3H, m, CHarom), 7.81 (1H, d, CHarom, J=9.2Hz), 6.28 (1H, d, CHarom, J=7.2Hz), 6.14 (1H, s, CHarom), 3.83-3.77 (2H, m), 3.71-3.67 (1H, m), 3.48 (2H, t), 3.29 (4H, s), 2.44 (4H, s), 2.23 (3H, s), 1.96- 1.89 (2H, m), 1.34-1.28 (2H, 111). 30-58: 13.71 (1H, 3, NH), 10.45 (1H, 3, NH), 8.32 (1H, d, CHarom, J=9.2Hz), 8.22 (1H, d, , J=8.8Hz), 8.02-7.96 (3H, m, CHarom), .81 (1H, In, NH), 7.83 (1H, d, Charom), 6.71 (1H, s, CHarom), 6.54 (1H, d, , J=7.6Hz), 3.85-3.78 (2H, m), 3.72-3.65 (1H, m), 3.48 (2H, t), 2.88 (2H, d, J=11.2Hz), 2.48-2.44 (1H, m), 2.21 (3H, s), 1.97-1.87 (4H, m), 1.76-1.70 (4H, m), 1.36-1.28 (2H, 111). 30-59: 13.69 (1H, 3, NH), 10.04 (1H, 3, NH), 8.34 (1H, d, NH, J=8.8Hz), .16 (3H, m, ), 7.81 (1H, dd, CHarom, J=8.4Hz), 7.74 (1H, d, CHarom, J=9.2Hz), 7.66 (1H, d, , J=8.4Hz), 6.24 (1H, dd, CHarom, J=9.2Hz), 6.10 (1H, s, CHarom), 3.82-3.76 (2H, m), 3.68-3.62 (1H, m), 3.48 (2H, t), 3.27 (4H, s), 2.43 (4H, s), 2.22 (3H, s), 1.93-1.86 (2H, m), 1.31-1.21 (2H, 111). 30-60: 13.74 (1H, 3, NH), 10.31 (1H, 3, NH), 8.35 (1H, d, CHarom, J=8.8Hz), 8.25 (1H, d, CHarom, J=8.8Hz), 8.21 (1H, s, CHarom), 7.85 (1H, (1, NH, J=7.2Hz), 7.81 (1H, dd, CHarom, J=8.8Hz), 7.76 (1H, d, CHarom, J=8.0Hz), 7.66 (1H, d, CHarom, J=8.8Hz), 6.67 (1H, s, CHarom), 6.50 (1H, d, CHarom, J=8.0Hz), 3.85-3.78 (2H, m), 3.68-3.62 (1H, m), 3.48 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.46-2.40 (1H, m), 2.20 (3H, s), 1.97-1.87 (4H, m), 1.75-1.67 (4H, m), 1.32-1.24 (2H, 111). 30-61: 13.61 (1H, 3, NH), 10.32 (1H, 3, NH), 8.71 (1H, (1, NH, J=8.0Hz), 8.21 (1H, d, CHarom, J=8.8Hz), 7.87 (1H, d, CHarom, J=9.2Hz), 7.80 (1H, d, CHarom, z), 7.17 (1H, t, CHarom), 7.05-7.02 (2H, m, CHarom), 6.29 (1H, d, CHarom, z), 6.14 (1H, s, CHarom), 4.93 (2H, s), 3.74- 3.68 (3H, m), 3.43 (2H, t), 3.29 (4H, s), 2.44 ( 4H, s), 2.28 (3H, s), 1.90-1.84 (2H, m), 1.28-1.20 (2H, 111). 30-62: 13.67 (1H, sl, NH), 10.59 (1H, 3, NH), 8.23 (1H, d, CHarom, J=8.8Hz), 8.10 (1H, (1, NH, J=7.6Hz), 7.92 (1H, d, CHarom, J=8.0Hz), 7.82 (1H, d, CHarom, J=8.8Hz), 7.17 (1H, t, CHarom), 7.05-7.02 (2H, m, CHarom), 6.71 (1H, s, CHarom), 6.56 (1H, d, CHarom, J=8.0Hz), 4.94 (2H, s), 3.77-3.70 (3H, m), 3.43 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.45-2.40 (1H, m), 2.20 (3H, s), 1.98-1.91 (2H, m), 1.89-1.95 (2H, m), 1.75-1.67 (4H, m), 1.30-1.20 (2H, 111). 30-63: 13.63 (1H, 31, NH), 10.28 (1H, 3, NH), 8.37 (1H, (1, NH, J=8.0Hz), 8.24 (1H, d, CHarom, J=8.8Hz), 7.88-7.82 (2H, m, CHarom), 7.24-7.17 (3H, m, CHarom), 6.29 (1H, d, CHarom, z), 6.14 (1H, s, CHarom), 4.87 (2H, s), 3.75-3.70 (3H, m), 3.43 (2H, t), 3.28 (4H, s), 2.45 (4H, s), 2.23 (3H, s), 1.90-1.85 (2H, m), .20 (2H, 111). 30-64: 13.69 (1H, sl, NH), 10.55 (1H, 3, NH), 8.26 (1H, d, CHarom, J=8.8Hz), 8.05 (1H, (1, NH, J=7.6Hz), 7.90 (1H, d, CHarom, z), 7.86 (1H, d, , J=8.8Hz), 7.24-7.15 (3H, m, CHarom), 6.70 (1H, s, CHarom), 6.56 (1H, d, CHarom, J=8.0Hz), 4.88 (2H, s), 3.80-3.65 (3H, m), 3.43 (2H, t), 2.87 (2H, d, J=11.2Hz), .40 (1H, m), 2.20 (3H, s), 2.00-1.86 (4H, m), 1.75-1.67 (4H, m), 1.29-1.23 (2H, 111). 30-65: 13.49 (1H, sl, NH), 10.45 (1H, 3, NH), 9.31 (1H, sl, COOH), 8.21 (1H, d, , J=8.8Hz), 8.06 (1H, sl, NH), 7.92 (1H, d, CHarom, J=8.4Hz), 7.57 (1H, d, CHarom, z), 7.17-7.11 (2H, m, CHarom), 6.96-6.91 (1H, m, CHarom), 6.67 (1H, s, CHarom), 6.53 (1H, d, CHarom, J=8.0Hz), 4.51 (1H, d, J=13.2Hz), 4.20 (1H, d, J=13.2Hz), 3.81-3.76 (2H, m), 3.71-3.62 (1H, m), 3.56-3.41 (4H, m), 3.08 (2H, t), 2.83 (3H, s), .40 (1H, m), 2.07-2.00 (2H, m), 1.95-1.86 (4H, m), 1.41-1.29 (2H, 111). 30-66: 13.62 (1H, sl, NH), 10.22 (1H, sl, NH), 8.36 (1H, (1, NH, J=7.6Hz), 8.23 (1H, d, CHarom, J=8.8Hz), 7.85 (1H, d, , J=9.2Hz), 7.80 (1H, d, CHarom, J=8.8Hz), 7.48 (1H, s, CHarom), 7.45-7.37 (2H, m, CHarom), 6.29 (1H, d, CHarom, J=7.2Hz), 6.14 (1H, s, CHarom), 4.97 (2H, s), 3.76-3.70 (3H, m), 3.44 (2H, t), 3.28 (4H, s), 2.44 ( 4H, s), 2.23 (3H, s), .86 (2H, m), 1.30-1.24 (2H, m). -67: 13.67 (1H, s1, NH), 10.49 (1H, s, NH), 8.25 (1H, d, CHarom, z), 8.02 (1H, d, NH, J=7.2Hz), 7.89 (1H, d, , J=8.0Hz), 7.82 (1H, d, , J=8.8Hz), 7.49 (1H, t, CHarom), 7.45-7.35 (2H, m, CHarom), 6.70 (1H, s, CHarom), 6.56 (1H, d, CHarom, J=8.0Hz), 4.97 (2H, s), .64 (3H, m), 3.44 (2H, t), 2.88 (2H, d, J=11.2Hz), 2.45-2.40 (1H, m), 2.20 (3H, s), 1.98-1.86 (4H, m), 1.76-1.66 (4H, m), 1.32- 1.22 (2H, m). 30-68: 13.46 (1H, s, NH), 10.36 (1H, s, NH), 8.21 (1H, d, CHarom, J=8.8Hz), 8.00 (1H, d, NH, J=7.6Hz), 7.86 (1H, d, CHarom, J=8.4Hz), 7.59 (1H, d, CHarom, J=8.8Hz), 7.43-7.33 (2H, m, ), 7.28 ( 1H, s, CHarom), 6.69 (1H, s, CHarom), 6.54 (1H, d, CHarom, J=7.6Hz), 4.58 (1H, d, J=12.8Hz), 4.30 (1H, d, J=12.8Hz), 3.78-3.75 (2H, m), .65 (1H, m), 3.46 (2H, t), 2.92-2.88 (2H, m), 2.45- 2.40 (1H, m), 2.24 (3H, s), 2.05-1.95 (2H, m), 1.93-1.89 (2H, m), 1.77-1.70 (4H, m), 1.34-1.24 (2H, m). (ND: not determined).

Example 30-bis: (S)(3-amin0pyrrolidinyl)—N-(5-(3,5-diflu0r0phenylthi0)—1H- pyrazolo [3,4-b] pyridinyl)—2-(tetrahydr0-2H-pyranylamin0)benzamide o O F S | N N N N F NH2 876 pl (20 eq) of triethylamine is added to a solution of 238 mg (0.314 mmol) of (S)-N— (5-(3,5-difluoropheny1thio)-1H—pyrazolo[3,4-b]pyridiny1)(2,2,2-trifluoro-N- (tetrahydro-2H—pyrany1)acetamido)(3-(2,2,2-trifluoroacetamido)pyrrolidin y1)benzamide in 6 m1 of methanol. The reaction medium is stirred at 65°C for 4 hours.

After returning to room temperature, 8 m1 of n-butanol and 260 mg (6 eq) of potassium carbonate are added. The reaction medium is stirred at 80°C for 24 hours. After returning to room temperature, the solvents are evaporated, water is added and the product is ted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried on ium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (8:2 dichloromethane/methanol as eluent) to yield 87 mg (yield=49%) of (S)(3-aminopyrrolidiny1)-N-(5-(3,5- difluorophenylthio)- 1H-pyrazolo [3 ,4-b]pyrazine-3 -y1)(tetrahydro-2H—pyran ylamino)benzamide in the form of a brown .

LCMS (E1, m/z): (M+1) 566.24. 1H NMR: 6H ppm (400 MHz, DMSO): 10.46 (1H, bs, NH), 8.60 (1H, s, ), 8.50 (1H, s, CHamm), 8.26 (1H, d, NH), 7.78 (1H, d, CHamm), 7.08 (1H, t, CHarom), 6.86 (2H, d, CHarom), 5.86 (1H, dd, CHarom), 5.71 (1H, d, ), 3.80-3.88 (2H, m, CH), 3.63- 3.70 (2H, m, CH), 3.40-3.55 (5H, m, CH), 3.01-3.08 (1H, m, CH), 2.08-2.13 (1H, m, CH), 1.92-1.99 (2H, m, CH3), 1.76-1.82 (1H, m, CH), 1.30-1.41 (2H, m, Cprranone).

Examples of method F2: reduction Example 31: N-(S-(3,5—diflu0r0phenethyl)—1H-pyrazolo[3,4-b]pyridinyl)—4-(4— methylpiperazinyl)—2-(tetrahydr0-2H-pyranylamin0)benzamide 10 mg of 10% Pd/C is added to 100 mg (0.175 mmol) of N—(5-((3,5- difluorophenyl)ethyny1)- 1H-pyrazolo [3 ,4-b]pyridin-3 -y1)(4-methy1piperaziny1) hydro-2H-pyrany1amino)benzamide in solution in a mixture of 10 m1 of tetrahydrofuran and 5 m1 of methanol before placing the reaction medium under an atmosphere of hydrogen. The reaction mixture is stirred for 12 hours at room temperature and then filtered on Celite and concentrated. 62 mg (yield=60%) of N—(5- (3 , 5-difluorophenethy1)-1H-pyrazolo[3 yridin-3 -y1)(4-methy1piperaziny1) (tetrahydro-2H-pyrany1amino)benzamide are isolated in the form of a white solid.

LCMS (E1, m/z): (M+1) 576.23. 1H NMR: 6prm (400MHz, DMSO): 13.14 (1H, bs, NH), 10.32 (1H, bs, NH), 8.40 (1H, d, CHamm), 8.22 (1H, d, NH), 7.96 (1H, d, CHamm), 7.80 (1H, d, CHamm), 7.03-6.98 (3H, m, CHamm), 6.23 (1H, d, CHarom), 6.16 (1H, bs, CHarom), 3.84-3.81 (2H, dt, CH), 3.70 (1H, m, CH), .46 (2H, m, CH), 3.04—2.93 (4H, m, CH), 2.59-2.69 (4H, m, CH), 2.42-2.46 (4H, m, CH), 2.38 (3H, s, CH3), 1.96-1.93 (2H, m, CH), 1.40—1.33 (2H, m, CH).

The following derivative was obtained according to the same method: nm—I- N-(5 -(3 , 5 -difluorophenethyl)- 1H- pyrazolo [3 ,4-b]pyrazin-3 -y1)(4_ methylpiperazinyl)(tetrahydro- 2H-pyranylamino)benzamide ** HNMR, dmso-d6, EX. : 31-1: 13.68 (1H, sl, NH), 10.11 (1H, s, NH), 8.52 (1H, s, CHarom), 8.35 (1H, dl, NH), 7.82 (1H, d, CHarom, J=9Hz), 7.05-6.97 (3H, m, CHarom), 6.27 (1H, dd, CHarom), 6.14 (1H, s, CHarom), 3.83-3.76 (2H, m), 3.74-3.64 (1H, m), 3.47 (2H, t), 3.32-3.20 (6H, m), 3.07 (2H, dd), 2.44 (4H, dd), 2.23 (3H, s), 1.91 (2H, d), .27 (2H, m). e 32: 5-(3,5-diflu0rophenylthi0)—N-(4—(4-methylpiperazinyl)—2- hydro-ZH-pyranylamin0)benzyl)—1H-pyrazolo [3,4-b] pyridinamine F s N N.N 100 mg (0.173 mmol) of N-(5-(3,5-difluorophenylthio)H-pyrazolo[3,4-b]pyridine yl)(4-methylpiperazineyl)(tetrahydro-2H-pyranylamino)benzamide is added, in small fractions, to a solution of 19.64 mg (0.518 mmol) of LiAlH4 in 3 ml of anhydrous tetrahydrofuran under argon at 0°C. The on e is heated at 90°C for 15 hours. An additional portion of 20 mg of LiAlH4 is then added and the reaction medium stirred at 90°C for 5 hours. 45 ul of water at 0°C is then added to the reaction mixture, followed by 45 ul of sodium hydroxide (15% wt) and finally 120 pl of water.

The reaction mixture is stirred at 25°C for 1 hour and then filtered on Dicalite. After evaporation of the solvents, the crude product is purified by chromatography. 16.80 mg (17%) of 5-(3 , 5-difluorophenylthio)-N—(4-(4-methylpiperazinyl)(tetrahydro-2H- pyranylamino)benzyl)-1H-pyrazolo[3,4-b]pyridinamine in the form of a yellow solid is obtained.

LCMS (E1, m/z): (M+1) 566.68. 1H NMR: 6H ppm (400 MHz, DMSO): 12.57 (1H, bs, NH), 8.45 (2H, d, CHamm), 6.97- 7.06 (2H, m, CHamm), 6.73-6.75 (2H, m, CHamm), 6.65 (1H, t, NH), 6.13-6.19 (2H, m, CHamm), 4.98 (1H, d, NH), 4.30 (2H, m, CH2), .77 (2H, m, CH), 3.60 (1H, m, CH), 3.45—3.50 (2H, m, CH), 3.04 (4H, m, CH), 2.42 (4H, m, CH), 2.18 (3H, s, CH3), 1.80-1.83 (2H, m, CH), 1.27—1.32 (2H, m, CH).

The following derivatives were obtained according to the same method: -(3 ,5 rophenylthio)-N- (4-(4-methylpiperazinyl)- 32- 2-(tetrahydro-2H-pyran N,ArXC,CH,N H 1% 567.3 ylam1no)benzyl)-1H-. 1 pyrazolo [4, 3 -b]pyrazin-3 - amine Example 33: 2-(4—amin0phenyl)-N-(5-(3,5—diflu0r0phenylthi0)—1H-pyrazolo[3,4- b] pyridinyl)acetamide F S N N.N A solution of 152 mg (2.72 mmol) of iron and 70 mg (1.3 mmol) of ammonium de in 100 pl of water is added to a solution of 0.24g (0.544 mmol) of N—(5-(3,5- difluorophenylthio)- azolo [3 ,4-b]pyridin-3 -yl)(4-nitrophenyl)acetamide in ml of a 2:1 ethanol/water mixture. Several drops of acetic acid are added to this mixture and it is heated at 60°C for 4 hours. After cooling and concentration of the solvents, the crude reaction product is extracted with ethyl acetate and is washed with ted sodium bicarbonate solution. The organic phases are combined, dried on magnesium e and then concentrated. The crude product is purified by silica gel chromatography eOH) to yield 11 mg (4%) of minophenyl)-N-(5-(3,5- difluorophenylthio)-1H-pyrazolo[3,4-b]pyridinyl) acetamide in the form of a brown solid.

LCMS (E1, m/z): (M+1) 412.09. 1H NMR: 6H ppm (400MHz, DMSO): 13.60 (1H, bs, NH), 10.96 (1H, bs, NH), 8.68 (1H, d, CHamm), 8.55 (1H, d, CHamm), 7.06 (1H, m, CHamm), 6.98 (2H, d, CHamm), 6.79 (2H, m, CHamm), 6.50 (2H, m, CHamm), 4.92 (2H, s, NH), 3.51 (2H, m, CH2).

Examples of method F3: sulfide oxidation Example 34: 5-(3,5-difluorophenylsulfonyl)—1H-pyrazolo[3,4-b]pyridinamine O\\ I? N H2 F S\\ |,NN A solution of 663 mg (1.078 mmol) of oxone in 1.1 ml of water is added to a solution of 300 mg (1.078 mmol) of 5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridinamine in 10 ml of a 1:1 mixture of tetrahydrofuran and methanol at 0°C. The reaction mixture is stirred at room temperature for 16 hours. An additional portion of 663 mg of oxone at 0°C is then added and the reaction medium stirred at room temperature for 24 hours.

The solvents are evaporated and the reaction medium is diluted with sodium bicarbonate solution, ted with ethyl acetate, dried on MgSO4 and then concentrated to yield 340 mg (81%) of 5-(3,5-difluorophenylsulfonyl)-1H-pyrazolo[3,4- b]pyridinamine in the form of a yellow solid.

LCMS (E1, m/z): (M+1) 311.03. thflflhoHpmnGMONflh,DNBO)1272OH,MgNH)892(HLd,CHmm)884 (1H, d, CHamm), 7.89-8.01 (1H, d, CHamm), 7.62-7.80 (2H, m, CHamm), 6.06 (2H, bs, The following compounds were also obtained by this : (3 5— difluorobenzylsulfonyl)- azolo[3 ,4- b]pyridin-3 -amine utyl 5-(3,5- dichlorophenylsulfonyl)- lH-pyrazolo[4,3- b]pyridinylcarbamate ** 1H NMR, DMSO-d6, Ex.: 33-2: 12.64 (1H, bs, NH), 8.56 (1H, d, CHamm), 8.49 (1H, d, CHamm), 7.24 (lH, ddd, CHamm), 6.94 (2H, bd, CHamm), 6.03 (2H, bs, NH), 4.80 (2H, s, CH). (ND: not determined).

Alternatively, a protection step can be carried out before the oxidation reaction, followed by a deprotection step which can lead to the preparation of the corresponding sulfones or sulfoxides.

Example 34-bis: 5-(3,5-diflu0r0phenylsulfinyl)-1H-pyrazolo[4,3-b]pyrazinamine Orflr 0.55 mL of triethylamine and 22 mg of 4-dimethylaminopyridine are added under argon to a on of 500 mg (1.790 mmol) of 5-(3,5-difluorophenylthio)-lH-pyrazolo[3,4- zinamine in 10 mL of tetrahydrofurane. The solution is stirred at 0°C and 0.915 mL of di-tert-butyl dicarbonate is added and the reaction medium is stirred overnight. An aqueous fraction is added to the reaction medium which is then extracted with ethyl acetate. The organic phases are dried on MgSO4 and concentrated in vacuum to give a crude product which is used in the oxidation step without further purification.

The crude product obtained is dissolved in 10 mL of a 1:1 mixture of tetrahydrofurane and ol at 0°C and then a solution of 1.103 g (1.794 mmol) of oxone in 2 mL of water is added. The reaction medium is d at room temperature for 16 hours. An additional portion of 550 mg of oxone is then added and the reaction medium is stirred at room temperature for 5 hours. The solvents are evaporated and the reaction medium is diluted with a sodium bicarbonate on, extracted with ethyl acetate, dried on magnesium e and concentrated to lead to a mixture of the corresponding e and sulfoxide which are used without further purification in the ection step. 0.373 mL of TFA in 4 mL of anhydrous THF is added at 0°C to a solution of 600 mg of the previously obtained e in 6 mL of dichloromethane. The mixture is d 1 hour at room temperature and an additional portion of 4 equivalents of TFA in 4 mL of THF is added. After 1 hour of stirring, this operation is repeated and the reaction medium is stirred for a total time of 3h45. The solvents are evaporated and the reaction medium is diluted with a potassium carbonate solution, extracted with ethyl acetate, dried on magnesium sulfate and concentrated to yield a 1:1 mixture of 5-(3,5- difluorophenylsulfonyl)-1H-pyrazolo[3,4-b]pyrazinamine and 5-(3,5-difluorophenyl sulfinyl)-1H-pyrazolo[3,4-b]pyrazinamine. This mixture is used in the following steps without further purification.

The ing compounds were also obtained by this method: ArX Y1 I \ Y4 fl i Mass MH+ -(2, 5 -difluoropheny1su1fonyl)-1H- 5 8% (M+1) pyrazolo [4,3 -b]pyridin-3 -amine 3 steps 3 10.9 -(3 5 -dichloropheny1su1fony1)-1H- 3 8% , (M+ 1) pyrazolo[4,3-b]pyridin-3 -amine 3 steps 342.8 -(2,5-dichloropheny1su1fony1)-1H- (M+1) pyrazolo[4,3-b]pyridin-3 -amine 342.9 -(3,5-difluorobenzylsulfonyl)-1H- (M+1) pyrazolo[4,3-b]pyridin-3 -amine 325 .0 -(2,5-difluorobenzylsulfonyl)-1H- (M+1) pyrazolo[4,3-b]pyridin-3 -amine 325.0 -(2,5-difluorobenzy1sulfiny1)-1H- (M+1) lo[4,3-b]pyridin-3 -amine 308.9 -(2, 5 orobenzy1sulfonyl)-1H- pyrazolo [4,3 -b]pyridin-3 -amine -(2, 5 -dichlorobenzy1sulfiny1)-1H- pyrazolo[4,3-b]pyridin-3 -amine ** H NMR, DMSO-d6, EX.: 34bis-1: 12.31 (1H, sl, NH), 8.08-8.18 (1H, m, CHarom), 8.05 (1H, d, CHarom, J=11.6Hz), 7.97 (1H, d, CHarom, J=11.6Hz), 7.87-7.93 (1H, m, CHarom), 7.64-7.76 (1H, m, CHarom), 5.81 (2H, sl, NHZ). 34bis-2: 12.32 (1H, sl, NH), 7.94-8.11 (5H, m, CHarom), 5.85 (2H, 31, NH2). 34bis-3: 12.34 (1H, sl, NH), 8.27 (1H, s, CHarom), 8.12 (1H, d, CHarom, J=11.6Hz), 8.01 (1H, d, CHarom, J=11.6Hz), 7.82- 7.89 (1H, m, ), 7.67 (1H, d, , J=11.2Hz), 5.70 (2H, sl, NHZ). 34bis-4: 12.28 (1H, 31, NH), 7.89 (1H, d, CHarom, J=8.8Hz), 7.68 (1H, d, CHarom, J=8.8Hz), 7.21 (1H, m, CHarom), 6.91-6.97 (2H, m, CHarom), 5.87 (2H, s, NH2), 4.94 (2H, s, CH). 34bis-5: 12.28 (1H, sl, NH), 7.89 (1H, d, CHarom, J=8.8Hz), 7.68 (1H, d, CHarom, J=8.8Hz), 7.20-7.25 (2H, m, ), 7.10-7.15 (1H, m, CHarom), 5.84 (2H, s, NH2), 4.87 (2H, s, CH). 6: 12.04 (1H, s, NH), 7.87 (1H, d, CHarom, J=8.8Hz), 7.40 (1H, d, CHarom, J=8.8Hz), 7.10-7.25 (2H, m, CHarom), 6.90-6.97 (1H, m, CHarom), 5.61 (2H, s, NH2), 4.47 (1H, d, CH, J=13.2Hz), 4.18 (1H, d, CH, J=13.2Hz). 34bis-7: 12.28 (1H, s, NH), 7.89 (1H, d, CHarom, J=8.8Hz), 7.64 (1H, d, , J=8.8Hz), 7.40-7.50 (3H, m, CHarom), 5.81 (2H, s, NH2), 4.96 (2H, s, CH).

Example of method F4: demethylation Example 35: 3,S-difluorophenylthi0)hydr0xy-1H-pyrazolo[3,4-b]pyridin- 3-yl)—4-(4-methylpiperazinyl)—2-(tetrahydro-ZH-pyranylamin0)benzamide FQOIIPA/I:Ns F Or 443 pl (3 eq) of a solution of 1 M boron tribromide in dichloromethane is added to a solution of 90 mg (0.148 mmol) of N-(5-(3,5-difluorophenylthio)methoxy-1H- pyrazolo [3 ,4-b]pyridin-3 -yl)(4-methylpiperazinyl)(tetrahydro-2H-pyran ylamino)benzamide (example 18) in 4 ml of 1,2-dichloroethane at 0°C. The reaction medium is stirred at 60°C for 3 hours and then cooled in an ice bath before adding methanol. The solvents are evaporated and the residue is redissolved in a mixture of ol and ethyl e. The solid formed is filtered, redissolved in 3 ml of tetrahydrofuran and is added to 1 N soda solution. The reaction medium is stirred for 18 hours at room temperature. The pH of the solution is adjusted to 8-9 and the s phase is extracted with ethyl acetate. The organic phase is dried on magnesium sulfate and the crude product is purified on a silica gel column oromethane/methanol as eluent) to yield 21 mg (24%) of N-(5-(3,5-difluorophenylthio)hydroxy-1H- pyrazolo [3 ,4-b]pyridin-3 -yl)(4-methylpiperazinyl)(tetrahydro-2H-pyran ylamino)benzamide in the form of a yellow powder.

LCMS (E1, m/z): (M+1) 596.13. 1H NMR: 5H ppm (400 MHz, DMSO): 12.96 (1H, broad flat singlet), 12.02 (1H, broad flat singlet), 10.64 (1H, bs, NH), 8.46 (1H, bs), 8.09 (1H, bs), 7.72 (1H, d, , 6.97-7.10 (1H, m, , 6.60-6.74 (2H, m, CHamm), 6.28 (1H, dd, CHamm), 6.13 (1H, d, CHamm), 3.80-3.90 (2H, m, Cprmnone), 3.65-3.77 (1H, m, Cprmnone), 3.50 (2H, t, Cprmnone), 3.25—3.32 (4H, m, 2*CH2), 2.37—2.45 (4H, m, 2*CH2), 2.22 (3H, s, CH3), .00 (2H, m, Cprmnone), 1.28-1.43 (2H, m, Cprranone).

II. Biological tests of the compounds according to the invention - Test for measuring tion of ALK kinase: A ViewPlate microplate rd) is incubated with 0.1 mg/ml GST-PLCyl substrate (purified recombinant form) in phosphate buffer (PBS, pH 7.4) (100 ul/well) for one hour under stirring. The plate is then saturated with blocking solution comprising 5% bovine serum albumin (BSA) (Sigma) in PBS , pH 7.4.

After having added a compound according to the invention to the desired final tration (typical range between 30 HM and 10 nM), the reaction is carried out by adding 180 ng/ml ALK to a reaction buffer comprised of 13 mM Tris, pH 7.5 (Sigma), 6.5 mM MgC12 (Merck), 0.65 mM threitol (DTT) (Acros), 39 mM sodium [3- glycerophosphate (TCI), 0.65 mM sodium orthovanadate (Sigma), and 250 uM ATP (Sigma). Incubation is carried out for 30 minutes at 30°C under stirring.

After three washings under stirring in 0.1% PBS/Tween-20 buffer ), an anti-phosphotyrosine antibody, coupled with HRP (UB1) diluted to 1/ 1000 in 5 mg/ml PBS/BSA buffer, is incubated for one hour with stirring. After three new washings in 0.1% PBS/Tween-20, the wells are incubated for two minutes with 100 pl of SuperSignal ELISA mixture (Pierce).

The signal is read in luminescence mode using a luminometer (SpectraMaX M5e, Molecular Devices).

IC50s are determined by nonlinear regression on the basis of a sigmoidal dose/response onship model, wherein the Hill coefficient is left variable, carried out on the GraphPad software package according to the algorithm provided.

- Test for measuring tion of cell (Karpas 299) proliferation: The antiproliferative activities of the compounds according to the invention were measured by the ATPlite technique n Elmer).

Nonadherent human anaplastic large-cell lymphoma cells (Karpas 299) are inoculated in l plates (300,000 cells/ml) at day l, at a concentration compatible with logarithmic growth for the 72 hours required for the tion of the compounds.

All of the cells are treated at day l and then placed in an incubator at 37°C under an here of 5% C02. Cell viability is evaluated at day 4 by ng released ATP, which is characteristic of viable cells. IC50s are determined by nonlinear regression on the basis of a sigmoidal dose/response relationship model, wherein the Hill coefficient is left variable, carried out on the GraphPad software package according to the algorithm provided.

The results of these two tests ed with the compounds of the invention are indicated below: -Enzymatic inhibition of Karpas 299 cell proliferation ALK (IC50, uM) inhibition (IC50, uM) ——2.2 (ND: not determined) - Pharmacological activity in vivo The molecules described and tested eXhibit marked antitumor activity in vivo which is expressed, in an cted manner, by a particularly wide therapeutic indeX, thus suggesting that these compounds are particularly well tolerated. This was demonstrated by evaluating the effects in vivo of the compounds on a human anaplastic large-cell lymphoma (ALCL) tumor model. The compounds were administered orally at various doses on a daily schedule to mice with ALCL tumors grafted subcutaneously.

Tumor size was ed regularly during the study and the animals were weighed several times per week in order to identify any adverse effects. A compound is declared active if it induces tion of ALCL tumor growth by at least 58%. Several compounds of the present invention, in particular molecules 30 and 30-9, induced 100% inhibition of tumor growth, with no adverse effects, which corresponds to complete regression of the tumors.

Furthermore, the molecules described and tested have general pharmacological ties which seem quite favorable. Notably, they accumulate within the experimental tumors in a long-lasting manner, after their administration in vivo. To that end, ALCL tumors were grafted subcutaneously in the mice and then when the tumors reached a size of approximately 70-130 mm3 the compounds were administered orally in a therapeutically-active dose. The tumors were d at various times after the administration of the compounds and then . The ce of the compounds within the ALCL tumors sampled was then investigated by assays using chromatography with UV and mass.

- Test for measuring inhibition of a panel of kinases: These s are produced by Millipore and are screened according to the manufacturer’s protocols.

The results are presented in the table below: Enzyme inhibition (IC50,OnM) Kinases —0-9

Claims (42)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A compound of following general formula (I): or a pharmaceutically able salt or solvate of same, a tautomer of same, or a 5 isomer or e of stereoisomers of same in any proportions, wherein: - Y1 and Y4 each represent, independently of each other, a CH group or a nitrogen atom, - Y2 represents a C-X-Ar group and Y3 represents a nitrogen atom or a C-W group, or 10 - Y2 represents a nitrogen atom or a CH group and Y3 represents a C-X-Ar group, on the ion that: at least one and at most two Y1, Y2, Y3, and Y4 groups represent a nitrogen atom, Y2 and Y4 cannot represent a nitrogen atom at the same time, 15 - Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (C1-C6)alkyl, (C1-C6)haloalkyl, )haloalkoxy, (C1- C6)halothioalkoxy, CN, NO2, OR11, SR12, NR13R14, CO2R15, CONR16RI7, SO2R18, SO2NR19R20, COR21, NR22COR23, NR24SO2R25, and 7R28 and/or optionally fused to a heterocycle, 20 - X represents a divalent group selected from O, S, S(O), S(O)2, NR4, S(NR4), S(O)(NR4), S(O)2(NR4), NR4S(O), NR4S(O)2, CH2, CH2S, CH2S(O), CH2S(O)2, SCH2, S(O)CH2, S(O)2CH2, CH2CH2, CH=CH, CC, CH2O, OCH2, NR4CH2, and CH2NR4, - W represents an R5, SR5, OR5 or NR5R6 group, - U represents a CH2 or NH group, one or more hydrogen atoms which may be replaced by a (C1-C6)alkyl group, - V represents C(O), C(S) or CH2, - n represents 0 or 1, - R1 represents a hydrogen atom, or an OR7 or NR7R8 group, 5 - R2 represents a hydrogen atom, an optionally substituted heterocycle, NO2, OR9 or NR9R10, - R3, R4, R11 to R25 and R27 to R28 each represent, independently of each other, a en atom or a (C1-C6)alkyl group, - R5 and R6 each represent, independently of each other, a en atom or a (C1- 10 C6)alkyl, optionally substituted aryl or optionally substituted benzyl group, - R7, R8, R9 and R10 each represent, independently of each other, a hydrogen atom or an optionally substituted (C1-C6)alkyl or 2)cycloalkyl group or an optionally substituted heterocycle, and - R26 represents a (C1-C6)alkyl group.

2. The compound according to claim 1, wherein the nd is a mixture of enantiomers.

3. The compound according to claim 1, wherein the nd is a racemic mixture.

4. The compound according to claim 1, wherein: - Y1 and/or Y4 = N, - Y2=CH or C-X-Ar, and - Y3=C-W or C-X-Ar.

5. The compound according to any one of claims 1 to 4, wherein X represents a divalent group ed from S, S(O), S(O)2, NR4, CH2, CH2S, CH2S(O), CH2S(O)2, CH2O, CH2NR4, NHS(O)2, SCH2, S(O)CH2, S(O)2CH2, S(O)2NH, OCH2, NR4CH2, CH2CH2, CH=CH, and CC.

6. The compound according to claims 5, wherein X is selected from S, S(O), S(O)2, NR4, CH2, SCH2, S(O)CH2, S(O)2CH2, S(O)2NH, , CC, OCH2, and NR4CH2.

7. The compound according to claim 5, n X represents a divalent group selected from S, S(O)2, CH2, SCH2, S(O)2CH2, S(O)2NH, CH2CH2, and CC wherein the first atom of these groups is bound to atom C of chain C-X-Ar.

8. The compound according to any one of claims 1 to 7, wherein Ar represents an aryl 5 group.

9. The compound ing to claim 8, wherein Ar is selected from phenyl, optionally substituted by one or more groups selected from a halogen atom, (C1-C6)alkyl, (C1- C6)haloalkyl, (C1-C6)haloalkoxy, (C1-C6)halothioalkoxy, CN, NO2, OR11, SR12, NR13R14, 10 CO2R15, and CONR16R17, SO2R18, SO2NR19R20, COR21, NR22COR23 or NR24SO2R25; or a pyridine group.

10. The compound ing to claim 8, wherein Ar ents a group selected from the following groups:

11. The compound according to any one of claims 1 to 10, wherein W represents an R5, SR5, OR5 or NR5R6 group, with R5 and R6 representing, independently of each other, a hydrogen atom or a (C1-C6)alkyl group. 20

12. The compound according to any one of claims 1 to 11, wherein: - R3=H, - U=CH2 or NH, - V=C(O) or C(S), and - n=0 or 1.

13. The nd according to claim 12, n V=C(O).

14. The compound according to claim 12 or claim 13, n n=0.

15. The compound according to any one of claims 1 to 14, wherein R1 represents a 5 en atom or an NR7R8 group, with R7 representing a hydrogen atom and R8 representing an optionally substituted (C3-C12)cycloalkyl group or an optionally substituted heterocycle.

16. The compound according to claim 15, wherein R1 represents one of the following groups:

17. The compound according to any one of claims 1 to 16, wherein R2 represents NO2, NR9R10 or a heterocycle optionally tuted by (C1-C6)alkyl or NH2.

18. The nd according to claim 17, wherein R2 represents one of the following groups:

19. The compound according to any one of claims 1 to 18, wherein it is selected from the 20 following compounds: 156 156 162 162

20. A compound according to any one of claims 1 to 19, for use as a drug. 5

21. A compound according to any one of claims 1 to 19, for use as a drug intended for the treatment of cancer, inflammation and neurodegenerative es.

22. A compound according to claim 21, for use as a drug intended for the treatment of Alzheimer's disease.

23. A compound according to any one of claims 1 to 19, for use as a drug intended for the treatment of cancer.

24. A compound ing to any one of claims 1 to 19, for use as an inhibitor of kinases.

25. A compound ing to claim 24, for use as an inhibitor of ALK, Abl and/or c-Src.

26. A compound according to any one of claims 1 to 19, for use as a drug intended for the treatment of a disease associated with a kinase.

27. A nd according to claim 26, for the treatment of a disease associated with ALK, Abl and/or c-Src.

28. A ceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 19, and at least one pharmaceutically acceptable ent.

29. The pharmaceutical composition ing to claim 28, further comprising at least one other active ingredient.

30. A pharmaceutical composition comprising: 10 (i) at least one nd of formula (I) according to any one of claims 1 to 19, and (ii) at least one other active ingredient, as a combination t for simultaneous, separate or sequential use.

31. A pharmaceutical composition according to claim 29 or claim 30, wherein the one 15 other active ingredient is an anticancer agent.

32. A method for the preparation of a compound of formula (I) according to any one of claims 1 to 19, wherein V=C(O) or C(S), comprising the following successive steps: (al) coupling between a compound of following formula (A): wherein Y1, 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): 25 wherein R1, R2, U and n are as defined in claim 1, V=C(O) or C(S), and R30=OH or a leaving group, to yield a compound of following formula (C): wherein Y1, Y2, Y3, Y4, R1, R2, U and n are as defined in claim 1, R29 is as defined 5 above and V=C(O) or C(S), (b1) optionally substitution of the nitrogen atom bound to V of the nd of formula (C) ed in the preceding step with an R3 group as defined in claim 1, other than H and/or deprotection of the nitrogen atom carrying an R29 group representing an N- ting group to yield a compound of formula (I) with V=C(O) or C(S), 10 (c1) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable salt of same.

33. A method according to claim 32, wherein V=C(O). 15

34. A method according to claim 32 or claim 33, wherein R30=OH or Cl.

35. A method according to any one of claims 32 to 34 wherein U=CH2.

36. A method for the preparation of a compound of formula (I) according to any one of 20 claims 1 to 19, wherein V=CH2, comprising the ing successive steps: (a2) reducing amination reaction between a compound of formula (A) as defined in claim 32 and an aldehyde of ing formula (D): wherein R1, R2, U and n are as defined in claim 1, to yield a nd of following formula (E): 5 wherein Y1, Y2, Y3, Y4, R1, R2, U and n are as defined in claim 1 and R29 is as defined in claim 32, (b2) optionally deprotection of the nitrogen atom carrying an R29 group enting an N- protecting group and/or substitution of the nitrogen atom bound to CH2 with an R3 group other than H of the compound of formula (E) obtained in the preceding step to 10 yield a compound of formula (I) with V=CH2, and (c2) optionally forming of a salt of the compound of a (I) obtained in the ing step to yield a pharmaceutically acceptable salt of same.

37. A method according to claim 36, wherein U=CH2.

38. A method for the preparation of a compound of formula (I) according to any one of claims 1 to 19 wherein V=C(O) or C(S), n=1 and U=NH, comprising the following successive steps: (a3) coupling between a compound of formula (A) as defined in claim 32 and a compound 20 of following formula (F): wherein R1 and R2 are as defined in claim 1 and Z=O or S, to yield a compound of following formula (G): 5 wherein Y1, Y2, Y3, Y4, R1 and R2 are as defined in claim 1, R29 is as defined in claim 32 and Z is 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 C(Z) with an R3 group other than H of the compound of formula (G) obtained in the preceding step to 10 yield a compound of formula (I) with V=C(O) or C(S), n=1 and U=NH, and (c3) optionally forming of a salt of the compound of formula (I) obtained in the preceding step to yield a ceutically acceptable salt of same.

39. A compound of formula (I) prepared by the method of any one of claims 32 to 38.

40. Use of a nd ing to any one of claims 1 to 19 in the ation of a medicament for the treatment of cancer, inflammation and neurodegenerative diseases.

41. Use of a compound ing to any one of claims 1 to 19 in the preparation of a 20 medicament for the treatment of a disease associated with a kinase.

42. A compound according to claim 1, substantially as hereinbefore bed, with reference to any one of the Examples.