OA16493A - Derivatives of azaindazole or diazaindazole type as medicament. - Google Patents

Abstract

The present invention relates to a compound of following formula (I) : <img file="OA16493A_A0001.tif"/> or a pharmaceutically acceptable salt or solvate of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture; as well as to the use of same as a drug, notably intended for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer's disease; to the use of same as a kinase inhibitor; to the pharmaceutical compositions comprising same; and to methods for the preparation of same.

Description

DERIVATIVES OF AZAINDAZOLE OR DIAZAINDAZOLE TYPE AS MEDICAMENT

The présent invention relates to azaindazole and diazaindazole fused bicyclic dérivatives, as well as to the therapeutic use of same, notably in the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer’s disease, as well as to methods for synthesizing same.

Protein kinases are enzymes that play a key rôle in cell signal transduction. They are involved in physiological processes such as cell prolifération, mitosis, différentiation, cell invasion and mobility, and apoptosis, for example.

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

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

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

Several cases of chromosomal translocatïons involving ALK, related to cancer pathologies, hâve already been documented. For example, the fusion protein NPM-ALKç is associated with anaplastic large-cell lymphoma (ALCL) for which an optimal treatment remains to be developed. Similarly, the fusion protein EML4-ALK is associated with tumor development in a subpopulation of patients suffering from nonsmall cell lung cancer. Mutated forms of ALK hâve also been observed in neuroblastoma.

c-Src is also a protein kinase whose activation state proved to be negatively correlated with the survîval of patients suffering from various forms of cancer, including non-small cell lung cancer (Byers L. A. et al., Clin. Cancer Res. 2009, J5(22), 6852-6861).

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

It has been shown in particular that the inhibition of this target, by both biochemical and pharmacological means, induced effects such as a réduction in cell prolifération, 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.

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

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

The compounds of the présent invention thus hâve the property of inhibiting or modulating the enzymatîc activity of protein kinases in general and ALK and c-Src in particular. Consequently, said compounds can be used as drug in the treatment of proliférative diseases such as cancer. Æ

Additîonal indications in inflammation or in affections of the central nervous System may also be pursued.

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

or a pharmaceutically acceptable sait or solvaté of same, a tautomer of same, a stereoisomer or a mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture, wherein:

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

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

- Y3 represents a nitrogen atom or a C-X-Ar or C-W group, on the condition that:

at least one and at most two Υι, Y2, Y3, and Y4 groups represent a nitrogen atom, ¥2 and Y4 cannot represent a nitrogen atom at the same time, when Y2=C-X-Ar, then Yj represents a nitrogen atom or a C-W group, and when Y₃=C-X-Ar, then Y2 represents a nitrogen atom or a CH group,

- Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (Cj-C(î)alkyl, (Ci-Cfijhaioalkyl, (CiCsjhaloalkoxy, (Ci-Cejhalothioalkoxy, CN, NO2, ORn, SR12, NR13R14, CO2R15, CONRieRn, SOîRis, SO2NR19R20, COR21, NR22COR23, NR24SO2R25, and R2ÛNR27R28 and/or optionally fused to a heterocycle,

r

- X represents a divalent group selected from O, S, S(O), S(O)î, NR4, S(NR4), S(O)(NR4), S(O)₂(NR4), NR4S, NR4S(O), NR4S(O)₂, CH_2j CH₂S, CH₂S(O), CH₂S(O)₂, SCH₂, S(O)CH₂, S(O)₂CH_2i ch₂ch₂, ch-ch, c=c, ch₂o, och_2> NR4CH₂₁ and CH2NIU,

- W represents an Rj, SRs, OR? or NRsR^ group,

- U represents a CH₂ or NH group, one or more hydrogen atoms which may be replaced by a (Ci-Ceialkyl group,

- V represents C(O), C(S) or CH₂₁

- n represents 0 or 1,

- Rt represents a hydrogen atom, or an OR7 or NR₇R« group,

- R₂ represents a hydrogen atom, an optionally substituted heterocycle, NO₂, OR9 or NR9R10,

Rj, R4, Ri 1 to R₂j and R₂₇ to R₂s each represent, independently of each other, a hydrogen atom or a (Ci-C6)alkyl group,

- Rj and Re each represent, independently of each other, a hydrogen atom or a (Ci· Ce)alkyl, optionally substituted aryl or optionally substituted benzyl group,

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

- Rîc represents (Ci-Cc)alkyl.

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

The term “halogen” refers to fluorine, chlorine, bromine or iodîne.

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

The term “(Ci-Ceialkoxy” refers to a (Ci-Ce) alkyl chain linked to the rest of the molécule via an oxygen atom. As an example, mention may be made of methoxy, ethoxy, propoxy, isopropoxy, butoxy or reri-butoxy groups.

* >

The term “(Ci-Ceithioalkoxy” refers to a (Cj-Cé) alkyl chain linked to the rest of the molécule via a sulfur atom. As an example, mention may be made of thiomethoxy, thioethoxy, thiopropoxy, thioisopropoxy, thiobutoxy or thio-ZerZ-butoxy groups.

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

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

The term “(Ci-C6)halothioalkoxy refers to a (C]-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 “(Ca-Cujcycloalkyl” refers to cyclic hydrocarbon Systems comprising from 3 to 12 carbon atoms and comprising one or more rings, in particular fused rings. As an example, mention may be made of an adamantyl or cyclohexyl group.

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

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

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

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

In the context of the présent invention, “optionally substituted” means that the group in question is optionally substituted by one or more substituents which may be selected in particular from a halogen atom, (Ci-Csjalkyl, (Ci-C6)haloalkyl, (CjCejhaloalkoxy, (Ci-Cejhalothioalkoxy, CN, NO2, ORn, SR12, NR13R14, CO2R1J, CONRiéRp, SO2R18, SO2NR19R20, COR21, NR22COR23, NR₂4SO2R2î, and R26NR27R28, wherein Ru to R28 are such as defined above.

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

“Pharmaceutically acceptable sait or solvaté” of a compound refers to salts and solvatés which are pharmaceutically acceptable, as defined herein, and which has the desired pharmacological activity of the parent compound.

Acceptable salts for the therapeutic use of the compounds of the présent invention include the conventional nontoxic salts of the compounds of the invention such as those formed from pharmaceutically acceptable organic or inorganic acids or from pharmaceutically acceptable organic or inorganic bases. As an example, mention may be made of salts derived fforn 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, toluenesulfonîc acid, methanesulfonic acid, stearic acid and lactic acid. As an example, mention may be made of salts derived from inorganic bases such as soda, potash or calcium hydroxide and salts derived from organic bases such as lysine or arginine.

ί

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 solvatés for the therapeutic use of the compounds of the présent invention include conventional solvatés such as those formed during the last step of the préparation of the compounds of the invention due to the presence of solvents. As an example, mention may be made of solvatés due to the presence of water or éthanol.

In the context of the présent invention, “stereoisomer” refers to a géométrie isomer or an optical isomer.

Géométrie isomers resuit from the different position of substituents on a double bond which can then hâve a Z or E configuration.

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

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

According to a first embodiment, Yi=N.

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

In particular:

- Yi=CH or N, and advantageously CH,

- Yi=C-X-Ar,

- Y₃=C-W, and

- Y<=N.

According to a second embodiment, Yi and/or Y< represent a nitrogen atom.

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

< à

In particular:

- Yi and/or Y₄ = N,

- Y₂=CH or C-X-Ar, and

- Y₃=C-W or C-X-Ar,

Advantageously, X represents a divalent group selected from O, S, S(O), S(O)₂, NRi, CH₂, CH₂S, CH₂S(O), CH₂S(O)_2i NHS(O)_2j SCH₂, S(O)CH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH_2j CH=CH, C=C, CH₂O, OCH₂, NR+CHî, and CH₂NR4.

In aprticular, X represents a divalent group selected from S, S(O), S(O)₂, NIL, CH₂, CH₂S, CH₂S(O), CH₂S(O)₂, NHS(O)_2j SCH₂, S(O)CH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH_2j C=C, CH₂O, OCH₂, NILCH₂, and CH₂NR|.

More particularly, X may be selected from S, S(O), S(O)₂, CH₂, CH₂S, CH₂S(O), CH₂S(O)_2i NHS(O)₂, SCH₂, S(O)CH₂, S(O)₂CH_2j S(O)₂NH, ch₂ch_2> CH=CH, and OC.

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)_2j CH₂CH₂, and C~C.

X may notably be selected from S, S(O), S(O)_2> NRi, CH₂, SCH₂, S(O)CH₂, S(O)₂CH₂₎ S(O)₂NH, CH₂CH₂, C=C, OCH₂₎ and NR|CH₂; notably from S, S(O)₂, CH₂, SCH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH₂₁ and C=C, wherein the first atom of these groups is bound to atom C of the Ç-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 Ç of the C-X-Ar chain.

Advantageously, Ar represents a heteroaryl group, such as pyridine, or an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-Ce)alkyl_t (Ci-Cfi)haloalkyl, (Ci-Cejhaloalkoxy, (CiCôjhalothioalkoxy, CN, NO₂₁ ORn, SRi_2> NR13R14, CO₂Ru, CONRiôRn, SO₂Ria, S0₂NRisR₂o, COR₂i, NR₂₂COR₂3, and NR₂₄SO₂R₂s; and/or optionally fused to a heterocycle.

More particularly, Ar may represent an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-C₆)alkyl, (CiCejhaloalkyl, (Ci-Cejhaloalkoxy, (Ci-Câ)halothioalkoxy, CN, NO₂, OR_It, SRi₂,

NRbRu, CO2R15, CONRicRp, SO2R18, SO2NR19R20, COR21, NR22COR23, and

NR24SO2R25·

Ar may notably represent an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-C&)alkyl, (Ci-C6)haloalkyl, 5 and CONRicRn, and in particular from a halogen atom such as fluorine, (Ci-Ce)alkyl such as methyl, and CONRigRj7 such as CONH2.

Ar can also represent a pyridïne group.

Ar may notably be selected from the following groups:

notably from the following groups:

> 1 > ï > J

Ar may advantageously represent the group:

*

ΙΟ

F

W may advantageously represent an Rj, SRs, ORj or NRsR« group, and preferabiy R5, OR5 or NR5R4;, with R? and Re representing, independently of each other, a hydrogen atom or a (Ci-Ce)alkyl group.

W may represent in particular H, OMe, Me, OH or NH_2i and notably H. Advantageously, R3 represents a hydrogen atom.

U may represent more partîcularly a CH₂ or NH group.

Advantageously, n may represent 0.

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

According to a particular embodiment of the invention:

- R₃=h,

- U=CH₂orNH,

- 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:

- RjH,

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

- n=0.

Rt may represent more partîcularly a hydrogen atom or an NR₇R« group, with R₇ notably representing a hydrogen atom and R« notably representing an optionally substituted (C3-Ci₂)cycloalkyl group or an optionally substituted heterocycle.

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

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

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

R₂ may represent more particularly an optionally substituted heterocycle 10 (notably substituted by (Ci-Cc)alkyI or NH₂), NO₂ or NR^Rw, with notably R9=Rio=H or else R9 and Rio each represent H or an optionally substituted (Ci-Cejalkyl.

R₂ may represent in particular an optionally substituted heterocycle, notably substituted by (Ci-Ce)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 15 two. The heterocycle may thus be selected from piperazine, piperidine and pyrrolidine.

R₂ may notably represent one of the foliowing groups:

—|-n' n— NH₂, NH(CH₂)₃NMe₂, NMe(CH₂)₃NMe₂, NO₂, \/

NH₂ ; and notably NH₂₍ NO₂, .NH₂

, and ; and in particular

and

\

N-/ ; and more particularly

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

14-2	ο o hnAT^·'' vvsyMn Q γ N h Χ-Νχ	14-10	0 J0 n Jl HN'X-J Çf hnA / T N N n-X Cl Y;
14-11	o fyysty^ Q F 4-N^	15	A Λ 7-0 F H.N >ssA. Q
26-4	F	26-8	0 __*. /'Aj— wr F
27	o _7^û Jl HN-k_J HN-\j ΎΥϊ Y Q Y F V-N X	27-1	À .P hn-CjO f °TY«Q N' B VN X
28	y ,ΝΛ F Vnx	29	ψ UV F

29-a	F	0 HnA X H	_CrO'	30	''Çr8 F	. N	J? HN-^J° HN-\J r\ Q « o
	HjN^O J. .s		HN	0 0 Jf HN-XA				o V^0 hnA3n<j
30-1	(Tj		τΛ	ζ-Α	30-3	X- V		a FS
				ο		l	^JL· N	N \A H p X—N X
			C	hn-CFf				P HN-'Ca0 hn-\j
30-4	Fçsi		r\		30-5	TJ		[$ Ό
	F	< -i* N	N	o Xns		yMeO'' F	Xr	« p
	v HN./		c ΗΝ-Λ	ΛΑ hnX^j				P HN-^J* HN-\A
30-8	Λ		N	Q	30-9	FÇT		ί^Ν ζχ
		w	N H	o X—Νχ		F	V	H O X^N^
30-10	A s.		HN	Q	30-11	V'	û N	o S'o HN<Ï*'X-J Λ Q N X—\
		X	R	o		F	H [ X <Nx
			HN	o a^° HN-VJ				o 0 J] hn-\ / ΗΝ-χ /
			rS
30-12	il i	11*	rf N		30-a	Il T T		N X-A
	AA s F	N	H	o X-N x	F	N	8 O™,

J»

31	F j? hn-XS·/0 F L hn YY Q A O Χ-Νχ	32	rx HN-\> HN-X^J fTstsyîY^n Q V N-Sj F X-N X
32-1	HN-XJ ___( F^X ΥΎ ï P U Y Π F X-Ns	33	Γ N T A F
35	o J''0 it HN-\ J HN-X/ — FyvsrMN Q N ^N-\ F <N X	26-12	O hn A. ΎΥ Yn M Y Y N-X f H Q X
30-69	jf HN-\ / HN-XJ FXx^sV^r4 #7 V A /nh F Y N /	27-2	? fOsXnX^n Ό F Χ-Νχ
27-3	P A J HN-/^3° JL JL ,P hn-x/ f VîYY Γ7 0 1I -N W kA X-ry	27-4	J hnY>° î HN y-k jrS jtMn Q Χ-Νχ
30-73	o _Y° y/ rrCTq ^αλα,ν X-N	14bis	j HN-O H H,N \L ΡγγΠγ^4Ν Q Y YV F Y

I5

30-70	o u hn-Aj hnA j FyvF fMN Q ^ΐΠΛιίΝ \-N%	30-71	o Γ\ Ji hn-Aj HN-A/ YfifAQ N ti py Α-Νχ
30-72	ο /ά> Jl HN^\J o H KF'V-Z 'y' n H .n-') F Χ-Νχ	27-5	j> hn-O HN-\J '-p-rW Uq F
30-13	? hn'^J0 HN-\J FyvvMN Q Y ΡΛ F <-Νχ	30-14	A J t-O pAA/VU Q W Q X-N^
30-15	A JjA	30-16	A J \ n hn-AJ f υγ \-Νχ
30-17	A A> tYq.CL <-Nx	30-18	î o Γ\ A hn-aA7 C1 AA-n'N h o
30-19	TXïpA Χ-Νχ	30-20	A J l· 11 ΗΝ·χ--Ζ. ί;γ\ζ°γ%Α ΑΧ) 4f ^,n Χ-Νχ

30-21	Î ο /-% Υ<^γΝγ\ Q F^F M-/ \	30-22	0 _N. U HnAJ \ Il hn-\/ Α-Νχ
30-23	A hnAT^O1 \— N	30-24	ην-ΑΛ^ J ΛΑ, ΥΎ Y ΙΑ Μ V A Q
30-25	O Ji hn-\j hn-\ / Xpr UÇN	30-26	ο /”% JJ ΗνΑα HN-\j ___N. J ΥΎ T n U kAF^' Χ-Νχ
30-27	ο /”% Ji HN-\J HN-\j WJ'Î \_Νχ	30-28	0 A J! HN-\__/ HNA/ — CK ,N._À r\ YY ΐ P M Y p- A>
30-29	o A <0 Ji hn-\j HN-\J XjÇn	30-30	o f 'b Jl hn-\/ HN-\/ Ckzx ,S___.N__J Γ\ ÏXXv ηλ Q
30-31	wa X-N	30-32	F O /”% i hnAa^ όΎΰ H Q

t

30-33	_ F _ O J Q F<>F h HN\ J T HN Aj — J /A U W	30-34	° J0 J1 hn-Aj hn-A/ XsXNri Q A * o F^-^F X-N^
30-35	A hn-C^O’ fXXs^Qn Χ~Νχ	30-36	O J \> Ji HnA/ HN-\ / — f XXjX ^-4 AF Q
30-37	H -^Jj*X-^° f xYn Q XI <3>	30-38	o J b hnAT^ ___n. J r^X « X XX> m AA q
30-39	c, X χ ri Χλ χχ^Χ	30-40	jl· hn-Xj° rS Tl H i! / y w 'q^
30-41	? HN-O H ψΑχ f^Q'Rv0Xn m.	30-42	ο /^° p ji hn-A/ J zTx> n ïX U t Q
30-43	o J Ko p jj hn-\j ï H hnAj FA	30-44	° ji hn-A__! H hn-AA/ αγγΝγΜΝ q Q

t

I8

30-45	0 r, jj hnA__/ Ç> h ΗΝ-χ / M.	30-46	Ο hn-V^ Ψ kA*N yN-x F mx
30-47	0 f o jj hn-\ / fyvvMn Q y k^'N	30-48	F Al / J< n> ^rr|f n— X N /
30-49	F f-UL hn-V/^ X-Μ rS l X? N H χ <-Νχ	30-50	° JJ HN-\/ hn-A__/ YyYA Q Ύ kA )- N /
30-51	? ΗίΛΤθ crsrj5Q T q	30-52	r F r 0 J o F<L,F Λ HN-\ J T HN-\j — èrY^N Q rP p
30-53	P hn-O° /=\X 33n F p) F	30-54	„ j rO F——\ F ν~Νχ
30-55	1 o J^O Cl? F ÔfTN'ipN Q n'x Q	30-56	Χ-Νχ

30-57	Cl --x ΙίΊ Ο -Λ HA° » Y T% M. A p	30-58	y5u? HN-CrO* d'txiN<L· A
30-59	IX? “^ŸlW A X-> \-Νχ	30-60	lÎVn J «“O 0 lOl ·ν χ-χ A
30-61	o X”% ΧΧ?γΝ A Q T A p X- Νχ	30-62	J HN-O ΤπΧ,πΑ fX) Y 0 YYN ^rx A
30-63	F X HnYZ/* Œ' rNA Q Y r> Χ-Νχ	30-64	j hnY3° WyY5 H Q
30-65	ο y π/ΊΙ-/5 ° hn — c ίΥΑ Ό U- (?	30-66	o X^O Λ Λ ΗΝ-χ/ ck/^/Ά H,N xX Cl XX \j-x h p \-Νχ
30-67	O J HN-θ’ CK^^/P HN Aj	30-68	0 Γ° n Jl HNXJ ° ΠΝ’χΧ „ fYH q Tl A A^ci X-N^

$

The présent invention also has as an object a compound according to the invention of formula (I) such as defined above, to be used as a drug, notably intended for the treatment of cancer, inflammation and neurodegenerative diseases such as

Alzheimer’s disease, in particular cancer.

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

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

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

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

The présent invention also has as an object 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 i

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

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

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

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

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

The active ingrédient may be administered in unit dosage forms of administration, in mixture with standard pharmaceutical carriers, to animais or to humans. The compounds of the invention as active ingrédients 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

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

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

The présent invention also has as an object a pharmaceutical composition comprising:

(i) at least one compound of formula (I) such as defined above, and (ii) at least one other active ingrédient, such as an anti cancer agent, as a combination product for simultaneous, separate or sequential use.

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

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

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

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

nh₂

N

wherein Yi, Y₂, Y3 and Y4 are such as defined above, and R29 represents a hydrogen atom or an N-protecting group, with a compound of foliowing formula (B): x' i

R₂

n (B) wherein R_b R₂, U and n are such as defined above, V=C(O) or C(S), and R)o=OH or a leaving group such as Cl, to yield a compound of foilowing formula (C):

(C) wherein Yj, Y₂, Yj, Y4, Ri, Rï, R39, 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 Rj group other than H and/or deprotection of the nitrogen atom carrying an R29 group representing an Nprotecting group to yield a compound of formula (I) with V=C(O) or C(S), and (cl) optionally forming of a sait of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable sait of same.

In the context of the présent invention, “N-protecting group” refers to any substituent that protects the NH or NH₂ group against undesirable reactions such as the N-protecting groups described in Greene, “Protective Groups in Organic Synthesis (John Wiley & Sons, New York (1981)) and Harrison et aL, “Compendium of Synthetic Organic Methods”, Vols. 1 to 8 (J. Wiley & Sons, 1971 to 1996). N-protecting groups include carbamates, amides, N-alkylated dérivatives, amino acetal dérivatives, N*. ?

benzylated dérivatives, imine dérivatives, enamine dérivatives and N-heteroatom dérivatives. In particular, the N-protecting group consiste of formyl, acetyl, benzoyl, pivaloyl, phenylsulfonyl, trityl (triphenyl methyl), ter/-butyl, benzyl (Bn), tbutyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), ρ-methoxybenzyloxycarbonyl, pnitrobenzyl-oxycarbonyl, trichloroethoxycarbonyl (TROC), allyloxycarbonyl (Alloc), 9fluorenylmethyloxycarbonyl (Fmoc), trifluoro-acetyl, benzyl carbamates (substituted or not) and the like. It may be in particular a trityl, terr-butyl or BOC group.

In the context of the présent invention, “leaving group” refers to a chemical group which may be easily displaced by a nucleophile during a nucleophilic substitution reaction, wherein the nucleophile is more particularly an amine, and notably a primary or secondary amine. Such a leaving group may be more particularly a halogen atom such as a chlorine atom, a mesylate (CHrS(O2)O-), a triflate (CFa-SfO^O-) or a tosylate (p-Me-CcFL-StO^O-).

Step (al):

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

When Rjo⁼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-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), 2-( 1 H-benzotriazole-1 -y 1 )-1,1,3,3 -tetramethyluroniu m hexaflu orophosphate (HBTU), 2-(l H-benzotriazole-l-yl)-l, 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 Nhydroxysuccinimide (NHS), N-hydroxybenzotriazole (HOBt), 3,4-dihydro-3-hydroxy-

4-oxo-l,2,3-benzotriazole (HOOBt), l-hydroxy-7-azabenzotriazole (HAt) or Nhydroxysulfosuccinimide (sulfo NHS). Peptide coupling may moreover be carried out in an aprotic solvent such as tetrahydrofuran, dioxane and dichloromethane.

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

S t

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

Step (b 1):

In the context of the présent invention, “deprotection” refers to the process by which a protecting group is elîmînated once the sélective reaction is completed. Certain protecting groups may be preferred over others due to their convenience or their relative ease of élimination.

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

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

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

Moreover, it may also be necessary to carry out additional steps of functionalization of the molécule by techniques known to the person skilled in the art.

Step (cl):

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

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

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

K f

wherein Rj, R₂, U and n are such as defined above, to yield a compound of following formula (E):

<

NH

^R29 (E) wherein Yi, Y₂, Y₃, Y₄, Ri, R₂, R₂s, 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 Rj group other than H of the compound of formula (E) obtained in the preceding step to yield a compound of formula (I) with V=CH_2> and (c2) optionally forming of a sait of the compound of formula (1) obtained in the preceding step to yield a pharmaceutically acceptable sait of same.

Step ia2):

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

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

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

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

Step (b2): see step (b 1 )

Step (c2): see step (cl)

According to a third embodiment, the présent invention relates to a method for the préparation of a compound of formula (I) according to the invention wherein V=C(O) or C(S), n=l 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 formula (F):

r₂

z (F) wherein Ri and R₂ are such as defined above and Z=O or S, to yield a compound of following formula (G):

wherein Y], Y₂, Y_3] Y₄, Ri, R₂, R₂s, 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 Rj group other than H of the compound of formula (G) obtained in the preceding step to yield a compound of formula (I) with V=C(O) or C(S), n=l and U=NH, and

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

Step (a3):

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

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

The compounds of formula (A) and (F) can be prepared by the methods 10 described in further detail below.

Step (b3): see step (b l )

Step (c3): see step (cl)

Once the compound of formula (I) is obtained by any one of the preceding 15 methods, it may be separated from the reaction medium by techniques well known to the person skilled in the art, and notably by évaporation of the solvent, crystallization and filtration, etc.

The compound obtained may be purified if necessary by techniques well known to the person skilled in the art, and notably by high-performance liquid chromatography 20 (HPLC), silica gel chromatography, recrystallization when the compound is crystalline, etc.

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

r

Method #

Method £

(I)

Ri = NO2, halogen, OH, OMe, SMe, S(O)Me, SO₂Me, OMs, OTf or OTs Rj = H or N-protecting group

Rrt = Hal, OMs, OTs orOTf (Tf represents an -SO2CF3 group and Ts represents a tosyl group)

Diagram lb ' t

Method A:

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

Method Al:

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

NH· w n a (Ha)

Diagram 2

In the context of diagram 2, the optionally substituted 2-chloro-5iodonicotinonitrile (lia) is obtained from the corresponding hydroxynicotinonitrile by the successive use of an iodination agent such as N-iodosuccinimide (NIS), or molecular iodine with an inorganic base such as, for example, K2CO3 or NaîCCh, notably in a polar solvent such as hot DMF, followed by treatment with phosphorus oxychloride, pure or diluted in a high boiling-point non-polar solvent, or any other équivalent chlorination agent well known to the person skîlled in the art. Reaction températures are between -20°C and 200°C. The compound (lia) thus obtained is then transformed into optionally substituted 5-iodo-pyrazolo[3,4-b]pyridine-3-amine (Va) by its reaction, preferably under heat, in the presence of a hydrazine optionally carrying an N-protecting group such as trityl, /erAbutyl 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 étal., Bioorg. Med, Chem. Lett., 2003,13, 1577-1580 and Lijuan Chen et al., Bioorg. Med. Chem. Lett., 2010, 20, 4273-4278. For reasons of convenience, these

1 molécules were obtained by the use of the reaction sequence presented in foilowing diagram 3.

NH.

W N Cl

W N (Vb)

Diagram 3

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

Method A2:

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

OMe OMe NH₂ ,CN

NH_:

N Haï (O

Diagram 4

The optionally functionalized 3-amino-6-iodopyrazine-2-carboxamides are typically obtained in two steps from the corresponding methyl 3-aminopyrazine-216493 carboxylates by iodination in the presence of N-iodosuccinimide or molecular iodine optionally in the presence of a cofactor such as KIO₃, AgCO₂CF₃₎ Ag₂SO₄₁ AlCl₃, CuCl₂ or HgO, followed by a conversion reaction of the methyl ester fonction into carboxamide, notably by the use of ammonia in a polar solvent such as water, methanol or THF at températures varying between 0°C and 100°C. The carboxamide function of the optionally functîonal ized 3-amino-6-iodopyrazine-2-carboxamide is then converted into nitrile by the use of déhydration agents such as, in particular, CC1₄/PPh₃, SOCl₂, PhSO₂CI, P₂Os, TsCI, COCl₂, DCC/py (Ν,Ν’-dicyclohexylcarbodiimide/pyridine) or (COCl)₂ used as the case may be in the presence of an organic base such as pyridine. The preferred method involves the use of phosphorus oxychloride in dimethylformamide (DMF). Deprotection of the dimethylformimidamide function is carried out by treatment with acid such as aqueous hydrochloric acid or any other reagent with équivalent properties. Formation of the pyrazole ring is carried out by a Sandmeyer reaction, well known to the person skilled in the art, followed by a reaction in the presence of a hydrazine, functionalized or not, under conditions as described in the methods above. Aiternatively, the diazonium sait, an intermediate of the Sandmeyer reaction, may be reduced by the use, for example, of tin chloride in an acid medium or any other équivalent agent, in order to form a hydrazine function that can undergo intramolecular cyclization under the effect of heat.

Method A3:

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

I

0	NH1
JL,co2a ^cn X	Base B°2C'vîî''S'^s'S©
vAo™ B.M.k? .
W = A*,Ar. CH;Ar			0
NC COjB >DC« HjN-S	nh2 Base 'y^jî^'s©	(M.1* (	00 W^N^SMe
CN CN
ElQjC CO2B Xe* ^OFI H2N^3	NHî Base		' W OH. NHjAlk, Ar, CHjAr
* HOjC CN

HOOC

CN

SMe

RjNHNHj S^X (Md)(°)lor2

W » OH. OAlk, NHj NHAlk, Alk, Ar. CHjAr Rj»H or N-protecting group

(Alk=(Ci-C6)alkyl, Ai=aryl, CHhAr^benzyl, H=halogen)

Diagram 5 y

·. <

Réaction of the cyanothioacetamide with ethyl 3-ethoxyacrilates variously substituted according to methods described notably by Litrivnor et al. in Russ. Chem. Bull., 1999, 48(1), 195-196 and Tsann-Long Sue/ al. in J. Med. Chem., 1988, 31, 12091215 make it possible to yield access, in two steps, to ethyl 5-cyano-6(methylthio)nicotinates carrying a variable functionality in position 2. These synthèses are typically carried out, for the first step, in an anhydrous polar solvent such as, for example, éthanol at a température ranging between 0°C and 70°C in the presence of an organic base such as methylmorpholine, triethylamine, DIPEA (N,Ndiisopropylethylamine) or DBU (l,8-diazabicyclo[5,4,0]undec-7-ene). The second step of intramolecular cyclization and of alkylation is typically carried out by the heating to a température ranging between 20°C and 100°C of a solution of the intermediate thioamidate in a polar solvent, for example éthanol in the presence of a suitable alkylating agent such as alkyl halide or dialkyl sulfate.

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

Halogénation reactions principalty aim at obtaining iodinated, bromînated or chlorinated dérivatives, more particularly iodinated dérivatives. The latter are typically obtained by a molecular iodine treatment in the presence of a silver sait such as, for example, AgîSOi in a polar solvent such as éthanol at a température ranging between 0°C and 70°C. Alternative methods, notably those based on other salts such as KIO₃, AgCOiCFî, AICI3, CuCl₂ or HgO, or other iodination agents such as Niodosuccinimide, are also considered. The conceivable bromination methods typically rely on agents such as N-bromosuccinimide or dibromine according to methods well known to the person skilled in the art.

In the case in which W=0H (typically resulting from the use of diethyl 2(ethoxymethylene)malonate), the corresponding compounds are protected by an alkylation reaction. This reaction is notably carried out by the use of methyl iodide or bromomethane, and silver carbonate in dioxane, THF, acetonitrile or acetone, or any other équivalent agent such as dimethylsulfate. The 5-halo-2-(methylthio)

I nicotinonitriles obtained are subjected to oxidation of their thîomethoxy fonction, typically by the use of m-CPBA (m-chloroperbenzoic acid), oxone or any other équivalent agent, to lead to the formation of the corresponding sulfoxide. These compounds, which may contain variable quantities of the corresponding sulfone, are engaged in a reaction in the presence of an optionally substituted hydrazine to form the corresponding 5-halogeno-pyrazolo[3,4-b]pyridin-3-amine carrying a variable functionality in position 6.

Method A4:

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

(IVb) (Ve)

Diagram 6

The compounds of general formula (Ilia), acetylated beforehand by one or another of the methods well known to the person skilled in the art, are subjected to the action of isoamyl nitrite, sodium nitrite or any other équivalent organic or inorganic nitrite, in water or acetic acid, for periods typically varying from 1 to 3 days at températures 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 concentrated nitric acid or potassium nitrate in sulfuric acid at températures varying between 0°C and 25°C..xi

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

The nitropyrazoles thus obtained are typically reduced into aminopyrazoles of general formula (Ve) by the use of SnCl₂ in hydrochloric acid. Alternative methods include the use of iron, zinc or tin in acidic conditions and methods of catalytic hydrogénation in the presence of complexes of platinum, nickel or Pd/C under an atmosphère of hydrogen or in the presence of équivalent 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 Bit

Method B1 is represented in diagram 7 below, with W notably representing H, (Cj-C6)alkyl, aryl or benzyl.

^Clvy (CN-l /'γ^Νγ^0Ν NaSH /A^CN Ar^S n CN vAyPN0₂ V7 y< no₂ wAZ no₂ w^y₄ no₂ (Via)

Diagram 7

The 3-nitro-6-thioxo-l,6-dihydropyridin-2-carbonitrile and 3-nitro-6-thioxo-l,6dihydropyrazine-2-carbonitrile dérivatives, optionally functionalized in position 5, are typically obtained from the correspondîng 2,6-dichloro-3-nitropyridînes or 2,6-dichloro-

·» t

3-nitropyrazines by the successive reactions of a cyanide sait, such as copper cyanide, in a high boiling-point polar solvent such as N-methylpyrrolîdone at températures ranging between 100°C and 200°C; followed by the reaction of aqueous sodium hydrosulfite in a polar solvent. These compounds are then alkylated, for example by the use of a substituted benzyl bromide, in basic medium, according to methods well known to the person skilled in the art. The preferred protocol includes the use of an aprotic and anhydrous polar solvent such as acetone carrid at its boiling point and an organic base such as pyridine, triethylamine or DIPEA, or an inorganic base such as sodium, potassium or calcium carbonate. Reactions for reducing the nitro fonction in amine are preferentially carried out by the use of SnCl₂ in hydrochloric acid. Alternative methods include the use of iron, zinc or tin in acidic conditions and methods of catalytîc hydrogénation in the presence of complexes of platinum, nickel or Pd/C under an atmosphère of hydrogen or in the presence of équivalent agents such as cyclohexadiene, cyclohexene, sodium borohydride or hydrazine.

In certain cases, the product of the réduction reaction, in addition to having a primary amine, has a carboxamide fonction resulting from hydrolysis of the nitrile fonction. In this case, isolation of the corresponding 3-aminopicolinonitriles or 3aminopyrazine-2-carbonitriles may be carried out by déhydration of the carboxamide into nitrile via the use of phosphorus oxychloride in the presence of DMF or any other method well known to the person skilled in the art. Lastly, formation of the amînopyrazole ring is carried out preferentially by the formation of a diazonium, obtaîned by the successive reaction at low température of isoamyl nitrite, sodium nitrite or any other équivalent organic or inorganic nitrite, in water, hydrochloric acid, acetic acid or sulfuric acid, at températures varying between 0°C and 20°C, followed by its réduction into hydrazine and intramolecular cyclization activated by heating of the reaction medium. The réduction reaction is preferentially carried out with tin chloride in acidic conditions but may also be carried out by catalytic hydrogénation 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 fonctional group is substituted by a halogen atom, such as iodine, by the reaction of an adéquate sait, such as Nal. If this option is preferred, formation of the aminopyrazole ring is carried out by the use of a hydrazine, fùnctîonalized or not, in a polar solvent such as éthanol at températures varying between 25°C and 150°C.

Method 132:

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 phénols, thiophenols, benzyl alcohols or thiobenzyl alcohols as well as anilines or benzylamines, fùnctîonalized or not. The general reaction diagram 8a is presented below, notably with W-H, (Ci-Cejalkyl, aryl or benzyl.

Diagram 8a

In the case in which X=O or S, the 6-chloro-3-nitropicolinonitriles and 6-chloro-

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

Alternatively, the use of bases such as pyridine, DIPEA, diisopropylamine, triethylamine, DBU, potassium /erAbutylate, NEt3 or NaH is also possible.

' 1

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

The foilowing steps, up to the compounds of general formula (Vllb), are identical to those documented in method B1 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 coupiing reaction between a benzyl boronate, in acid or ester form, and a 6-chloro-3-nitropicolinonitrile or 6-chloro-

3-nitropyrazine-2-carbonitrile dérivative. It is also well known to the person skilled in the art that catalytic coupiing reactions using alternative catalysis and benzyl dérivatives are also possible. Among these, the Stille reaction, based on tin complexes, or those based on organozinc compounds may be considered.

ï X ⁺

W Y₄ NOa

[Pd°] _r

CN

NH₂

CN

NOj [Red] _r

Ar

(Vig)

1. [ONO]

2. [Red]

(Vif)

Diagram 8b

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

*. » benzyl-3-nitropyrazîne-2-carbonitrile or 5-benzyl-2-nitronicotinonitrile dérivatives for which the following transformation steps are reproduced from method BI above. Method 114:

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

2. U0H

1. AfNHR,/[base]

R2

RjNHNH2

Diagram 9

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

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

The saponification reaction of the product thus obtained, notably by the use of lithium hydroxide in a THF/water mixture, gives access to the corresponding 2-chloro-

5-(N-phenylsulfamoyl)nicotinic acids.

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

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

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

Method B5:

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

HO

CN

Ar [base]

W N

(VII) nh₂

V/'Z'N

...... Rj (Vile)

Diagram 10

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

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

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

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

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

Method B6:

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

h₂n w

CN

Cl

CIO₂S-Ar [base] (Vlj)

RjNHNH₂

(Vi it) ^R‘

Diagram 10a

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

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

Method C:

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

Method Cl:

Method Cl, presented in diagram 11 below, is intended for the préparation of pyrazolopyridines and pyrazolopyrazines functionalized at position 6 with R_n=haiogen,

·· I mesylate, tosylate or triflate, X=O, S, NH, N-(Ci-C.)alkyl, and optionally CH₂ for (Xc) and (Xd), and Rj=H or N-protecting group.

This method can also be used to cany out the synthesis of molécules comprising a diatomtc X group corresponding notably to an ArX group representing: -ArCH₂NH-, AiCH₂N(R4)-, -ArCH₂O-, -ArCH₂S-, -ArCH₂CH₂-, -ArCHCH-, or -ArCC-,

Diagram 11

The 6-hydroxy-2-(methylthio)nicotinonitriles or 5-hydroxy-3-(methylthio) pyrazine-2-carbonitriles are subjected to a dehydrochlorination reaction, typically in the presence of phosphorus oxychloride, with or without solvent, at températures 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. Aiternatively, it is possible to activate the 6hyd roxy-2-(methy lthio)nicotinonit ril es and 5-hydroxy-3 - (methy It hio)pyrazine-2carbonitriles by their dérivation into sulfonic esters via the formation of the corresponding tosylates, mesylates or triflates. If this option is preferred, the use of tosyl, mesyl or triflyl chlorides in a solvent such as toluene, dichloromethane, THF, acetonitrile, acetone or dioxane in the presence of an organic or inorganic base gives access to these dérivatives.

The 6-chloro-2(methylthio)nicotinonitriles and 5-chloro-3-(methylthio)pyrazine2-carbonitriles respectively obtained, or their sulfonic ester analogues if this option is preferred, are then reacted with a nucleophile such as a phénol, 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 teri-butylate or NaH. If necessary, these réactions may be catalyzed by the action of copper and may also be carried out without solvent. Typically, the preferred protocol involves températures ranging between 20°C and l50°C.

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

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

The dérivatives obtaîned by one or another of these methods are then oxidized, typically by the use of m-CPBA or oxone to form the corresponding methyl sulfoxides or methyl sulfones. These compounds, sometimes obtaîned 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 éthanol at températures varying between 25°C and 150°C.

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

Method C2:

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

·. I

(Xlla)

----------*

Diagram 12

(XlVa)^RJ

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

The pyrazolopyridines and pyrazolopyridazines thus obtained are subjected to a dehydrochlorination reaction, typically in the presence of phosphores oxychloride, with or without solvent, at températures varying between 70°C and 180°C. If a solvent is used, a high boiling-point non-polar solvent such as toluene or xylene will be preferred. The optionally substituted 6-chloro-pyrazolo[4,3-c]pyridin-3-amine and 6-chloropyrazolo[4,3-c]pyridazin-3-amine respectively obtained are then reacted with a nucleophile such as a phénol, 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 te/7-butylate or NaH. If necessary, these reactions may be catalyzed by the action of copper and may also be carried out without solvent. Typically, the preferred protocol involves températures ranging between 20°C and 150°C.

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

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

2-benzyl-4,4,5,5-tetramethyl-l,3,2-

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

Method C3:

Method C3, presented in diagram 12a below, is a variant of method Cl based on the regioselective functionalization of 2,6-dichloronicotinonitrile either by an anionic nucteophile 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 obtained in the corresponding pyrazolopyridine, in the case where Yi = CH, is carried out as previously described in method Al.

ArXH, base

ArCH^CI

PdCI₂

Diagram 12a

Method D:

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

Method Dit

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

I

Diagram 13

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

Method D2:

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

Rj=H or N-protecting group «2 (Cul

Rk H or n®Qor 1

Diagram 14^

*. »

This réaction 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 métal sait such as copper iodide (Cul) and an excess of an inorganic base such as potassium carbonate, calcium carbonate or sodium carbonate. The reaction températures typically vary between 50°C and 100°C.

Method D3:

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

Rj=H or N-protecting group

Rî

|Pd·]

or n 0 or I

Diagram 15

Such a reaction is typically carried out by the reaction under an inert atmosphère of a heteroaryl halide with a stoichiometric quantity of an optionally substituted ethynylbenzene in the presence of a catalytic quantity of a palladium complex, for example PdC12(PPhj)2 or Pd(PPhj)4, a catalytic quantity of a copper sait, for example Cul, and an organic base such as triethylamine or DIPEA, or an inorganic base such as potassium or césium carbonate, The protocol generally involves reaction températures ranging between 20°C and 45°C in solvents including DMF, THF, dioxane or diethyl ether.

1

Method E:

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

Method El:

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

Diagram 16

These compounds are synthesized via the corresponding 3-aminopyrazole by the addition of adéquate 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 thionyl chloride or phosphores oxychloride, well known to the person skilled in the art. The condensation of acid chlorides on aminopyrazoles is typically carried out in an aprotic solvent such as tetrahydroforan, 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 conducted in a biphasic system according to the well-known Schotten-Baumann method.

V t

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

Method E2:

Dérivatives 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.

R_k <

NH

Rj=H or N-protecting group

R₂

NH₂

Diagram 17

Reducing amination reactions are typically carried out by mixing adéquate stoichiometric quantities of aminopyrazole and aldéhyde in a solvent such as DCE (dichloroethane), THF or acetonitrile, optionally in the presence of a quantity of water, TFA (trifluoroacetic acid) or acetic acid, by adding successive fractions of a reducing agent such as NaBHi, NaBH(0Ac)î or NaBHaCN. These reactions are typically carried out at room température.

Method E3:

Dérivatives 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.

NH

Z

C nh₂

Rj=H or N-protecting group Z — O or S

NH

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 carried at températures varying between 20°C and the boiling point of the chosen solvent. ïf necessary, recourse to a weakly nucleophilic organic or inorganic base may prove to be necessary. In this case, sodium hydride is a possible option.

Method F: post-synthetic deprotections and modifications

Method Fl: deprotections

The trifluoroacetate protecting groups are removed by the action of an organic base such as triethylamine or pyridine in a polar solvent such as methanol, éthanol or THF at the reflux températures of the solvents used.

The ferf-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. /V

Method F2: alkyne réductions

Ar

[Redl

Rj=H or N-protecting group R_S

Rk H or

Diagram 19

Reactions for reducing diaryl alkynes into diaryl alkanes are typically carried out by catalytic hydrogénation, under hydrogen pressure, in the presence of catalysts such as PtO₂, Pt, Pd/C, Ni or Rh. Altematively, the use of DIBAL-H (diisobutylaluminum hydride) in the presence or the absence of a catalyst such as Cp₂TiCl₂ is conceivable. Method F3: oxidation ofsulfides into sulfones and sulfoxides

Ri

R.

R

Rj=H or N-protecting group

Diagram 20

Oxidation reactions of sulfides into sulfoxides are typically carried out via the use of oxone in a mixture of polar solvents such as THF/MeOH or DMF/water. The optimal reaction températures are typically between 25°C and 50°C.(<f

Many alternative methods are available, and some give the possibility of producing semi-oxidized dérivatives, namely sulfoxides. Such alternative methods include the use of m-CPBA, KMnO₄/MnO₂ in dichloromethane, H₂O₂ (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 H₂O₂ and métal complexes such as Sc(OTf)3 promûtes partial oxidation dérivatives.

Other known methods include, for example, the use of CAN/NaBrO₃ (CAN=ceric ammonium nitrate).

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

EXAMPLES

The following abbreviations are used:

DMSO Dimethylsulfoxide

El

ES

LCMS mg mL

NMR

Dimethylsulfoxide

Electron impact

Electro spray

Liquid chromatography - mass spectrometry milligram milliliter

Nuclear magnetic résonance

I, Synthesis of the compounds according to the invention

Examples of method Al

Example 1: 5-iodo-lH-pyrazolo[3,4-b]pyridine-3-amine nh₂

I

Example la: 2-hydroxy-5-iodonicotinonitrile g (0,5 eq) of N-iodosuccinimide at room température is added to a solution of 10 g (83 mmol) of 2-hydroxynicotinonîtrile in 150 ml of anhydrous dimethylformamide, The reaction mixture is stirred at 60°C. After 30 minutes of stirring, 9 g (0.5 eq) of Niodosuccinimide 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-5iodonicotinonitrile in the form of a beige powder.

LCMS (El, m/z): (M+l) 246.93 ^lHNMR: ÔHppm (400MHz, DMSO): 12.79 (IH, s, OH), 8.36 (IH, d, CH_arom), 8.04 (IH, d, CHarom)·

Example 1b: 2-chloro-5-iodonicotinonitrile

30.7 ml (329 mmol) of phosphorus oxychloride at 0°C and 6 drops of sulfurie acid are added to 9 g (6.6 mmol) of 2-hydroxy-5-iodonicotinonitrile. The reaction mixture is heated at 110°C for 5 hours and then at room température overnight. The reaction mixture is poured in a beaker containing ice and a lîttle water, and a precipitate is formed. The mixture is allowed to gradually return to room température and then is filtered and rinsed with water. The solid is dried to yield 6.8 g (70%) of 2-chloro-5iodonicotinonitrile.

LCMS (El, m/z): (M+l) 265.45 ‘HNMR: ÔH ppm (400 MHz, DMSO): 9.61 (IH, d, CHarom), 9.14 (IH, d, CH_arom).

Example 1: 5-iodo-lH-pyrazoloI3,4-b]pyridine-3-amine

Hydrazine (3.86 ml, 79 mmol) is added at room température to 7 g (26.5 mmol) of a solution of 2-chloro-5-iodonicotinonitrîle in 25 ml of propan-2-ol. The reaction mixture is heated at 85°C for 7 hours and then at room température 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 5-iodo-lH-pyrazolo[3,4-b]pyridine-3-amine,

LCMS (El, m/z): (M+l) 260.95 ‘HNMR: ÔH ppm (400 MHz, DMSO): 12.12 (IH, bs, NH), 8,51(1H, d, CH_arani), 8,45 (IH, d, CHarom)» 5.64 (2H, bs, NH₂). xf

The following compounds were obtained according to the same method.

nh₂

Ex.**	W	Rj I Compound name 1 Yield	Mass MH+
1-2	H	t-butvi 1-teri’buty1 s‘iodo 1H'pyrazoIo[3>4-blpyri^n· 1 ™ 3-amine 0	317.05
1-3	Me	|5-iodo-6-methyl-lH-pyrazolo[3,4-b]pyridin-3- 1 % [amine [ 0	275.02
** *H1	WR, DMSO-d*, Ex. 1-2: 8.55 (1H, bs, CHarom), 8.42 (1H, bs, CHaram), 6.33 (1H,

bs, CH_aroin), l .57 (9H, s, CH).; 1-3: 11.92 (1H, s, NH), 8.55 (1H, s, CHa_ram), 5.59 (2H, bs, NH₂), 2.66 (3H, s, CH₃).

Examnle 2: 5-bromo-lH-pyrazolo[3,4-b]pyridine-3-amine

Examplc 2a; 2-methoxy-nicotinonitriIe

4.98 g (217 mmol) of sodium is added to 80 ml of anhydrous methanol. The reaction medium is stirred at room température for 10 minutes and then 10 g (72.2 mmol) of 2chloronicotinonitrile is added at 0°C. The reaction medium is stirred at 25°C for hours. The reaction is hydrolyzed by slowly adding water at 0°C. After retumingto room température, the precipitate obtained is filtered, rinsed with water and then dried 15 at 50°C to yield 7.85 g (81%) of 2-methoxy-nicotinonitrile in the form of a yellow solid.

LCMS (El, m/z); (M+1) 135.04 ^lH NMR: ÔH ppm (400 MHz, DMSO): 8.46-8.48 (1H, dd, CH_nrom), 8.25-8.27 (1H, dd, CH_urom), 7.17-7.20 (1H, dd, CH_arom), 3.99 (3H, s, CH₃).

Ex a mole 2b; 5-bromo-2-methoxy-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-nicotinonïtrile in 29 ml of acetic acid. The reaction mixture is heated at 70°C ovemight. After retuming to room température, 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-2methoxy-nicotinonitrile in the form of a white solid. XÎ ΐ

LCMS (El, m/z): (M+1) 214.95 'H NMR: ÔH ppm (400 MHz, DMSO): 8.61 (1H, d, CH_arom), 8.60 (1H, d, CH_aram), 3.98 (3H, s, CH₃)

Examplc 2: 5-bromo-lH-pyrazolo[3,4-b]pyridine-3-amine ml (23.47 mmol) of hydrazine is added at room température to 5 g (23.47 mmol) of 5-bromo-2-methoxynicotinonitrile. The reaction medium is carried at 100°C for 3 hours. After retuming to room température, the precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 3.6 g (72%) of 5-bromo-lH-pyrazolo[3,4b]pyridine-3-amine in the form of a yellow solid.

LCMS (El, m/z): (M+1) 214.05 ‘H NMR: ÔH ppm (400 MHz, DMSO): 12.18 (1H, s, NH), 8.38 (1H, d, CH_arom), 8.37 (1H, d, CH_arom), 5.66 (2H, s, NH).

Examples of method A2

Ex ample 3: 5-iodo-lH-pyrazolo[3,4-b)pyrazine-3-amine . . .^NH2

Examplc 3a: methyl 3-amino-6-îodopyrazine-2-carboxylate

1.5 équivalents ofN-îodosuccinimide are added at room température to 5 g (32.7 mmol) of a methyl 3-aminopyrazine-2-carboxylate solution in 25 ml of dimethylformamide. The reaction medium is heated at 65°C for 1 hour, added together with 0.5 équivalents of N-iodosuccinimide and maintained at 65°C for 24 hours. After returning to room température, the solvent is evaporated and then the product is extracted several times with dichloromethane. The organic phases are combined, washed with 10% sodium bisulfite solution, dried on magnésium sulfate and concentrated to yield 8 g (88%) of methyl 3-amino-6-iodopyrazine-2-carboxylate in the form of a yellow solid.

LCMS (El, m/z): (M+1) 280 ^lH NMR: ÔH ppm (400 MHz, DMSO): 8.50 (1H, s, CH_nro,„), 7.50 (2H, bs, NH₂), 3.20 (3H, s, CH₃). Λ

Example 3b: 3-amino-6-iodopyrazine-2-carboxamide ml of ammonia in water is added under magnetic stirring to 15 g (53.8 mmol) of a solution of methyl 3-amino-6-iodopyrazine-2-carboxylate in 150 ml of methanol. The reaction medium is stirred at 25°C for 48 hours. After évaporation of the solvents, the 5 precipitate obtained is filtered, rinsed with water and then dried at 50°C to yield 12.50 g of 3-amino-6-iodopyrazine-2-carboxamide (88%) in the form of a beige solid.

LCMS (El, m/z): (M+1) 265.02 ^lHNMR: ÔHppm (400 MHz, DMSO): 8.35 (1H, s, CH_arom), 7.85 (1H, bs, NH), 7.60 (3H, bs, NH), 3.25 (3H, s, CH₃)

Example 3c: N’-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimetliylformimidaniide

13.59 ml (146 mmol) of phosphores oxychloride is added drop by drop at 0°C to 11 g (41.7 mmol) of a solution of 3-amino-6-iodopyrazine-2-carboxamide in 80 ml of dimethylformamide. The reaction mixture is stirred at room température overnight and then poured in a beaker containing ice and a little water. The pH is adjusted to 8 with 15 1 N soda solution; a precipitate is formed. The mixture is allowed to gradually retum to room température and then the solid formed is filtered, rinsed with water and dried at 50°C to yield 10.50 g of N’-(3-cyano-5-iodopyrazine-2-yl)-N,N-dimethyl formimidamide (84%) in the form of a beige solid.

LCMS (El, m/z): (M+1) 302.07 *H NMR: ÔH ppm (400 MHz, DMSO): 8.69 (1H, s, CH_arom), 8.67 (1H, s, CH_ethyi), 3.20 (3H, s, CH₃), 3.11 (3H, s, CH₃).

Example 3d: 3-amino-6-iodopyrazme-2-carbonitri!e ml (77 mmol) of 1 M hydrochloric acid solution is added to 7.7 g (25.6 mmol) of N’(3-cyano-5-iodopyrazin-2-yl)-N,N-dimethylformimidamide. The reaction medium is 25 heated at 50°C for 4 hours and then stirred at room température overnight. The precipitate formed is filtered, rinsed with water and dried at 50°C to yield 6 g (95%) of 3-amino-6-iodopyrazine-2-carbonitrile in the form of a beige solid.

LCMS (El, m/z); (M+1) 247.0 ‘H NMR: ÔH ppm (400 MHz, DMSO): 8.49 (1H, s, CH_arort1), 7.53 (2H, bs, NH₂).

Examole 3e: 3-chloro-6-iodopyrazine-2-carbonitrile

64.3 ml of hydrochloric acid is added at -5°C to 7.7 g (31.3 mmol) of 3-amino-6iodopyrazine-2-carbonitrile. At this température, a sodium nitrite 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 température overnight. Another équivalent 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-chloro-6-iodopyrazine-2-carbonitrile in the form of a beige solid.

LCMS (El, m/z): (M+l) 266.49 ’H NMR: SH ppm (400 MHz, DMSO): 9.13 (IH, s, CH_aroni)

Example 3: 5-iodo-lH-pyrazolo[3,4-b|pyrazine-3-amine

0.74 ml (9.8 mmol) of hydrazine is added to 2.6 g (9.80 mmol) of a solution of 3chloro-6-iodopyrazine-2-carbonitrile in 15 ml of butanol. The reaction mixture is heated at 110°C for 5 hours and then left at room température overnight. The suspended solid is filtered, rinsed with butanol and then dried in an oven at 50°C to yield 2.2 g (86%) of 5-iodo-lH-pyrazolo[3,4-b]pyrazine-3-amine in the form of a brown solid.

LCMS (El, m/z): (M+1) 262.02 *H NMR: SH ppm (400 MHz, DMSO): 12.59 (IH, bs, NH), 8.60 (IH, d, CHa_rom), 5.83 (2H, bs, NH₂).

Examples of method A3

Example 4: 5-iodo-6-methoxy-lH-pyrazolo[3,4-b]pyrîdin-3-amme nh₂

Example 4a: ethyl 5-cyano-2-hydroxy-6-(methylthio)nicotinate

Ethyl 5-cyano-2-hydroxy-6-(methylthio)nicotinate is obtaîned by following the procedure of Ya. Yu. Yakunin et al., Russian Chemical Bulletin, 1999, 48(1), 195-6 with a total yield of 34%.

LCMS (El, m/z): (M-l) 237.22 ’H NMR: SH ppm (400 MHz, DMSO): 12.72 (IH, bs, OH), 8.40 (IH, s, CH_arom), 4.29 (2H, q, CH₂), 2.64 (3H, s, CH₃), 1.30 (3H, t, CH,). Jf

Example 4b: 5-cyano-2-hydroxy-6-(methylthio)nicotÎnic acid

4,16 g (2 eq) of lithium hydroxide monohydrate is added at room température to a solution of 11.8 g (49,5 mmol) of ethyl 5-cyano-2-hydroxy-6-(methylthio)nicotinate in 100 ml of éthanol and 100 ml of water. The reaction mixture is stirred at 60°C for 2 hours. The éthanol is evaporated and 1 N aqueous soda is added. The aqueous phase is washed with ethyl acetate and then re-acidîfied by adding 1 N aqueous hydrogen chloride (pH=l). 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-cyano-2-hydroxy-6(methylthio)nicotinic acid in the form of a brown powder.

LCMS (El, m/z): (M-l) 209.09 'H NMR: ÔH ppm (400 MHz, DMSO): 8.32 (IH, s, CH_arom), 2.61 (3H, s, CH₃).

Example 4c; 6-hydroxy-2-(methy 1 thio)nicotinonitrile

A solution of 6 g (28,5 mmol) of 5-cyano-2-hydroxy-6-(methylthio)nicotinic acid in 35 ml of diphenyl ether is stirred at 250°C for 4 hours. After returning to room température, 100 ml of cyclohexane is added and the reaction medium is triturated for 30 minutes. The solid formed is filtered, rinsed thoroughly with cyclohexane and then dried under vacuum to yield 2.87 g (60%) of 6-hydroxy-2-(methylthio)nicotinonitrile in the form of a brown powder.

LCMS (El, m/z): (M+1) 167.12 ‘H NMR: ÔH ppm (400 MHz, DMSO): 12.16 (IH, bs, OH), 7.92 (IH, d, CH_aroni), 6.46 (IH, d, CH_arom), 2.59 (3H, s, CH₃).

Example 4dt 6-hydroxy-5-iodo-2-(methylthio)nicotinonitrile g (1.6 eq) of silver sulfate and 4.58 g (1.5 eq) of iodine are added successively to a solution of 2 g (12 mmol) of 6-hydroxy-2-(methylthio)nicotinonitrile in 200 ml of éthanol. The reaction medium is stirred at room température 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 magnésium sulfate and evaporated to yield 3.18 g (90%) of 6~hydroxy-5-iodo-2(methylthio)nicotinonitrile in the form of a yellow powder.

LCMS (El, m/z): (M+1) 292.93 ‘H NMR: ÔH ppm (400 MHz, DMSO): 12.96 (IH, bs, OH), 8.38 (IH, s, CH_arom), 2.62 (3H, s, CH₃).4

Exampîe 4e; 5-iodo-6-methoxy-2-(methylthio)nicotinonÎtrile

905 μΐ (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-hydroxy-5-iodo-2(methylthio)nicotinonitrile in 20 ml of 1,4-dioxane. The reaction medium is stirred at 60°C for 5 hours. The solid is filtered and the residue 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 5-iodo-6-methoxy-2(methylthio)nicotinonitrile in the form of a white powder.

LCMS (El, m/z): (M+l) 306.95 ’HNMR: ÔHppm (400MHz, DMSO): 8.50 (1H, s, CH_arom), 4.04 (3H, s, CH₃), 2.63 (3H, s, CH₃).

Ex ample 4f: 5-iodo-6-methoxy-2-(niethylsulfinyl)nicotinonitrilc

1.42 g (1.1 eq) of 70% 3-chloroperbenzoic acid is added to a solution of 1.6 g (5.23 mmol) of 5-iodo-6-methoxy-2-(methylthio)nicotinonitrile in 20 m I o f dichloromethane. The reaction medium is stirred at room température for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnésium sulfate, filtered and evaporated to yield 1.63 g (97%) of 5-iodo-6-methoxy-2-(methylsulfinyl)nîcotinonitrile in the form of a white powder which may also contain 5-iodo-6-methoxy-2-(methylsulfonyl)nicotinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.

LCMS (El, m/z): (M+l) 322.95 ’H NMR: ÔH ppm (400 MHz, DMSO): 8.86 (1H, s, CH_arom), 4.05 (3H, s, CH₃), 2.95 (3H, s, CH₃).

Example 4: 5-iodo-6-methoxy-lH-pyrazolo[3₍4-b]pyridin-3-amine

294 μΙ (1.2 eq) of hydrazine monohydrate is added to a solution of 1.63 g (5.05 mmol) of 5-iodo-6-methoxy-2-(methylsulfinyl)nicotinonitrile in 30 mi of 2-propanol. The reaction medium is stirred at 80°C for 9 hours. After retuming to room température, the solid formed is filtered and rinsed with 2-propanol to yield 1.14 g (78%) of 5-iodo-6methoxy-l//-pyrazolo[3,4-b]pyridin-3-amine in the form of a white powder.

LCMS (El, m/z): (M+l) 291.00 ’HNMR: ÔHppm (400MHz, DMSO): 11.87 (1 H, s, NH), 8.49 (1H, s, CH_aroin), 5.49 (2H, bs, NHi), 3.90 (3H, s, CH₃).

Example 5: 5-iodo-lH-pyrazolo[3,4-b|pyridine-3,6-diamine nh₂

YY

Example 5a: 4-methyIniorpholinium (2,4)-ethyl-5-amino-2,4-dicyano-5mercaptopenta-2,4-dienoate

4-methylmorpholinium (2,4)-ethyl-5-amino-2,4-dicyano-5-mercaptopenta-2,4-dienoate is prepared according to the procedure described by V.D. Dyachenko et al., Chemistry of Heterocyclic Compounds, 2005, 41(4), 503-10 with a yield of 50%.

‘H NMR: 6H ppm (400 MHz, DMSO): 9.60 (IH, bs, NH), 8.66 (IH, s, CH), 8.33 (IH, bs, NH), 7.43 (IH, bs, NH), 4.08 (2H, q, CH₂), 3.82-4.02 (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-amino-5-cyano-6-(methylthio)iiicotinate

2.73 ml (1 eq) of methyl iodide is added to a solution of 14.2 g (43.8 mmol) of 4methylmorpholinium (2,4)-ethyl-5-amino-2,4-dicyano-5-mercaptopenta-2,4-dienoate in 78 ml of AN-dimethylforrnamide The reaction mixture is stirred at room température for 1 hour and then at 75^qC for 20 hours. After returning to room température, water is added and the solid formed is filtered and dried under vacuum to yield 10.31 g (100%) of ethyl 2-amino-5-cyano-6-(methylthio)nicotînate in the form of a beige powder. LCMS (El, m/z): (M+l) 238.20 ‘HNMR: SHppm (400MHz, DMSO): 8.25 (IH, s, CH, mm), 8.19 (IH, bs, NH), 7.99 (IH, bs, NH), 4.27 (2H, q, CH₂), 2.58 (3H, s, CH₃), 1.31 (3H, t, CH₃).

Example 5c: 2-amino-5«cyano-6-(methylthio)nicotinic acid

3.08 g (2 eq) of lithium hydroxîde monohydrate is added at room température to a solution of 8.7 g (36.7 mmol) of ethyl 2-amino-5-cyano-6-(methylthio)nicotinate in 87 ml of éthanol and 87 ml of water. The reaction mixture is stirred at 60°C for 2 hours. The éthanol 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=l). 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-amino-5-cyano-6(methylthio)nicotinic acid in the form of a brown powder. Y

LCMS (El, m/z): (M+1) 210.16 *H NMR: ÔH ppm (400 MHz, DMSO): 13.28 (1H, bs, CO₂H), 8.21 (1H, s, CH_aron!),

8.13 (2H, bs, NH₂), 2.57 (3H, s, CH₃).

Example 5d: 6-amino-2-(methylthio)nicotinonitrile

A solution of 3 g (14.3 mmol) of 2-amino-5-cyano-6-(methylthio)nicotinîc acid in 30 ml of diphenyl ether is stirred at 255°C for 60 hours. After retuming to room température, 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 magnésium sulfate, filtered and then evaporated to yield 1.32 g (55%) of 6-amino-2(methylthio)nîcotinonitrile in the form of a brown powder.

LCMS (El, m/z): (M+1) 166.13 'H NMR: ÔH ppm (400 MHz, DMSO): 7.58 (1H, d, CH_arom), 7.12 (2H, bs, NH₂), 6.20 (1H, d, CH_arem), 2.51 (3H, s, CH₃).

Example 5e: 6-amino-S-iodo-2-(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-2-(methylthio)nicotinonitrile in 65 ml of éthanol. The reaction medium is stirred at room température for 3 hours. The solid is filtered and the residue rinsed thoroughly with methanol. The filtrate is evaporated and redissolved in ethyl acetate. The organic phase is washed with water three times, dried on magnésium sulfate and evaporated to yield 1.89 g (81%) of 6-amino-5-iodo-2(methylthio)nicotinonitrile in the form of a brown powder.

LCMS (El, m/z): (M+1) 291.99 ’HNMR: ÔHppm (400 MHz, DMSO): 8.13 (1H, s, CH_arom), 7.19 (1H, broad fiat singlet, NH₂), 2.51 (3H, s, CH₃).

Example 5f: 6-amino-5-iodo-2-(methylsulfinyl)nicotinonitrilc

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-amino-5-iodo-2-(methylthio)nicotinonitrile in 60 m i of dichloromethane. The reaction medium is stirred at room température for 1 hour. Ethyl acetate is added and the organic phase is washed with saturated sodium bicarbonate solution, dried on magnésium sulfate, filtered and evaporated to yield 1.5 g (75%) of 6amino-5-iodo-2-(methylsulfinyl)nicotinonitrile in the form of a white powder which may also contain 6-amino-5-iodo-2-(methylsulfonyl)nicotinonitrile in small proportions (<20%). If necessary, the mixture is used as-is in the following steps.

LCMS (El, m/z): (M+l) 307.98 ‘H NMR: δΗ ppm (400 MHz, DMSO): 8.45 (1 H, s, CH_orom), 7.70 (2H, broad fiat singlet, NH₂), 2.84 (3H, s, CH₃).

Example 5: 5-iodo-lH-pyrazoIo[3,4-b]pyridine-3,6-diamine

275 μΐ (2 eq) of hydrazine monohydrate is added to a solution of 872 mg (2.84 mmol) of

6-amino-5-iodo-2-(methylsulfmyl)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 magnésium 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-lH-pyrazolo[3,4-b]pyridin-3,6-diamine in the form of a brown powder.

LCMS (El, m/z): (M+l) 276.00 ‘HNMR: δΗ ppm (400MHz, DMSO): 11.23 (1H, s, NH), 8.26 (1H, s, CH_arom), 6.11 (2H, bs, NH₂), 5.25 (2H, bs, NH₂).

Examples of method Bl

Example 6: 5-(3,5-difluorobenzylthio)-lH-pyrazolo[4,3-b]pyridin-3-amine

F

Example 6a: 6-chloro-3-nitropicolinonitrile

2,6~Dichloro-3-nitropyridine (5.18 mmol, 1 g) is mixed with 5 ml of N-methyl-2pyrrolidinone 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 magnésium sulfate and dry concentrated. The crude product thus obtained is purified by silica gel chromatography (heptane/AcOEt) to yield, after concentration, 0.62g (65%) of a brown oil. Æ ’H NMR: ÔH ppm (400 MHz, DMSO): 8.81 (IH, d, CH_arom), 8.18 (IH, d, CH_arom).

Example 6b: 3-nitro-6-thioxo-l,6-dihydropyridine-2-carbonitrÎIe

One équivalent of NaSH:H₂O is added to a solution of 6-chloro-3-nitropicolinonitrile (5.45 mmol, 1 g) in 20 ml of EtOH. The color turns orange. The reaction medium is stirred at room température for 30 minutes. The crude reaction product is then concentrated, redissolved in ethyl acetate and extracted several times using an acidic aqueous phase (1 N HCl) 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.

*H NMR: ÔH ppm (400 MHz, DMSO): 8.71 (IH, d, CHU, 8.27 (IH, d, CH_arom)

Example 6c: 6-(3,5-dinuorobenzyhhio)-3-nitropicolinonitriIe

A mixture of 3-nitro-6-thioxo-l,6-dihydropyridin-2-carbonitrile (4.42 mmol, 1.34g), 3,5-diflurobenzylbenzylbromide (8.83 mmol, 1.828 g), and K₂CO₃ (11.04 mmol, 1.525 g) in 5 ml of acetone is heated at 70°C for 10 hours and then evaporated 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 (M-H+).

’HNMR: ÔH ppm (400MHz, DMSO): 8.53 (IH, d, CH_arom), 7.91 (IH, d, CH_arom), 7.21 (2H, m), 7.17 (IH, m), 4.55 (2H, CH₂).

Examnlc 6d: 3-amino-6-(3,5-difluorobenzylthio)picolinamide

A mixture of 6-(3,5-difluorobenzylthio)-3-nitropicolinonîtrile (0.05 g, 0.163 mmol) and PtO2 (0.739 mg, 3.25 gmol) in 10 ml 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+).

^lH NMR: ÔH ppm (400 MHz, DMSO): 7.84 (IH, broad s, NH), 7.40 (IH, broad s, NH),

7.14 (IH, d, CHarom), 7.08 (4H, m, CH_arom), 6.80 (2H, broad s, NH₂), 4.43 (2H, s, CH₂).

Example 6e: 3-amino-6-(3,5-difluorobenzylthio)picolinonitrïle

A mixture of 3-amino-6-(3,5-difluorobenzylthio)picolinoamide (2.37 mmol, 0.7 g) and P2CI5 (9,48 mmol, 1.346 g), 20 ml of toluene and 1 ml of ionic solvent (l-butyl-3methylimidazolium tetrafluoroborate) are placed in a microwave reactor and then heated ·> , 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 NaHCCh solution. The organic phase is dried on magnésium sulfate and then concentrated to yield 0.7 g of a brown oil. This crude reaction product is purified by silica gel chromatography (AcOEt/heptane + 0.1% of NEtî) to yield, after concentration, 0.15 g (23%) of orange crystals.

’H NMR: ÔH ppm (400 MHz, DMSO): 7.73 (1H, d, CH_arom), 7.25 (2H, m, CHa_ron,), 7.18 (1H, m), 6,85 (1H, d), 5.43 (2H, CH₂).

Ex a ni nie 6: 5-(3,5-difluorobenzylthio)-lH-pyrazolo[4,3-b]pyridin-3-amÎne

A solution cooled to 0°C of NaNOz in 3 ml of water is added drop by drop to a solution at 0°C of 3-amino-6-(3,5-difluorobenzylthio)picolinonitrile (1.587 mmol, 0.44g) in 15 ml of 6 N HCl solution. After 15 minutes, a solution cooled to 0°C of SnC12^-2H2O 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 saturated NaHCOj solution and then saturated NaCI solution. The organic phase is collected, dried on magnésium sulfate and then concentrated under reduced pressure. The residue is purified by silica gel chromatography (AcOEt/heptane) to yield, after concentration ofthe organic phases, 0.07 g (15%) ofblack crystals.

‘HNMR: ÔH ppm (400 MHz, DMSO): 11.64 (1H, s, NH), 7.63 (1H, d, CH_arom), 7.21 (2H, m, CHarom), 7.13 (1H, d, CHU. (1H, m, CH_arom), 5.38 (2H, s, NH₂), 4.51 (2H, s, CH₂).

The following compounds are obtained by a similar method:

t

Ex.**	ArX	w		R)	Compound naines	Yield	Mass MH+
6-2	A	H	CH	H	5-{2,5-difluorobenzylthio)-lH~ pyrazolo[4,3-b]pyridin-3 -amine	5% 4 steps	293.0
6-3		H	CH	H	5-(2,5-dichIorobenzy lüiio)-1Hpyrazolol 4,3-b|pyridin-3-amine	3% 4 steps	324.9

** 'H NMR: δΗ 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, CHarom), 7.14 (1H, dd, CHarom, J=8.8Hz), 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, J=8.8Hz), 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-dichlorophenylthio)-lH-pyrazolo[4,3-b]pyridin-3-amme nh₂

Example 7a: 6-(3,5-dichlorophenyItliio)-3-nitropicoIinonitrile

A mixture of 6-chloro-3-nitropicoiinonitrile (3.70g, 0.02 mol), 3,5-dichlorobenzenethiol (3.60 g, 0.02 mol) and K2CO3 (5.6 g, 0.04 mol) in 100 ml of acetonitrile is carried at 70°C for 16 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using an aqueous phase. The organic phase is dried with sodium sulfate and the residue is purified by silica gel chromatography (AcOEt/petroleum ether) to yield 5.4 g (80%) of a yellow solid.

Example 7b: 3-amino-6-(3,5-dichlorophenylthio)picolinonitrile ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenylthio)-3nitropicolinonitrile (3.4 g, 0.01 mol) in 50 ml of methanoi under stirring. The reaction medium is refluxed, added together with 1,68 g (0.03 mol) of iron and stirred for 10 minutes. After retuming to room température, 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 extracted 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-dichlorophenylthio)-lH-pyrazolo[4,3-b]pyridin-3-aminc

A solution of 350 mg of NaNO₂ (5.07 mmol) in water (2 ml) is added to a stirring solution of 1.5 g of 3-amino-6-(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 solution of 2.9 g of SnCl₂-2H₂O (12.7 mmol, 2.5 eq) in hydrochloric acid (12 N solution, 10 ml) is then added and the solution is stirred for 1 hour at room température. The solid formed is filtered and then washed twîce 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⁺) 'HNMR: ÔH ppm (400 MHz, DMSO): 11.91 (IH, bs, NH), 7.79 (IH, d, CH_arom), 7.55 (IH, S, CHarom), 7.36 (2H, s, CHarom), 7.33 (IH, m, CHanjtn)» 5.42 (2H, s, NH₂).

The following compounds are obtained by a similar method:

NH₂

N

Ex.·*	ArX	Y*	W	Rj	Compound names	Yield	Mass MH+
7-1	λ	CH	H	H	5-(3,5-difluorobcnzyloxy)- 1Hpyra7X)lo[4,3-b]pyridin-3-aminc	28%	277
7-2	A	CH	H	H	5-(3,5-<iiiluorophenylthio)- 1Hpyrazolo(4,3-b]pyridin-3-amine	33% 3 steps	278,9
7-3	!>’ F	CH	H	H	5-(2,4 -difluorophenylthio)-l Hpyrazolo[4,3-b]pyridin-3-amine	24% 3 steps	279,0
7-4	sx φ· a	CH	H	H	5-{2,4-dichioropheny llhio)-1Hpyrazolo[4,3-b]pyridin-3 -amine	24% 3 steps	311,0
7-5	;\5	CH	H	H	5-(2-(tiiiluoromcthyl)phcnylthio)-lHpyrazo!ol4,3-b]pyridin-3-amine	17% 3 steps	311,0
7-6	A	N	H	H	5-(3,5-difluorophenylthio)- 1Hpyrazolo[3,4-b]pyrazin-3-amine	6% 7 steps	279,9
7-7	Cl	N	H	H	5-(2,4-<iiclilorophenylthio}- 1Hpyrazolo[3,4-b]pyrazin-3-amine	4% 7 steps	311,9
7-8		N	H	H	5-(2-(trifluoromcÜiyl)phenylthio)-l Hpyrazo!o[3,4-b] pyrazin-3-amine	6% 7 steps	311.9
7-9	λ	CH	H	H	5-(3,5-difluorobcnzyloxy)-lHpyrazoloH3-b]pyridin-3 -amine	6% 3 steps	277.0

7-10	F	CH	H	H	5-(2,5-difluorobenzyloxy)-lHpyrazolo|4,3-b]pyridin-3 -amine	3% 3 steps	277.0
7-11	’fc Cl	CH	H	H	5-(2,5-dichlorobcnzyloxy)-lH- pyraz.o!o(4,3-b]pyridin-3-amine	32% 3 steps	309.0
7-12	Cl	CH	H	H	5-(5-chloro-2-(trifluoromeÜiyl)benzyloxy)lH-pyrazoloI4,3-bJpyridin-3-amine	8% 3 steps	343.1
7-13	°à	CH	H	H	5-(pyridin-3-ylmclhoxy)-lH-pyrazolo[4,3- b]pyridin-3-amine	6% 3 steps	342.1
** Ipj	NMR: ÔH ppm (4<	)0 MHz, DMSO): 7-1: 11,61 (IH, s large, NH)	, 7,73 (IH, d,

CHarom), 7,24 (2H; m, CHarom), 7,18 (1 H, m, CHarom), 6,86 (IH, d, CHarom). 7-2: 11.95 (IH, si, NH), 7.78 (IH, d, CHarom, J=11.6Hz), 7.33 (IH, d, CHarom, J=11.6Hz),

7.19 (IH, t, CHarom), 7.04 (2H, 2d, CHarom, J=8.8Hz), 5.51 (2H, s, NH₂). 7-3: 11,80 (IH, si, NH), 7.70 (IH, d, CHarom, J=8.8Hz), 7.60 (IH, t, CHarom), 7.49 (IH, q, CHarom), 7.27-7.33 (IH, m, CHarom), 7.11 (IH, d, CHarom, >8.8Hz), 5.41 (2H, s, NHî). 7-4: 11.93 (IH, si, NH), 7.80 (IH, d, CHarom, J=11.6Hz), 7.62 (IH, d, CHarom, J=11.6Hz), 7.40 (IH, dd, CHarom, J=11.2Hz), 7.29 (IH, d, CHarom, J=11.6Hz), 7.1 (IH, s, CHarom), 5.51 (2H, s, NH₂). 7-5: 11.86 (IH, si, NH), 7.87 (IH, d, CHarom, J=9.6Hz), 7.73 (1H, d, CHarom, >11.6), 7.50-7.68 (2H, m, CHarom), 7.44 (IH, d, CHarom, J=10.4Hz), 7.11 (1H, d, CHarom, J=11.6Hz), 5.46 (2H, s, NH₂). 7-6: 12.66 (IH, si, NH), 8.52 (IH, s, CHarom), 7.12-7.20 (IH, m, CHarom), 7.02-7.10 (2H, m, CHarom), 5.90 (2H, s, NH₂). 7-7: 12.70 (IH, s, NH), 8.52 (IH, s, CHarom), 7.60 (IH, d, CHarom, J=8.8Hz), 7.38 (IH, dd, CHarom, J=8.4Hz), 7.12 (IH, s, CHarom), 5.92 (2H, s, NH₂). 7-8: 12.66 (IH, s, NH), 8.39 (IH, s, CHarom), 7.84 (IH, d, CHarom, J=7.6Hz), 7.58 (IH, ζ CHarom), 7.50 (IH, t, CHarom), 7.34 (IH, d, CHarom, J=7.6Hz),

5.87 (2H, s, NH₂). 7-9: 11,57 (IH, s, NH), 7,74 (IH, d, Charom, J=9Hz), 7,25 (3H, m,

CHarom), 6,88 (IH, d, Charom, J=9Hz), 5,44 (2H, s), 5,08 (2H, s). 7-10: 11.58 (IH, 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, si, NH₂). 7-11:

11.60 (1H, si, 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, si, NH₂). 7-12: 11.60 (1H, si, NH), 7.91 (1H, s, CHarom), 7.83 (1H, d, CHarom, J=11.2Hz), 7.75 (1H, d, CHarom, 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, si, NH₂). 7-13: 11.56 (1H, si, NH),

8.77 (1H, s, CHarom), 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, CHarom, J=10.0Hz), 6.83 (1H, d, CHarom, J=11.6Hz), 5.45 (2H, s, CH), 5.15 (2H, si, NH₂).

Example 8: N5-(3,5-difluorophenyI)-lH-pyrazolo[4,3-b]pyridine-3,5-diamine

Example 8a: 6-(3,5-dinuorophenylamino)-3-nitropicolinonitrile

A mixture of 6.5 g of 6-chloro-3-nitropicolinonitrîle (0.065 mol) and 6.2 g of 3,5diftuoroaniline (0.048 mol) in 100 ml of toluene is heated at 70°C for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction 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: 3-amino-6-(3,5-difluorophenylamino)picolinonitrile ml of concentrated HCl is added to a solution of 6-(3,5-dichlorophenylthio)-3nitropicolinonitrile (3.9 g, 0.0141 mol) in 150 ml of éthanol 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 retuming to 0°C the pH is adjusted to 8 using 1 N soda solution and the reaction medium is filtered on Celite. The reaction mixture is added together 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-dïfluorophenylamino)-lH-pyrazolo[4,3-b]pyridin-3-amine

A solution of 713 mg of NaNO₂ (10.3 mmol) in water (5 ml) is added, drop by drop, to a stirring solution of 2.3 g of 3-amino-6-(3,5-dif1uorophenylamino)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 SnCl₂ 2H₂O (23.5 mmol, 2.5 eq) in hydrochloric acid (12 N solution, 30 ml) is then added drop by drop and the solution is stirred for 1 hour at room température. The reaction medium is then cooled at 0°C and basified to pH 8 using 30% soda solution. The mixture 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*).

’H NMR: ÔH 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 following compounds are obtained by a similar method:

NH₂

Ex.·*	ArX		W	«i	Compound namcs	Yield	Mass MH*
8-1	hn V F	CH	H	H	N-(2,5-difluorophcnyl)- 1H- pyrazolo[4,3-b|pyridinc-3,5-diaminc	4% 4 steps	262.0
8-2	hn αΊφ Cl	CH	H	H	N-(2,5-didi]orophenyl)-l Hpyrazolo|4,3-b]pyridinc-3,S-diamine	9% 4 steps	294.0
· ’hn	MR: ÔH ppm (400 M	Hz, DMSO): 8-1: 11.46(1 H, s, N	H), 8.75-	8.82 (2H, il

CHarom), 7.65 (1H, dd, CHarom, J-9.2Hz), 7.19-7.31 (2H, m, CHarom), 6.67-6.63 (1H, si, CHarom), 5.06 (2H, s, NH₂). 8-2: 11.58 (1H, si, NH), 8,65 (1H, s, CHarom),

8.35 (1H, s, CHarom), 7.69 (1H, d, CHarom, J= 12.0Hz), 7,45 (1H, d, CHarom,

·. t

J=ll.6Hz), 7.24 (1H, d, CHarom, J=l2.0Hz), 6.96 (ÎH, dd, CHarom, J=ll.2Hz), 5.03 (2H, si, NH₂).

Example of method B3

Examnle 9: 5-(3,5-difIuorobenzyl)-lH-pyrazolo|4,3-b]pyridin-3-amine nh₂

This compound can be prepared from the following intermediates, according to method B3.

Examplc 9a; 2-(3,5-difluorobenzyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane

Examnle 9b: 6-(3,5-dinuorobenzyl)-3-nitropicolinonitrile

Examplc 9c: 3-amino-6-(3,5-dîfluorobenzyl)picolinonitrile

Example of method B4

Examnle 10: 3-amino-N-(3,5-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5sulfonamide

Example 10a: 5-(N-(3,5-dinuorophenyI)sulfamoyi)nicotinic acid

2,74 g (9.64 mmol) of ethyl 2-chloro-5-(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 10 ml of anhydrous dichloromethane. The solution is stirred at room température 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 solution of 0.421 g (10.04 mmol) of lithium monohydrate hydroxide in 10 ml of water.

The reaction mixture is left under stirring for 3 hours at 35°C and then diluted in water, acidified with 1 N hydrochloric 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)nicotimc acid in the form of an orange solid (yield=67%).

’HNMR: ÔH ppm (400 MHz, DMSO): 8.91 (1H, s, CH_amm), 8.51 (1H, s, CH_arom), 7.02 (IH, dd, CiUm), 6.83 (2H, d, CH_nrom).

Example 10b: 2-chloro-5~(N-(3,5-dÎfluorophenyl)sulfamoyl)nicotÎnamide

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-5-(N-(3,5-difluorophenyl)sulfamoyl)nicotinic acid in 5 ml of anhydrous toluene. The mixture is placed under stirring, at reflux of toluene, for 2 hours. The acid chloride 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 température for 30 minutes. The reaction medium is extracted several times with ethyl acetate. The combined organic phases are dried on anhydrous sodium sulfate and then concentrated.

0.315 g of 2-chloro-5-(N-(3,5-difluorophenyl)sulfamoyl)nicotinamide in the form of a light brown solid is obtained (yield=72%).

’H NMR: ÔH ppm (400 MHz, DMSO); 11.18 (1H, bs, NH), 8.86 (1H, s, CH_arom), 8.22 (1H, s, CH_nrom), 8.21 (1H, bs, NH), 7.98 (1H, bs, NH), 6.96 (1H, dd, CH_arara), 6.79 (2H, d, CH_arom),

Example 10c: 6-chloro-5-cyano-N-(3,5-difluorophenyl)pyrïdine-3-sulfonamide

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-5-(N-(3,5-difluorophenyl) sulfamoyl)nicotinamide. The reaction mixture is stîned 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-chloro-5-cyano-N-(3,5-difluorophenyl)pyridine-3sulfonamide is obtained in the form of a light brown solid (yield=72%).

’H NMR: ÔH ppm (400 MHz, DMSO): 11.34 (1H, bs, NH), 9.04 (1H, s, CH_arom), 8.92 (1H, S, CHnrom), 7.03 (1H, dd, CHarom), 6.85 (2H, d, CHarom).

Example 10: 3-amino-N-(3,5-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-5sulfonamide

0.377 ml (2.63 mmol) of 35% hydrazine is added to 0.217 g (0.658 mmol) of 6-chloro-

5-cyano-N-(3,5-difluorophenyl)pyridine-3-sulfonamide diluted in 6 mi of isopropanol. The solution is heated at 75°C for 2 hours. The solvent is evaporated to yield 0.214 g of 3-amino-N-(3,5-difluorophenyl)-lH-pyrazoio[3,4-b]pyridine-5-sulfonamide in the form of a yellow solid (yield=l 00%).

‘H NMR: ÔH ppm (400 MHz, DMSO): 8.74 (1H, d, CH_arom), 8.68 (1H, d, CH_arom), 6.88 (1H, dd, CHarom), 6.80 (2H, d, CH_arora), 6.04 (2H, bs, NH).

Examples of method B5

Example 11: 5-(3,5-difluorobenzyloxy)-l H-pyrazolo[3,4-b]pyridin-3-amine

This compound can be prepared from the following intermediates, according to method B5.

Example lia: 5-hydroxynicotinonitrile

A mixture of 1g of 5-methoxynicotinonitrile (7.46 mmol) and 8.62 g of pyridine hydrochloride is heated at 200^QC for 2 hours. The crude reaction product is diluted in a water fraction several times with diethyl ether. The aqueous phase is basifïed 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*).

‘HNMR: ÔH 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)nicotinonitrile

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 bromide. 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 organic phases are isolated, dried and concentrated. The solid residue obtained is recrystallized in methanol to yield 1.1 g (68 % of 5-(3,5-difluorobenzyloxy) nicotïnonitrile in the form of a beige powder,

LCMS: m/z 247.11 (M+H⁺).

’H NMR: ÔH 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-cyano-5-(3,5-dinuorobenzyloxy)pyridine 1-oxide

224 mg of m-CPBA is added at 0°c to a solution in acetonitrile of 250 mg of 5-(3,5difluorobenzyloxy)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-5-(3,5-difluorobenzyloxy)pyridine 1-oxide in the form of a white powder.

LCMS: m/z 263,06 (M+H⁺).

Example 1 Id: 2-chloro-5-(3,5-difluorobenzyloxy)nicotinonitrile

A mixture of 650 mg of 3-cyano-5-(3,5-difiuorobenzyloxy)pyridine 1-oxîdein 2.3 mL of POCI3 added with few drops of H2SO4 is heated at 110°C for lh30. 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 regïoisomers comprising mainly the desired 2-chloro-5-(3,5difluorobenzyloxy)nicotinonitrile which is used without further purification.

LCMS: m/z 281,02 (M+H⁺).

Example 11: 5-(3,5-dif1uorobenzyloxy)-lH-pyrazolo[3,4-b]pyridin-3-amine

313 mg of hydrazine hydrate (5 eq) is added to a solution of 1.6 g of 2-chloro-5-(3,5difluorobenzyloxy)nicotinonitrile (450 pmol) in 10 mL of propan-2-ol. The reaction mixture is heated at 100°C for 6 hours, After retum to room température leadingto a précipitation, the crude reaction medium is filtered, the solid is removed and the filtrate is dry evaporated. 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 5-(3,5-difluorobenzyloxy)lH-pyrazolo[3,4-b]pyridin-3-amine in the form of a beige solid wich is used without further purification. rf

LCMS: m/z 277,07 (M+H*).

Example of method B6

Examnle 1 tbis: N-(3-amïno-lH-pyrazolo[3,4-b]pyridin-5-yl)-3,5-difluorobenzene sulfonamide

Exam pie 11 b i s-a: N-(6-chloro-5-cyanopyridin-3-yl)-3,5-difluorobenzenesulfonamide

1.132 g (5.32 mmol) of 3,5-difluorobenzene-l-sulfonyle chloride is added under argon to a solution of 545 mg (3.55 mmol) of 5-amino-2-chloronicotinotrile 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 température. The solvent is dry evaporated and the crude reaction product is redtssolved in ethyl acetate and washed with several aqueous fractions. The organic phase is dried on magnésium sulfate, filtered, concentrated and then purified by silica gel chromatography to yield 784 mg (67%) of N-(6-ch loro-5 -cyanopyridin-3-yl)-3,5 - d ifl uorobenzene-su I fonam i de.

^lH NMR: δΗ ppm (400 MHz, DMSO) : 11,39 (1H, si, NH), 8. 34 (1H, m, CHarom),

8,10 (1H, m, CHarom), 7,67 (1H, m, CHarom), 7,59 (2H, m, CHarom).

Example 11 bis; N-(3-amino-lH-pyrazolo[3,4-b]pyridin-5-yl)-3,5-difluorobenzenesulfonamide

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-chloro-5-cyanopyridin-3-yl)-3,5-difluorobenzene-sulfonamide in 6 mL of éthanol. The solution is heated to 100°C for 20 hours and then cooled to room température. The solvent is evaporated to yield 810 mg ofN~(3-amino-lH-pyrazolo[3,4b]pyridin-5-yl)-3,5-difluorobenzene-sulfonamide (100%) which is used without further purification in the following steps.

LCMS: m/z 326,07 (M+H⁺) r »

Example of method Cl

Example 12: N6-(2,4-dinuorophenyl)-lH-pyrazolo[3,4-b]pyridine-3,6-diamine nh₂

This compound can be prepared from the following intermediates, according to method Cl.

Example 12-a; 5-cyano-6-(methyIthio)pyridin-2-yl trifluoromethanesulfonate

15.26 mL (1.2 eq) of potassium 2-methylpropan-2-olate and then 9.03 g (1.2 eq) of 1,1,1 -trifluoro-?/-phenyl-A^/-(trifluorornethylsulfonyl)methanesulfonamide are added dropwise to a solution of 3.5 g (21.06 mmol) of 6-hydroxy-2-(methylthio)nicotinonitrile in 180 mL of tetrahydrofurane under nitrogen. The reaction mixture is stirred at room température for 2h45. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on anhydrous magnésium sulfate, filtered and evaporated to yield an orange solid. The product is purified on a silica gel column (eluent: cyclohexane/dichloromethane 5:5) to yield 5.31 g (85%) of 5-cyano-6(methylthio)pyridin-2-yl trifluoromethanesulfonate in the form of a yellow solid.

’H NMR: ÔH ppm (400 MHz, DMSO): 8,57 (IH, d, CH), 7,52 (IH, d, CH), 2.59 (3H, s, CH₃).

Example 12-b; 6-(2,4-difluorophcnylaniino)-2-(methylthÎo)nicotinonitrile

0.81 mL (1.2 eq) of ,4-difluoroaniline 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-6(methylthio)pyridin-2-yl trifluoromethanesulfonate in 30 mL of 1,4-dioxane. The medium is degased for 5 minutes under argon before adding 0.25 g (0.06 eq) of de 2,2’bis(diphenylphosphino)-l,r-bïnaphthyl and 0.08 g (0.04 eq) of (1E,4E)-1,5diphenylpenta-l,4-dien-3-one, palladium(II) complex. The reaction medium is stirred at 100°C for 2 hours. After retum to room température, ethyl acetate and brine are added. The organic phase is dried on anhydrous magnésium sulfate, fitered and evaporated. The residue obtained îs purified on silica gel chromatography (eluent: cyclohexane/ethyl acetate 8:2 then 7:3) to yield 1.52 g (82%) of 6-(2,4-difluorophenylamino)-2(methylthio)nÎcotinonitrile in the form of a white solid.

LCMS (IE, m/z): (M+1) 278,06.

‘HNMR: ÔH ppm (400 MHz, DMSO): 9,57 (IH, s, NH), 7,73-7,86 (2H, m, CH), 7,287,44 (IH, m, CH), 7,02-7,18 (IH, m, CH), 6,60 (IH, d, CH), 2.41 (3H, s, CH₃).

Example 12; N6-(2,4-difluorophenyl)-lH-pyrazolo[3,4-b|pyiïdine-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)-2(methylthio)nicotinonitrile in 25 mL of dichloromethane. The reaction medium is stirred 1 hour at room température before adding a fraction of ethyl acetate and washed this organic phase with a NaHCOs saturated solution. The combined organic phases are dried on magnésium sulfate and dry evaporated. The crude reaction product is dissolved again in 10 mL of propanol and 2 équivalents of hydrazine hydrochloride in water are 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 magnésium sulfate and dry evaporated before being purified by silica gel chromatography to yield 495 mg of N6(2,4-difluorophenyl)-lH-pyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yelloworange solid (67%).

LCMS (IE, m/z): (M+1) 262,14.

‘H NMR: ÔH ppm (400 MHz, DMSO): 11,40 (IH, s, NH), 8,76 (IH, s, NH), 8,15 (IH, m, CH), 7,81 (IH, d, CH), 7,28 (IH, m, CH), 7,06 (IH, m, CH), 6,55 (IH, d, CH), 5,24 (2H, s, NH₂).

The following compound is obtained by a similar method:

NH_Z

Λ X ^N

ArX^N^f]

Ex.·*	ArX	Yi	Compound π âmes	Yield	Masse MH+
12-1	Γχγτ F	CH	N6-(3,5-difluorobenzyl)- 1Hpyrazolol3,4-b]pyridinc-3,6diaminc	70%	276,15
♦♦ *HNM	dmso-df,, Ex.: 12-	: 11,17 (IH, s, NH), 7,66 (IH, d, CH	l), 7,37 (IH, s, NH),

7,04 (3H, m, CH), 6,24 (IH, d, CH), 5,11 (2H, s, NH₂), 4,52 (2H, s, CH₂).

·< t

Example 12bis: N6-(2,4-dinuorophenyl)-N6-nietliyl-lH-pyrazolo|3,4-b]pyridine3,6-diamine nh₂

Example 12bis-a: 6-((3,5-difluorophenyI)(methyl)amino)-2-(methylthio) nicotinonitrile

3,05 mL (5,04 mmol) of potassium 2-methyipropan-2-olate and then 286 pL (1.8 eq) of iodomethane are added dropwise under nitrogen to a solution of 700 mg (2.52 mmol) of

6-(2,4-difluorophenylamino)-2-(methylthio)nicotinonitrile in 20 mL of W.JV-dimethyl formamide. The reaction medium is stirred at room température for 24 hours and then 126 pL (0.8 eq, 2.02 mmol) of iodomethane is added. The reaction medium is stirred at room température for 2 additional hours. Water is added and the product is extracted with ethyl acetate. The organic phase is dried on anhydrous magnésium 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+l) 292,09.

‘H NMR: ÔH ppm (400 MHz, DMSO): 7,74-7,80 (IH, m, CH), 7,55-7,63 (IH, m, CH), 7,43-7,52 (IH, m, CH), 7,18-7,27 (IH, m, CH), 6,16-6,30 (IH, m, CH), 3,43 (3H, s, CH₃), 2.42 (3H, s, CH₃).

Example 12bis: N6-(2,4-dinuorophenyl)-N6-methyl-lH-pyrazolo[3,4-b|pyridine3,6-diamine

452 mg (1.84 mmol) of mCPBA is added under argon to a stirring solution of 486 mg (1,67 mmol) of 6-((2,4-difluorophenyl)(methyl)amino)-2-(methylthio)nicotinonitrile in 15 mL of dichloromethane. The reaction medium is stirred 30 min at room température before adding an ethyl acetate fraction. The organic phase is washed with a NaHCO₃ saturated solution, dried on magnésium sulfate and dry evaporated. The crude reaction product îs dissolved again in 6 mL of propanol and 164 pL (3.38 mmol) of hydrazine 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 magnésium sulfate and dry evaporated before being purified by silica gel chromatography to yield 328 mg of N6-(2,4-difluorophenyl)-N6-methyl-lHpyrazolo[3,4-b]pyridine-3,6-diamine in the form of a yellow-orange solid (70%), LCMS (ΓΕ, m/z); (M+1) 276,15.

^lH NMR: ÔH ppm (400 MHz, DMSO): 11,41 (IH, s, NH), 7,75 (IH, d, CH), 7,51-7,55 (IH, m, CH), 7,40-7,43 (IH, m, CH), 7,17-7,22 (IH, m, CH), 6,03 (IH, d, CH), 5,23 (2H, s, NH₂), 3,28 (3H, s, CHj).

Example of method C3

Examnle 12ter: 6-(2,4-difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-amine

NH₂

Example 12ter-a: 2-chloro-6-(2,4-difluorophenylthio)nicotinonitrile

A solution of 362 mg (1.05 eq) of potassium hydroxide in 10 mL of éthanol is added, under nitrogen, to a solution of 698 pL (6.16 mmol) of 2,4-difluorobenzenethiol in 30 mL of éthanol, The reaction medium is stirred at room température for 15 minutes and then cooled in ice before adding a solution of 1.015 g (0.95 eq) of 2,6dichloronicotinonitrile in 30 mL of éthanol. 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 magnésium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (eluent: cyclohexane/ethyl acetate 94:6) to yield 1.09 g (66%) of 2chloro-6-(2,4-difIuorophenylthio)-nicotinonitrile in the form of a white solid, LCMS (IE, m/z): (M+1) 282,98.

’H NMR: ÔH ppm (400 MHz, DMSO): 8,24 (IH, d, CH), 7,77-7,85 (IH, m, CH), 7,52-

7,63 (IH, m, CH), 7,25-7,35 (2H, m, CH), 2,41 (3H, s, CH,).

Examnle 12ter: 6-(2,4-difluorophcnylthio)-lH-pyrazolo|3,4-b|pyridin-3-aminc

0.561 mL (11.57 mmol) of hydrazine monohydrate is added under nitrogen to a stirring solution of 1.09 g (3.86 mmol) of 2-chloro-6-(2,4-difluorophenylthio)nicotinonitrile in 15 mL of propanol, The reaction medium is heated at 80°C for 4 hours. A precipitate is obtained when the reaction medium is retumed to room température. This precipitate is

8l filtered and rinced with éthanol. The solîd is dissolved in an ethyl acetate fraction and washed with a IN HCl solution. The organic phase is dried on magnésium sulfate and dry evaporated to yield 420 mg (39%) of 6-(2,4-difluorophenylthio)-lH-pyrazolo[3,4b]pyridîn-3-amine in the form of a yellow solid.

’H NMR: ÔH ppm (400 MHz, DMSO): 12,10 (1H, s, NH), 8,11 (1H, d, CH), 7,827,89(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, NH₂).

The following compound is obtained by a similar method:

NH_Z

Ex.**	ArX	Yl	Rj	Compound namcs	Yield	Mass MH+
12ter-l	ox C>' F	CH	H	6-(2,4-difluorophcnoxy)- 1Hpyrazolo[3,4-b]pyridin-3-amine	ND	263,06

Examplc 12quater: 6-(3,5-difluorobenzyl)-lH-pyrazolo[3,4-b]pyridin-3-amine

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 reaction is refluxed for 7 hours, then cooled to room température. A IN soda aqueous solution is added and the product is extracted with several successive ethyl acetate fractions. The organic phases are dried on magnésium sulfate and dry evaporated before being purified by silica gel chromatography to yield 680 mg of a mixture of 2-chloro-6(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 pL of 35% 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 6-(3,5-difluorobenzyl)-lHpyrazolo[3,4-b]pyridin-3-amine (64%).

LCMS (IE, m/z): (M+1) 261.16.

’H NMR: δΗ ppm (400 MHz, DMSO): 11,82 (1 H, s, NH), 8,01 (1H, d, CH), 6,99-7,04 (3H, m, CH), 6,91 (1H, d, CH), 5,49 (2H, s, NH₂), 4,12 (2H, s, CH₂).

Example of method Dl:

Examole 13: 5-(3,5-difluorobenzyl)-l H-pyrazolo[3,4-b]pyridine-3-amme nh₂

0.575 g (0.704 mmol) of (dppf)₂PdCl₂ CH₂Cl₂ and 28 mi (14.08 mmol) of 3,5difluorobenzyl zinc (II) chloride are added to 1.5 g (7.04 mmol) of a solution of 5bromo-lH-pyrazolo[3,4-b]pyridin-3-amine in 10 ml of tetrahydrofuran. The reaction medium is heated at 90°C for 18 hours. After returning to room température, 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 filtrate is extracted several times with ethyl acetate. The organic phases are combined, dried on magnésium sulfate and concentrated, The residue is purified by silica chromatography (95:4.5:0.5 and then 95:4:1 dichloromethane/methanol/ammonium as eluent) to yield 1.7 g (93%) of 5-(3,5-difluorobenzyl)-lH-pyrazolo[3,4-b]pyridine-3-amine in the form of a beige solid.

LCMS (El, m/z); (M+1) 261.41.

^!HNMR: ôHppm (400 MHz, DMSO): 11.87 (1H, s, NH), 8.31 (1H, d, CH_aroitl), 7.92 (1H, d, CH_nram), 6.98-7.08 (3H, m, CH_arom), 5.47 (2H, s, NH), 4.04 (2H, s, CH₂).

The following compounds are obtained by a similar method

I nh₂

W^yP-N

Rj

Ex.**	ArX		W	Rj	Compound names	Yield	Mass MH+
13-1	A.	CH	H	H	5-(3,5-difluorobenzy 1)-1Hpyrazolo[4,3-b]pyridin-3-amine	8% 4 steps	261.1
13-2	A.	N	H	H	5-(3,5-difluorobenzyl)-1Hpyrazolo[3,4-blpyrazin-3-aminc	21% 3 steps	262.1

·* ‘h NMR: 8H ppm (400 MHz, DMSO): 13-1: 11.61 (1H, si, NH), 7.65 (1H, d,

CHarom, J=11.6Hz), 7.20 (1H, d, CHarom, J=11.2Hz), 6,95-7.10 (3H, m, CHarom),

5.32 (2H, si, NH₂), 4.18 (2H, s, CH₂). 13-2: 12.31 (1H, si, NH), 8.44 (1H, s, CHarom), 7.03-7.08 (3H, m, CHarom), 5,61 (2H, si, NH₂), 4.25 (2H, s, CH₂).

Examples of method D2

Examplc 14: 5-(3,5-dinuorophenylthio)-lH-pyrazolo|3,4-b]pyrazin-3-amine

F

0.7 g (2.68 mmol) of 5-iodo-lH-pyrazolo[3,4-b]pyridine-3-amîne, 0.74 g (5.36 mmol) of anhydrous potassium carbonate and 0.10 g of copper iodide (0.536 mmol) are mixed în a 50 ml round-bottom flask. 15 ml of propan-2-ol, 0.01 g (0.2 mmol) of polyethylene glycol and 0.43 g (2.95 mmol) of 3,5-difluorothiophenol 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-diflurophenylthio)-lH-pyrazolo[3,4-b]pyrazin-3-amine in the form of a brown solid.

LCMS (El, m/z): (M+1) 280.03.

*H NMR: ÔH ppm (400 MHz, DMSO): 12.65 (1H, bs, NH), 8.52 (1H, s, CH_nrom), 7.18 (1H, t, CHarom), 7.05-7.18 (2H, m, CH_nrom), 5.89 (2H, s, NH).

The following dérivatives were obtained according to the same method:

Ex.**	Ar	Ru	n	Yl,Y3,Y4	Ra	Ri	Compound name	Yield	Mass MH+
14-1	O^NHî σ	H	0	CH, CH, N	H	H	2-(3-amîno-lHpyrazolo[3,4-b]pyridin-5ylthio)benzamide	ND	ND
14-2	y	o-L ή I	0	CH, CH, N	H	H	N-(5-(3,5dimethylphenylthio)-lHpyrazolo[3,4-b]pyridin-3yl)-4-(4-methy!piperazin1 -yl)-2-(tetrahydro-2Hpyran-4ylamino)benzamide	ND	ND
14-3	v F	H	0	CH, CH, N	H	H	5-(3,5d ifîuoropheny lthio)- 1Hpyrazolo[3,4-b] pyrid in-3amine	45%	(M+l) 279.28
14-4	Cl Φ' Cl	H	0	CH, C- OMe, N	H	H	5-(2.5dichlorophenylthio)-6methoxy-1 H-pyrazolo[3,4b] pyridin-3-amine	80%	ND
14-5	Cl φ- Cl	H	0	CH, C-NH2, N	H	H	5-(2.5dichloropheny lthio)-1Hpyrazo lo[3,4-b] pyridi ne3,6-diamine	35%	ND
14-6	A	H	0	CH, CH, N	H	'Bu	1 -ter/-butyl-5-(3,5difluorobenzy lthio)-1Hpyrazolo [3,4-b] pyrid in-3amine	ND	(M+l) 293.08
14-7	v F	H	0	CH, CMe, N	H	H	5-(3,5- difluorophenylthio)-6methyl-1 H-pyrazolo[3,4b]pyridin-3-amine	ND	(M+l) 293.06
14-8	v F	H	0	CH, C- OMe, N	H	H	5-(3,5difluorophenylthio)-6methoxy-1 H-pyrazolo[3,4 b]pyridin-3-amine	28%	(M+l) 610.30

14-9	v F	H	0	CH, CH, N	H	‘Bu	1 -/i?r/-butyl-5-(3,5difluorophenylthio)-lHpyrazoIo[3,4-b]pyridin-3amine	79%	(M+1) 335.26
14-10	Cl Cl	C) N 1	0	CH, CH, N	H	H	N-(5-(2.5dichlorophenyîthio)-1Hpyrazolo[3,4-b]pyridin-3yl)-4-(4-methylpiperazin1 -yl)-2-(tetrahydro-2Hpyran-4ylamino)benzamide	31%	(M+1) 612.37
14-11	v F	ô N t	0	CH, C-NH2, N	H	H	N-(6-amino-5-(3,5difluorophenylthio)- 1Hpyrazolo[3,4-b]pyridin-3yl)-4-(4-methylpiperazin1 -yl)-2-(tetrahydro-2Hpyran-4ylamino)benzamide	68%	ND
** ‘H NN	R, DMSO-de,	Ex.: 14-3: 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). 14-6: 8.21 (2H, bs, CH_arom), 7.07 (1H, m, CHarom), 6.90 (2H, m, CH_arom), 6.27 (2H, bs, NH), 4.03 (2H, s, CH), 1.63 (9H, s, CH). 14-7: 12.16 (1H, bs, NH), 8.39 (1H, s, CH_nrom), 7.00-7.08 (1H, m, CHarom), 6.645 6.72 (2H, m, CHarom), 5.73 (2H, bs, NH₂), 2.54 (3H, s, CH₃). 14-9: 8.51 (1H, bs,

CHarom), 8.35 (1H, bs, CH_arom), 7.02 (1H, m, CHarom), 6.72 (2H, bs, CHarom), 6.52 (2H, bs, NH), 1.67 (9H, s, CH). (ND: not determined).

Example 14bis: N-(5-(3,5-difIuorophenylamino)-lH-pyrazolo|3,4-b]pyridin-3-yl)-4 (4-methylpiperazïn-l-yl)-2-(tetrahydro-2H~pyran-4-yIamino)benzamide.

A solution of 225 mg of N-(5-iodo-]-trityl-lH-pyrazolo[3,4-b]pyridin-3-yl)-

4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide (0.25 mmol), mg of difluoroaniline (0.275 mmol), 19 mg of R-(+)-2,2’-bis(diphenylphosphino)15 Ι,Γ-binaphtyle (0.030 mmol), 11 mg (0.013 mmol) of tris(dibenzylideneacetone) dipalladium(O) and 75 mg (0,75 mmol) of sodium tert-butoxide in 10 mL of THF is .

refluxed under argon overnight. The crude reaction medium is cooled, extracted with ethyl acetate and washed with water. The organic phase is dried on magnésium sulfate and purified by silica gel chromatography to yield N-(5-(3,5-difluorophenylamtno)-ltrityl-1 H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1 -yl)-2-(tetrahydro-2Hpyran-4-ylamino)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 NaHCO₃ solution. The aqueous phase is collected, basified (pH 9-10) with a concentrated K2CO3 solution and extracted with dichloromethane. The organic phase is collected, dried on magnésium sulfate and dry ccentrated to yield 40 mg of N-(5-(3,5-difluorophenylamino)-lHpyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4ylamino)benzamide.

LCMS (IE, m/z): (M+1) 562.12.

‘HNMR: ÔH ppm (400 MHz, DMSO): 13,45 (1H, si, NH), 10,47 (1H, si, NH), 8,65 (1H, s, CH_ann„), 8,55 (1H, s, CH_aroni), 8,14 (1H, d, NH), 7,77 (1H, d, CH_amm), 7,26 (2H, m, CHarom), 7,05 (1H, m, CH_arom), 6,25 (1H, d, CH_arom), 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), 1,37-1,39 (2H, m, CH).

Examples of method D3:

Ex ample 15: N-(5-((3,5-difliiorophenyl)ethynyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-4(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4-ylaniino)benzamide

0.94 mg (0.926 mmol) of triethylamine is added to 400 mg (0.712 mmol) of N-(5-iodo1 H-pyrazolo [3,4-b] pyridi n-3 -y l)-4-(4-methy lpiperazi η-1 -y l)-2-(tet rahydro-2H-pyran-4ylamino)benzamide, 67.8 mg (0.356 mmol) of Cul, and 50 mg (0.071 mmol) of Pd(PPh3)îC12 under argon in 12 ml of anhydrous dioxane under stirring. The reaction is 5 heated for 3.5 hours at 100°C. The reaction mixture is diluted with 30 ml of water and extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The residue obtained is purified by siiica gel chromatography (dichloromethane/methanol) to yield 152 mg of N-(5~((3,5-difluorophenyl)ethynyl)-lHpyrazo lo [3,4-b] pyridi n-3 -y l)-4-(4-methy lpip erazi η-1 -y l)-2-(tetrahy dro-2H-pyran-410 ylamino)benzamide in the form of a yellow solid (yield=37%).

LCMS (El, m/z): (M+1) 572.17.

‘H NMR: ÔH ppm (400 MHz, DMSO): 13.57 (1H, bs, NH), 10.56 (1H, bs, NH), 8.68 (1H, s, CH,_rom), 8.43 (1H, s, CH_nrom), 8.13 (1H, d, NH), 7.80 (1H, d, CH_arom), 7.38 (2H, m, CHarom), 6.27 (1H, d, CH_arom), 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 following dérivative was obtained according to the same method:

Ex.·*	ArX	Yi.Yî, Yi	Compound name	Yield	Mass MH+
15-1	U-	N,CH,N	5-((3,5 -difluorophenyl)cthynyl)-1Hpyrazolo[3,4-b] pyrazin-3-ami ne	6% 6 stops	272.1

CHarom’ ·* Ή NMR, dmso-d6, Ex.: 15-1: 12.71 (1H, si, NH), 8.66 (1H, s, (3H, m, CHarom), 6.01 (2H, si, NH₂).

, 7.40-7.47

Examples of method £

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 aldéhyde.

Préparation of the reaction intermediates

Ex a mule 16: 2-(N-(4,4-dinuorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methyI piperazin-l-yl)benzoic acid

Example 16a: tert-butyl 4-(4-methylpiperazin-l-yl)-2-nitrobenzoate

This compound was previously described in WO 2008/74749.

5.28 ml (47.6 mmol) of 1-methylpiperazine is added to 4.1 g (17 mmol) of tert-butyl 4fluoro-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 tert-butyl 4-(4-methylpiperazin-l-yl)-2-nitrobenzoate in the form of a yellow solid.

LCMS (El, m/z): (M+l) 322.37.

‘H NMR: ÔH ppm (400 MHz, DMSO): 7.69 (1H, d, CH_arom), 7.30 (1H, d, CH_aram), 7.20 (1H, dd, CH_aitim), 3.38 (4H, m, CH), 2.40 (4H, m, CH), 2.22 (3H, s, CH₃), 1.45 (9H, s, CH₃).

Examole 16b: tert-butyl 2-amino-4-(4-methylpiperazin-l-yl)benzoate

This compound was previously described in WO 2008/74749.

0.160g (1.500mmol) of palladium on carbon (10%) and 15.19 ml (150 mmol) of cyclohexene are added to a solution of 4.82 g (15 mmol) of /ert-butyl 4-(416493 methylpiperazin-l-yl)-2-nitrobenzoate in 100 ml of éthanol. The reaction mixture is heated at a température of 80°C for 8 hours. The reaction mixture is filtered and then rinsed with éthanol to yield 4.2 g (yield=96%) of ferf-butyl 2-amino-4-(4methylpiperazin-l-yl)benzoate in the form of a yellow solid.

LCMS (El, m/z): (M+l) 292.39, ‘H NMR: ÔH ppm (400 MHz, DMSO): 7.44 (1H, d, CH_arom), 6.40 (2H, bs, NH₂), 6.19 (1H, dd, CH_aroin), 6.12 (1H, d, CH_arom), 3.17 (4H, m, CH), 2.40 (4H, m, CH), 2.22 (3H, s, CH₃), 1.49 (9H, s, CH₃).

Example 16c: ferf-butyl 2-(4,4-difluûrocyclohexylamino)-4-(4-methylpiperazin-lyl)benzoate

1.045 mi (13.57 mmol) of trifluoroacetic acid, lg (7.46 mmol) of 4,4difluorocyclohexanone and 2.158 g (8,20 mmol) of tétraméthylammonium triacetoxyborohydride are added to 1.521 g (5.22 mmol) of ferf-butyl 2-amino-4-(4methylpiperazin-l-yl)benzoate dissolved in 60 ml of dichloromethane. The reaction is left under stirring at room température 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 solution, 0.5 M soda solution and finally with saturated NaHCO₃ solution. The organic phase is dried on sodium sulfate, filtered and concentrated to obtain 2.2 g of ferf-butyl 2-(4,4-difluorocyclohexylamino)-4-(4methylpiperazin-l-yi)benzoate in the form of a light brown gum (yield=72%).

LCMS (El, m/z): (M+l) 410.3.

’H NMR: ÔHppm (400 MHz, DMSO): 7.73 (1H, bs, NH), 7.58 (1H, m, CH_arom), 7.77 (1H, m, CHarom), 6.09 (1H, bs, CH_arom), 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).

Example 16d: ferf-butyl 2-(N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamÎdo)-4(4-methylpiperazin-l-yl)benzoate

0.99 ml (6.98 mmol) of trifluoroacetic anhydride and 1.12 ml (8.06 mmol) of triethylamine are added to 2.2 g (5.3 mmo I ) o f ferf-butyl 2-(4,4difluorocyclohexylamino)-4-(4-methylpiperazin-l-yl)benzoate dissolved in 40 ml of dichloromethane. The reaction is left under stirring at room température 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 NaHCO₃ solution. The organic phase is dried on sodium sulfate, filtered and concentrated to obtain 2.5 g of fôri-butyl 2-(N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methylpiperazin-l-yl) benzoate in the form of a light brown gum (yield=92%).

LCMS (El, m/z): (M+l) 506.26.

‘H NMR: ÔH ppm (400 MHz, DMSO): 7.84 (1H, m, CHa_rom), 7.09(lH, m, CH_arom), 6.89 (1H, bs, CH_arom), 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-diniiorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methyl piperazin-l-yl)benzoic acid

7.62 ml (99 mmol) of trifluoroacetic acid is added to 2.5 g (4.95 mmol) of teri-butyl 2(N-(4,4-difluorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methylpiperazin-l-yl) benzoate dissolved in 30 ml of dichloromethane. The reaction is left under stirring at room température ovemight. The solvent is evaporated and then the crude reaction product 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-(4,4difluorocyclohexyl)-2,2,2-trifluoroacetamido)-4-(4-methylpiperazin-l-yl)benzoic acid in the form of a trifluoroacetic sait is obtained (yield=79%).

LCMS (El, m/z): (M+l) 450.1.

*H NMR: ÔH ppm (400 MHz, DMSO): 10,01 (1H, bs, OH), 7.92 (1H, m, CH_arom), 7.13 (1H, m, CHarom), 7.01 (1H, bs, CH_arom), 4.39 (1H, m, CH), 3.12-3.52 (8H, m, CH), 2.86 (3H, s, CH), 1.75-2.0 (8H, m, CH).

The following compounds are also obtained by this method:

4-(4-methylpiperazin-l-yl)-2-(2,2,2-trinuoro-N-(tetrahydro-2H-pyran-4-yI) acetamido)benzoic acid.

This compound was previously described in WO 2008/74749, WO 2009/13126 and WO 2010/69966.

LCMS (El, m/z): (M+l) 416.40.

^lH NMR: ÔH ppm (400 MHz, DMSO): 12.60 (1H, bs, OH), 10.08 (1H, bs, OH), 7.90 (1H, d, CH_arom), 7.13 (1H, dd, CH_arom), 6.90 (1H, d, CH_arom), 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-(dimethylanuno)propyl)(niethyl)amÎno)-2-(2,2,2-trifluoro-N-(tetrahydro-2Hpyran-4-yI)acetamido)benzoic acid.

This compound was previously described in WO 2009/13126 and WO 2008/74749.

Example 17: (S)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)-4-(3(2,2,2-trifluoroacetamïdo)pyrrolidin-l-yl)benzoic acid

Example 17a: tert-butyl (S)-4-(3-(tert-butoxycarbonylamino)pyrrolidin-l-yl)-2(tetrahydro-27/-pyran-4ylamino)benzoate

This compound was obtained by reproducing example 16d using tert-butyl (S)pyrrolidin-3-ylcarbamate.

Example 17b: (S)-4-(3-aminopyrrolidin-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino) benzoic acid

19,7 ml (25 eq) of trifluoroacetic acid is added to a solution of 4.72 g (10.23 mmol) of tert-butyl (S)-4-(3-(ter/-butoxycarbonylamino)pyrrolidîn-1 -yl)-2-(tetrahydro-2//-pyran-

4-ylamino)benzoate in 100 ml of dichloromethane. The reaction medium is stirred at room température 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-(3aminopyrrolidin-l-yl)-2-(tetrahydro-27/-pyran-4-ylamino)benzoic acid in the form of a trifluoroacetic acid sait.

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

Example 17: (S)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yI)aceta mi do)-4-(3(2,2,2-trifIuoroacetamido)pyrrolidin-l-yl)benzoic acid

1,74 ml (3.5 eq) of triethylamine and 1.6 ml (2,1 eq) of trifluoroacetic anhydride are added to a solution of 1.5 g (3.58 mmol) of (S)-4-(3-aminopyrrolidin-l-yl)-2(tetrahydro-2Z7-pyran-4-ylamino)benzoic acid in the form of a trifluoroacetic acid sait in 40 ml of dichloromethane at 0°C. The reaction medium is stirred at room température for 24 hours. Water (10 ml) is added drop by drop and then the organic phase is washed with saturated sodium chloride solution, dried on magnésium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (96:4 dichloromethane/methanol as eluent) to yield 250 mg (14%) of (8)-2-(2,2,2-trifluoro-N(tetrahydro-2H-pyran-4-yl)acetamido)-4-(3-(2,2,2-trifluoroacetamido)pyrrolidin-l-yl) benzoic acid in the form of a yellow powder.

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

Examplc 18; 2-(2-fluoroethoxy)-4-(4-methyIpiperazin-l-yl)benzoic acid

This compound can be prepared from the following intermediates.

Example 18a: tert-butyl 4-fluoro-2-(2-iluoroethoxy)benzoate Example 18b: tert-butyl 2-(2-fluoroethoxy)-4-(4-methylpiperazin-l-yl)benzoate

The following compound was also obtained by this method:

2-(2-nuoroethoxy)-4-(4-(l-methylpipeiïdin-4-yl)piperazm-l-yl)benzoic acid.

Example 19: 4-(4-methylpiperazin-l-yl)-2-(2,2,2-trifluoro-N-(2-fluoroethyl)acetamido)-benzoic acid

This compound can be prepared from the following intermediates.

Example 19a: terr-butyl 4-fluoro-2-(2-fluoroethylamino)benzoate Example 19b: tert-butyl 4-fluoro-2-(2,2,2-trifluoro-N-(2-fluoroethyl)acetamido) benzoate

Example 19c: tert-butyl 4-(4-methylpiperazin-l-yl)-2-(2,2,2-trifluoro-N-(2fluoroethyl)-acetamido)-benzoate

The following compound was also obtained by this method: 4-((3-(dimethylamino)propyl)(methyl)amino)-2-(2,2,2-trifluoro-N-(2-fluoroethyl) acetamido)benzoic acid,

·. t

Example 20; 4-(l-methvlpiperidin-4-vn-2-f2.2.2-trifluoro-N-ftetrahydro-2Hpyran-4-yl)acetamido)benzoic acid hydrotrifloroacetate ’OH

This compound can be prepared from the following intermediates.

Example 20a: tert-butyl 2-nitro-4-(pyridin-4-yl)benzoate

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-2nitrobenzoate (59.6 mmol) and 10.98 g of pyridine-4-ylboronic acid (89 mmol) in a mixture of 200 mi of dimethoxyethane and 100 mL of water. The réaction medium is heated at 100°C for 24 hours and then concentrated under reduced pressure. The residue obtained is purified by flash chromatography (CHîCh/AcOEt: 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+l) 301.0.

*H NMR: δΗ 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, J=4.4Hz), 1.54 (9H, s).

Exemple 20b: 4-f4-Üert-butoxvcarbonvlÎ-3-nitrophenvh-l-methvlDvridinium iodide

7.55 mL od iodomethane (121 mmol) is added to a solution of 16.2 g of tert-butyl 2nitro-4-(pyridin-4-yl)benzoate (60.6 mmol) in 20 mL of acetone. The reaction medium is heated at 60°C for 4 hours and then at room température overnight. After dry concentration, 27 g of orange crystals are isolated (100%).

MS (m/z): (M+l) 315.0.

^JH NMR: ÔH 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). JT : t

Example 20c: tert-butyl 2-amino-4-(l-methylpiperidin-4-yl)benzoate

0.48 g of platine (IV) oxide (2,12 mmol) is added to a solution of 26.8 g of 4-(4-(tertbutoxycarbonyl)-3-nitrophenyl)-l-methylpyridinium iodide (60.6 mmol) in 200 mL of methanol placed in a reactor made in stainless steel. The reaction medium isbrought 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, ’H NMR: ÔH ppm (400 MHz, DMSO): 9.18 (1 H, s, HI), 7.60 (IH, d, CHarom, J=8.4Hz), 6.54-6.40 (3H, m, CHarom), 6.39 (IH, d, CHarom, J=8.0Hz), 3.48-3.53 (2H, m, CH), 3.06 (2H, t, CH), 2.81 (3H, s, CH), 2.60-2.70 (IH, m, CH), 1.89-1.97 (2H, m, CH), 1.70-1.80 (2H, m, CH), 1.52 (9H, s).

Example 20d: tert-butvl 4-(l-methyIpiperidin-4-yl)-2-(tetrahydro-2H-pyran-4ylamino)benzoate

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 tétraméthylammonium triacetoxyborohydride (53.8 mmol) are successively added to a solution of 15 g of tert-butyl 2-amino-4-(lmethylpiperidin-4-yl)benzoate in 200 mL of dichloromethane under stirring. The reaction medium is stirred at room température for 2 h and then taklen up with a IN soda solution. The organic phase is îsolated, dried on magnésium sulfate and then dried concentrated. The residue contained always HI. It is thus taken up in dichloromethane and washed with 100 mL of a IH soda solution. The organic phase is decanted, dried on magnésium sulfate and dry concentrated to yield 14.6 g of a yellow solid (quantitative yield).

MS (m/z): (M+1) 375.2.

’H NMR; ÔH ppm (400 MHz, DMSO): 7.69 (IH, d, CHarom, J=8.4Hz), 7.63 (IH, d, CHarom, J=7.6Hz), 6.65 (IH, s, CHarom), 6.44 (IH, dd, CHarom, J=8.4Hz), 3.74-3.86 (2H, m, CH), 3.66-3.71 (IH, m, CH), 3.51 (2H, t, CH), 3.05-3,12 (2H, m, CH), 2.6-2.5 (IH, 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).

Example 20e: tert-butyl 4-(l-methylpiperidin-4-yl)-2-(2,2,2-trifluoro-N(tetrahydro-2H-pyran-4-yl)acetaniido)benzoate Λ : ι

6.35 mL of triethylamine and 5.50 mL of 2,2,2-trîfluoroacetic anhydride (39.6 mmol) are added at 0°C to a solution of 11.4 g of tert-butyl 4-(l-methylpiperidin-4-yl)-2(tetrahydro-2H-pyran-4-ylamino)benzoate (30.4 mmol) in 240 mL of dichloromethane under stîrring. The reaction medium is stirred at room température for lh and then 100 mL of water is added dropwise. The organic phase is decanted, dried on magnésium 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 dise and 12.06 g of white crystals is isolated. The filtrate is concentrated (4.5g) and then purified by flach chromatography on silica (CH₂Cl₂/meOH: 95:5 to 90:10,20 min). The product obtained is recrysltallized in diethyl ether to yield 1.04 g of additional white crystals (global yield = 74%).

MS (m/z): (M+1) 471.1.

’H NMR: ÔH ppm (400 MHz, DMSO): 9.45 (IH, si, NH), 7. 96 (IH, d, CHarom, J=8Hz), 7.51 (IH, d, CHarom, J=8Hz), 7.31 (IH, s, CHarom), 4.6-4.5 (IH, m, CH), 3. 90-3.75 (2H, m, CH), 3.5-3.35 (4H, m, CH), 3.1-2.85 (3H, m, CH), 2.79 (3H, s, CH₃), 2.1-1.95 (3H, 3, CH), 1.9-1.75 (2H, m, CH), 1.55-1.40 (1 IH, m), 1.0-0.85 (IH, m, CH).

Example 20: 4-( 1 -m et hy I pi peridin-4-yl)-2-(2,2,2-trif]uoro-N-(tetrahydro-2Hpyran-4-yl)acetamido)benzoic 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-(l-methyipiperidin-4-yl)-2-(2,2_J2-trifluoro-N-(tetrahydro-2Hpyran-4-yl)acetamido)benzoate (5.47 mmol) (in the form of a sait of trifluoroacetic acid) in 30 mL of dichloromethane. The reaction medium is stirred at room température for 16h, and then evaporated under reduced pressure. The residue is taken up in éthanol, and the white solid formed is filtered on a fritted dise to yield 1.61 g (53%) of white crystals.

MS (m/z): (M+1 )415.1.

’H NMR: ÔH ppm (400 MHz, DMSO): 13.39 (IH, si, COOH), 9.46 (IH, si, COOH du TFA), 7.99 (IH, d, CHarom, J=8.4Hz), 7.49 (IH, d, CHarom, J=8.4Hz), 7.30 (IH, s, CHarom), 4.53 (IH, 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), 1.44-1.54 (2H, m, CH).

Example 21: l-(4-isothiocyanatophenyl)-4-methylpiperazine

This compound was prepared by adapting the method described in EPI215208.^

·. \

The foliowing compound was also obtained by this method:

tert-butyl 2-isothiocyanato-5-(4-niethylpiperazin-l-yl)phenylcarbaniate

Example 22: tert-butvl 2-isocyanato-5-(4-methylpiperazin-l-yl)phenykarbamate

This compound can be prepared from the foliowing intermediates.

Example 22a: tert-butyl 5-(4-methylpiperazin-l-yi)-2-nitrophenykarbamate Example 22b: tert-butyl 2-amino-5-(4-methylpiperazln-l-yl)phenylcarbamate Example 22: tert-butvl 2-isocyanato-5-(4-methylpiperazin-l-yl)phenylcarbamatc

Example 23: 4-(4-methvlpÎperazin-l-vl)-2-(tetrahvdro-2H-pvran-4-vlamino) benzaldehyde

Example 23a: i4-(4-methvlpinerazin-l-vl)-2-(tetrahvdro-2H-nvran-4-vlamino) phenyl)methanol

500 mg (1.060 mmol) of 4-(4-methylpiperazine-l-yl)-2-(2,2,2-trifluoiO-N-(tetrahydro2H-pyran-4-yl)acetamido)benzoic acid dissolved in 5 mi of tetrahydrofuran is added at 0°C to a suspension of 201 mg (5.30 mmol) of LiAIH» in 9 ml of tetrahydrofuran. The reaction mixture is stirred at 0°C for 1 hour and then at room température for 3 hours. The reaction mixture is cooled at 0°C and then, drop by drop, 200 μΐ water, then 200 μΐ of soda solution (15% by weight) and finally 1 ml of water are added. The reaction mixture is stirred at room température for 2 hours and then filtered and rinsed with tetrahydrofuran, The filtrate is concentrated to yield 250 mg (yield=77%) of (4-(4methylpîperazine-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)phenyl)methanol in the form of a white solid.

LCMS (El, m/z): (M+l) 306,14.

*H NMR: ÔHppm (400 MHz, DMSO): 6.85 (IH, d, CH_nrom), 6.20 (IH, d, CH_arom), 6.10 (IH, d, CHarom), 4.95 (IH, bs, OH), 4.87 (IH, 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).

Example 23: 4-(4-niethvlniDerazin-l-vl)-2-itetrahvdro-2H-Dvran-4-vlamino) benzaldehyde mg (0.982 mmol) of manganèse dioxide is added at room température to a solution of (4-(4-methylpiperazine-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)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-methylpiperazine-l-yl)-2(tetrahydro-2H-pyran-4-ylamino)benzaldehyde in the form of a white solid.

LCMS (El, m/z): (M+l) 304.19.

‘HNMR: ÔHppm (400 MHz, DMSO): 9.43 (1H, d, CH), 7.32 ( 1 H, d, CH_lirom)> 6.36 (1H, d, CHarom), 6.08 (1H, d, CH_aram), 3.94-3.99 (2H, m, CH), 3.77 (1H, m, CH), 3.61-3.63 (2H, m, CH), 3.42-3.45 (4H, m, CH), 2.57-2.60 (4H, m, CH), 2.36 (3H, s, CH₃), 2.042.08 (2H, m, CH), 1.51-1.60 (2H, m, CH).

Example 24: 2-(4-(4-methylpiperazin-l-yl)phenyl)acetic acid .COOH

Examplc 24a: 2,2,2-trichloro-l-(4-(4-methylpiperazin-l-yl)phenyl)ethanoI

1,0 ml (10.00 mmol) of trichloroacetic acid and, in small portions, 1.854 g (10 mmol) of sodium 2,2,2-trichloroacetate are added at room température to a solution of 1.362 g (6.67mmol) of 4-(4-methylpiperazine-l-yl)benzaldehyde in 13.5ml of dimethylformamide. The reaction mixture is stirred for 3 hours at room température. The solvent is concentrated and the crude reaction product extracted with ethyl acetate. The organic phase is washed using saturated sodium bicarbonate solution. The organic phases are combined, dried on magnésium sulfate and then concentrated to yield

1.760 g (yield=82%) of 2,2₁2-trichloro-l-(4-(4-methylpiperazine-l-yl)phenyl)ethanol In the form of a white solid.

LCMS (El, m/z): (M+1) 324.04.

‘H NMR: Ôh ppm (400 MHz, DMSO): 7.41 (2H, d, CH_nrom), 7.02 (IH, bs, OH), 6.90 (2H, d, CHarom), 5.08 (IH, bs, CH), 3.14-3.16 (4H, m, CH), 2.42-2.47 (4H, m, CH), 2.21 (3H, s, CH₃).

Exemple 24: 2-(4-(4-methylpiperazin-l-yI)phcnyl)acetic acid

0.559 g (14.77 mmol) of sodium borohydride is added quickly to 2.294 g (7.35 mmol) of dibenzyl diselenide in 28 ml of éthanol. The reaction mixture is stirred at room température for 1 hour. 2.266 g (7 mmol) of 2,2,2-trichloro-l-(4-(4-methylpiperazine-lyl)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 magnésium sulfate and then concentrated to yield 2-(4-(4-methylpiperazine-l-yl)phenyl)acetic acid which is used without additional purification.

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

Example 25; 2-(4-(4-methylpiperazin-l-yl)-2-nitrophenyl) acetic acid

This compound can be prepared from the following intermediates.

Example 25a: diethyl 2-(4-fluoro-2-nitrophenyl)malonate

Example 25b: diethyl 2-(4-(4-methyIpiperazin-l~yl)-2-nïtrophenyl)malonate

Example of method El:

Example 26: N-(5-(3,5-difIuorophenylthio)-lH-pyrazolo|3,4-b]pyridin-3-yl)-4-(4methylpiperazin-l-yl)-2-(2,2,2-trif]uoro-N-(tetrahydro-2H-pyran-4-yl) acetamido)benzamide X

0.95 ml (11.21 mmol) of oxalyl chloride and 2 drops of anhydrous dimethyiformamide are added to 2.97 g (5.61 mmol) of a solution of 4-(4-methylpiperazin-l-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid in 95 m 1 o f dichloromethane. The reaction mixture is stirred for 2 hours at room température. The solvents are evaporated, the solid formed is taken up in toluene and the solvent 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-(3,5difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-amine and 3.71 ml (21.30 mmol) of N-ethyl-N-isopropylpropan-2-amine in 30 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 3 hours at -20°C and then overnight at room température. The precipitate obtained is filtered and rinsed with tetrahydrofuran and water and then dried to yield 2 g (53%) of N-(5-(3,5-difluorophenyIthio)-lH-pyrazolo[3,4-b]pyridin-3yl)-4-(4-methylpiperazin-l-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4yl)acetamido)benzamide.

LCMS (El, m/z): (M+1) 676.20.

*H NMR: SH ppm (400 MHz, DMSO): 13.66 (1H, bs, NH), 11.08 (1H, bs, NH), 8.61 (1H, s, CHnrom)i 8.46 (1H, s, CH_aroili), 7.83 (1H, d, CH_arom), 7.05-7.10 (2H, m, CH_arOtn), 6.83-6.89 (3H, m, CH_arom), 4.39-4.44 (1H, m, CH), 3.83-3.85 (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).

ιοο

The following dérivatives were obtained according to the same method:

r₂

El.**	Y	Ri	Rï	n	w	R,	Y1,Y<	Compound namcs	Yield	MasjMH*
26-1	ΟγΝΗ2 ir	Q F^F	ό ♦	0	H	H	CH, N	N-(5-(2-caibamoylphenylthio)-lHpyrazoloI3,4-blpyridin-3-yl)-4-(4methylpiperazin- l-yI)-2-(2,2,2triÎluoro-N-(telrahydrô-2H-pyran-4yl)acctamido)bcnzamidc	ND	ND
26-2	o. FÀF	Q ,ΝγΟ f'T'f	ό t	0	H	H	CH, N	N-(5-(3,5-difluorophenylsulfonyl)lH-pyrazolo[3,4-b]pyridÎn-3-yl>4(4-meÜiy Ipiperazin-1 -yl)-2(tetrahydro-2H-pyran-4ylami no)bcnzamidc	ND	ND
26-3	1	Q F^F	(S N t	0	H	H	CH, N	N-(5-iodo-lH~pyrazoloI3,4bjpy ridi n-3-y])-4-(4-nielhylpiperazinl-yl)-2-(2,2,24rifluoro-N(telrahydro-2H-pyran-4vl)acctamido)beiranüdc	ND	ND
26-4	s' fJÔLf	H	NOj	1	H	H	CH, N	N-(5-(3,5-difluoropheny 1 (h io)-1Hpyrazolo[3,4-b]pyridin-3 -yl)-2-(4nitroplicnvljacctamidc	ND	442.21
26-5	o. v F	Q ,N^O F^Tf Γ F	(5 N ♦	0	H	H	CH, N	N-(5-(3,5-difluorobenzylsulfonyl)1 H-pyrazolol3,4-b]pyridin-3-y l)-4(4-mcthylpiperazin-l-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acetamido)benzamide	ND	ND
26-6	s' A	5 ρφρ	N t	0	H	H	CH, N	2-(N-(4,4-difluorocyclohexyl)-2,2,2lrilluoroacetamido)-N-(5-(3,5difluorophcny lsulfony 1)- 1Hpyrazolo[3,4-b]pyridin-3-yl)-4-(4mcthylpiperazin-l -yljbenzamidc	ND	ND
26-7	fÆ	5 F^F	ù N ♦	0	H	H	CH, N	N-(5-(3,5-difluorobenzyl)-lHpyrazolo[3,4-b]pyridin-3-yl)-4-(4mcthylpipcrazin-1 -yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4yl)acetamîdo)bcnzamide	22%	676.2

i

101

26-8	.ώ.	H	ό N »	l	H	H	CH, N	N-(5-(3,5-dif]uorophenyIthio)-lHpyrazolo[3,4-b]pyridin-3 -yl)-2-(4-(4methylpipcrazin-tyl)phcnyl)acctamidc	ND	495.17
26-9	I	Q χΝγΟ F^F	Λ N 1	0	OMe	H	CH, N	N-(5-iodo-6-mcÜioxy-1Hpyrazolo[3,4-b]pyridin-3-yl)-4-(4nieüiy Ipipcrazin-1 -yl)-2-(2,2,2lri(luoro-N-(telrahydro-2H-pyraii-4yl)acctamido)bcnzainidc	ND	688.18
26-10	I	Q χΝγΟ fTf r	ό N ♦	0	NHj	H	CH, N	N-(6-amino-5-iodo-1 H-pyrazolo]3,4b]pyridin-3-yl)-4-(4-nicthylpiperazin1 -y 1)-2-(2,2,2-trifluoro-N(tetrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	673.06
26-11	A	Q ,ΝγΟ f+f Γ	'Άο b 1	1	H	H	CH, N	(S)-N-(5-(3,5-difliionophenylthio)lH-pyrazolo[3,4-b]pyridin-3-yl)-2(2,2,2-üiÎluoroN-(tctrahydr(>-2Hpyran-4-yl)accianùdo)-4-(3-{2,2,2lrifluoroacctamido)pyrTolidin-l yl)bcnzamidc	ND	ND
26-12	A	H	ù N t	0	H	H	CH, N	N-(5-(3,5-difluorophcnylthÎo)-lHpyrazolo[3,4-b]pyridin-3-yl)-4-(4mcthy Ipipcrazin-1 -yl)benzamidc	46%	481.38
26-13	A	O IL	ό N i	0	H	H	N, CH	N-(5-(3,5-<iifluorDbcnzyl)-lHpyrazolo[4,3-b]pyridin-3-yl)-4-(4mcthylpipcrazin-1 -yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acetamido)bcnzamide	35%	658.1
26-14	A F	Q ζΝγΟ ρφρ	ù N »	0	H	H	N, CH	N-(5-(3,5-difIuoiObcnzyloxy)-lHpyrazolo[4,3-b]pyridin-3 -yl)-4-(4mcthylpipcrazin-l-yl)-2-(2,2,2trifluoro-N^tctrahydrô-2H-pyran-4yl)acctamido)bcnzamidc	63%	674.1

102

26-15	t/ F	Q F^F	Φ	0	H	H	N, CH	N-(5-(3,5-diiluorobenzy loxy)-1Hpyrazplo[4,3-b]pyridin-3-yl)-4-( 1mcthylpipcridin-4-yl)-2-<2,2,2triiluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	673.1
26-16	nf	Q ,ΝγΟ	ù N ♦	0	H	H	N, CH	N-(5-(2,5-difluorobcnzyloxy)-lHpyrazolo[4,3-b]pyridin-3-yl)-4-(4mcthylpipcrazin-l-yl)-2-<2,2,2tri(luoro-N-(tctrahydro-2H-pyran-4yl)acctainido)bcnzamidc	62%	674.2
26-17		Q ,ΝγΟ F'T'F	Φ	0	H	H	N, CH	N-(5-(2,5-diflitorobenzyloxy)-lHpyrazolo[4,3 -b]pyridin-3-y 1)-4-( 1 mcthylpipcridin-4-yl)-2-(2^,2trifluoro-N-<tctrahydro-2H-pyran-4yl)acctamido)benzaniide	ND	673.3
26-18	a	Q f+f Γ	Φ ♦	0	H	H	N, CH	N-(5-(2,5-dichlorobcnzyloxy)-!HpyrazoloI4,3-b| pyridin-3-yl)-4-(4mcthylpipcrazin-1 -yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzarnidc	ND	ND
26-19	y a	Q ,ΝγΟ F'T'F	Φ	0	H	H	N, CH	N-(5-(2,5-didilorobenzyloxy)-lHpyrazolo[4,3-b]pyridin-3-yl)-4-(lmclhylpiperidin-4-yl)-2-(2,2,2trinuoro-N-(tetrahydro-2H-pyran-4yl)acctamido)benzamidc	ND	ND
26-20	a	Q ^NyO f'T'f	(5 N 1	0	H	H	N, CH	N-(5-(5-chloro-2(trinuoromclhyl)benzyloxy)-lHpyrazx)lo[4,3-b]pyridin-3-yl)-4-(4mcthylpipcrazin-l-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4yl)acctaniido)bcnzamidc	55%	740.2

103

26-21	y α	Q F^F	Φ	0	H	H	N, CH	N-(5-(5-cliloro-2(trifluoroincthyl)bcnzyloxy)- 1Hpyrazolo[4,3-bjpyridin-3-yI)-4-(lmcthy lpipcridin-4-yl)-2-<2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	739.3
26-22	c/ Ν	Q ,N^O F^F	ù N t	0	H	H	N, CH	4-{4-mcÜiylpipcrazin-l-yl)-N-(5(pyridin-3-y lmcthoxy)-1Hpyrazolo[4,34)jpyridin-3-yl)-2(2,2,2-trifluoro-N-(tctrahydro-2Hpyran-4-yl)acetamido)benzamide	90%	639.2
26-23	r/ Ν	Q „ΝγΟ f'T'f	Φ	0	H	H	N, CH	4-( 1-methylpipcridin-4-yl)-N-<5(pyridin-3-ylmcthoxy)-l Hpyrazolo|4,3 -b]pyridin-3 -y 1)-2(2,2,2'trifluoro-N-(tclrahydro-2Hpyran-4-yl)acctamido)bcnzamidc	ND	638.2
26-24	sx	Q χΝγΟ F^F	û N ♦	0	H	H	N, CH	N-(5-(3,5-difluorophcnylÜiio)-lHpyrazolo[4,3-bJpyridin-3-yl)-4-(4mcthylpipcrazin-1 -yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4yl)acctamîdo)bciizaniidc	ND	ND
26-25	sx A	Q ^w»O F^F	Φ	0	H	H	N, CH	N-(5-(3,5-diiluorophenyllhio)-l Hpyrazolo[4,3-b]pyridin-3-yl)-4-(lmcthylpiperidin-4-yl)-2H(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4yl)acetamido)benzamidc	50%	ND
26-26	sx 4xF	Q Fyp	Λ N ♦	0	H	H	N, CH	N-(5-(2,5-difliiorophcnylthio)-lHpyrazolo[4,3-b}pyridin-3-yl)-4-(4mcthy Ipipcrazin-1 -yl)-2-(2,2,2trinuoro-N-(tetrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	ND

I04

26-27	,ώ·1	Q ,Ν^Ο F jTF	φ	0	Η	Η	Ν, CH	Ν-(5-(2,5-difluorophenylüiio)-1Ηpyrazolo[4,3-bJpyridin-3-yl)-4-(lmcthy]pipcridin-4-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcn»unîdc	ND	ND
26-28	s'	Q ^,Ν^Ο ρφρ	Λ Ν »	0	Η	Η	N.CH	N-(5-(3,5-dichlorophenyllhio)-l Hpyrazolo[4,3-b]pyridin-3-yl)-4-<4mcthylpipcrazin-1 -yI)-2-(2,2,2trinuoro-N-(lctrahydro-2H-pyran-4yl)acctamido)bcnzamide	ND	ND
26-29	sx Λ	Q ,Ν^Ο F*T*F	Φ	0	Η	Η	Ν, CH	N-(5-(3,5-dichlorophcny Ithio)-1Hpyrazolo[4,3 -b]pyridin-3 -yl)-4-( 1 mcthylpiperidin-4-yl)-2-<2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)benzamide	ND	ND
26-30		Q χΝγΟ FyF	ό Ν t	0	Η	Η	N.CH	N-(5-(2s5-dichlorophenylthio)-l Hpyrazolo[4,3 -b]pyridîn-3-yl)-4-(4methylpipcrazin-l-yl)-2-(2,2,2triiluoro-N-(tctrahydn>-2H-pyran-4yl)acetamido)bcnzamide	ND	ND
26-31	ά.	ψ ,Ν^Ο F'T'f Γ F Γ	Φ	0	Η	Η	Ν, CH	N-(5-(2,5 -diclilorophcny Ithio)- IHpyrazolo[4,3-blpyridin-3-yl)-4-( 1methylpipcridin-4-yl)-2-(2,2)2tri(luoro-N-(tctfahydrD-2H-pyian-4yl)acctamido)bcnzamidc	ND	ND
26-32		Q f'J'f Γ	Û Ν ♦	0	Η	Η	Ν, CH	4-(4-mcthylpiperazin-l-yl)-2-(212,2irifl uoro-N-(tctrahydro-2H-pyran-4yl)acctamido)-N-(5-(2(trifluoromcthyl)phcnylthio)-1Hpyrazolo[4,3-b]pyridin-3yl)benzamidc	ND	ND

105

26-33	~x5 t	Q F p F	Φ	0	H	H	N, CH	4-(l-mcthylpipcridin-4-yI)-2-(2,2>2trifluoro-N-(tctrahydn>-2H-pyran-4yl)acetamido)-N-(5-(2(Iri(luoromcÜiyl)phcnyUhio)-1Hpyrazolo[4,3-b]pyridin-3yl)bcnzamidc	ND	ND
26-34	V F	Q F^F	ό N »	0	H	H	N, CH	N-(5-(3,5-difliiorobenzylthio)-1Hpyrazolo|4,3-b|pyridin-3-yl)-4-(4methylpiperazin-1 -yl)-2 -(2,2,2trî Îluoro-N-(tctrahydro-2H-py ran-4yl)acctamido)bcnzamidc	ND	ND
26-35	v F	Q F^F	Φ	0	H	H	N, CH	N-(5-(3,5-diiIuorobcnzylthio)-lHpyrazolo|4,3-b]pyridin-3-yl)-4-(lmcthylpipcridin-4-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4yl)acctamido)bcnzatnidc	73%	ND
26-36	•xZ	Ψ F'T'F	ù N »	0	H	H	N, CH	N-(5-(2,5-diiliK>iObenzylthio)-l Hpyrazolol4,3-b|pyridin-3-yl)-4-(4mcthylpiperazin-1 -yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	ND
26-37	xi	Q XN^O F-^F	Φ	0	H	H	N, CH	N-(5-(2,5-difluorobenzylthio)-1Hpyrazolo[4,3-b]pyridin-3-yl)-4-(lmelhylpipcridin-4-yl)-2-<2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	ND
26-38	xi	Q >ΝγΟ f'T'f	ό 1	0	H	H	N, CH	N-(5-(2,5-dichlorobcnzylthio)-lHpyrazolo[4,3-blpyridin-3-ylH-(4methylpiperazin-1 -y 1)-2-(2,2,2lrifluoro-N-(tetrahydro-2H-pyran-4yl)acctainido)bcnzamidc	ND	ND

106

26-39	uf	χΝγ,Ο F^F	Φ	0	Η	Η	Ν, CH	N-(5-(2,5-dichlorobenzylthio)-lHpyrazolo[4,3-b] pyridin-3 -yl)-4-( 1 methy Ipi pcridin-4-y 1)-2-(2,2,2trifluoro-N-(tctnihydro-2H-pyran-4yl)acetamido)bcnzanude	ND	ND
26-40	ην A	χΝγΟ F t F Γ	c5 Ν ♦	0	Η	Η	Ν, CH	N-(5-(3,5-difIuorophcnylanùno)-lHpyrazolo[4,3-b]pyridin-3-yl)-4-(4methy lpiperazin-1 -yl)-242,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acetamido)bcnzaniide	79%	659.2
26-41	ΗΝ' A	Q χΝ^Ο f'T'f	Φ	0	Η	Η	Ν, CH	N-(5-(3,5-difluorophenylamino)-lHpyrazolo[4,3-b|pyridin-3-yl)-4-( 1 nicthylpipcndin-4-yl)-2-(2,2,2trifluono-N-(teirahydro-2H-pyraii-4yl)acetamido)bcnzamide	ND	658.2
26-42	ΗΝΧ A	Q >ΝγΟ FJF Γ	ό Ν ♦	0	Η	Η	Ν, CH	N-(5-(2,5-<lifluorophenylainino)-1Hpyrazolo|4,3 -b]pyridin-3-yl)-4-(4mcthylpiperazin-1-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acclamido)bciizamidc	ND	659.2
26-43	ΗΝ* A	ψ χΝγΟ F-T-F	Φ	0	Η	Η	N.CH	N-(5-(3,5-dinuorophenylaniino)-lHpyrazolo[4,3-b[pyridin-3-yl)-4-(lmethylpipcridin-4-yl)-2-(2,2,2trifluoro-N-(tctrahydn>-2H-pyran-4yl)acetatnido)benzamidc	ND	658.2
26-44	ΗΝ*	ψ χΝ^Ο F^F	ό Ν ♦	0	Η	Η	Ν, CH	N-(5-(2,5-dichlorophcnylanajio)-lHpyrazolo[4,3-b)pyridin-3 -yl)-4-(4mcthylpipcrazin-1 -yl)-2-(2,2,2trifluoro-N-(tetrahydro~2H-pyran-4yl)acctamido)bcnzamidc	26%	691.2

<^Γ t

I07

26-45	HN*	Q r F r	Φ	0	H	H	N, CH	N-(5-(2,5-dichlorophenylamino)-lHpyrazolo(4,3-b|pyridin-3-yl)-4-(lmcthylpipcridin-4-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)benzanude	98%	692.2
26-4«	A	Q ,ΝγΟ	ό ♦	0	H	H	N, N	N-(5-{3l5-difluorobenzyl)-lHpyrazoIo[3,4-b]pyrazin-3-yl)-4-(4methylpiperazin-1 -yl)-2-(2,2,2trifluon>-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamide	ND	ND
26-47	A	ψ /ΝγΟ F*T*F	Φ	0	H	H	N, N	N-(5-(3,5-difluorobenzyl)-1Hpyrazolo[3,4-b]pyrazin-3-yl)-4-(lmethylpiperidin-4-yl)-2-(2,2,2trinuoro-N-(tctrahydrt>-2H-pyran-4yl)acctamido)bcnzatnide	ND	ND
26-48	I	Y I	Q F'+'F	Φ	0	H	H	N. N	N-(5-((3,5-dinuorophenyl)ethynyl)- 1 H-pyrazo1o[3,4-b]pyrazin-3 -yl)-4«3- (dimcthy lamino)propy l)(mcthy l)amin o)-2-(2,2,2-triflüoro-N-(tctrahydro2H-pyran-4-yl)acctamido)benzamidc	ND	ND
26-49	X I	Y I	Q f'+'f	Φ	0	H	H	N, N	N-(5-((3,5-dîfluorophcnyl)ethynyl)- 1 H-pyrazolo[3,4-b]pyrazin-3 -y 1)-4( l -methylpiperidin-4-y 1)-2-(2,2,2trifluoro-N-(tctrahydn>-2H-pyran-4yl)acetamido)bcnzamide	ND	ND
26-50	A	Q FjF	Φ	0	H	H	N, N	N-(5-(3,5-difluorophcnylthTO)-lHpy razolo(3,4-b] pyrazin-3-yl)-4-((3(dimcthylamino)propyiXmcthyl)amin 0)-2-(2,2,2-triiluoro-N-(telrahydro2H-pyran-4-yl)acctamido)benzamidc	43%	693.2

108

26-51	K	Q χΝγ° F^F F r	Φ	0	H	H	N, N	N-(5-(2,5-dichlorophenylthio)-lHpyrazolo[3,4-b] pyrazm-3-y 1)-4-(4mcthylpipcrazin-l-yl)-24[2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	ND
26-52	A	Q χΝγΟ fÇf	ό ♦	0	H	H	N, CH	4-(4-metliylpipcrazin-l-yl)-2-(2,2,2lrifluoro-N-(tctrahydro-2H-pyran-4yl)acetamido)-N-(5-(2(trifluoromcthyl)phenylthio)-lHpyrazolo[3,4-b]pyrazin-3yl)bcnzamide	66%	709.1
26-53	o> FYXp	Q χΝγΟ F'+'F	ô N •	0	H	H	N, CH	N-{5-(3,5-difluorophenylsulfonyl)lH-pyrazolol4,3-b]pyridin-3-yl)-4(4-mcthylpiperazin- l-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	28%	708.2
26-54	°v A	Q ,ΝγΟ F^F	Φ	0	H	H	N, CH	N-(5-(3,5-difluorophcnylsulfonyl)lH-pyrazolo[4,3-b]pyridin-3-yl)-4( l-mcthylpipcridin-4-yl)-2-(2,2,2trifluoro-N-(tctrahydn>-2H-pyran-4yl)acctamido)bcnzamidc	74%	707.2
26-55	V °'l Λ	Q χΝ^Ο F'T'F	ù N »	0	H	H	N, CH	N-(5-(2,5-difliiorophenylsulfonyl)lH-pyrazolo[4,3-b]pyridin-3-yl)-4(4-methylpÎpcrazin-1 -yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acetamido)benzamidc	ND	ND
26-56	V	Q χΝγΟ f+f r	Φ	0	H	H	N, CH	N-(5 -(2,5-difluorophcny lsulfonyl)lH-pyrazolo(4,3-b]pyridin-3-yl)-4( l-mcthylpipcridin-4-yl)-2-(2,2,2lriiluoro-N-(tclniliydro-2H-pyran-4yl)acctamido)bcnzaniidc	ND	ND

109

26-57	h	Q ,ΝγΟ F^F	ό N ♦	0	H	H	N, CH	N-(5-(3,5-dichloFophenylsidfonyl)lH-pyrazolo[4,3-bJpyridin-3-yl)-4(4-methylpiperazin-l-yl)-2-(2,2,2triHuoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	ND
26-58	V ÏX	Q F-'T’F r F	Φ	0	H	H	N, CH	N-(5-(3,5-dichlorophenylsiilfonyl)lH-pyrazolo[4,3-b]pyridin-3-yl)-4(l-mcthylpiperidin-4-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4yl)acetamido)bcnzamide	ND	ND
26-59	V A	Ψ ^NyO F^F	Φ ♦	0	H	H	N, CH	N-(5-(215-dichlorophcnylsulfonyl)lH-pyrazolo[4,3-b]pyridin-3-yl)-4(4-methylpiperazin- 1 -y 1)-2-(2,2,2trifluon>-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	ND
26-60	V Ο'? A	Q F^F	Φ	0	H	H	N, CH	N-(5-(2,5-dichlorophenylsulfonyl)I H-pyrazolol 4,3-b| pyridîn-3-yl)-4( 1 -methylpiperidin-4-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	ND	ND
26-61	F	Q χΝγΟ F^F	ό N 1	0	H	H	N, CH	N-(5-(3,5-difliiorobenzylsulfonyl)lH-pyrazolo[4,3-b|pyridin-3-yl)-4(4-methyîpiperazin-l-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctainido)benzamidc	94%	ND
26-62	F	Q F'T'F	Φ	0	H	H	N, CH	N-(5-(3,5-dinuorobcnzylsulfonyl)1 H-pyrazolo[4,3-b}pyridin-3-yl)-4( 1 -mcthylpipcridin-4-yl)-2-(2,2,2lri(luoro-N-(lcirahydrt>-2H-pyran-4yl)acctamido)bcnzamidc	99%	ND

I ΙΟ

26-43	ο n- O-S Υς	Q χΝ^-Ο F^F	ù N t	0	H	H	N, CH	N-(5-(2,5-difluorobenzylsulfonyl)lH-pyrazolo[4,3-b]pyridin-3-yl)-4(4-mcthylpipcrazin-l-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4yl)acctamido)bcnzamidc	60%	ND
26-44	?x A	Q ,ΝγΟ F^F	Φ	0	H	H	N, CH	N-(5-(2,5-difluorobenzylsulfonyl)lH-pyrazo1o[4,3-b]pyridin-3-yl)-4( i -mcthylpipcridin-4-yl)-2-{2)2,2trifluoro-N-(tctrahydro-2H“pyran-4yl)acctamido)bcnzainidc	36%	ND
26-65	Ά	Q xNyO F^F	Φ	0	H	H	N, CH	N-(5-(2,5-difluorobenzylsulfînyl)' I H-pyrazolo[4,3-b]pyridin-3-yl)-4(l-methy]pipcridin-4-yl)-2-<2,2,2trifluoro-N-(tetrahydro-2H-pyraii-4yl)acclamido)bcnzamidc	ND	ND
26-46	A	Q >ΝγΟ F^F	Φ	0	H	H	N, CH	N-(5-(2,5-dichlorobcnzylsulfonyl)1 H-pyrazoloI4,3-blpyridin-3-yl)-4(4-methylpiperazin-l-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzamidc	52%	ND
26-47	?x 0—s A	Q /NyO F“1*F r F r	Φ	0	H	H	N, CH	N-(5-(2,5-dichlorobcnzylsulfonyl)lH-pyrazolo[4,3-b]pyridin-3-yl)-4( 1 -methylpiperidin-4-yl)-2-(2,2,2trifluoro-N-(tctrahydro-2 H-pyran-4yl)acetamido)bcnzaniidc	90%	ND
26-68		Q xN^O F'T'F	Φ	0	H	H	N, CH	N-(5-(2.5-dichlorobcnzylsulfinyl)1 H-pyrazolo| 4,3-b}pyridin-3-yl)-4(l*methylpipcridin-4-yl)-2-(2,2,2lriiluoro-N-((etrahydro-2H-pyran-4yl)acctamido)bcnzamidc	50%	ND

I lll

26-69	I	-Π -π O	ό N »	0	H	*3	CH, N	N-(5-iodo-l -trityl-1 H-pyrazolo[3,4- b]pyridin-3-yl)-4-(4-melhylpipcrazinl-yl)-2-(tetrahydro-2H-pyran-4y]amino)bcnzamidc	67%	900.23
26-70	F	Q ,ΝγΟ	(b N t	0	H	H	CH, N	N-(5-(3,5dinuorophenylsulfonamido)-1Hpyrazolo|3,4-b|pyridin-3-yl)-4-(4niclhylpipcrazin- ! -yl)-2-(2,2.2triÎluoro-N-(tctrahydro-2H-pyran-4yl)acctamido)bcnzaniidc	11%	ND
** Ή NM1	<, dmso-ds, Ex.:	26-4: 13,64(1 H	[, si, NH), 11,26(1 H, si, NH), S	1.68 (	IH, d,

CHarom), 8,58 (IH, d, CH_arom), 8,20 (2H, d, CH™), 7.64 (2H, d, CH™), 7,03 (IH, m, CH™), 6,78 (2H, m, CH_arom), 3,95 (2H, m, CH₂). 26-8: 13,59 (IH, si, NH), 11,05 (IH, si, NH), 8,68 (IH, d, CH_arom), 8,57 (IH, d, CH nrom)_f 71 19 (2H, d, CH™), 6,99-7,08 (IH, m, CHarom), 6,88 (2H, d, CH_arom), 6,75-6,79 (2H, m, CH_arom), 3,61 (2H, m, CH₂), 3,073,09 (4H, m, CH), 2,41-2,44 (4H, m, CH), 2,20 (3H, s, CH₃). 26-9: 13,17 (IH, si, NH),

10,90 (IH, si, NH), 8,55 (IH, s, CHarom), 7,79 (IH, d, CHarom), 7,07 (IH, dd, CHarom), 6,90 (IH, d, CHarom), 4,40-4,50 (IH m, CH), 3,96 (3H, s, CH₃), 3,82-3,89 (IH, m, CH), 3,74-3,80 (IH, m, CH), 3,34-3,41 (2H, m, CH), 3,28-3,33 (4H, m, 10 2*CH₂), 2,43-2,47 (4H, m, 2*CH₂), 2,23 (3H, s, CH₃), 1,85-1,92 (IH, m, CH), 1,58-

1,63 (IH, m, CH), 1,45-1,53 (IH, m, CH), 1,22-1,33 (IH, m, CH). 26-10: 12,48 (IH, si,

NH), 10,72 (IH, si, NH), 8,30 (IH, s, CHarom), 7,77 (IH, d, CHarom), 7,06 (IH, dd, CHarom), 6,88 (IH, d, CHarom), 6,40 (2H, si, NH₂), 4,40-4,50 (IH, m, CH), 3,82-3,89 (IH, m, CH), 3,74-3,80 (IH, m, CH), 3,34-3,41 (2H, m, CH), 3,28-3,33 (4H, m, 15 2*CH₂), 2,43-2,47 (4H, m, 2*CH₂), 2,23 (3H, s, CH₃), 1,85-1,92 (IH, m, CH), 1,581,65 (IH, m, CH), 1,45-1,55 (IH, m, CH), 1,22-1,34 (IH, m, CH). (ND: not determined). 26-14: 12.99 (IH, si, NH), 10.25 (IH, s, NH), 7.96 (IH, d, CHarom, J=9,2Hz), 7.90-7,80 (IH, m, CHarom), 7.23-7.16 (3H, m, CHarom), 7.12-7.08 (IH, m,

CHarom), 6.96 (IH, d, CHarom, J=8.8Hz), 6.87 (IH, s, CHarom), 5.31 (2H, s), 4.4920 4.42 (IH ,m), 3.86-3.75 (2H, m), 3.45 (IH, m), 3.37 (lH,m), 3.35 (4H, s), 2.42 (4H, s),

2.22 (3H, s), 1.90-1.75 (2H, m), 1.53-1.49 (IH, m), 1.31-1.25 (IH, m). 26-16: 13.00 (IH, s, NH), 10.27 (IH, s, NH), 7.95 (IH, d, CHarom, J=8.8Hz), 7.89-7.84 (IH, m, »

ll2

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, CHarom, 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), 1.60-1.52 (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, CHarom), 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 (1 H, 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 additional 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-(5-(3,5-difluorophenylthio)-l-H-pyrazolo[3,4-b]pyrazine-3-yI)-4-(4methylpiperazine-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzaniide

Example 27a: N-(5-(3,5-dinuorophenyIthio)-l-(4-(4-methylpiperazine-l-yl)-2(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoyl)-lH-pyrazolo[3,4bIpyrazine-3-yl)-4-(4-methylpiperazine-l-y!)-2-(2,2,2-trifluoro-N-(tetrahydro-2Hpyran-4-yl)acetamido)benzamide

1.51 ml (17.90 mmol) of oxalyl chloride and 2 drops of anhydrous dimethylformamide are added to 4.74 g (8.95 mmol) of a solution of 4-(4-methylpiperazine-l-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid in 60 m I o f dichloromethane. The reaction mixture is stirred for 2 hours at room température. The solvents are evaporated, the solid formed is taken up in toluene and the solvent is evaporated; this operation is repeated three times until a white solid is obtained.

l ll3

The acid chloride is added at 0°C in small fractions to 1 g (3.58 mmol) of 5-(3,5difluorophenylthio)-lH-pyrazolo[3,4-b]pyrazine-3-amine dissolved in 15 ml of pyridine, The reaction mixture is stirred at 25°C ovemight at room température. After évaporation 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/ methanol/ammonium as eluent) to yield N-(5-(3,5-difluorophenylthio)-1-(4-(4methylpiperazine-l-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido) benzoyl)-lH-pyrazolo[3,4-b]pyrazine-3-yl)-4-(4-methylpiperazine-l-yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide.

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

Examplc 27: N-(5-(3, 5-difluorophenylthio)-l-H-pyrazolo[3,4-b|pyrazine-3-yl)-4(4-methylpiperazine-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide.

0.27 ml (1.95 mmol) of triethylamine is added to 0.21 g (0.19 mmol) of a solution of N(5-(3,5-difluoropheny Ithio)-1 -(4-(4-methy Ipiperaz i ne-1 -yl)-2-(2,2,2-trifluoro-N(tetrahydro-2H-pyran-4-yl)acetamido)benzoyl)-lH-pyrazolo[3,4-b]pyrazine-3-yl)-4-(4methylpiperazine-l-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido) benzamide in 5 ml of methanol. The reaction medium is heated at 65°C for 4 hours, and then ovemight at room température. After évaporation of the solvent, the product is extracted several times with ethyl acetate. The organic phases are combined, washed with saturated sodium bicarbonate solution, dried on magnésium sulfate and concentrated. The residue is purified by silica gel chromatography (95:4:1 dichloromethane/methanol/ammonium as eluent) to yield 0.065 g (57%) of N-(5-(3,5difluoropheny Ithio)-1 -H-pyrazolo[3,4-b] pyrazi ne-3 -yl)-4-(4-methy Ipip erazine-1 -yl)-2(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a yellow solid.

LCMS (El, m/z): (M-l) 579.21.

‘HNMR: ÔHppm (400MHz, DMSO): 13.95 (1H, bs, NH), 10.25 (1H, bs, NH), 8.62 (1H, s, CHarom), 8.27 (1H, d, NH), 7.80 (1H, d, CH_arom), 7.17-7.27 (3H, m, CH_arom), 6.27 (1H, d, CH_arom), 6.12 (1H, d, CH^m), 3.79-3.82 (2H, m, CH), 3.67 (1H, m, CH), 3.453.50 (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), s

U4

The following compounds were obtained by the same method:

r₂

Ex,*·	Y	Ri	Rï	Yl	n	w	Rj	Compound names	Yield	Mass
27-1	o »» JT o=s A	Q XNH	Ô N	CH	0	H	H	N-(5-(3,5difluorophcnylsiil ionyl)-1Hpyrazolo[3,4-b]pyridin-3 yl)-4 -(4-mcthylpiperazin-1yl)-2-(tetrahydro-2H-pyran4-ylamino)benzamtde	18,6%	(M+H) 612.13
27-2	°s' F-^F	Q ^NH	Λ N 1	N	0	H	H	N-(5-(3,5di(luorophenylsulfinyl)-l Hpyrazolo[3,4-b]pyrazin-3yl)-4-(4-incthylpiperazin-lyl)-2-(tetrahydro-2H-pyran4-ylanûno)bcnzamidc	ND	(M+Na) 619.6
27-3	A,	Q ,NH	ù N i	N	0	H	H	N-(5-(3,5di ÎIuorophcnylsulfonyl)-l Hpyrazolo[3,4-b]pyrazin-3yl)-4-(4-methylpiperazin-lyl)-2-(tctrahydro-2H-pyran4-ylamino)bcnzanudc	ND	(M+H) 613.5
27-4	H	Q ,NH	ù N t	CH	0	F-ά,	H	N-(6-(3,5-difluorobenzyljlH-pyrazolo[3,4-b]pyridîn3-yl)-4-(4-nicthylpiperazinl -yl)-2-(tetrahydro-2Hpyran-4~ylamino)bcnzaniide	24%	(M+H) 562.00
27-5	H	ç> ,NH	ό N t	CH	0	f UN F	H	N-(6-(3,5difluorobcnzylamino)-1Hpyrazolo[3,4-b] pyridin-3 yl)-4-(4-nieÜiylpipetazin-lyl)-2-(tctrahydro-2H-pyran4-ylamino)bcnzamidc	ND	(M-H) 275.1

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-(5-(N-(3,5-difliiorophenyl)sulfamoyl)-lH-pyrazolo|3,4b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2Hpyran-4-yl)acetamido)benzamide

115

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-(2,2,2trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzoic acid in 20 m I o f dichloromethane. The reaction mixture is stirred for 2 hours at room température. 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-(3,5difluorophenyl)‘lH-pyrazolo[3,4-b]pyridine-5-sulfonamide in 5 ml of pyridine at 0°C. The reaction mixture is stirred for 3 hours at 0°C, and then overnight at room température. The pyridine is evaporated and the crude reaction product is redissolved in toluene and then dry concentrated. The reaction mixture is diluted with saturated NaHCOj solution and extracted with ethyl acetate. The organic phase is dried on MgSÛ4, 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:

116

Ex.**	Y	Ri	Ri	Yl	n	w	Ri	Compound names	Yield	Mass
27bis-l	H	Q	cS N i	CH	0	($rF F	H	N-(6-(2,4-difluorophenylthÎo)-1Hpyrazolo[3,4-b]pyridin-3-yl)-4-(4mcthylpiperazin-1 -yl)-2-(2,2,2trifluoro-N-(tetrahydro-2H-pyran4-yl)acetamido)benzamide	ND	676.18 (M+H)
27bis-2	H	Q f-'tf p	ύ N i	CH	0	HNX φ·' F	H	N-(6-(2,4-difIuorophenylamino)- 1 H-pyrazo!o[3,4-b]pyridin-3-yl)4-(4-methylpiperazin-1 -yl)-2(2,2,2-trifluoro-N-(tetrahydro-2Hpynui-4-yl)acctamido)bcnzamide	28%	657,13 (M-H)
27bis-3	H	Ψ fTf F	Ô N ♦	CH	0	’-Q-K Π	H	N-(6-((2,4dtfluorophenyl)(methyl)amino)lH-pyrazolo[3,4-b]pyridin-3-yl)4-(4-methylpiperazin-l -y!)-2(2,2,2-trifluoro-N -(tctrahydro-2Hpyran-4-yl)acetamido)benzamide	ND	671.05 (M-H)

Example of method E2:

Example 28: 5-(3,5-difluorophenylthio)-N-(4-(4-methylpiperazin-l-yl)benzyl)-lH5 pyrazolo[3,4-b]pyridin-3-amine

41.5 μΐ 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)-lH-pyrazolo[3,4-b]pyridin-3-amine and 10 81 mg (0.395 mmol) of 4-(4-methylpiperazin-l-yl)benzaldehyde in 20ml of a 1:1 mixture of dichloromethane and tetrahydrofuran. The reaction medium is stirred for 16 hours at room température. An additional fraction of 125 μΐ of trifluoroacetic acid and 388 mg of sodium triacetoxyborohydride are added and the reaction medium is stirred for an additional 24 hours. The solvent is then concentrated and the reaction 15 medium extracted with ethyl acetate and washed using saturated sodium bicarbonate solution. The organic phases are combined, dried on magnésium sulfate and then concentrated to yield a yellow oil, A trituration of this oil in methanoi leads to the isolation of 135 mg of a yellow solid.

117

LCMS (El, m/z): (M+1) 467.57.

*H NMR: ÔH ppm (400 MHz, DMSO): 12.43 (IH, bs, NH), 8.49 (IH, d, CH_nrom), 8.47 (IH, d, CH_nrom), 7.25 (2H, d, CH_nrom), 7.03-7.08 (IH, m, CHnrom), 6.89 (2H, d, CH_nrom), 6.76-6.77 (3H, m, NH and CH_arotn), 4.34 (2H, d, CH), 3.08 (4H, m, CH), 2.44 (4H, m, 5 CH), 2.21 (3H, s, CH₃).

The following dérivative was obtained according to the same method:

Ex.**	ArX	Ri	Ri	n	W	Rj	Compound name	Yield	Mass MH*
28-1	s' A	NO2	ό N ♦	0	H	H	5-(3,5-difluorophenylthio)-N-(4(4-methylpiperazin-1 -yl)-2nitrobenzy 1)-1 H-pyrazolo[3,4b]pyridin-3-amine	91%	512.16

**'HNMR, DMSO-de, Ex.: 28-1: 12.43 (IH, bs, NH), 8,49 (IH, d, CH_arom), 8.47 (IH, d,

CHnrom), 7.51 (IH, d, CH_arom), 7.45 (IH, m, CH_arom), 7.27 (IH, m, CH_arom), 7.03-7.08 (IH, m, CH_arom), 7.00 (IH, t, NH), 6.77-6.80 (2H, m, CH_arom), 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

Examnle 29; 1-(5-(3,5-difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4methylpiperazin-l-yl)phcnyl)thiourea

F

0.507 g (2.17 mmol) of l-(4-isothiocyanatophenyl)-4-methylpiperazine is added at 25°C to 0.540g (2.17mmol) of 3,5-difluorophenylthio-lH-pyrazolo[3,4-b]pyridin-3-amine t

ll8 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 chromatography (15:1 dichloromethane/methanol as eluent) to yield 0.156 g (yield=15%) of 1 -(l-/cv/-butyl-5(3,5-difluorophenylthio)- lH-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-1 yl)phenyl)thiourea in the form of a light brown solid.

LCMS (El, m/z): (M+l) 512.08.

‘H NMR: ÔH ppm (400 MHz, DMSO): 13.69 (IH, bs, NH), 11.50 (IH, bs, NH), 11.19 (IH, bs, NH), 8.96 (IH, d, CH_arom), 8.66 (IH, d, CH_arom), 7.41 (2H, d, CH_arom). 7.10 (IH, ddd, CHarom), 6.95 (2H, d, CHarom), 6.89 (2H, bd, CHarom), 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-difluorophenylthio)-lH-pyrazolo|3,4-b]pyridin-3-yl)-3(4-(4-methylpiperazin-l-yl)phenyl)urea

0.048 g (L19 mmol) of sodium hydride is added at 0°C to 0.200 g (0.598 mmol) of 1/«7-buty 1-5-(3,5-difluorophenylthio)-1 H-pyrazolo[3,4-b]pyridin-3-aminedissolved in 10 ml of anhydrous dimethylacetamide. The reaction is left under stirring for 10 minutes. 0.130 g (0.598 mmol) of l-(4-isocyanatophenyi)-4-methylpiperazine is then added at 0°C. The mixture is left under stirring for 3 hours at room température. The reaction is treated by adding 20 ml of water drop by drop at 0°C and then is extracted with ethyl acetate. The organic phase is dried on sodium sulfate, filtered and concentrated. The product is purified by silica chromatography to yield 0,150 g (yield=45%) of l-(l-/er/-butyl-5-(3,5-difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3yl)-3-(4-(4-methylpiperazin-l-yl)phenyl)urea in the form of a light brown solid.

LCMS (El, m/z): (M+l) 552,21.

^lHNMR: ÔH ppm (400 MHz, DMSO): 8.92 ( 1 H, bs, NH), 8.58 (IH, bs, NH), 8.51 (IH, bs, CHarom), 8.30 (IH, bs, CHa rom)j 7*3 1 (2H, d, CHa romX 7.05 (IH, m, CHarom), 6.83-6.85

119 (2H, m, CH_ttrom), 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 l-(1-/t?r/-butyl-5-(3,5-difluorophenyithio)-lHpyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-l-yl)phenyl)urea dissolved in 20 ml of TFA (trifluoroacetic acid) is refluxed for 3 hours. The solvent is evaporated and the crude reaction product is diluted with saturated NaHCCL solution 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-(3,5difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-yl)-3-(4-(4-methylpiperazin-l-yl) phenyl)urea in the form of a beige solid is obtained.

LCMS (El, m/z): (M+1): 496.06.

*H NMR: ÔH ppm (400 MHz, DMSO): 10.85 (1H, bs, NH), 9.57 (1H, bs, NH), 8.57 (1H, bs, CHarom), 8.30 (1H, bs, CHarom), 7.39 (2H, d, CHarom), 6.99 (1H, m, CHarom), 6.89 (2H, d, CHarom), 6.70 (2H, bd, CH_arom), 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 Fl: deprotection

Examplc 30: N-(5~(3, 5-difluorophenylthio)-l-H-pyrazolo[3, 4-b]pyridine-3-yl)-4(4-methylpiperazine-l-yl)-2-(tetrahydro-2H-pyran-4-ylaniino)benzamide

9,08 ml (65.1 mmol) of triethylamîne is added to 2 g (2.96 mmol) of a solution of N-(5(3,5-difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide in 65 m I o f methanol. The reaction medium is heated at 65°C for 2 hours, and then overnight at room température. 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 (N16493

120 (5-(3,5-difluorophenylthio)-l-H-pyrazolo[3,4-b]pyridine-3-yl)-4-(4-methylpiperazine-lyl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a white solid, LCMS (El, m/z): (M+1) 580.23.

’HNMR: ÔH ppm (400 MHz, DMSO): 13.59 (1H, bs, NH), 10.56 (1H, bs, NH), 8.61 5 (1H, s, CHU 8.50 (1H, s, CH_ntom), 8.17 (1H, d, NH), 7.80 (1H, d, CH.™). 7.07 (1H, m, CHarom), 6.86 (2H, m, CH_1)ran,), 6.23 (1H, d, CH_aram), 6.13 (1H, d, CH_arom), 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).

121

The following dérivatives were obtained according to the same method:

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131 *♦ ‘H NMR, DMSO-îU, 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, CH_arom), 7.22 (1H, m, CH_arom), 6.95 (2H, d, CHarom), 6.26 (1H, d, CHarom), 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, CHarom), 8.11 (1H, d, NH), 7.76 (1H, d, CHarom), 7.00-7.10 (1H, m, CH_arom), 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, CHa_rom), 8.12 (1H, d, NH), 7.75 (1H, d, CH^m),

6.23 (1H, dd, CHarom), 6.14 (1H, d, CH_arom), 3.97 (3H, s, CH₃), 3.80-3.86 (2H, m, CH), 3.62-3,74 (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). 307: 12.43 (1H, bs, NH), 10.22 (1H, bs, NH), 8.32(1H, s, CH_arom), 8.13(1H, d, NH), 7.73 (1H, d, CHarom), 6.37 (2H, bs, NH₂), 6.22 (1H, dd, CH_arom), 6,13 (1H, d, CH_aram), 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), 1.90-1.99 (2H, m, CH), 1.32-

l. 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, CH_arotn), 8.18 (1H, d, NH), 7.80 (1H, d, CHarom), 6.82-

6.75 (3H, m, CH_arom), 6.26 (1H, d, CHarom), 6.15 (1H, d, CH_arom), 3.87-3.82 (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), 1.97-1.95 (2H, m, CH), 1.43-1.36 (2H, m, CH). 30-13: 12,99 (1H, s, NH), 9.92 (1H, s, NH), 8.38 (1H, d, NH, J=7.6Hz), 7.92 (1H, d, CHarom, J=8.4Hz), 7,84 (1H, d, CHarom, J-9.2Hz), 7.32 (1H, d, CHarom, 1=8.4 Hz), 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, m). 30-14: 12.96 (1H, si, NH), 9.84 (1H, s, NH),

8.34 (1H, d, NH, J=7.6Hz), 7.96 (1H, d, CHarom, J=9.2Hz), 7.81 (IH, d, CHarom, J=8.8Hz), 7.25 (1H, s, CHarom), 7.23 (1H, s, CHarom), 7.17 (1H, t, CHarom), 6.96 (1H, d, CHarom, J=9.2Hz), 6.25 (1H, d, CHarom, J=7.6Hz), 6.14 (1H, s, CHarom), 5.35 (2H, s), 3.82-3.77 (2H, m), 3.67 (1H, si), 3.46 (2H, t), 3.29 (4H, s), 2.50 (4H, s), 2.29

132 (3H, s), 1.93-1,88 (2H, m), 1.35-1.25 (2H, m). 30-15: 13.01 (1H, sl,NH), 10.11 (1H, si, NH), 7.99 (1H, si, 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, si, 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, m). 30-16: 12.95 (1H, si, NH),

9.85 (1H, s, NH), 8.33 (1H, d, NH, J=7.6Hz), 7.95 (1H, d, CHarom, 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, si), 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, m). 30-17: 13.06 (1H, si, NH), 10.12 (1H, si, NH), 7.93 (1H, si, 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, si, CHarom), 6.64 (1H, si, CHarom), 6.49 (1H, si, 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), 1.75-1.65 (4H, m), 1.40-1.30 (2H, m). 30-18: 12.94 (1H, si, NH), 9.81 (1H, s, NH), 8.32 (1H, d, CHarom, J=7.7Hz), 7.96 (1H, d, CHarom, J=9Hz), 7.81 (lH,d, CHarom, 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, m). 30-19: 13.01 (1H, si, NH), 10.09 (1H, s, NH), 7,97 (2H, d, CHarom, J=9Hz), 7.83 (lH,d, CHarom, J=8.2Hz), 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, m). 30-20: 12.97 (1H, si, NH), 9.82 (1H, s, NH), 8.32 (1H, d, NH, J=8.0Hz), 7.97 (1H, d, CHarom, J=8.8Hz), 7.87 (1H, s, CHarom), 7.80-7.76 (2H, m, CHarom), 7.64 (1H, d, CHarom, J=8,4Hz), 6.96 (1H, d, CHarom, 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, si), 3.46 (2H, t), 3.26 (4H, s), 2.43 (4H, s), 2.29 (3H, s), 1.93-1.88 (2H, m), 1.35-1.25 (2H, m). 30-21: 13.03 (1H, s, NH), 10.08 (1H, s, NH), 8.00-7.95 (2H, m, CHarom), 7.87-7.75 (3H, m, CHarom), 7.63 (1H,

133 d, CHarom, J=8.4Hz), 6.97 (IH, d, CHarom, J=8.8Hz), 6.67 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=8.0Hz), 5.47 (2H, s, CHarom), 3.83-3.76 (2H, m), 3.68-3.64 (IH, m),

3.47 (2H, t), 2.87 ( 2H, d, J=10.4Hz), 2.45-2.40 (IH, m), 2.20 (3H, s), 2.00-1.87 (4H,

m), 1.74-1.65 (4H, m), 1.36-1.25 (2H, m). 30-22: 12.93 (IH, s, NH), 9.86 (IH, s, NH), 8.70 (IH, s, CHarom), 8.51 (IH, dd, CHarom, J=5.2Hz), 8.38 (IH, d, NH, J=8.0Hz),

7.96-7.90 (2H, m, CHarom), 7.84 (IH, d, CHarom, J=8.8Hz), 7.73-7.33 (IH, m, CHarom), 6.91 (IH, d, CHarom, J=8.8Hz), 6.27 (IH, d, CHarom, J=8.8Hz), 6.15 (IH, s,

CHarom), 5.35 (2H, s), 3.83-3.77 (2H, m), 3.70-3.64 (IH, 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, m). 30-23: 13.03 (IH, s, NH), 10.17 (IH, s, NH), 8.70 (IH, s, CHarom), 8.52 (IH, dd, CHarom, J=4.8Hz), 8.06 (IH, d, NH, J=7.6Hz), 7.96 (IH, d, CHarom, J=8.8Hz), 7.94-7.88 (2H, m, CHarom), 7.37-7.34 (IH, m, CHarom), 6.93 (IH, d, CHarom, J=9.2Hz), 6.69 (IH, s, CHarom),

6.52 (IH, d, CHarom, J=8.0Hz), 5.36 (2H, s, CHarom), 3.83-3.79 (2H, m), 3.68-3.64 (IH, 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, m). 30-24: 13.21 (IH, s, NH), 10.00 (IH, s, NH), 8.30 (IH, d, NH, J=7.6Hz), 8,00 (IH, d, CHarom, J=8.8Hz), 7.79 (IH, d, CHarom, J=9.2Hz), 7.33 (IH, d, CHarom, J=8.8Hz), 7.26-7.16 (3H, m, CHarom), 6.24 (IH, d, CHarom, J=8.8Hz), 6.13 (IH, s, CHarom), 4.06-3.99 (2H, m), 3.67 (IH, si), 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, m). 30-25: 13.26 (IH, s, NH), 10.28 (IH, s, NH), 8,02 (IH, d, CHarom, J=8.8Hz), 7.97 (IH, d, NH, J=7.6Hz), 7.83 (IH, d, CHarom, J=8.0Hz), 7.34 (IH, d, CHarom, J=8.8Hz), 7.27-7.17 (3H, m, CHarom), 6.68 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=8.0Hz), 3.85-3.78 (2H, m), 3.71-3.65 (IH, m), 3.47 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.48-2.40 (IH, m), 2.19 (3H, s), 1.98-1.88 (4H, m), 1.74-1.66 (4H, m), 1.36-1.27 (2H, m\ 30-26: 13.12 (IH, s, NH), 9.95 (IH, s, NH), 8.32 (IH, d, NH, J=7.6Hz), 7.93 (IH, d, CHarom, J=8.8Hz), 7,79 (IH, d, CHarom, J=8.8Hz), 7,73 (IH, t, CHarom), 7.52-7,40 (2H, m, CHarom), 7.12 (IH, d, CHarom, J=8,8Hz), 6.25 (IH, d, CHarom, J=8.8Hz), 6.13 (IH, s, CHarom), 3.83-3.77 (2H, m), 3.69 (IH, si), 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, m). 30-27: 13.17 (IH, s, NH), 10.21 (IH, s, NH), 7.99-7.92 (2H, m, CHarom et NH), 7.81 (IH, d, CHarom, J=8.4Hz), 7.77-7.70 (IH, m, CHarom), 7.51-7.40 (2H, m, CHarom), 7.13 (IH, dd, CHarom, J=8.8Hz), 6.69 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=8.4 Hz), 3.85-3.78 (2H, m), 3.72-3.67 (IH,

134

m), 3.48 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.47-2.40 (IH, m), 2.20 (3H, s), 1.96-1.87 (4H, m), 1.75-1.65 (4H, m), 1.38-1.28 (2H, m). 30-28: 13.31 (IH, si, NH), 9.95 (IH, si, NH), 8.31 (IH, d, NH, J=7.6Hz), 7.99 (IH, d, CHarom, J=7.6Hz), 7.78 (IH, d, CHarom, J=9.2Hz), 7.58-7.49 (3H, m, CHarom), 7.31 (IH, d, CHarom, J=8.8Hz), 6.24 (IH, d, CHarom, J=8.8Hz), 6.10 (IH, s, CHarom), 3.83-3.76 (2H, m), 3.70-3.60 (IH, 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, m). 30-29: 13.26 (IH, s, NH), 10.25 (IH, s, NH), 8.01 (IH, d, CHarom, J=8.8Hz), 7.94 (IH, d, NH, J=7.6Hz), 7.82 (IH, d, CHarom, J=8.4Hz), 7.59-7.54 (3H, m, CHarom), 7.32 (IH, d, CHarom, J=8.8Hz), 6,67 (IH, s, CHarom), 6.54 (IH, d, CHarom, J=7.6Hz), 3.84-3.78 (2H, m), 3.71-3.62 (IH, m), 3.47 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.45-2.41 (IH, m), 2.19 (3H, s), 1.96-1.90 (4H, m), 1.74-1.68 (4H, m), 1.34-1.27 (2H, m). 30-30:

13.23 (IH, s, NH), 9.98 (IH, s, NH), 8.29 (IH, d, NH, J=7,6Hz), 8.01 (IH, d, CHarom, J=8.8Hz), 7.79 (IH, d, CHarom, J=8.8Hz), 7.62 (IH, d, CHarom, J=8.4Hz), 7.52 (IH, s, CHarom), 7,44 (IH, d, CHarom, J=7.6Hz), 7.24 (IH, d, CHarom, J=8.4Hz), 6.25 (IH, d, CHarom, J=8.0Hz), 6.12 (IH, s, CHarom), 3.82-3.75 (2H, m), 3.73-3.67 (IH, 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, m). 30-31: 13.28 (IH, s, NH), 10.25 (IH, s, NH), 8.02 (IH, d, CHarom, J=8.8Hz), 7.95 (IH, d, NH, J=7.6Hz), 7.81 (IH, d, CHarom, J=8.0Hz), 7.61 (IH, d, CHarom, J=8.4Hz), 7.56 (IH, s, CHarom), 7.43 (IH, dd, CHarom, J=8.4Hz), 7.25 (1 H, d, CHarom, J=8,8Hz), 6.68 (IH, s, CHarom), 6.51 (IH, d, CHarom, J=7.2 Hz), 3.84-3.78 (2H, m),

3.69-3.61 (IH, m), 3.47 (2H, t), 2.87 (2H, d, J=11.2Hz), 2.47-2.41 (IH, m), 2.20 (3H, s), 2.00-1.90 (4H, m), 1.76-1.69 (4H, m), 1.40-1.30 (2H, m). 30-32: 13,16 (IH, s, NH), 9.95 (IH, s, NH), 8.33 (IH, d, NH, J=8.0Hz), 7.93 (IH, d, CHarom, J-8.8Hz), 7.89 (IH, d, CHarom, J=9.2Hz), 7.79 (IH, d, CHarom, J=9.2Hz), 7.70-7.63 (2H, m, CHarom),

7.60 (IH, t, CHarom), 6.97 (IH, d, CHarom, J=8.8Hz), 6.25 (IH, d, CHarom, J=9.2Hz),

6.14 (IH, s, CHarom), 3.83-3.78 (2H, m), 3.68 (IH, si), 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, m). 30-33: 13.21 (IH, s, NH), 10.22 (IH, s, NH), 7.99 (IH, d, NH, J=7.6Hz), 7.94 (IH, d, CHarom, J=9.2Hz), 7.89 (IH, d, CHarom, J=7.2Hz), 7.82 (IH, d, CHarom, J=8.4Hz), 7.71-7.57 (3H, m, CHarom), 6.98 (IH, d, CHarom, J=8.8Hz), 6.69 (IH, s, CHarom), 6.52 (IH, 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=ll,2Hz), 2.47-2.41 (IH, m), 2.19 (3H, s), 2.00-1.90 (4H, m), 1.76-1.69 (4H, m), 1,4016493

135

1.30 (2H, m). 30-34: 13.07 (1H, s, NH), 10.11 (1H, s, 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, si), 3.80-3.74 (2H, m), 3.67 (1H, si), 3.44 (2H, t),

3.10 (4H, s), 2.84 (3H, s), 1.89-1,84 (2H, m), 1.30-1.14 (4H, m). 30-35: 13.08 (1H, s, NH), 10.28 (1H, s, NH), 7.96 (1H, d, NH, J=7,6Hz), 7.88 (1H, d, CHarom, 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, si), 3.44 (2H, t), 2.892.84 (2H, m), 2.43 (1H, si), 2.20 (3H, s), 1.98-1.95 (2H, m), 1.89-1.84 (2H, m), 1.72-

l. 69 (4H, m), 1.29-1.20 (2H, m). 30-36: 13.10 (1H, si, NH), 10.11 (1H, s, NH), 9.73 (1H, si, COOH), 8.34 (1H, si, 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, CHarom), 7.11-7.05 (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), 1.34-1.22 (2H, m). 3037: 13.09 (1H, s, NH), 10.29 (1H, s, 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), 7,11-7,05 ( 1H, m, CHarom), 6.67 (1H, s, CHarom), 6.52 (1H, d, CHarom, 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), 1.74-1.65 (4H, m), 1.33-1.23 (2H, m). 30-38; 13.02 (1H, s, NH), 10,04 (1H, s, NH), 8.28 (1H, d, NH, J=8,0Hz), 7.88-7.84 (2H, m, CHarom), 7.74 (IH, s, CHarom), 7.43 (1H, d, CHarom, 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 (IH, s, CHarom), 4.50 (2H, s), 3.78-3.74 (2H, m), 3.66-3.62 (IH, 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, m). 30-39: 13.09 (IH, s, NH), 10.32 (IH, s, NH), 8.28 (IH, d, NH, J=8.0Hz), 7,90 (2H, D, CHarom), 7.74 (IH, s, CHarom), 7.43 (IH, d, CHarom, J=8.4Hz), 7.29 (IH, dd, CHarom, J=8.4Hz), 7.25 (IH, d, CHarom, J=8.8Hz), 6.67 (IH, s, CHarom), 6.54 (IH, dd, CHarom, J=8,4Hz), 4.51 (2H, s), 3.79-3.76 (2H, m), 3.70-

3.64 (IH, m), 3.44 (2H, t), 2.95-2.92 (2H, m), 2,52-2,51 (IH, m), 2.27 (3H, s), 2.132,01 (2H, m), 1,90-1,87 (2H, m) 1.77-1,69 (4H, m), 1.32-1.24 (2H, m). 30-40: 12.77

136 (ÎH, s, NH), 9.86 (1H, s, NH), 9.60 (IH, s, 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, CHarom, J=8.8Hz), 6.93 (1H, d, CHarom, J=9.2Hz), 6.55 (ÎH, t, CHarom), 6.23 (IH, dd, CHarom, 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, m). 30-41: 12,85 (1H, si, NH), 10.13 (1H, s, NH), 9.62 (1H, s, 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), 3.683.63 (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), 1.75-1.65 (4H, m), 1.37-1,27 (2H, m). 30-42: 12.77 (1H, s, NH),

9,87 (1H, s, NH), 9.02 (1H, s, 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), 7,22-7,15 (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 (1 H, 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, m). 30-43: 12.84 (1H, s, NH), 10.13 (IH, s, NH), 9.05 (1H, si, NH), 8.81-8.74 (1H, m, CHarom), 8,05 (IH, d, NH, J=7.2Hz ), 7,89-7.84 (2H, m, CHarom), 7.30 (IH, d, CHarom, J=8.8Hz), 7.23-7.15 (IH, m, CHarom), 6.67 (IH, s, CHarom), 6.64-6.58 (IH, m, CHarom), 6.51 (IH, d, CHarom, J=8.4Hz), 3.83-3.76 (2H, m), 3.68-3.64 (IH, m),

3.47 (2H, t), 2.89 ( 2H, d, J=10.8Hz), 2.45-2.40 (IH, m), 2.21 (3H, s), 2.01-1.91 (4H, m), 1,74-1.66 (4H, m), 1.38-1.27 (2H, m). 30-44: 12.80 (IH, s, NH), 10.16 (IH, s, NH), 8,89 (IH, s, CHarom), 8.52 (IH, s, NH), 8.34 (IH, d, NH, J=7.6Hz), 7.89 (IH, d, CHarom, J=9.2Hz), 7,81 (IH, d, CHarom, J=9.2Hz), 7.41 (IH, d, CHarom, J=8.8Hz),

7,35 (IH, d, CHarom, J=9.2Hz), 6.89 (IH, dd, CHarom, J=8.4Hz), 6.21 (IH, d, CHarom, J=9.2Hz), 6.11 (IH, s, CHarom), 3.83-3.75 (2H, m), 3.66-3.60 (IH, 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, m). 30-45: 12.86 (IH, s, NH), 10.10 (IH, s, NH), 8.91 (IH, s, CHarom), 8.54 (IH, s, NH), 8,00 (IH, d, NH, J=7.6Hz ), 7.90 (IH, d, CHarom, J=9,2Hz), 7.85 (IH, d, CHarom, J=8.0Hz), 7.41 (IH, d, CHarom, J=8.4Hz), 7.37 (IH, d, CHarom, J=9.2Hz), 6.88 (IH, dd, CHarom, J=8.4Hz), 6.64 (IH, s, CHarom), 6.48 (IH, d, CHarom, J=8.4Hz), 3,83-

3.77 (2H, m), 3.67-3.60 (IH, m), 3,47 (2H, t), 2.88 (2H, d, J=11.2Hz), 2.45-2.38 (IH, m), 2.21 (3H, s), 2.00-1.87 (4H, m), 1.75-1.65 (4H, m), 1.37-1.26 (2H, m). 30-46: 13.74

137 (1H, si, NH), 10.14 (1H, s, NH), 8.62 (1H, s, CHarom), 8.33 (1H, d, NH), 7.81 (1H, d,

CHarom, J=8.7Hz), 7.12-7.03 (3H, m, CHarom), 6.26 (1H, d, CHarom, J=8.8Hz), 6.13 (1H, s, CHarom), 4.31 (2H, s), 4.14-4.07 (4H, m), 3.68 (1H, si), 3.28 (4H, s), 2.43 (4H,

s), 2.23 (3H, s), 1.92 (2H, d, J=12.4Hz), 1,38-1.26 (2H, m). 30-47: 13.80 (1H, si, NH), 10.41 (1H, s, NH), 8.64 (1H, s, CHarom), 8.02 (1H, d, NH), 7.85 (1H, d, CHarom, 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=ll.lHz), 3.68 (1H, si), 3.48 (2H, t), 2.87 (2H, d,

J=10.5Hz), 2.47-2.39 (1H, si), 2.19 (3H, s), 2-1.88 (4H, m), 1.76-1,66 (4H, m), 1.39-

1.27 (2H, m). 30-48: 13.99 (1H, si, NH), 10.17 (1H, s, NH), 8.34 (1H, s, CHarom), 8.29 (1H, dl, 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, dl), 3.62 (1H, si), 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, m). 30-49: 14.06 (1H, si, NH), 10.56 (1H, s, NH), 8.85 (1H, s, CHarom),

7.97 (1H, si, 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,lHz), 3.83-3.76 (2H, m), 3.70 (1H, si),

3.48 (2H, t), 2.88 (2H, d, J=10.6Hz), 2.48-2.40 (1H, m), 2.20 (3H, s), 2.01-1.89 (4H, m), 1.76-1.66 (4H, m), 1.40-1.28 (2H, m). 30-50: 13,94 (1H, si, NH), 10.11 (1H, si, NH), 8.59 (1H, s, CHarom), 8.30 (1H, si, NH), 7.76 (1H, d, CHarom, J=9,2Hz), 7.277.13 (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, m). 30-51: 13,95 (1H, si, NH),

10.17 (1H, si, NH), 8.54 (1H, s, CHarom), 8.28 (1H, si, 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, si), 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, m). 30-52:

13.97 (1H, si, NH), 10.20 (1H, s, 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), 2.61-2.52 (4H, m), 2.32 (3H, si),

1.96-1.88 (2H, m), 1.39-1.26 (2H, m). 30-53: 13.64 (1H, s, NH), 10.20 (1H, s, 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,

138

CHarom, J=8.8Hz), 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, m). 30-54: 13.64 (1H, si, NH), 10.48 (1H, si, NH), 8.32 (1H, d, CHarom, J=8.8Hz), 8.19 (1H, d, CHarom, J=8.8Hz), 7.91 (1H, si, 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), 3.863.80 (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, m). 30-55: 13.64 (1H, s, NH), 10.16 (1H, s, NH), 8.29 (1H, d, CHarom, J=8.8Hz), 8.24 (1H, d, NH, J=7.6Hz), 8.17 (1H, d, CHarom, 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, CHarom), 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, m). 30-56: 13.67 (1H, s, NH), 10.43 (1H, s, 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), 7.907.82 (2H, m, CHarom), 7.66 (1H, q, CHarom), 6.71 (1H, s, CHarom), 6.54 (IH, d, CHarom, J=8.4Hz), 3.85-3.80 (2H, m), 3.73-3.65 (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, m). 30-57: 13.66 (1H, s, NH), 10.17 (1H, s, 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, >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), 1.961.89 (2H, m), 1.34-1.28 (2H, m). 30-58: 13.71 (1H, s, NH), 10.45 (1H, s,NH), 8.32 (1H, d, CHarom, J=9.2Hz), 8.22 (1H, d, CHarom, J=8.8Hz), 8.02-7.96 (3H, m, CHarom), 7.86-7.81 (1H, m, NH), 7.83 (1H, d, Charom), 6.71 (1H, s, CHarom), 6.54 (1H, d, CHarom, 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, m). 30-59: 13.69 (1H, s, NH), 10.04 (1H, s, NH), 8.34 (1H, d, NH, J=8.8Hz), 8.26-8.16 (3H, m, CHarom), 7.81 (1H, dd, CHarom, J=8.4Hz), 7.74 (1H, d, CHarom, J=9.2Hz), 7,66 (1H, d, CHarom, 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, m). 30-60: 13.74 (1H, s, NH), 10.31 (1H, s, NH), 8.35 (1H, d, CHarom, J=8.8Hz), 8.25 (1H, d, CHarom,

139

J=8.8Hz), 8,21 (IH, s, CHarom), 7.85 (IH, d, NH, J=7.2Hz), 7.81 (IH, dd, CHarom, J=8,8Hz), 7.76 (IH, d, CHarom, J=8.0Hz), 7.66 (IH, d, CHarom, J=8.8Hz), 6.67 (IH, s, CHarom), 6.50 (IH, d, CHarom, J=8.0Hz), 3.85-3.78 (2H, m), 3.68-3.62 (IH, m), 3.48 (2H, t), 2.87 (2H, d, J=ll.2Hz), 2.46-2.40 (IH, m), 2.20 (3H, s), 1.97-1.87 (4H, m),

1.75-1.67 (4H, m), 1.32-1.24 (2H, m). 30-61: 13.61 (IH, s, NH), 10.32 (IH, s, NH),

8.71 (IH, d, NH, J=8.0Hz), 8.21 (IH, d, CHarom, J=8.8Hz), 7.87 (IH, d, CHarom, J=9.2Hz), 7.80 (IH, d, CHarom, J=8.8Hz), 7.17 (IH, t, CHarom), 7.05-7.02 (2H, m, CHarom), 6.29 (IH, d, CHarom, J=9.2Hz), 6.14 (IH, 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, m). 30-62: 13.67 (IH, si, NH). 10.59 (IH, s, NH), 8.23 (IH, d, CHarom, J=8.8Hz), 8.10 (IH, d, NH. J=7.6Hz), 7.92 (IH, d, CHarom, J=8.0Hz), 7.82 (IH, d, CHarom, J=8.8Hz), 7.17 (IH, t, CHarom), 7,05-7.02 (2H, m, CHarom), 6.71 (IH, s, CHarom), 6.56 (IH, d, CHarom, A8.0Hz), 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 (IH, 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, m). 30-63: 13.63 (IH, si, NH), 10.28 (IH, s, NH), 8.37 (IH, d, NH, J=8,0Hz), 8.24 (IH, d, CHarom, J=8.8Hz), 7.88-7.82 (2H, m, CHarom), 7.24-7.17 (3H, m, CHarom), 6.29 (IH, d, CHarom, J=9.2Hz), 6.14 (IH, 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), 1.32-1.20 (2H, m). 30-64: 13,69 (IH, si, NH), 10,55 (IH, s,

NH), 8.26 (IH, d, CHarom, J=8.8Hz), 8.05 (IH, d, NH, J=7.6Hz), 7.90 (IH, d, CHarom,

J=8.4Hz), 7.86 (IH, d, CHarom, J=8.8Hz), 7.24-7.15 (3H, m, CHarom), 6.70 (IH, s,

CHarom), 6.56 (IH, d, CHarom, J=8.0Hz), 4.88 (2H, s), 3.80-3.65 (3H, m), 3.43 (2H, t),

2.87 (2H, d, J=ll.2Hz), 2.46-2.40 (IH, m), 2.20 (3H, s), 2.00-1.86 (4H, m), 1.75-1.67 (4H, m), 1.29-1.23 (2H, m). 30-65: 13.49 (IH, si, NH), 10.45 (IH, s, NH), 9.31 (IH, si, COOH), 8.21 (IH, d, CHarom, J=8.8Hz), 8.06 (IH, si, NH), 7,92 (IH, d, CHarom, J=8.4Hz), 7,57 (IH, d, CHarom, J=8.8Hz), 7.17-7.11 ( 2H, m, CHarom), 6.96-6.91 (IH, m, CHarom), 6.67 (IH, s, CHarom), 6.53 (IH, d, CHarom, J=8.0Hz), 4.51 (IH, d, J=13.2Hz), 4.20 (IH, d, J=13.2Hz), 3.81-3.76 (2H, m), 3.71-3.62 (IH, m), 3.56-3.41 (4H, m), 3.08 (2H, t), 2.83 (3H, s), 2.45-2.40 (IH, m), 2.07-2.00 (2H, m), 1.95-1.86 (4H, m), 1.41-1.29 (2H, m). 30-66: 13.62 (IH, si, NH), 10.22 (IH, si, NH), 8.36 (IH, d, NH, J=7.6Hz), 8.23 (1H, d, CHarom, J=8.8Hz), 7,85 (1H, d, CHarom, J=9.2Hz), 7.80 (IH, d, CHarom, J=8.8Hz), 7,48 (1H, s, CHarom), 7.45-7.37 ( 2H, m, CHarom), 6.29

140 (ÎH, d, CHarom, J=7.2Hz), 6.14 (ÎH, 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), 1.91-1.86 (2H, m), 1.30-1.24 (2H, m). 30-67: 13.67 (1H, si, NH), 10.49 (1H, s, NH), 8.25 (1H, d, CHarom, J=8.8Hz), 8.02 (1H, d, NH, J=7.2Hz), 7.89 (1H, d, CHarom, J=8.0Hz), 7.82 (1H, d, CHarom, 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), 3.78-3.64 (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, CHarom), 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), 3,70-3.65 (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)-4-(3-aminopyrrolidin-l-yl)-N-(5-(3,5-dinuorophenylthio)-lHpyrazolo[3,4-b]pyridin-3-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide

876 μΐ (20 eq) of triethylamine is added to a solution of 238 mg (0.314 mmol) of (S)-jV(5-(3,5-difluorophenylthio)-l#-pyrazolo[3,4-Z»]pyridin-3-yl)-2-(2,2,2-trifluoro-N(tetrahydro-2//-pyran-4-yl)acetamido)-4-(3-(2,2,2-trifluoroacetamido)pyrrolidin-lyl)benzamide in 6 ml of methanol. The reaction medium is stirred at 65°C for 4 hours. After retuming to room température, 8 ml 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 retuming to room température, the solvents are evaporated, water is added and the product is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried on magnésium 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)-4-(3-aminopyrrolidin-l-yl)-A/-(5-(3,5-

141 difluorophenylthio)-lZ/-pyrazolo[3,4-ô]pyrazine-3-yl)-2-(tetrahydro-2/7-pyran-4ylamino)benzamide in the form of a brown powder.

LCMS (El, m/z): (M+l) 566.24.

’H NMR: δΗ ppm (400 MHz, DMSO): 10.46 (IH, bs, NH), 8.60 (IH, s, CH_nroin), 8.50

3.70 (2H, m, CH), 3.40-3.55 (5H, m, CH), 3.01-3.08 (IH, m, CH), 2.08-2.13 (IH, m, CH), 1.92-1.99 (2H, m, CH₃), 1.76-1.82 (IH, m, CH), 1.30-1.41 (2H, m, CH^,™).

Examples of method F2: réduction

Example 31: N-(5-(3,5-difliiorophenethyl)-lH-pyrazolo|3,4-b]pyridin-3-yl)-4-(4methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4“ylamino)benzamide mg of 10% Pd/C is added to 100 mg (0.175 mmol) of N-(5-((3,5difluorophenyl)ethynyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methyipiperazin-l-yl)-2(tetrahydro-2H-pyran-4-ylamino)benzamide in solution in a mixture of lOmlof tetrahydrofuran and 5 ml of methanol before placing the reaction medium under an atmosphère of hydrogen. The reaction mixture is stirred for 12 hours at room température and then filtered on Celite and concentrated. 62 mg (yield=60%) of N-(5(3,5-difluorophenethyl)-lH-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2(tetrahydro-2H-pyran-4-ylamino)benzamide are isolated in the form of a white solid.

LCMS (El, m/z): (M+l) 576.23.

’H NMR: ÔH ppm (400 MHz, DMSO): 13.14 (IH, bs, NH), 10.32 (IH, bs, NH), 8.40 (IH, d, CHarom), 8.22 (IH, d, NH), 7.96 (IH, d, CH_arem), 7.80 (IH, d, CH_arom), 7.03-6.98 (3H, m, CHarom), 6.23 (IH, d, CHarom), 6.16 (IH, bs, >), 3.84-3.81 (2H, dt, CH),

3.70 (IH, m, CH), 3.52-3.46 (2H, m, CH), 3,04-2.93 (4H, m, CH), 2.59-2.69 (4H, m,

142

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 dérivative was obtained according to the same method:

r₂

Ex.**	ArX	Ri	Ri	Yl	n	W	Rj	Compound names	Yield	Mass
31-1	A	Q _,NH	ù N ♦	N	0	H	H	N-(5-(3,5-difluorophencthyl)-1H- pyrazolo[3,4-b]pyrazin-3-yl)-4-(4mcthylpiperazin-1 -yl)-2-(tctrahydro2H-pyran-4-ylamino)benzamide	47%	577.07 (M+H)
	NMR, dmso-de, Ex. : 31-1:	3.68 (1H, si, 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 10 (2H, d), 1.38-1.27 (2H,m).

Eiample 32: 5-(3,5-difluoropheny11hio)-N-(4-(4-methyIpiperazin-1 -yl)-2(tetrahydro-2H-pyran-4-ylamino)benzyl)-lH-pyrazolo[3,4-b]pyridin-3-amine

100 mg (0.173 mmol) of N-(5-(3,5-difluorophenylthio)-l-H-pyrazolo[3,4-b]pyridine-3yl)-4-(4-methylpiperazine-l-yI)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide is added, in small fractions, to a solution of 19.64 mg (0.518 mmol) of L1AIH4 in 3 ml of f

143 anhydrous tetrahydrofuran under argon at 0°C. The reaction mixture îs heated at 90°C for 15 hours. An additional portion of 20 mg of LiAlH< is then added and the reaction medium stirred at 90°C for 5 hours. 45 μΐ of water at 0°C is then added to the reaction mixture, followed by 45 μΐ of sodium hydroxide (15% wt) and finally 120 μΐ of water. The reaction mixture is stirred at 25°C for 1 hour and then filtered on Dicalite. After évaporation of the solvents, the crude product is purified by chromatography, 16.80 mg (17%) of 5-(3,5-difluorophenylthio)-N-(4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2Hpyran-4-ylamino)benzyl)-lH-pyrazolo[3,4-b]pyridin-3-amine in the form of a yellow solid is obtained.

LCMS (El, m/z): (M+l) 566.68.

^lHNMR: ÔH ppm (400 MHz, DMSO): 12.57 (IH, bs, NH), 8.45 (2H, d, CH_nrom), 6.977.06 (2H, m, CH_arem), 6.73-6.75 (2H, m, CH_arom), 6.65 (IH, t, NH), 6,13-6.19 (2H, m, CHarom), 4.98 (IH, d, NH), 4,30 (2H, m, CH₂), 3.73-3.77 (2H, m, CH), 3.60 (IH, 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 dérivatives were obtained according to the same method:

Ex.**	ArX			(U).	V	Yt,¥*¥*¥<	Rj	Compound name	Yield	Mass
32- 1	A	Q XNH	ό N 1	n=0	CH2	N,ArXC,CH,N	H	5-(3,5-difluorophenylthio)-N(4-(4-methylpipcrazin-l-yl)2-(tetrahydro-2H-pyran-4y lamino)bcnzyl)-l Hpyrazolo|4,3-b]pyrazin-3aminc	1%	567.3

Example 33; 2-(4-aminophenyl)-N-(5-(3,5-diÎluorophenylthio)-lH-pyrazolo[3,4

nh₂

A solution of 152 mg (2.72 mmol) of iron and 70 mg (1.3 mmol) of ammonium chloride in 100 μΐ of water is added to a solution of 0.24g (0.544 mmol) of N-(5-(3,516493

144 difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-yl)-2-(4-nitrophenyl)acetamide in 10 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 saturated sodium bicarbonate solution. The organic phases are combined, dried on magnésium sulfate and then concentrated. The crude product is purified by siiica gel chromatography (DCM/MeOH) to yield 11 mg (4%) of 2-(4-aminophenyl)-N-(5-(3,5difluorophenylthio)-lH-pyrazolo[3,4-b]pyridin-3-yl) acetamide in the form of a brown solid.

LCMS (El, m/z): (M+1) 412.09.

^lH NMR: ÔH ppm (400 MHz, DMSO): 13.60 (1H, bs, NH), 10.96 (1H, bs, NH), 8.68 (1H, d, CH_arom), 8.55 (1H, d, CHa_rom), 7.06 (1H, m, CH_arom), 6.98 (2H, d, CH_arora), 6.79 (2H, m, CH_aram), 6.50 (2H, m, CH_arom), 4.92 (2H, s, NH), 3.51 (2H, m, CH₂).

Examples of method F3: sulfide oxidation

Example 34: 5-(3,5-dinuorophenylsulfonyl)-lH-pyrazolo[3,4-b]pyridin-3-amine

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)-lH-pyrazolo[3,4-b]pyridin-3-amine in 10 ml of a 1:1 mixture of tetrahydrofuran and methanol at 0°C. The reaction mixture is stirred at room température for 16 hours. An additional portion of 663 mg of oxone at 0°C is then added and the reaction medium stirred at room température for 24 hours. The solvents are evaporated and the reaction medium is diluted with sodium bicarbonate solution, extracted with ethyl acetate, dried on MgSCU and then concentrated to yield 340 mg (81%) of 5-(3,5-difluorophenylsulfonyl)-lH-pyrazolo[3,4b]pyridin-3-amine in the form of a yellow solid.

LCMS (El, m/z): (M+1) 311.03.

145 ’HNMR: ôHppm (400 MHz, DMSO): 12.72 (IH, bs, NH), 8.92 (IH, d, CH_atom), 8.84 (IH, d, CHnrom), 7.89-8.01 (IH, d, CH_aroni), 7.62-7.80 (2H, m, CH_arom), 6.06 (2H, bs, NH).

The following compounds were also obtained by this method:

’ïiS

Ex.*·	ArX	Q	Yi. ¥<	W	Compound name	Yield	Mass MH+
34-2	o. v F	H	CH, N	H	5-(3,5- d i fluorobenzy Isu ifony 1)lH-pyrazolo[3,4b]pyridin-3-amine	ND	(M+1) 325.07
34-3	C|OCI	--O '0^	N, CH	H	/er/-butyl 5-(3,5dichiorophenylsu 1 fonyl)- IH-pyrazolo[4,3bjpyri d i n-3-ylcarbamate	ND	ND
·· lH NMR, D	MSO-ds, Ex.: 33-2: 12.64 (IH, bs, NH), 8.56 (IH, d, Cl	Tarom), 8.49 (IH, d,

CHarom), 7.24 (IH, ddd, CH_aram), 6.94 (2H, bd, CHarom), 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 préparation of the corresponding sulfones or sulfoxides.

Examnle 34-bis: 5-(3,5-difliiorophenyIsulfinyl)-lH-pyrazolo|4,3-b|pyrazin-3-amine

NH₂

0.55 mL of triethylamine and 22 mg of 4-dimethylaminopyridine are added under argon to a solution of 500 mg (1.790 mmol) of 5-(3,5-difluorophenylthio)-lH-pyrazolo[3,416493

146

b]pyrazin-3-amine 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 methanol 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 stirred at room température for 16 hours. An additional portion of 550 mg of oxone is then added and the reaction medium is stirred at room température for 5 hours. The solvents are evaporated and the reaction medium is diluted with a sodium bicarbonate solution, extracted with ethyl acetate, dried on magnésium sulfate and concentrated to lead to a mixture of the corresponding sulfone and sulfoxide which are used without further purification in the deprotection 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 mixture in 6 mL of dichloromethane. The mixture is stirred 1 hour at room température and an additional portion of 4 équivalents 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 magnésium sulfate and concentrated to yield a 1:1 mixture of 5-(3,5difluorophenylsulfonyl)-lH-pyrazolo[3,4-b]pyrazin-3-amine and 5-(3,5-difluorophenyl sulfinyl)-lH-pyrazolo[3,4-b]pyrazin-3-amine. This mixture is used in the following steps without further purification.

The following compounds were also obtained by this method:

ArX

147

Ex.**	ArX	Yi,Y<	Compound names	Yield	Mass MH+
34bis-l	F ©	CH, N	5-(2,5 -difluoropheny lsulfonyl)-1Hpyrazolo[4,3-b]pyridin-3 -amine	58% 3 steps	(M+1) 310,9
34bis-2	Cl Cl /'K	CH, N	5-(3,5-dichlorophcnylsulfonyl)-lHpyrazolo[4,3-b]pyridin-3-aminc	38% 3 steps	(M+1) 342.8
34bîs-3	Cl Cl O	CH, N	5-(2,5-dichlorophcnylsuIfonyl)-1Hpyrazolo[4,3-b]pyridin-3-amine	41% 3 steps	(M+1) 342.9
34bis-4	F	CH, N	5 -(3,5-difluorobenzylsulfbny 1)-1Hpyrazolo[4,3-b]pyridin-3-amine	58% 3 steps	(M+1) 325.0
34bis-5	F	CH, N	5 -(2,5-difluorobenzy lsulfonyl)-1Hpyrazolo [4,3-b]pyndin-3-amine	45% 3 steps	(M+1) 325.0
34bis-6	F	CH, N	5-(2,5-difluorobenzylsulfinyl)-1Hpyrazo!o[4,3-b]pyridm-3-amine	5% 3 steps	(M+1) 308.9
34bis-7		CH, N	5 -(2,5-dichlorobenzylsulfonyl)-1Hpyrazolo[4,3-b]pyridin-3-aminc	3% 3 steps	ND
34bis-8	Cl Cl	CH, N	5~(2,5-dichlorobcnzylsulfinyl)-1Hpyrazolo[4,3 -b]pyridin-3 -amine	18% 3 steps	ND

** Ή NMR, DMSO-cU, Ex.: 34bis-l: 12.31 (1H, si, 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, si, NH₂). 34bis-2: 12.32 (1H, si, NH), 7.94-8.11 (5H, m, CHarom), 5.85 (2H, si, NH₂). 34bis-3: 12.34 (1H, si, NH), 8.27 (1H, 5 s, CHarom), 8.12 (1H, d, CHarom, J=11.6Hz), 8.01 (1H, d, CHarom, J=11.6Hz), 7.827.89 (1H, m, CHarom), 7,67 (1H, d, CHarom, J=11.2Hz), 5.70 (2H, si, NH₂). 34bis-4:

12.28 (1H, si, NH), 7,89 (1H, d, CHarom, J=8.8Hz), 7.68 (1H, d, CHarom, J=8.8Hz), »

148

7.21 (IH, m, CHarom), 6.91-6.97 (2H, m, CHarom), 5.87 (2H, s, NH2), 4.94 (2H, s, CH). 34bis-5. 12,28 (IH, si, NH), 7.89 (IH, d, CHarom, J=8.8Hz), 7.68 (IH, d, CHarom, J=8.8Hz), 7.20-7.25 (2H, m, CHarom), 7.10-7.15 (IH, m, CHarom), 5.84 (2H, s, NH2), 4.87 (2H, s, CH). 34bis-6: 12.04 (IH, s, NH), 7.87 (IH, d, CHarom, J=8.8Hz),

7.40 (IH, d, CHarom, J=8.8Hz), 7.10-7.25 (2H, m, CHarom), 6.90-6.97 (IH, m, CHarom), 5.61 (2H, s, NH2), 4.47 (IH, d, CH, J=13.2Hz), 4.18 (IH, d, CH, J=13.2Hz). 34bis-7: 12.28 (IH, s, NH), 7.89 (IH, d, CHarom, J=8.8Hz), 7.64 (IH, d, CHarom, J=8.8Hz), 7,40-7.50 (3H, m, CHarom), 5.81 (2H, s, NH2), 4.96 (2H, s, CH).

Example of method F4: déméthylation

Example 35; N-(5-(3,5-difluorophenylthio)-6-hydroxy-lH-pyrazolo[3,4-b]pyridïn3-yI)-4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide

443 μΐ (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)-6-methoxy-lHpyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4ylamino)benzamide (example 18) in 4 ml of 1,2-dichioroethane 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 methanol and ethyl acetate. 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 température. The pH of the solution is adjusted to 8-9 and the aqueous phase is extracted with ethyl acetate. The organic phase is dried on magnésium sulfate and the crude product is purified on a silica gel column (dichloromethane/methanol as eluent) to yield 21 mg (24%) of N-(5-(3,5-difluorophenylthio)-6-hydroxy-lHpyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-l-yl)-2-(tetrahydro-2H-pyran-4ylamino)benzamide in the form of a yellow powder.

LCMS (El, m/z): (M+l) 596.13,

149 'H NMR: ÔH ppm (400 MHz, DMSO): 12.96 (1H, broad fiat singlet), 12.02 (1H, broad fiat singlet), 10.64 (1H, bs, NH), 8.46 (1H, bs), 8.09 (1H, bs), 7.72 (1H, d, CH_aroro),

6.97-7.10 (1H, m, CH_arom), 6.60-6.74 (2H, m, CH_arom), 6.28 (1H, dd, CH_arom), 6.13 (1H, d, CH_arom), 3.80-3.90 (2H, m, CHpy_ranone), 3.65-3.77 (1H, m, CHpy_ranone), 3.50 (2H, t, CHpytanone), 3.25-3.32 (4H, m, 2*CH₂), 2.37-2.45 (4H, m, 2*CH₂), 2.22 (3H, s, CH₃),

I. 91-2.00 (2H, m, CHpy_ranonc), 1.28-1.43 (2H, m, CHpy_ranonc)·

II, Biological tests of the compounds according to the invention

- Test for measuring inhibition of ALK kinase:

A ViewPlate microplate (Packard) is incubated with 0.1 mg/ml GST-PLCyl substrate (purified recombinant form) in phosphate buffer (PBS, pH 7.4) (100 μΐ/well) for one hour under stirring. The plate is then saturated with blocking solution comprising 5% bovine sérum albumin (BSA) (Sigma) in PBS buffer, pH 7.4.

After having added a compound according to the invention to the desired final concentration (typical range between 30 μΜ 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 MgCl₂ (Merck); 0.65 mM dithiothreitol (DTT) (Acros); 39 mM sodium βglycerophosphate (TCI); 0.65 mM sodium orthovanadate (Sigma); and 250 μΜ 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 (Sigma), an anti-phosphotyrosine antibody, coupied with HRP (UBI) 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 μΐ of SuperSignal ELISA mixture (Pierce).

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

IC50S are determined by nonlinear régression 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.

- Test for measuring inhibition of cell (Karpas 299) prolifération:

The antiproliférative activities of the compounds according to the invention were measured by the ATPlite technique (Perkin El mer).

150

Nonadherent human anaplastic large-cell lymphoma cells (Karpas 299) are inoculated ΐη 96-well plates (300,000 cells/ml) at day 1, at a concentration compatible with logarithmic growth for the 72 hours required for the évaluation of the compounds. Ail of the cells are treated at day 1 and then placed in an încubator at 37°C under an atmosphère of 5% CO₂. Cell viability is evaluated at day 4 by assaying released ATP, which is characterïstic of viable cells. ICjos are determined by nonlinear régression 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 obtained with the compounds of the invention are indicated below:

Moiecule	Enzymatic inhibition of ALK (ICso, μΜ)	Karpas 299 cell prolifération inhibition (ICjo, μΜ)
30-1	0,020	2.2
30	0.001	0.16
30-9	0.001	ND
28	0.036	ND
31	0.017	0.83
30-5	0.066	2.6
(ND: no	determined)

- Pharmacological activity in vivo

The moiecules described and tested exhibit marked antitumor activity in vivo which is expressed, in an unexpected 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 adminîstered orally at various doses on a daily schedule to mice with ALCL tumors grafted subcutaneously. Tumor size was measured regularly during the study and the animais were weighed several times per week in order to identify any adverse effects. A compound is declared active if it induces inhibition of ALCL tumor growth by at least 58%. Several

151 compounds of the présent invention, in particular molécules 30 and 30-9, induced 100% inhibition of tumor growth, with no adverse effects, which corresponds to complété régression of the tumors.

Furthermore, the molécules described and tested hâve general pharmacological properties 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 grafled 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 removed at various times after the administration of the compounds and then ground. The presence 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 kinases are produced by Millipore and are screened according to the manufacturer’s protocols.

The results are presented in the table below:

Kinases	Enzyme inhibition (IC50, nM)
30-9	30
ALK	15	7
Abl	38	18
c-Src	9	4

8 JUIl. 2013 atélNET CAZENAVE sari

152

Claims (22)

1, A compound of following general formula (I): (I) or a pharmaceutically acceptable sait or solvaté of same, a tautomer of same, or a stereoisomer or mixture of stereoisomers of same in any proportions, such as a mixture of enantiomers, notably a racemic mixture, wherein:

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

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

- Y3 represents a nitrogen atom or a C-X-Ar or C-W group, on the condition that:

at least one and at most two Yi, Y₂, Y3, and Y4 groups represent a nitrogen atom, Y₂ and Y4 cannot represent a nitrogen atom at the same time, when Y2=C-X-Ar, then Y3 represents a nitrogen atom or a C-W group, and when Y3=C-X-Ar, then Y₂ represents a nitrogen atom or a CH group,

- Ar represents an aryl or heteroaryl group optionally substituted by one or more groups selected from a halogen atom, (Ci-Cfi)alkyl, (Cj-CeJhaloalkyl, (CiCejhaloalkoxy, (Ci-C6)halothioalkoxy, CN, NO₂, ORu, SRi₂, NR13R14, CO₂Ru, CONRj6Rn, SO₂Ri8, S0₂NRi9R₂o, COR₂i, NR₂₂COR₂3, NR₂4SO₂R₂j, and R2fiNR₂7R₂8 and/or optionally fused to a heterocycle,

153

- X represents a divalent group selected from O, S, S(O), S(O)₂, NR|, S(NR4), S(O)(NR4), S(O)₂(NR4), NR4S, NRaSCO), NR4S(O)₂, CH₂, CH₂S, CH₂S(O), CH₂S(O)₂, SCH₂, S(O)CH₂, S(O)₂CH₂, ch₂ch₂, ch=ch, c=c, ch₂o, och_2> NKîCHî, and CH2NR4,

- W represents an R?, SRs, OR5 or NRjRe group,

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

- V represents C(O), C(S) or CH₂,

- n represents 0 or l,

- Rj represents a hydrogen atom, or an OR7 or NR7R8 group,

- R₂ represents a hydrogen atom, an optionally substituted heterocycle, NO₂, OR9 or NR^Rio,

- Rj, R4, R11 to R₂5 and R₂? to R₂h each represent, independently of each other, a hydrogen atom or a (Ci-Cejalkyl group,

- Rs and Rr, each represent, independently of each other, a hydrogen atom or a (CiCfi)alkyl, optionally substituted aryl or optionally substituted benzyl group,

- R7, R«, R» and Rio each represent, independently of each other, a hydrogen atom or an optionally substituted (Ci-Cfi)alkyl or (C3-Ci₂)cycloaikyl group or an optionally substituted heterocycle, and

- R₂6 represents a (Ci-Ccjalkyl group.

2. The compound according to claim 1, characterized in that:

- Yi and/or Y₄ = N,

- Y₂=CH or C-X-Ar, and

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

3. The compound according to either claim 1 or claim 2, characterized in that X represents a divalent group selected from S, S(O), S(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; notably from S, S(O), S(O)₂, NR4, CH₂, SCH₂, S(O)CH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH_2> CsC, OCH₂₁ and NR₄CH₂; in particular from.

154

S, S(O)2, CH2, SCH₂, S(O)₂CH₂, S(O)₂NH, CH₂CH₂, and OC, wherein the first atom of these groups is bound to atom Ç of chain Ç-X-Ar.

4. The compound according to any one of daims 1 to 3, characterized in that Ar represents an aryl group, such as phenyl, optionally substituted by one or more groups selected from a halogen atom, (Ci-C_e)alkyl, (Ci-Cû)haloalkyl, (Ci-C₆)haloalkoxy, (CiCfi)halothioalkoxy, CN, NO₂, ORh, SRi₂, NRbRm, CO₂Ri_S, and CONR^Rn, SO₂Ri8, S0₂NRi9R₂o, COR₂i, NR₂₂COR₂₃ or NR₂4SO₂R₂î; or a pyridine group,

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

,CFs

Cl and

6. The compound according to any one of daims 1 to 5, characterized in that W represents an Rj, SR?, ORj or NRsRe group, with Rs and Rt representing, independently of each other, a hydrogen atom or a (Ci-Ce)alkyl group.

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

- R3=H,

- U=CH₂orNH,

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

- n=0 or 1, and notably 0.

8. The compound according to any one of daims 1 to 7, characterized in that Ri represents a hydrogen atom or an NRjRe group, with R? representing a hydrogen atom

155 and R« representing an optionally substituted (C₃-Ci₂)cycloalkyl group or an optionally substituted heterocycle.

9. The compound according to claim 8, characterized in that Ri represents one of

5 the following groups:

10, The compound according to any one of claims 1 to 9, characterized in that K₂ represents NO_2j NRgRio or a heterocycle optionally substituted by (Ci-Ce)alkyl or NH₂.

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

NH₂, NH(CH₂)₃NMe2, NMe(CH₂)₃NMe₂, NO₂,

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

156

14-2 O 0 Ji hn-\y hn-\J y '^N N 14-10 O J⁰ -, Ji HN-X / Ç’ ΗΝχ i — Ay^sym_n Q T N-N ^C1 N X 14-11 Ο Γ*0 ^HN-yT^ M* ⁿ rⁿ ^n-\ ^F <u X 15 F ijl ? HN-O HN Aj Vn_x 26-4 w F 26-8 0 ^^%N HN<O^Ns> W F ^M 27 ΗΧ-ζτΟ w% ^F ^-N X 27-1 A P ηηΑ?Ό ^F W Q U V-N X 28 F Y V_M ^F ^-^Nx 29 ^ην^_ν-^Ύ'^Νχ->^Ν y y^a<z 29-a ΗνΛ /'V\_UJ'‘ w F 30 ? hnA3° HH J Y X Y ^Mp f X-N^ 30-1 H₂N^O P HN-Çj° ^N Ï \—N X 30-3 V Thh-O L .p hn-vù '^N Jf Χ-Ν_χ

t

157

30-4 hnAJjⁿAA^f F? t +V (-x 30-5 P HN-O HNAj ΎΎ⁸ΥΎ^ Q a' n ^F X-N X 30-8 V, „_ν<!Τ-Ο HN.-r , X-r< o fl T N ^N B ,^Νχ 30-9 P»O y A V f*-') ^F x-\ 30-10 F ^sO6Q ft N-^ 30-11 J? hn-^3° ^{f s hn} \””S — \ 30-12 _hn7™-O T Ά¹» X-N^ 30-a hnAtO’ w%. F XZ’NHj 31 F _FJ^jL J hnA3° ^F L ^{HN x} n 32 Y HN-X> ? A ;jx ^F XXN_S 32-1 r^° V VfT^x r«~> F 33 hn<O^NHî vxx· F

158

35 1 Ο 0 ^ΗΝ y’*HCT'kl· f| N-^ ^F Χ-Ν_χ 26-12 O Ό” ^ΊζΧ^Ν'^,^ηκ ^F \A_X 30-69 Ο / ο J! ΗΝ-Χ__f HN-\j ^ργν⁵γ>Λ Q V ^ΝΗ F ¢. / 27-2 o J ^h,ⁿO ΥΥ Y A Q t soi ,k ^F X 27-3 jÔl° τΛ-Γθ’ ^Ν Ν ₍ ^ΝΑ Χ-Ν_χ 27-4 f ψΛχθ A rA m. <-N_s 30-73 ΑΛΑ¹ \χΝ_χ 14bis J HN-C° ΡγγγυζΥ) γ W ^F \-Ν_χ 30-70 9 _/Αο JF ΗΝ-\7 'oc'jYÔ -Sni p) Χ-Ν_χ 30-71 _HN7 «rC° ^Frr^F γτΑa N A Χ—Ν_χ 30-72 o /Ao JJ HN-XJ ΊΓΎ ° Xi? Ιψ 'N U N-^ F Χ-Ν_χ 27-5 J HN-O ^HN /Àx γρηΜ' Yz F

I

159

30-13 y w q 30-14 n hnAJ?·^ _ρ'ΧΑζ°γΝ.Α ZTXk 30-15 A 30-16 A J «,-Ο \ fl HN Ά/ ¹^sAx_xO_x<N_<SfJ ^F ^ΑΓ ' ,ή 30-17 A » -ΐψΌ 30-18 À O -ΓΎ A] hnA7<^ Ϋ^γΰ YA ^C‘ H Χ-Ν_χ 30-19 Χ~Ν_χ 30-20 A j ™O \ fl HN-\J ΑΑ/°γΆ /TA 4^f ?s ν_Νχ 30-21 a â +-o r fl hn-\_/ _F+_F AA/ 30-22 .n J hn-^jC3° r 11 ^HN x_-/ %Αζ°γ^ΝΑ //% U/ \-Ν_χ 30-23 C_Ny 30-24 j A HN-\J — m__J rx ΥΎ T n U V Q

160

30-25 U ΗΝΑ J HNÂ J ^FvÇT^sXjC^ⁿ 30-26 g HF-O hn-A J Fy^s^N^ ΛΑ LA ΜΧ A 30-27 _ην4>Ό 30-28 J? ^hnXa° hn-A__i HT O O ° ^K Q 30-29 Ρ η«Ό ηνΑ_1 \Γ V/ 30-30 _H _? <y-O ^clv^s^Sx.N sJ /X Xx χτ> M ^ci Ny 30-31 J? HN-X^J⁰ Q 30-32 _c F _ o Λθ Xs N ^KN VV Q XXJ“ M Χ-Ν_χ 30-33 ^Γ^^{Ρ Η} '^Γθ^> çr ⁵Ά$ 30-34 ⁰ -/ P A hn-\j H N'A/ ✓ΆχΑ /A jCXX> Χλ AX Q 30-35 ,AA° UÇ^N A. X 30-36 θ P° f X XX M XX q 30-37 ° -ZX _faXc$ q. X ^h χ 30-38 ° -C'? HN-VT'YcuCOVu AX q

161

30-39 O /A) Λ ΗΝ-Χ/ ΗΝ-\__/ °'Ρ Α 3040 ? ™-O r> Ψ ^tT Ά ^F An_x 30-41 J? ^fYV^hïMn Q 3042 o -/A» p Jl ί H ^H,^N VA y w -q 30-43 ο /Αθ P U ΗΝ-χ__! 1 H hn-A/ M. 3044 ⁰ _7 ° Jj HN-\J γΑνζη ^CI LA|f \-Ν_χ 3045 Cl Λ ^HNC>^O Çi h hn-x__i çj A3 Ct 304« J HN-O HN”\j Ηγγ^Ν^ Q T “^N 'q 3047 9 -O _hnJhn<j Εγ^-γΝA Q Ύ W ^{F v}\ 3048 F A HN-X^J³ >τΉ’ N- A / 30-49 _fÆ UjrO ^Τχ<<5 ^N ΓΧ An_s 30-50 --Ο'θ’ r

162

30-51 9 ΗΝ-ζτΌ’ T Z Q 30-52 ψ ΗΗ-ζϊΌ¹ στζο '-y>_> 30-53 J ηνΌ °^'Lⁿ F Χ-\ 30-54 o J ,Ζ° °^γ^Νγ4 ( Q_x 30-55 _Χ ° ζχ □ n Τ2'Υ^ντΛ Ό Π 30-56 wc A 30-57 A] ο J ΗΝ-Ο =ΆΖή ο* γ r% Μ Μ-ν' 30-58 jÔl o hnA2? A? “ 30-59 ΠΑ hULtO ^αΛ<ΎγΜ_ΝΟ ^ν\ 30-60 a-O/ h υΖΖθ 30-61 „ J HH-θ’ 'P un A / VMj q T ^T1 p 30-62 _ iï hn-\_j ^h,ⁿ AJz 30-63 F J? HnA--^ ÔÛY A Q T n 30-64 JJ ΗνΆΧ νν^υπΑ V>XjD<

163

30-65 OrU⁰ ôAa 30-66 O J „ J! HN-\/ U/m M p Χ-Ν_χ 30-67 o _Λ u HN-Xy 30-68 .'_W-A •όΑΆ 31-1 I o Q A

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

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

5 for the treatment of cancer, inflammation and neurodegenerative diseases such as Alzheimer’s disease, in particular cancer.

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

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

17. A pharmaceutical composition comprising at least one compound of formula (I)

15 according to any one of claims 1 to 12, and at least one pharmaceutically acceptable excipient.

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

I64

19. A pharmaceutical composition comprising:

(i) at least one compound of formula (I) according to any one of daims 1 to 12, and (ii) at least one other active ingrédient, such as an anticancer agent, as a combination product for simultaneous, separate or sequential use.

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

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

wherein Yi, Yj, Y3 and Y4 are as defined in claim 1, and Ris represents a hydrogen atom or an N-protecting group, with a compound of following formula (B): wherein Ri, R2, U and n are as defined in claim 1, V=C(O) or C(S), and R3o=OH or a leaving group such as Cl, to yield a compound of following formula (C): xY (bl) (cl)

165 wherein Yi, Y₂, Yj, Y.», Ri, R₂, U and n are as defined in claim 1, R29 is such as defined above and V=C(O) or C(S), optionally substitution of the nitrogen atom bound to V of the compound of formula (C) obtained in the preceding step with an R3 group other than H and/or deprotection of the nitrogen atom carrying an R29 group representing an Nprotecting group to yield a compound of formula (I) with V=C(O) or C(S), optionally forming of a sait of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable sait of same.

A method for the préparation of a compound of formula (I) according to any one

21.

of daims 1 to 12, wherein V=CH₂, and notably U=CH₂, comprising the following successive steps:

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

r₂ (D) wherein Rj, R₂, U and n are as defined in daim 1, to yield a compound of following formula (E):

f

166 (b2) (c2) (E) wherein Yj, Y₂, Y3, Y₄, Ri, R₂, U and n are as defined in claim 1 and R29 is such as defined in claim 20, optionally deprotection of the nitrogen atom carrying an R29 group representing an N-protecting group and/or substitution of the nitrogen atom bound to V with an R3 group other than H of the compound of formula (E) obtained in the preceding step to yield a compound of formula (I) with V=CH₂, and optionally forming of a sait of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable sait of same.

A method for the préparation of a compound of formula (I) according to any one

22.

of claims 1 to 12 wherein V=C(O) or C(S), n=l and U=NH, comprising the following successive steps:

(a3) coupling between a compound of formula (A) such as defined in claim 1 and a compound of following formula (F):

R₂ (F) wherein Rj and Rj are such as defined above and Z=O or S, to yield a compound of following formula (G): s

167 wherein Yt, Yj, Y₃, Y-i, Ri and Ri are as defined in claim l, R29 is such as defined in claim 20 and Z is such as defined above, (b3) optionally deprotection of the nitrogen atom carryîng an Rî? group representing an N-protecting group and/or substitution of the nitrogen atom bound to V with an R₃ group other than H of the compound of formula (G) obtained in the preceding step to yield a compound of formula (I) with V=C(O) or C(S), n=l and U=NH, and (c3) optionally forming of a sait of the compound of formula (I) obtained in the preceding step to yield a pharmaceutically acceptable sait of same.