WO2012038905A1

WO2012038905A1 - Thienopyridine nicotinamide derivatives, preparation thereof and therapeutic use thereof

Info

Publication number: WO2012038905A1
Application number: PCT/IB2011/054144
Authority: WO
Inventors: Jérôme ARIGON; Claude Bernhart; Michael Bosch; Monsif Bouaboula; Frederico Nardi; Samir Jegham; Romain Combet
Original assignee: Sanofi
Priority date: 2010-09-24
Filing date: 2011-09-21
Publication date: 2012-03-29
Also published as: FR2965263A1

Abstract

The present invention relates to thienopyridine nicotinamide derivatives of general formula (I). It also relates to the compositions containing same and to the therapeutic use thereof, in particular as anticancer agents. The invention also relates to the process for preparing these compounds.

Description

THIENOPYRIDINE NICOTINAMIDE DERIVATIVES, THEIR PREPARATION AND

THEIR APPLICATION IN THERAPEUTICS

The present invention relates to thienopyridine nicotinamide derivatives, the compositions containing them and their therapeutic application, especially as anti-cancer agents. The invention also relates to the process for the preparation of these compounds.

The international application WO 2005/051366 describes compounds of formula eneral (A):

wherein Z is phenyl or indanyl.

International Application WO 2007/016538 describes compounds of general formula (B):

in which Q may represent a group R 1 -NR 12 -C (= O) -, R 3 may be a 2-, 3- or 4-pyridinyl group, R 4 and R ₅ represent a hydrogen atom, an alkyl group or an alkoxy group; , -OH, -CF ₃ or -CN. These compounds are used in the treatment of obesity.

According to one aspect, the subject of the present invention is a compound of general formula (I):

in which :

D represents a 5- or 6-membered aromatic or heteroaromatic ring;

Ri and R ₂ represent, independently of one another:

o a hydrogen atom,

a (C ₁ -C ₆ ) alkyl group, optionally substituted by one or more hydroxyl or (C ₁ -C ₄ ) alkoxy groups,

o a -CF _3i group

o a -CF ₂ CF _{3 group} ,

o a group -NRaR,

o a -CO-NRaRb group,

with R _a and R _b representing, independently of one another, a hydrogen atom or a (C ₁ -C ₆ ) alkyl, phenyl or (C ₃ -C ₆ ) cycloalkyl group, said (C ₁ -C ₆ ) alkyl group being possibly substituted by:

. one or more hydroxy, (C ₁ -C ₄ ) alkoxy, (C ₃ -C ₆ ) cycloalkyl groups, or

. a group -NR _c R _d in which R _c and R _d represent, independently of one another, a hydrogen atom or a group (Ci

C ₆ ) alkyl or together with the nitrogen atom to which they are connected form a (C ₄ -C ₆ ) heterocycloalkyl group optionally comprising in the ring the group -S (O) _q with q = 0, 1 or 2, said heterocycloalkyl group (C ₄ -C ₆ ) being optionally substituted with a hydroxyl, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy group,

It being understood that at least one of R 1 or R ₂ is different from a hydrogen atom; R 3 represents at least one substituent of the thieno [2,3-b] pyridine ring chosen from a hydrogen or fluorine atom, a (C ₁ -C ₄ ) alkyl group and a group -NR _e R _f in which R _e and R _f represent a hydrogen atom or a (C 1 -C ₄ ) alkyl group;

N is an integer of 0, 1 or 2, representing the number of fluorine atom (s) attached to the central phenyl ring;

• L represents a simple covalent bond.

In the context of the present invention, the following terms mean:

· Halogen atom: a fluorine, chlorine, bromine or iodine atom;

Alkyl group: a saturated aliphatic hydrocarbon group comprising from 1 to 6 carbon atoms (advantageously from 1 to 4 carbon atoms) obtained by removing a hydrogen atom from an alkane. The alkyl group can be linear or branched. By way of examples, mention may be made of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, 2,2-dimethylpropyl and hexyl groups;

Alkoxy group: an -O-alkyl group, wherein the alkyl group is as defined above;

Cycloalkyl group: a cyclic alkyl group comprising between 3 and 6 carbon atoms, all the carbon atoms being involved in the cyclic structure. By way of examples, mention may be made of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups;

• heterocycloalkyl group: a cycloalkyl group comprising at least one heteroatom (O, S, N) engaged in the ring and connected to the carbon atoms forming the ring. By way of examples, mention may be made of pyrrolidinyl, piperidinyl, piperazinyl or N- (C ₁ -C ₄ ) alkyl-piperazinyl, azepanyl, thiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl groups;

A 5- or 6-membered aromatic ring: a monocyclic aromatic group comprising 5 or 6 carbon atoms, and furthermore having at least one unsaturation center, preferably 2 or even 3. As examples of such groups, mention may be made of the phenyl group.

A 5- or 6-membered heteroaromatic ring: a monocyclic aromatic group comprising 5 or 6 members, comprising one to several heteroatoms such as than the atoms of nitrogen, oxygen or sulfur. Nitrogen atoms can be in the form of N-oxides. By way of examples of such groups, there may be mentioned thiazolyl, thiadiazolyl, thienyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, furanyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, pyridazinyl, more particularly thiazolyl, pyrrolyl, pyrazolyl, furanyl.

The heterocycloalkyl group formed by R _c and Rd may be, for example, the group

H NU.

pyrrolidinyl () piperidinyl (^), piperazinyl () or N- (C 1-6)

C alkyl piperazinyl

), especially N-methyl-piperazinyl, azepanyl

), 1-oxo-thiomorpholinyl), 1,1-dioxo

J

thiomorpholinyl ( ⁰

As indicated above, the heterocycloalkyl group formed by Rc and Rd may be optionally substituted with one or more substituents, which are identical to or different from each other when there are several of them, chosen from: -OH; (Cl- _C6) alkoxy: for example methoxy; (C1-C6) alkyl: for example meth le. So,

Substituted heterocycloalkyl may be the 3-hydroxypiperidinyl group (

hydroxy-piperidinyl

dimethyl-piperidinyl (

), cis-2,6-dimethyl-piperidinyl ().

According to a preferred embodiment, the compounds according to the invention are of general formula (I) in which D (R 1) (R ₂ ) represents:

a heteroaromatic 5-membered ring of formula (A) which follows:

In which :

R 1 and R ₂ are as defined above for the compound of general formula (I), and

X, Y, Z ₁ , Z ₂ and Z ₃ represent, independently of one another, a heteroatom selected from nitrogen, sulfur or oxygen or a carbon atom, more particularly they form together a thiazolyl or pyrrolyl, pyrazolyl or furanyl;

Or

a 6-membered aromatic or heteroaromatic ring of formula (B) which follows:

In which :

R 1 and R ₂ are as defined above for the compound of general formula (I), and Z and Z 'represent, independently of one another, a nitrogen atom or a radical - CH -, more particularly Z' represents -CH- and Z represents a nitrogen atom.

According to another preferred embodiment, the compounds according to the invention are of general formula (I) as defined according to one of the preceding variants, in which the thieno [2,3-b] pyridine ring may comprise from 1 to 4 substituents R 3, preferably R ₃ , being chosen from a hydrogen or fluorine atom, preferably a hydrogen atom, a (C ₁ -C ₄ ) alkyl group and a group -NReR _f in which R _e and R _f represent a hydrogen atom or a (C ₁ -C ₄ ) alkyl group.

According to another preferred embodiment of the invention, it will be possible to choose R ₃ from those described in Table I. According to a preferred embodiment of the invention, R ₃ is in position 5 and / or 6, preferably 6 on the thieno [2,3-b] pyridine ring. According to another preferred embodiment, the number of substituents R 3 is equal to 1 and / or R ₃ is in position 5 or 6 on the pyridine ring as shown below:

position 6 position 5

R ₃ is even more preferably in the 6-position. Preferably, R ₃ represents a hydrogen atom or -NH ₂ , more particularly in the 6-position.

According to another preferred embodiment of the invention, the compounds according to the invention are of general formula (I) in which n is an integer of 0, 1 or 2, representing the number of attached fluorine atom (s) (s) central phenyl nucleus. More particularly, n is 0 or 1 and preferably 0.

According to another embodiment of the invention, the compounds according to the invention are of general formula (IA) which follows:

wherein R 1, R ₂ , R ₃ , L and n are as defined for the compound of the general formula (I) and X, Y, Z ₁ , Z ₂ and Z ₃ are as defined for the group (A) above.

According to a preferred embodiment, the compounds according to the invention are of general formula (I) or (IA) in which the 5-membered heteroaromatic ring represents a thiazolyl, pyrrolyl, pyrazolyl or furanyl.

According to another preferred embodiment, the compounds according to the invention are of general formula (I) or (IA) in which n is equal to 0.

According to yet another preferred embodiment, the compounds according to the invention are of general formula (I) or (IA) in which R3 represents a hydrogen atom.

According to yet another preferred embodiment, the invention relates to compounds of general formula (IA) in which:

X, Y, Z ₁ , Z ₂ and Z ₃ are as defined for the group (A) above;

R ₃ represents a hydrogen atom;

L represents a single covalent bond;

n represents 0; and

Ri and R ₂ represent independently of one another:

o a hydrogen atom,

a (C ₁ -C ₆ ) alkyl group, preferably ethyl, isopropyl or n-butyl, a -CF _3i -CF ₂ CF _{3i group;}

o a -CO-NRaRb group,

with R _a and R _b representing, independently of one another, a hydrogen atom or a (C ₁ -C ₆ ) alkyl group, preferably methyl, ethyl, isopropyl, butyl or (CH ₂ ) -isobutyl, or C ₃ -C ₆ ) cycloalkyl, preferably cyclopropyl,

said (C ₁ -C ₆ ) alkyl group, preferably ethyl or butyl, being optionally substituted with a (C ₃ -C ₆ ) cycloalkyl group, preferably cyclohexyl, or a group - NR _c R _d in which R _c and R _d represent, independently of each other, a (C 1 -C ₆ ) alkyl group, preferably isopropyl, or R _c and R _d together with the nitrogen atom to which they are attached form a (C ₄ -C ₆₎ heterocycloalkyl, preferably piperidinyl, said heterocycloalkyl (C ₄ -C ₆ ) group, preferably a piperidinyl, being optionally substituted by a hydroxyl or (C ₁ -C ₆ ) alkoxy group, preferably methoxy; it being understood that at least one of Ri or R ₂ is different from a hydrogen atom.

According to yet another variant embodiment, the compounds according to the invention are of general formula (IA) in which:

X, Y, Z ₁ , Z ₂ and Z ₃ form a 5-membered heteroaromatic ring selected from thiazolyl, furanyl, pyrrolyl and pyrazolyl;

R3 represents a hydrogen atom;

L represents a single covalent bond;

n represents 0; and

Ri and R ₂ represent independently of one another:

a hydrogen atom,

a (Ci-Ce) alkyl group, preferably an isopropyl,

a -CF _3i group

a group -CO-NRaRb,

with R _a and R _b independently of one another a hydrogen atom or a (C ₁ -C ₆ ) alkyl group, preferably an ethyl or butyl, said (C 1 -C ₆ ) alkyl group being substituted by -NRcRd in which R _c and Rj together with the nitrogen atom to which they are attached form a (C4-C6) heterocycloalkyl group, preferably a piperidinyl;

it being understood that at least one of Ri or R ₂ is different from a hydrogen atom.

According to yet another embodiment, the compounds according to the invention are of general formula (IB) which follows:

Wherein R ₁ , R ₂ , R ₃ , L and n are as defined for the compound of formula (I) and Z 'and Z are as defined for group (B). According to a particularly preferred embodiment, the compounds according to the invention are of general formula (IB) in which: Z and Z 'represent N or CH. For example, Z and Z 'may respectively represent N and CH; CH and CH or N and N:

c, c ₃

Preferably, Z and Z 'represent the structure Ci.

According to another embodiment, the invention relates to compounds of general formula (IB) in which:

Z and Z 'independently of one another represent a nitrogen atom or a radical -CH-;

Ri represents a group -CO-NRaRb;

with R _a and R _b representing, independently of one another, a hydrogen atom or a (C 1 -C 6) alkyl group, preferably a methyl, - (CH ₂ ) -isobutyl, ethyl or isopropyl group, said group ( Ci-Ce) alkyl being optionally substituted with:

. one or more hydroxy groups, (C 1 -C 4) alkoxy, preferably methoxy, (C ₃ -C e) cycloalkyl, preferably cyclohexyl, or

. a group -NR _c R _d in which R _c and R _d together with the nitrogen atom to which they are attached form a (C ₄ -C ₆ ) heterocycloalkyl group, preferably piperidinyl, optionally comprising in the ring the group -S (0) _q with q = 1 or 2.

R ₂ represents a group -NR _a R _b ,

with R _a and R _b independently of one another represent a hydrogen atom or a (Ci-Ce) alkyl group, preferably methyl or ethyl or isopropyl, phenyl or (C ₃ -C ₆ ) cycloalkyl, of cyclopropyl preference.

According to a preferred embodiment, the compounds according to the invention are of formula (ΓΒ):

in which

Z, Z 'are as defined in group (B) or the compound of formula (IB) or (ΓΒ), n and R3 are as defined above for the compound of formula (I);

* R'i represents:

a (Ci-Ce) alkyl group, optionally substituted with:

one or more hydroxyl or (C ₁ -C ₄ ) alkoxy groups;

a (C ₃ -C e) cycloalkyl group;

a group -NR _c R _d in which R _c and R _d form together with the nitrogen atom to which they are attached a (C ₄ -C ₆ ) heterocycloalkyl group optionally comprising in the ring the group -S (0) _q with q = 1 or 2, said heterocycloalkyl group (C ₄ -C ₆ ) being optionally substituted by a hydroxyl or (C ₁ -C ₆ ) alkoxy group;

R ' ₂ representing a (C ₁ -C ₆ ) alkyl, (C ₃ -C ₆ ) cycloalkyl group, or a phenyl; and · R " ₂ representing a hydrogen atom.

Advantageously, it is possible in particular to choose R 'and R' ₂ from any of those described in Table I. According to a preferred embodiment of the invention, in compounds of formula (ΓΒ), Z 'represents CH and Z represents N.

According to another preferred embodiment, the compounds according to the invention are of formula (I "B):

in which R'i, R ' ₂ , Z and n are as defined in the general formula (I), (ΓΒ).

Advantageously, Z represents N. Advantageously, a group of compounds consists of compounds of formula

(I "B) in which:

Z represents N;

R 1 represents a (C 1 -C 6) alkyl group, preferably a methyl or ethyl, said (C ₁ -C ₆ ) alkyl group preferably an ethyl being optionally substituted by a group -NR _c R _d in which R _c and R _d together with the nitrogen atom to which they are attached a heterocycloalkyl (C4-C6) group, in particular a piperidinyl; and

R ' ₂ represents a (C 1 -C 6) alkyl group, in particular an ethyl.

Advantageously, R'i and R ' ₂ are chosen from those of Table I or II.

Among the compounds of general formula (I), a subgroup of compounds is constituted by compounds of general formula (I) in which both R 1 and / or R ₂ and / or R 3 and / or L and / or n and / or D are as defined in the subgroups and formulas above.

Advantageously, among the compounds that are the subject of the invention, mention may be made of those of Table I.

The compounds of the invention, including the exemplified compounds, may exist in the form of bases or addition salts with acids. Such addition salts are also part of the invention. These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids that are useful, for example, for purification or isolation of the compounds are also part of the invention. The compounds according to the invention may also exist in the form of hydrates or solvates, namely in the form of combinations or combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.

The compounds may have one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures are part of the invention.

According to the present invention, the N-oxides of compounds containing an amine or a nitrogen atom are also part of the invention.

According to a second aspect, the subject of the invention is the process for preparing the compounds of the invention.

These compounds can be prepared according to one of the following Schemes 1-3.

As for synthetic intermediates are generally commercial products and / or where appropriate, can be prepared as indicated below.

Diagram 1

A Suzuki type coupling of Pi and P _{2 is carried out} . Hal represents a halogen atom (chlorine, bromine, iodine). The coupling is carried out in the presence of a palladium complex (in the oxidation state (O) or (II)) in a basic medium. The complex may be, for example, Pd (PPh ₃ ) ₄ , PdCl ₂ (PPh ₃ ) ₂ , Pd (OAc) ₂ , PdCl ₂ (dppf) or bis (di-tertiary butyl (4- dimethylaminophenyl) phosphine) dichloropalladium (II). The most frequently used complexes are palladium (0) complexes. The base can be for example K ₂ CO ₃ , NaHCO ₃ , and ₃ N, K ₃ PO ₄ , Ba (OH) ₂ , NaOH, KF, CsF, Cs ₂ CO _3. The coupling can be carried out in a mixture an ethereal solvent and an alcohol, for example a dimethoxyethane (DME) / ethanol mixture; it can also be a toluene / water mixture. The temperature is between 50 and 120 ° C. The duration of the reaction can in some cases be long.

More details on the Suzuki coupling, the operating conditions as well as the palladium complexes usable in: N.Miyaura and A.Suzuki, Chem. Rev. 1995, 95, 2457-2483; A.Suzuki in "Metal-catalyzed cross-coupling reactions"; Diederich, F .; Stang, P.J. Eds. Wiley-VCH: Weinhein, Germany, 1998, chap. 2, 49-97; Littke, A. and Fu, G., Angew. Chem. Int., Ed. 1999, 38, 3387-3388 and Chemler, S. R. Angew.Chem.Int.Ed. 2001, 40, 4544-4568.

In the compound P ₂ , K and K 'represent a hydrogen atom, an alkyl or aryl group, optionally linked together to form together with the boron atom and the two oxygen atoms a 5 to 7-membered ring. optionally substituted by at least one (C ₁ -C ₄ ) alkyl group or to which is optionally attached to two consecutive carbon atoms of said ring a phenyl group. For example, one of the following groups can be used:

Figure 2

According to Scheme 2, a Suzuki coupling (see above) is made between Pi and P ₃ to obtain P ₄ . The compound of general formula (I) is then obtained by an amidation reaction from P5 and amine P ₄ or a salt of this amine, for example the hydrochloride. The amidifïcation can be conducted advantageously in the presence of an acid activator (also called "coupling agent") such as benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33- 6, see also B.Castro., Dormoy, JR Tetrahedron Letter 1975, 16, 1219). The reaction is preferably carried out in the presence of a base (such as triethylamine) at room temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).

Figure 3

According to Scheme 3, the compound of general formula (I) with R2 represents

-CONHRa, by an amidation reaction from Ρβ and the amine R ₂ NH ₂ or a salt of this amine, for example the hydrochloride (see ex.3.2). The amidifïcation can be conducted advantageously in the presence of an acid activator (also called "coupling agent") such as benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33- 6, see also B.Castro., Dormoy, JR Tetrahedron Letter 1975, 16, 1219). The reaction is preferably carried out in the presence of a base (such as triethylamine) at room temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF). As regards more particularly the compounds of formula (I) for which D represents a 5-membered heteroaromatic ring, they can in particular be prepared as described in the examples which follow.

preparation of V

P _δ is obtained for its part by a Suzuki coupling reaction between P ₂ and the compound Ps in which R 1 represents more particularly a group -NRaRb, of formula:

H

according to a scheme similar to Figure 1. preparation of P ^

Figure 4

with R = -NHR _a R _b with R ₂ = -CONHR _a

P8 is obtained from P ₇ acid by monosubstitution with an amine R 1. In the case of an aliphatic amine, the reaction may be conducted at room temperature and in a protic solvent such as an alcohol or water or in an aprotic solvent such as THF. In the case of aniline, a strong base such as for example LiHMDS (((CH ₃ ) ₃ Si) ₂ NLi) is added and the reaction is carried out under heat. The monosubstitution is described on pages 14-15 of FR 2917412 in the case where D represents a 6-membered heteroaromatic ring where Z = N and Z '= CH but can be applied to other Z / Z'.

More particularly, when D represents a 6-membered heteroaromatic ring: When Z = N, Z '= CH: P ₇ is a 2,6-dihalogenonicotinic acid, for example 2,6-dichloronicotinic acid which is commercially available (see Example 1.1);

When Z = N, Z '= N: P ₇ is a 2,4-dihalogenopyrimidine carboxylic acid, for example 2,4-dichloropyrimidine carboxylic acid which is commercial (CAS No. 37131- 89-8) ;

When Z = CH, Z '= CH: P ₇ is a 2,4-dihalobenzoic acid, for example 2,4-dichlorobenzoic acid which is commercial (CAS No. 50-84-0).

In the case where Z and Z 'are both N and Hal represents a chlorine atom, P8 in which Hal represents a chlorine atom, D is a 6-membered heteroaromatic ring of formula (B) above with Z = Z' = a nitrogen atom and R 1 = -NR _a R _b , can also be obtained from the commercial compound 5-pyrimidinecarboxylic acid, 2,4-dichloro-ethyl ester:

Figure 5

CAS: 51940-64-8

Scheme 5 using an ester function subsequently converted to an acidic function also applies to the case where Z = N and Z '= CH: see the conditions in Chem.Pharm.Bull. 2000, 48 (2), 1847-1853.

Pi is obtained from Ps acid by amidifi cation using the amine R ₂ NH ₂ or a salt of this amine, for example the hydrochloride. The amidifïcation can be conducted advantageously in the presence of an acid activator (also called "coupling agent") such as benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate (or BOP, CAS No. 56602-33- 6, see also Castro, B., Dormoy, JR Tetrahedron Letter 1975, 16, 1219). The reaction is preferably carried out in the presence of a base (such as triethylamine) at room temperature, in a solvent such as tetrahydrofuran (THF) or dimethylformamide (DMF).

preparation of P ^ Compounds P3 for which K and K 'form the following group:

are commercially available or can be prepared according to the coupling reaction between a fluorinated bromoaniline and the bis (pinacolato) diboron which is described in Scheme 2 on page 150-151 of WO 2007/064931: 3-F (4-amino) 3-fluorophenylboronic acid pinacol ester, CAS No. 819058-34-9, Boron Molecular Inc, PO Box 12592, Research Triangle Park, NC 27709); 2-F (4-amino-2-fluorophenylboronic acid pinacol ester, CAS No. 819057-45-9, Boron Molecular, described on page 185 of WO 2007/064931); 2-F, 5-F (CAS No. 939807-75-7, compound described on page 184 of WO 2007/064931); 3-F, 5-F (CAS No. 939968-08-8, described on page 182 of WO 2007/064931).

Compounds P3 for which K and K 'represent a hydrogen atom may be prepared from fluorinated bromoaniline by the reactions described in Tetrahedron Letters 2003, 44, 7719-7722. P preparation?

The compounds P ₂ are obtained from the compounds P 3 by amidifïcation, according to a reaction as described above. compounds R? NH?

Amines R ₂ NH ₂ are commercial products or already described in published documents; for example :

1- (2-aminoethyl) piperidine: CAS No. 27578-60-5, described in Justus Liebigs Annalen der Chemie 1950, 566, 210-44, marketed by ACROS;

1-Piperidinepropanamine: CAS No. 3529-08-6, described in Bioorganic & Med. Chem.Lett. 2006, 16 (7), 1938-1940;

1-Piperidinebutanamine: CAS No. 74247-30-6, described in Bioorganic & Med. Chem.Lett. 2006, 16 (7), 1938-1940;

4-piperidinol, 1- (2-aminoethyl) - CAS No. 129999-60-6, described in J.Med.Chem. 2005, 48 (21), 6690-6695 and on page 17 of WO 2005/061453 (ref.ex.10);

3-piperidinol, 1- (2-aminoethyl) - CAS No. 847499-95-0, described in J.Med.Chem. 2005, 48 (21), 6690-6695 and on page 16 of WO 2005/061453 (ref.ex.8); 2- (4-methoxy-1-piperidinyl) ethylamine: CAS No. 911300-69-1, described in J.Med.Chem. 2007, 50 (20), 4818-4831;

Pyrrolidineethanamine: CAS No. 7154-73-6, described in Anales de Quimica 1974, 70 (9-10), 733-737, sold by International Laboratory Ltd, 1067 Sneath Ln, San Bruno, CA94066, USA;

1-piperazineethanamine: CAS No. 140-31-8, described in EP 151232;

• Azepan-1-ylethylamine: CAS No. 51388-00-2, described in Anales de Quimica 1974, 70 (9-10), 733-737;

2- (1,1-dioxothiomorpholin-4-yl) ethylamine: CAS No. 89937-52-0, sold by Intern. Lab. Ltd;

• N- (2-aminoethyl) thiamorpholine-1-oxide: CAS No. 1017791-77-3, sold by Sinova Inc. 3 Bethesda Metro Center, Suite 700, Bethesda, MD, 20814, USA.

A method for obtaining the compounds for which R ₂ represents a (C ₁ -C ₆ ) alkyl group substituted by the group -NR _a R _b in which R _a and R _b form together with the nitrogen atom to which they are attached the (C ₄ -C 6) heterocycloalkyl group optionally comprising in the ring the group -S (O) _q with q = 0, 1 or 2 or the group -NH- or -N (C ₁ -C ₄ ) alkyl is described on the Figure 6 which is inspired by scheme 3 of Bioorg. Med. Chem. 2007, 15, 365-373 or diagram 2 of Bioorg. Med. Chem. Lett. 2008, 18, 1378- 1381:

Figure 6

NH ₂ - (C, -C _e ) Alk-NR _a R ₆

Another method described in Figure 6 'is based on Figure 2 of Bioorg. Med. Chem. Lett. 2006, 16, 1938-1940:

Figure 6

hydrogenation base

NC- (C 1 -C ₅ ) Alk-Br + NHR _a R _b '- NC- (C 1 -C ₅ ) Alk-NR _a R _b ' ^■ NH ₂ - (C ₁ -C ₆ ) Alk- NR _to R _b

Protection of the primary or secondary amine function It may be necessary to use at least one of the steps a protecting group (PG) to protect one or more chemical function (s), including a primary or secondary amine function. For example, when Ra and Rb both represent a hydrogen atom, the amidification of Scheme 3 is carried out using for R ₂ NH ₂ the compound ₂ HN- (C 1 -C ₆ ) alkyl-NH-PG, where PG advantageously represents BOC (tert-butoxycarbonyl). Similarly, when the heterocycloalkyl group formed by Ra and Rb represents the piperazinyl group, the

-NH- function using the following compound R ₂ NH ₂ , where PG advantageously represents BOC. Similarly, when R3 represents the -NH ₂ or -NHRc group, the amine function can advantageously be protected by one or two PG group (s), preferably BOC or 9-fluorenylmethyl carbamate (FMOC). We can

example use the following compound:

The chemical function (s) is / are then obtained by a deprotection step (final or intermediate) whose conditions depend on the nature of the protected function (s) and protective group used. Reference may be made to "Protective groups in Organic Synthesis" of T.Greene, Wiley, ^4th ed., Isbn = 978-0-471-69754-1, especially for chap.7 regarding protecting groups amine function. In the case of the protection of the -NH ₂ or -NH- functions by the BOC, the deprotection step is carried out in acidic medium using, for example, HCl or trifluoroacetic acid (TFA). The corresponding salt (hydrochloride or trifluoroacetate) is thus obtained, if appropriate.

Obtaining salts

The salts are obtained during the deprotection step described above or by contacting the acid and the compound in its base form.

In the above Schemes, the starting compounds and the reagents, when their method of preparation is not described, are commercially available or described in the literature, or they can be prepared according to the methods described therein or are known to those skilled in the art. Those skilled in the art may also be inspired by the operating conditions given in the examples which are described below.

Obtaining N-oxides

The N-oxides of the compounds containing an amine or a nitrogen atom are prepared according to the methods known to those skilled in the art by reaction of the amine with organic peracids such as peracetic, trifluoroperacetic, performic, perbenzoic or its derivatives such as 3-chloroperbenzoic acid, at temperatures between 0 ° C and 90 ° C, preferably at temperatures below 50 ° C.

According to a third aspect, the invention relates to a pharmaceutical composition comprising a compound as defined above in combination with a pharmaceutically acceptable excipient. The excipient is selected from the usual excipients known to those skilled in the art according to the pharmaceutical form and the desired mode of administration. The mode of administration can be, for example, orally or intravenously.

According to a fourth aspect, the subject of the invention is a medicinal product which comprises a compound as defined above as well as the use of a compound as defined above, for the manufacture of a medicament. It can be useful for treating a pathological condition, especially cancer. The drug (as well as a compound according to the invention) may be administered in combination with one (or more) anticancer drugs. This treatment can be administered simultaneously, separately or sequentially. The treatment will be adapted by the practitioner according to the patient and the tumor to be treated.

According to a fifth aspect, the invention also relates to a method for treating the pathologies indicated above which comprises the administration to a patient of an effective dose of a compound according to the invention or a pharmaceutically acceptable salt or hydrate thereof or solvates.

An object of the invention therefore also relates to a compound according to the present invention for its use for the treatment or prevention of cancer. The following examples illustrate the preparation of certain compounds according to the invention. The numbers of the exemplified compounds refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

The numbering of the compounds in parentheses refers to the numbering of the compounds of Tables I and II.

In the examples the following abbreviations are used:

AcOEt: ethyl acetate

MeOH: methanol

BOP: benzotriazol-1-yloxytris (dimethylamino) -phosphonium hexafluorophosphate

TEA: triethylamine

P2O5: diphosphorus pentoxide

TA: room temperature

THF: tetrahydrofuran

EtOH: ethanol

NaCl: sodium chloride

DME: dimethylether

CH2Cl2: dichloromethane

Na ₂ S0 ₄ : sodium sulfate

NaHCC "3: sodium bicarbonate

The compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection). The device used consists of an Agilent chromatographic chain equipped with an Agilent diode array detector and a ZQ Waters single quadrupole mass spectrometer or a Quattro triple-quadrupole mass spectrometer -Micro Waters. The compounds were analyzed by HPLC-UV-MS coupling (liquid chromatography, ultraviolet (UV) detection and mass detection). The apparatus used is composed of a chromatographic chain equipped with a diode array detector (HP1110 Agilent or UPLC Acquity Waters) and a quadrupole mass spectrometer (ZQ, QM or SQD Waters). mass spectrometry conditions

The liquid chromatography / mass spectrometry (LC / MS) spectra were recorded in electrospray (ESI) positive mode, in order to observe the ions resulting from the protonation of analyzed compounds (MH ⁺ ) or the formation of adducts with other cations such as Na ⁺ , K ⁺ , etc. . HPLC conditions are chosen from one of the following methods:

TFA: trifluoroacetic acid

NMR conditions

^1H NMR spectra were recorded on a Bruker Avance 250 / Bruker Avance 400 or Bruker Avance II 500. The central peak of the DMSL-d6 (2.50 ppm) is used as an internal reference. The following abbreviations are used: s: singlet; d: doublet; dd: double doublet; t: triplet; q: quadruplet; m: massive / multiplet; br.s: wide signal. Example 1 N- (4- {6- (ethylamino) -5 - [(2-piperidin-1-ylethyl) carbamoyl] pyridin-2-yl} phenyl) thieno [2,3-b] pyridine-2-carboxamide (compound 2)

In a nonlimiting manner, the synthetic scheme followed for this example is Scheme 2. 1.1 / 6-chloro-2-ethylamino-nicotinic acid

In a flask, solubilize 10.5 g (55 mmol) of 2,6-dichloro-nicotinic acid in 105 mL (1.3 mmol) of 70% aqueous ethylamine solution. Stir at room temperature (RT) for 5 days. Concentrate the mixture, take up the mixture in 30 mL of water and then acidify with a 5N solution of hydrochloric acid HCl. Filter the precipitate, wash with water and dry in an oven in the presence of P2O5. 9.6 g of 6-chloro-2-ethylamino-nicotinic acid are obtained in the form of a white powder.

1.2 / 6-chloro-2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide

In a flask, solubilize 8.0 g (40 mmol) of 6-chloro-2-ethylamino-nicotinic acid in 200 mL of THF. Add 16.7 mL (120 mmol) of triethylamine, then 6.8 mL (48 mmol) of 1- (2-aminoethyl) piperidine and then 19.7 g (48 mmol) of BOP. Shake at RT for 12 hours. Evaporate the solvent under reduced pressure and take up the residue with ethyl acetate. Wash the organic phase with water and saturated NaCl solution. Collect the organic phases, dry them over Na ₂ S0 ₄ and then evaporate the solvents under reduced pressure. The residue is taken up in a minimum of CH ₂ C1 ₂ and then chromatographed by flash chromatography (CH ₂ C1 ₂ 100% at CH ₂ Cl ₂ / MeOH-90/10). 10.5 g of 6-chloro-2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide are obtained in the form of a colorless oil. 1.3 / 6- (4-amino-phenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide

Solubilize 2.5 g (8 mmol) of 6-chloro-2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide in a mixture of DME / EtOH (50/10 mL). Add 2.1 g (9.6 mmol) of 4- (4,4,5,5-tetramethyl- [1,2,3] dioxaborolan-2-yl) -phenylamine. Stir the mixture and bubble under argon for 15 minutes. Add to this mixture 50 ml of a saturated solution of NaHCO 3 and 0.92 g (0.8 mmol) of palladium tetrakis Pd (PPh) ₄ . Heat the reaction medium to 110 ° C. and put under argon for 3 hours. Evaporate the solvent under reduced pressure. The residue is taken up in an ethyl acetate / water mixture and then the residue is washed successively with water and saturated NaCl solution. Collect the organic phases, dry them over Na ₂ S0 ₄ and then evaporate the solvents under reduced pressure. Take up the residue in a minimum of CH ₂ C1 ₂ and then chromatograph chromatofiash (CH ₂ C1 ₂ 100% CH ₂ Cl ₂ / MeOH-90/10). 2 g of 6- (4-aminophenyl) -2-ethylamino-N- (2-piperidin-1-yl-ethyl) -nicotinamide are obtained in the form of a yellow oil.

1,4 / N- (4- {6- (ethylamino) -5 - [(2-piperidin-1-ylethyl) carbamoyl pyridin-2-yl] phenyl] thieno [2,3-b] pyridine-2-carboxamide

Solubilize 100 mg (0.6 mmol) of thieno [2,3-b] pyridin-2-carboxylic acid in 40 mL of THF. Add successively 0.23 ml (1.8 mmol) of triethylamine, 246 mg (0.72 mmol) of 6- (4-aminophenyl) -2- (ethylamino) -N- (2-piperidin-1-ylethyl) nicotinamide and 250 mg (0.6 mmol) of BOP. Stir the mixture at room temperature overnight. Concentrate and resume with a CH ₂ C1 ₂ / THF mixture. Wash with water and then with saturated NaCl solution. Dry over sodium sulphate and concentrate. Purify by flash chromatography (solid deposition, eluent CH ₂ Cl ₂ / MeOH gradient 99/1 up to 80/20). 80 mg of N- (4- {6- (ethylamino) -5 - [(2-piperidin-1-ylethyl) carbamoyl] pyridin-2-yl} phenyl) thieno [2,3-δ] pyridine-2 are obtained carboxamide.

Example 2: N - [4- (6-isopropylamino) -5- [(2-piperidin-1-ylethyl) carbamoyl] pyridin-2-yl] phenyl) thieno [2,3-61 pyridine-2-carboxamide (Compound No. 8)

In a nonlimiting manner, the synthesis scheme followed for this example is diagram 1.

2.1 / N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenylthieno [2,3-b] pyridine-2-carboxamide

Solubilize 5 g (28 mmol) of thieno [2,3-b] pyridin-2-carboxylic acid in 150 ml of dichloromethane. 6.7 g (30.7 mmol, 1, 1 eq) of 4- (4,4,5,5-tetramethyl- [1,2,3] dioxaborolan-2-yl) -phenylamine and 1 1, 6 are added. mL (83.7 mmol) of triethylamine.

Leave at room temperature with magnetic stirring for 14 hours then concentrate.

Take up the residue in ethyl acetate. Wash with water and then with NaCl solution.

Dry over sodium sulphate and concentrate. Resume cold with ethyl acetate and filter the insoluble material. Rinse the insoluble material with ethyl acetate and dry in an oven. 8.8 g of N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] thieno [2,3-b] pyridine-2-carboxamide are obtained. in the form of a whitish powder.

2.2 / N- (4- (6-nsopropylamino) -5 - [(2-piperidin-1-ylethyl) carbamoylpyridin-2-yl} phenyl) thieno [2,3-61 pyridine-2-carboxamide

In a 100 mL tricolor, introduce 250 mg (0.77 mmol) of 6-chloro-2- (isopropylamino) -N- (2-piperidin-1-ylethyl) nicotinamide. Add 0.32 g (85 mmol) of N- [4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] thieno [2,3-b] pyridine. 2-carboxamide, 15 ml of a saturated solution of NaHCO 3, 38 ml of 1,2-dimethoxyethane and 7 ml of ethanol. Incubate argon for 20 minutes, then add 17.5 mg (0.07 mmol) of palladium tetrakis. Heat to reflux (about 100 ° C) for 4 hours, then concentrate. Resume the crude in a dichloromethane / water mixture, extract the phase organic, wash with organic phase with water and saturated sodium chloride solution. Dry over sodium sulphate and concentrate. Purify by flash chromatography (eluent dichloromethane / methanol gradient 99/1 up to 80/20). 320 mg of N- (4- {6- (isopropylamino) -5 - [(2-piperidin-1-ylethyl) carbamoyl] pyridin-2-yl} phenyl) thieno [2,3-o] are thus obtained pyridine-2-carboxamide.

Example 3 N- (4- {6- (cyclopropylamino) -5 - [(3-methylbutyl) carbamoyl pyridin-2-yl} phenyl) thieno [2,3-61 pyridine-2-carboxamide (Compound No. 20)

In a nonlimiting manner, the synthesis scheme followed for this example is diagram 3.

3.1 / 2- (Cyclopropylamino) -6- {4- 1 (thieno [2,3-dichloro-2-pyridin-2-ylcarbonyl) phenyl) phenylicotinic acid

In a tricolor, introduce 800 mg (3.76 mmol) of 6-chloro-2- (cyclopropylamino) nicotinic acid, 1.57 g (4.1 mmol) of N- [4- (4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl] thieno [2,3-b] pyridine-2-carboxamide, 25 ml of saturated NaHCO 3 solution, 38 ml of 1,2-dimethoxyethane and 7 mL of ethanol. Flake argon for 20 minutes, then add 32 mg (0.04 mmol) of palladium tetrakis. Heat to reflux (about 100 ° C) for 8 hours, then concentrate. Take the crude in a little water, then slowly acidify with HC1 10N. Filter and dry in an oven. Purify by flash chromatography on a silica column (solid deposit, eluent dichloromethane / methanol gradient 99/1 up to 80/20). 1.2 g of 2- acid are obtained. (Cyclopropylamino) -6- {4 - [(thieno [2,3-b] pyridin-2-ylcarbonyl) amino] phenyl} nicotinic acid as a yellowish powder.

3.2 / V- (4- (6-cyclopropylamino) -5- [(3-methylbutyl) carbamoyl) pyridin-2-

5H-phenyl-thieno [2,3-61 pyridine-2-carboxamide

In a 100 ml flask, dissolve 300 mg (0.7 mmol) of 2- (cyclopropylamino) -6- {4 - [(thieno [2,3-b] pyridin-2-ylcarbonyl) amino] phenyl} acid. nicotinic in 30 ml of anhydrous THF. Add successively 0.29 ml (2.1 mmol) of triethylamine, 85 mg (0.7

10 mmol) of 4-dimethylaminopyridine, 0.16 ml (1.4 mmol) of isoamylamine and 308 mg (0.7 mmol) of BOP. Stir at room temperature overnight. Concentrate, take up the residue in ethyl acetate. Wash with water and then with NaCl solution. Dry over sodium sulphate and concentrate. Purify by flash chromatography on a silica column (eluent dichloromethane / methanol gradient 100% up to 95/5). We obtain 200 mg of

N- (4- {6- (cyclopropylamino) -5 - [(3-methylbutyl) carbamoyl] pyridin-2-yl} phenyl) thieno [2,3-b] pyridine-2-carboxamide.

Example 4: Di-Fe-Butyl [5 - ({[(4- {5 - [(2-piperidin-1-ylethyl) carbamoyl-2-furylphenyl) carbamoyllaminolmethyl) pyridin-2-yl] imidicarbicarbonate (Compound No. 28)

4.1 / 5-4-Nitro-phenyl) -N- (2-piperidin-1-yl-ethyl) -furan-2-carboxamide

Stirring 1 g (4.29 mmol) of 5- (4-nitro-phenyl) -furan-2-carboxylic acid, 0.75 ml (15 mmol) of 2-piperidin-1-yl-ethylamine, 2.1 g (4.72 mmol) of BOP, 1.5 ml (8.6 mmol) of DiPEA in 43 ml CH ₂ C1 ₂ .

After stirring for 18 hours at room temperature, wash the organic phase with saturated Na ₂ CO ₃ solution and then with water. Evaporate the solvent and purify the residue by chromatography CH ₂ Cl ₂ 95 / MeOH 5. 1.4 g is obtained.

30 4.2 / 5-4-Amino-phenyl) -N- (2-piperidin-1-yl-ethyl) -furan-2-carboxamide

Hydrogenate under pressure of a column of water in the presence of 0.13 g of Pd / C 10% 1.4 g of 5- (4-nitro-phenyl) -N- (2-piperidin-1-yl-ethyl) -Furan-2-carboxamide previously solubilized in 100 ml of a mixture of ethanol / AcOEt (70/30). Filter the catalyst on celite, evaporate the solvents. 1.4 g of product are obtained. The compound is used without further purification.

4.3 di-tert-butyl [5 - ({[(4- {5 - [(2-piperidin-1-ylethyl) carbamoyl] -2-furyl} phenyl) carbamoyl] amino} methyl) pyridin-2-yl] imidodicarbonate

Add 100 mg (0.6 mmol) of thieno [2,3-b] pyridine-2-carboxylic acid in 40 ml of THF, successively 0.23 ml (1.8 mmol) of triethylamine, 225 mg (0.72 g). mmol) 5- (4-Amino-phenyl) -N- (2-piperidin-1-yl-ethyl) -furan-2-carboxamide and 250 mg (0.6 mmol) BOP. Stir at room temperature overnight. Concentrate, continue with a mixture of dichloromethane / THF, wash with water and then with saturated NaCl solution, dry over sodium sulfate and concentrate. Purify by flash chromatography, solid deposition, eluent dichloromethane / methanol gradient 99/1 up to 80/20. 95 mg of di-tert-butyl [5- ({[(4- {5 - [(2-piperidin-1-ylethyl) carbamoyl] -2-furyl} phenyl) carbamoyl] amino} methyl) pyridin-2 -yl] imidodicarbonate. Example 5: N- [4- (5-Cyclopropylcarbamoyl-1-isopropyl-1H-pyrrol-3-yl) -phenylthieno [2,3-b] pyridine-2-carboxamide (Compound No. 33)

Methyl 5.1 / 4-iodo-1-isopropyl-1H-pyrrole-2-carboxylate

Solubilize 1.25 g (4.98 mmol) of iodo-4-methylcarboxylate 2-1H-pyrrole in 33 ml of acetone, add 0.63 ml (7.47 mmol) of bromopropane and 1.38 g (9.96 mmol) ) of K ₂ C0 ₃ . Heat the mixture for 5 hours under reflux. Evaporate the solvent, resume with ethyl acetate and wash with water. The organic phase is dried over Na ₂ SO ₄ and the solvent is then evaporated. The crude reaction product is purified by chromatography (heptane / CH ₂ Cl ₂ 80/20). 1.2 g of methyl 4-iodo-1-isopropyl-1H-pyrrole-2-carboxylate are obtained.

Methyl 5.2 / l-Iso ropyl-4- (4-nitro-phenyl) -1H-pyrrole-2-carboxylate

Mix with stirring and in an inert medium 1 g (3.58 mmol) of methyl 4-iodo-1-isopropyl-1H-pyrrole-2-carboxylate previously dissolved in 40 ml of acetone, 0.66 g (3.94 g). mmol) of nitro-4-phenylboronic acid, and 11 ml of a 2M aqueous solution of K ₂ CO ₃ . Then add 0.09 g (0.9 mmol) of palladium acetate and reflux for 3 hours. After returning to RT, filter the insoluble, evaporate the acetone, take up in AcOEt and wash with water. Dry the organic phase over Na ₂ SO ₄ and then evaporate the solvent. The product crystallizes in a mixture of isopropyl ether / AcOEt 80/20. 0.55 g of a white powder is obtained.

5.3 / 1-Isopropyl-4- (4-nitro-phenyl) -1H-pyrrole-2-carboxylic acid

Agitate for 48 hours at rt 0.5 g (1.82 mmol) of methyl 1-Isopropyl-4- (4-nitrophenyl) -1H-pyrrole-2-carboxylate and 4 ml of sodium hydroxide solution in 20 ml. ml of ethanol. Evaporate ethanol, take up in water, bring acidic pH with acetic acid. Extract the aqueous phase with ethyl acetate and wash with water. Dry the organic phase over Na ₂ SO ₄ and then evaporate the solvent. The product crystallizes in isopropyl ether. 0.5 g of a white powder is obtained.

5.4 / N-Clopropyl-1-Isopropyl-4- (4-nitro-phenyl) -1H-pyrrole-2-carboxamide

Stir with stirring for 5 hours at rt. 0.395 g (1.52 mmol) of 1-Isopropyl-4- (4-nitrophenyl) -1H-pyrrole-2-carboxylic acid, 0.12 ml (1.82 mmol). of cyclopropylamine, 0.74 g (1.67 mmol) of BOP, 0.53 ml (3.04 mmol) of DIPEA, previously solubilized in 15 ml of CH ₂ C1 ₂ . Then wash the reaction mixture with water and dry the organic phase over Na ₂ SO ₄ . Evaporate the solvent and purify the crude reaction by chromatoflash (CH ₂ Cl ₂ / MeOH 95/5). 0.55 g of N-cyclopropyl-1-isopropyl-4- (4-nitrophenyl) -1H-pyrrole-2-carboxamide are obtained.

5.5 / 4- (4-Amino-phenyl) -N-cyclopropyl-1-isopropyl-1H-pyrrole-2-carboxamide

Hydrogenation under pressure of a column of water in the presence of 0.120 g of 10% Pd / C, 0.5 g (1.26 mmol) of N-cyclopropyl-1-Isopropyl-4- (4-nitro-phenyl) 1H-pyrrole-2-carboxamide in 50 ml of a mixture of EtOH / AcOEt 70/30. Filter the catalyst on celite, evaporate the solvent. 0.5 g of crude product is obtained.

5.6 / N- [4- (5-Cyclopropylcarbamoyl-1-isopropyl-1H-pyrrol-3-yl) -phenyl] -thieno [2,3-bpyridine-2-carboxamide

Add to 100 mg (0.6 mmol) of thieno [2,3-b] pyridin-2-carboxylic acid in 40 ml of THF, successively 0.23 ml (1.8 mmol) of triethylamine, 203 mg (0. 72 mmol) 4- (4-Amino-phenyl) -N-cyclopropyl-1-isopropyl-1H-pyrrole-2-carboxamide and 250 mg (0.6 mmol) of BOP. Stir at room temperature overnight. Concentrate, continue with a mixture of dichloromethane / THF, wash with water and then with saturated NaCl solution, dry over sodium sulfate and concentrate. Purify by flash chromatography, solid deposition, eluent dichloromethane / methanol gradient 99/1 up to 80/20. We get 95 mg N- [4- (5-cyclopropylcarbamoyl-1-isopropyl-1H-pyrrol-3-yl) -phenyl] -thieno [2,3-b] pyridine-2-carboxamide.

Example 6 N- [4- (5-Cyclopropylcarbamoyl-1-isopropyl-1H-pyrazol-3-yl) -phenylthieno [2,3-b] pyridine-2-carboxamide (Compound 29)

6.1 / 4- (4-Nitro-phenyl) -2,4-dioxo-ethyl butyrate

Dissolve 1.7 g of sodium in 10.5 ml of ethanol and 300 ml of toluene at 80 ° C. Cool to RT and add 10 g (60.55 mmol) of nitro-4-acetophenone and 8.2 ml (60.55 mmol) of diethyl oxalate. Stir the mixture at RT for 18 hours. Add 100 ml of acetic acid and 150 ml of water, decant, extract the aqueous phase with ethyl acetate, and then wash with water the organic phase. Dry this phase on Na ₂ S0 ₄ , then evaporate the solvent. The expected product crystallizes during evaporation. Filter, wash with isopropyl ether. 5 g of a white powder are obtained. Ethyl (4-nitro-phenyl) -2H-pyrazole-3-carboxylate

4.65 g (17.53 mmol) of ethyl 4- (4-nitro-phenyl) -2,4-dioxo-butyrate and 5 ml (87.66 mmol) of acetic acid in 88 ml of THF are solubilized. . Add dropwise, at a temperature of 25 ° C, 21 ml (21.04 mmol) of a 1M solution of hydrazine in THF. Stir the mixture for 16 hours at RT. Add 150 ml of cold water and shake for 45 minutes. A beige precipitate is formed. Filter, wash with water and isopropyl ether, dry. 2.7 g of a beige powder are obtained.

Ethyler 6.3 / 2-Isopropyl-5- (4-nitro-phenyl) -2H-pyrazole-3-carboxylate

Refluxed for 20 hours, 1.2 g (4.59 mmol) of ethyl 5- (4-nitro-phenyl) -2H-pyrazole-3-carboxylate, 0.65 ml (6.96 mmol) of bromine were added. 2-propane, 1.27 g (9.2 mmol) of K ₂ CO ₃ , previously solubilized in 30 ml of butanone-2. Evaporate the solvent, continue with ethyl acetate, wash with water. Dry the organic phase over Na ₂ SO ₄ and then evaporate the solvent. 1.25 ethyl 2-Isopropyl-5- (4-nitro-phenyl) -2H-pyrazole-3-carboxylate are obtained.

6.4 / 2-Isopropyl-5- (4-nitro-phenyl) -2H-pyrazole-3-carboxylic acid

Agitate for 5 hours at RT 1.25 g (4.12 mmol) of ethyl 2-isopropyl-5- (4-nitro-phenyl) -2H-pyrazole-3-carboxylate, 0.3 g (12 g). , 36 mmol) of lithium hydroxide, previously solubilized in 40 ml of a 5/1 THF / water mixture. Evaporate the THF, resume with a water / ethyl acetate mixture, acidify with acetic acid, extract the organic phase. Dry this phase over Na ₂ SO ₄ and then evaporate the solvent. 0.9 g of a powder is obtained.

6.5 / N-Cyclopropyl-2-Isopropyl-5- (4-nitro-phenyl) -2H-pyrazole-3-carboxamide

Agitate for 18 hours at rt 1.5 g (9.73 mmol) of 3-Isopropyl-1H-pyrazole-4-carboxylic acid, 0.82 ml (11.68 mmol) of cyclopropylamine, 4.73 g ( 10.7 mmol) of BOP, 3.4 ml (19.5 mmol) of DiPEA previously solubilized in 108 ml of methylene chloride. Resume the reaction mixture in water. Filter the precipitate formed then dry in an oven. 0.8 g of a white powder is obtained.

6.6 / N-c Clopropyl-5- (4-Amino-phenyl) -2-isopropyl-2H-pyrazole-3-carboxamide

Hydrogenation under pressure of a column of water, in the presence of 0.28 g of Pd / C 10%, 0.8 g (0.54 mmol) of N-cyclopropyl-2-Isopropyl-5- (4-nitro) phenyl) -2H-pyrazole-3-carboxamide in 30 ml of ethanol. Filter the catalyst on celite, evaporate the solvent. 0.8 g of crude product is obtained. 6.7 / N- [4- (5-Cyclopropylcarbamoyl-1-isopropyl-1H-pyrazol-3-yl) -phenyl] -thieno [2,3-b] pyridine-2-carboxamide

Add to 100 mg (0.6 mmol) of thieno [2,3-b] pyridin-2-carboxylic acid in 40 ml of THF, successively 0.23 ml (1.8 mmol) of triethylamine, 203 mg (0. 72 mmol) 5- (4-Amino-phenyl) -N-cyclopropyl-2-isopropyl-2H-pyrazole-3-carboxamide and 250 mg (0.6 mmol) BOP. Stir at room temperature overnight. Concentrate, continue with a mixture of dichloromethane / THF, wash with water and then with saturated NaCl solution, dry over sodium sulfate and concentrate. Purify by flash chromatography, solid deposition, eluent dichloromethane / methanol gradient 99/1 up to 80/20. 95 mg of N- [4- (5-cyclopropylcarbamoyl-1-isopropyl-1H-pyrrol-3-yl) -phenyl] -thieno [2,3-b] pyridine-2-carboxamide are obtained.

Example 7: N- {4- [4-butyl-5- (2-morpholin-4-yl-ethylcarbamoyl) -thiazol-2-yl-phenyl-thieno [2,3-b] pyridine-2-carboxamide (Compound No. ° 30)

7.1 / 2-Ethyl Chloro-3-oxo-heptanoate

Add dropwise at RT 10 g (138 mmol) of pentanoyl acetate to a solution of 9.2 g (68.1 mmol) of sulfuryl chloride in 150 ml of CH ₂ Cl ₂ . Stir 30 min at RT and then hydrolyze with 50 ml of water. Extract 3 times with 100 ml of CH ₂ Cl ₂ . Wash the organic phases with water, then with a saturated solution of NaHCO ₃ and then dry over Na sulphate and concentrate. 12 g of oil are obtained. The compound obtained is used extemporaneously in the next step.

Ethyl 7.2 / 4-butyl-2- (4-nitro-phenyl) -thiazole-5-carboxylate

Reflux for 16 hours a solution of 9 g (49 mmol) of para nitro phenylthioamide and 12.25 g (59.5 mmol) of ethyl-2-chloro-3-oxo-heptanoate in 100 ml of ethanol. Cool the mixture, filter the precipitate formed. Wash the resulting powder with ethanol then with pentane and finally dry. 8.05 g of white powder are obtained.

7.3 / 4-Butyl-2- (4-nitro-phenyl) -thiazole-5-carboxylic acid

Suspend 8 g (23.8 mmol) of ethyl 4-butyl-2- (4-nitro-phenyl) -thiazole-5-carboxylate and 11.96 ml (4.8 mole) of 10N sodium hydroxide in 150 g. ml of a THF solution and heat at 40 ° C for 4 hours. Cool the mixture and then acidify with 10N HCl. Filter and wash with water the precipitate formed. Dissolve the powder formed in CH ₂ Cl ₂ . then dry the organic phase over sodium sulfate. Evaporate the solvent. 6 g of 4-butyl-2- (4-nitro-phenyl) -thiazole-5-carboxylic acid are obtained.

7.4 / 4-Butyl-2- (4-nitro-phenyl) -N- (2-piperidin-1-yl-ethyl) -thiazole-5-carboxamide

Stir at RT for 2 hours at a solution of 1.2 g (3.9 mmol) of 4-butyl-2- (4-nitrophenyl) -thiazole-5-carboxylic acid, 0.76 g (3.9 mmol). ) of DiPEA, 1.5 g (3.9 mmol) of BOP and 0.5 g (3.9 mmol) of 2-piperidin-1-yl-ethylamine in 50 ml of CH ₂ Cl ₂ . Then wash the reaction mixture with water with a solution of Na ₂ CO ₃ 2% and dry the organic phase over sodium sulfate. Evaporate the solvent and purify the crude by chromatofiash (CH ₂ Cl ₂ /95% MeOH / 5%). 1.3 g of product are obtained.

7.5 / 2- (4-Amino-phenyl) -4-butyl-N- (2-morpholin-4-yl-ethyl) -thiazole-5-carboxamide

Hydrogenate at atmospheric pressure and AT a suspension of 1.25 g (3 mmol) of 4-butyl-2- (4-nitro-phenyl) -N- (2-piperidin-1-yl-ethyl) -thiazole 5-carboxamide and 0.03 g (0.3 mmol) of 10% Pd / C in 170 ml of AcOEt. Filter the Pd on celite, then evaporate the solvent. 0.108 g of an oil is obtained.

7.6 / N- {4- [4-butyl-5- (2-morpholin-4-yl-ethylcarbamoyl) -thiazol-2-yl] -phenyl} -thieno 2,3-b] pyridine-2-carboxamide

Add to 50 mg (0.3 mmol) of thieno [2,3-b] pyridin-2-carboxylic acid in 40 ml of THF, successively 0.13 ml (0.9 mmol) of triethylamine, 100 mg ( 0.3 mmol) 2- (4-amino-phenyl) -4-butyl-N- (2-morpholin-4-yl-ethyl) -thiazole-5-carboxamide and 250 mg (0.6 mmol) of BOP. Stir at room temperature overnight. Concentrate, continue with a mixture of dichloromethane / THF, wash with water and then with saturated NaCl solution, dry over sodium sulfate and concentrate. Purify by flash chromatography, solid deposition, eluent dichloromethane / methanol gradient 99/1 up to 80/20. N- {4- [4-Butyl-5- (2-morpholin-4-yl-ethylcarbamoyl) -thiazol-2-yl] -phenyl} -thieno [2,3-b] pyridine-2 (60 mg) is obtained. -carboxamide.

Example 8: N- [4- (5-methylcarbamoyl-4-trifluoromethyl-thiazol-2-yl) -phenyl-thieno [2,3-b] pyridine-2-carboxamide (Compound No. 40) -Amino-4-trifluoromethyl- ethyl thiazole-5-carboxylate

Reflux for 16 hours a solution of 7.8 g (130 mmol) of thiourea and 24.6 g (13 mmol) of 2-chloro-trifluoroacetoacetate ethyl in 100 ml of ethanol. Evaporate the solvent, then resume the crude in a minimum of heptane. Filter the crystallized product and dry. 24.6 g of powder are obtained.

Ethyl-bromo-4-trifluoromethyl-thiazole-5-carboxylate

Saturate with HBr gas at T <25 ° C., a solution of 4 g (16.6 mmol) of ethyl 2-amino-4-trifluoromethyl-thiazole-5-carboxylate in 100 ml of CHCl ₃ . Add 3.33 ml (20 mmol) of bromine at RT dropwise and then 3.36 ml (20 mmol) of isoamyl nitrite. Stir for 5 hours at RT. Evaporate the solvent to dryness and then purify the crude by chromatoflash (CF Cyheptane 50/50). 4.8 g of an oil are obtained. Ethyl (4-Amino-phenyl) -4-trifluoromethyl-thiazole-5-carboxylate

Reflux for 12 hours a heterogeneous solution of 3.5 g (1 l, mmol) of ethyl 2-bromo-4-trifluoromethyl-thiazole-5-carboxylate, 0.665 g (0.6 mmol) of palladium tetrakis, 2 39 g (17 mmol) of K ₂ CO ₃ , and 3.03 g (14 mmol) of pinacol 4-aminophenylboronate in 30 ml of a toluene / water / ethanol mixture (90/5/5). Concentrate the reaction medium, take it up with AcOEt and wash with water. Extract the organic phase then dry on sodium sulphate and concentrate. Purify the crude by chromatoflash (CH ₂ C1 ₂ 100%). 0.7 g of a yellow powder is obtained. - (4-Amino-phenyl) -4-trifluoromethyl-thiazole-5-carboxylic

A solution of 0.7 g (2.2 mmol) of ethyl 2- (4-aminophenyl) -4-trifluoromethyl-thiazole-5-carboxylate and 2.21 ml (22 g) is stirred for 16 hours at RT. mmol) of 10N sodium hydroxide in 10 ml of methanol. Take up the reaction medium in water and acidify it with acetic acid. Filter the formed precipitate, wash with water, then dry. 0.41 g of powder is obtained.

8.5 / 2- (4-Amino-phenyl) -N-methyl-4-trifluoromethyl-thiazole-5-carboxamide

Stir at RT for 2 hours a solution of 0.4 g (1.4 mmol) of 2- (4-aminophenyl) -4-trifluoromethyl-thiazole-5-carboxylic acid, 0.27 g (2.1 g). mmol) of DiPEA, 0.65 g (1.5 mmol) of BOP and 2.08 ml (1.5 mmol) of a 2M solution of methylamine in methanol. Wash the reaction mixture with water and then with 2% Na2CO3 solution. Dry the organic phase over sodium sulphate and concentrate to dryness. Purify the crude by chromatofiash (CH ₂ Cl ₂ / MeOH 98/2). 0.25 g of oil is obtained.

8.6 / N- [4- (5-methylcarbamoyl-4-trifluoromethyl-thiazol-2-yl) -phenyl] -thieno [2,3-b pyridine-2-carboxamide

Add to 50 mg (0.3 mmol) of thieno [2,3-b] pyridin-2-carboxylic acid in 40 ml of THF, successively 0.13 ml (0.9 mmol) of triethylamine, 150 mg ( 0.5 mmol) 2- (4-amino-phenyl) -N-methyl-4-trifluoromethyl-thiazole-5-carboxamide and 250 mg (0.6 mmol) of BOP. Stir at room temperature overnight. Concentrate, continue with a mixture of dichloromethane / THF, wash with water and then with saturated NaCl solution, dry over sodium sulfate and concentrate. Purify by flash chromatography, solid deposition, eluent dichloromethane / methanol gradient 99/1 up to 80/20. 98 mg of N- [4- (5-methylcarbamoyl-4-trifluoromethyl-thiazol-2-yl) -phenyl] -thieno [2,3-b] pyridine-2-carboxamide are obtained. Example 9: N- [4- (5-Cyclopropylcarbamoyl-4-pentafluoroethyl-thiazol-2-yl) -phenylthieno [2,3-b] pyridine-2-carboxamide (Compound No. 49) -Chloro-4,4, Ethyl 5,5,5-pentafluoro-3-oxo-pentanoate

Add dropwise at RT 6.18 ml (70 mmol) of sulfuryl chloride, on a solution of 15 g (64 mmol) of pentafluoropropionyl ethyl acetate previously solubilized in 150 ml of CH ₂ Cl ₂ . Stir the mixture for 2 hours at RT, then wash with 50 ml of water. Dry the organic phase over sodium sulphate and concentrate to dryness. 16.1 g of an oil is obtained which will be used extemporaneously in the next step. -Amino-4-pentafluoroethyl-thiazole-5-ethyl carboxylate

Reflux for 4 hours a solution of 16.5 g (61.5 mmol) of ethyl 2-chloro-4,4,5,5,5-pentafluoro-3-oxo-pentanoate and 4.21 g ( 55.4 mmol) of thiourea in 50 ml of ethanol. Concentrate the mixture to dryness. Purify the crude by chromatography (CH 2 Cl 2 / MeOH 99/1). 4.2 g of a white powder are obtained. Ethyl-bromo-4-pentafluoroethyl-thiazole-5-carboxylate

Saturate with HBr gas at T <25 ° C a solution of 2 g (6.9 mmol) of ethyl 2-amino-4-pentafluoroethyl-thiazole-5-carboxylate in 50 ml of CHCl ₃ . Add dropwise 1.38 ml (55 mmol) of bromine at RT and then 1.39 ml (10 mmol) of isoamyl nitrite. Stir for 5 hours at RT. Concentrate the mixture dry, then purify the crude by chromatoflash (He tane / CH ₂ Cl ₂ 50/50). 2.3 g of ethyl 2-bromo-4-pentafluoroethyl-thiazole-5-carboxylate are obtained.

Ethyl 9.4 / 2- (4-Amino-phenyl) -4-pentafluoroethyl-thiazole-5-carboxylate

Reflux for 12 hours with a heterogeneous solution of 2.3 g (6.5 mmol) of ethyl 2-bromo-4-pentafluoroethyl-thiazole-5-carboxylate, 0.375 g (0.3 mmol) of tetrakis palladium, 1.347 g (10 mmol) of K ₂ CO ₃ , and 1.707 g (7.8 mmol) of 4-aminophenylboronate pinacol in 50 ml of a toluene / water / ethanol mixture (90/5/5). Concentrate the mixture dry, then take in AcOEt and wash with water. Dry the organic phase over sodium sulphate and concentrate to dryness. Purify the crude by chromatoflash CH ₂ Cl ₂ / MeOH (97/3). 1.1 g of a yellow oil are obtained. - (4-Amino-phenyl) -4-pentafluoroethyl-thiazole-5-carboxylic

A solution of 1.1 g (3 mmol) of ethyl 2- (4-aminophenyl) -4-pentafluoroethyl-thiazole-5-carboxylate and 3 ml of 10N sodium hydroxide solution in 10 ml is stirred for 16 hours at RT. ethanol. Resume the medium with water and acidify with acetic acid. Extract the aqueous phase with AcOEt, and wash with water the organic phase obtained, dry over sodium sulfate and then concentrate to dryness. Crystallized the product in isopropyl ether, then filter and dry. 0.75 g of white powder is obtained.

9.6 / 2- (4-Amino-phenyl) -N-cyclopropyl-4-pentafluoroethyl-thiazole-5-carboxamide

A solution of 0.38 g (1.1 mmol) of 2- (4-aminophenyl) -4-pentafluoroethyl-thiazole-5-carboxylic acid, 0.22 g (1.7 g), is stirred for 3 hours at RT. mmol) of DiPEA, 0.55 g (1.2 mmol) of BOP, and 0.077 g (1.3 mmol) of cyclopropylamine in 20 ml of CH ₂ Cl ₂ . Wash the reaction medium with water and then with a solution of 2% Na ₂ CO ₃ . Dry the organic phase over sodium sulphate and concentrate to dryness. Crystallize the expected product in isopropyl ether. Filter and dry the resulting powder. 0.37 g of white powder is obtained. 9.7 / N- [4- (5-cyclopropylcarbamoyl-4-pentafluoroethyl-thiazol-2-yl) -phenyl] -thi no [2,3-b] pyridine-2-carboxamide

Add to 50 mg (0.3 mmol) of thieno [2,3-b] pyridin-2-carboxylic acid in 40 ml of THF, successively 0.13 ml (0.9 mmol) of triethylamine, 188 mg ( 0.5 mmol) 2- (4-amino-phenyl) -N-cyclopropyl-4-pentafluoroethyl-thiazole-5-carboxamide and 250 mg (0.6 mmol) of BOP. Stir at room temperature overnight. Concentrate, continue with a mixture of dichloromethane / THF, wash with water and then with saturated NaCl solution, dry over sodium sulfate and concentrate. Purify by flash chromatography, solid deposition, eluent dichloromethane / methanol gradient 99/1 up to 80/20. 124 mg of N- [4- (5-cyclopropylcarbamoyl-4-pentafluoroethyl-thiazol-2-yl) -phenyl] -thieno [2,3-b] pyridine-2-carboxamide are obtained.

Example 10: N- [4- (4-Cyclopropylcarbamoyl-3-isopropyl-pyrazol-1-yl) -phenyl-thieno [2,3-b] pyridine-2-carboxamide (Compound 32) -cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxamide

-cyclopropyl-3-Isopropyl-l- (4-nitro-phenyl) -LH-pyrazole-4-carboxamide

Dissolved in N-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxamide, 0.690 g (4.14 mmol) of 4-nitro-phenylboronic acid and dissolved in 15 ml of methanol, and 0.33 g (2.28 mmol) of cuprous oxide. Stirring the mixture is at RT for 24 hours. Filter the mineral on celite, then evaporate the solvent. Purify the crude by chromatoflash (CH ₂ Cl ₂ / MeOH 95/5). 0.43 g of N-cyclopropyl-3-isopropyl-1- (4-nitro-phenyl) -1H-pyrazole-4-carboxamide are obtained.

10.3 / 1- (4-Amino-phenyl) -N-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxamide

Hydrogenation under pressure of a column of water, in the presence of 0.06 g of 10% Pd / C, 0.17 g (0.54 mmol) of N-cyclopropyl-3-isopropyl-1- (4-nitro) phenyl) -1H-pyrazole-4-carboxamide in 30 ml of ethanol. Filter the catalyst on celite, evaporate the solvent. 0.17 g of crude product is obtained.

10.4 N- [4- (4-Cyclopropylcarbamoyl-3-isopropyl-pyrazol-1-yl) -phenyl] -thieno [2,3-b pyridine-2-carboxamide

Add to 50 mg (0.3 mmol) of thieno [2,3-b] pyridin-2-carboxylic acid in 40 ml of THF, successively 0.13 ml (0.9 mmol) of triethylamine, 142 mg ( 0.5 mmol) 1- (4-Amino-phenyl) -N-cyclopropyl-3-isopropyl-1H-pyrazole-4-carboxamide and 250 mg (0.6 mmol) BOP. Stir at room temperature overnight. Concentrate, continue with a mixture of dichloromethane / THF, wash with water and then with saturated NaCl solution, dry over sodium sulfate and concentrate. Purify by flash chromatography, solid deposition, eluent dichloromethane / methanol gradient 99/1 up to 80/20. 110 mg of N- [4- (4-cyclopropylcarbamoyl-3-isopropyl-pyrazol-1-yl) -phenyl] -thieno [2,3-b] pyridine-2-carboxamide are obtained. 1H NMR of the compounds of Tables I and II

The chemical displacements δ are given in ppm.

The numbering of the compounds in parentheses refers to the numbering of the compounds of Tables I and II. compound no. 48:

1 H NMR (400 MHz, DMSO-d6) δ ppm 1.33 - 1.43 (m, 2H); 1.45 - 1.56 (m, 4H); 2.41 (m, 6H); 3.36 (t, 2H); 7.55 (dd, 1H); 7.95 - 8.08 (m, 4H); 8.42 (s, 1H); 8.47 (d, 1H); 8.71 (d, 1H); 8.82 (br.t, 1H); 10.91 (s, 1H) Compound No. 49:

1H NMR (400 MHz, DMSO-d6) d ppm 0.49 - 0.56 (m, 2H); 0.70 - 0.78 (m, 2H); 2.78 - 2.87 (m, 1H); 7.55 (dd, 1H); 8.01 (q, 4H); 8.42 (s, 1H); 8.47 (d, 1H); 8.71 (dd, 1H); 9.01 (d, 1H); 10.91 (s, 1 H)

Table I

with R " ₂ = a hydrogen atom

(I'B)

** And: ethyl; n-Bu: n-butyl; i-Bu: isobutyl; n-Pr: n-propyl; i-Pr: isopropyl

Table II

53

"-" denotes a simple covalent bond

The compounds of Tables I and II (the numbering of the compounds in parentheses refers to the numbering of the compounds of Tables I and II) have the chemical name (obtained from the Autonom ^® software):

^■ N- [4- (6-ethylamino-5-methylcarbamoyl-pyridin-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. l)

^■ N- {4- [6-ethylamino-5- (2-piperidin-1-yl-ethylcarbamoyl) -pyridin-2-yl] - phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. # 2)

^■ N- {4- [6-ethylamino-5- (2-piperidin-1-yl-ethylcarbamoyl) -pyridin-2-yl] -2-fluoro- phenyl} thieno [2,3-b] pyridine-2- carboxamide (compound no. 3)

N- {4- [5- (1,1-Dimethyl-2-piperidin-1-yl-ethylcarbamoyl) -6-ethylamino-pyridin-2-yl] phenyl} thieno [2,3-b] pyridine 2-carboxamide (Compound No. 4)

^■ N- {4- [6-ethylamino-5- (2-methyl-2-piperidin-1-yl-propylcarbamoyl) -pyridin-2-yl] - phenyl} thieno [2,3-b] pyridine-2- carboxamide (compound 5)

^■ N- [3'-ethylamino-4 '- (2-piperidin-1-yl-ethylcarbamoyl) -biphenyl-4-yl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 6)

^■ N- {4- [6-cyclopropylamino-5- (2-piperidin-1-yl-ethylcarbamoyl) -pyridin-2-yl] - phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 7)

^■ N- {4- [6-isopropylamino-5- (2-piperidin-1-yl-ethylcarbamoyl) -pyridin-2-yl] - phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. # 8)

N- {4- [6-phenylamino-5- (2-piperidin-1-yl-ethylcarbamoyl) -pyridin-2-yl] phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. # 9)

^■ N- [4- (4-ethylamino-5-methylcarbamoyl-pyrimidin-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 10)

^■ N- [4- (4-ethylamino-5-methylcarbamoyl-pyrimidin-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 11)

^■ N- {4- [5- (2-piperidin-1-yl-ethylcarbamoyl) -6-propylamino-pyridin-2-yl] - phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 12)

^■ N- [4- (6-ethylamino-5-methylcarbamoyl-pyridin-2-yl) -phenyl] 6-amino-thieno [2,3-b] pyridine-2-carboxamide (Compound No. 13)

N- {4- [6-ethylamino-5- (3-methyl-butylcarbamoyl) -pyridin-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 14)

^■ N- {4- [5- (2-cyclohexyl-ethylcarbamoyl) -6-ethylamino-pyridin-2-yl] -phenyl} thieno [2,3- b] pyridine-2-carboxamide (compound No. 15)

^■ N- [4- (6-ethylamino-5-isopropylcarbamoyl-pyridin-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 16)

^■ N- {4- [5- (3-methyl-butylcarbamoyl) -6-phenylamino-pyridin-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 17)

^■ N- [4- (5-isopropylcarbamoyl-6-phenylamino-pyridin-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 18)

^■ N- {4- [5- (2-cyclohexyl-ethylcarbamoyl) -6-phenylamino-pyridin-2-yl] - phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 19)

N- {4- [6-Cyclopropylamino-5- (3-methyl-butylcarbamoyl) -pyridin-2-yl] phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 20)

^■ N- [4- (6-cyclopropylamino-5-isopropylcarbamoyl-pyridin-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 21)

^■ N- {4- [5- (2-cyclohexyl-ethylcarbamoyl) -6-cyclopropylamino-pyridin-2-yl] - phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 22)

^■ N- (3'-ethylamino-4'-isopropylcarbamoyl-biphenyl-4-yl) thieno [2,3-b] pyridine-2-carboxamide (Compound No. 23)

^■ N- {4- [6-ethylamino-5- (2-hydroxy-ethylcarbamoyl) -pyridin-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 24)

N- {4- [6-ethylamino-5- (2-methoxy-ethylcarbamoyl) -pyridin-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 25)

^■ N- {4- [6- (ethylamino) -5 - {[2- (l-oxidothiomorpholin-4-yl) ethyl] carbamoyl} pyridin-2- yl] phenyl} thieno [2,3-b] pyridine 2-carboxamide (Compound No. 26)

^■ N- {4- [5- {[2- (l, 1 -dioxidothiomorpholin-4-yl) ethyl] carbamoyl} -6- (ethylamino) pyridin-2-yl] phenyl} thieno [2,3-b] pyridine-2-carboxamide (compound No. 27)

^■ N- {4- [5- (2-piperidin-1-yl-ethylcarbamoyl) -furan-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 28)

^■ N- [4- (5-Cyclopropylcarbamoyl-l-isopropyl-lH-pyrazol-3-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 29)

N- {4- [4-butyl-5- (2-piperidin-1-yl-ethylcarbamoyl) -thiazol-2-yl] -phenyl} -thieno [2,3-b] pyridine-2-carboxamide (compound # 30)

^■ N- {4- [5- (2-piperidin-1-yl-ethylcarbamoyl) -4-trifluoromethyl-thiazol-2-yl] -phenyl} - thieno [2,3-b] pyridine-2-carboxamide (compound 31)

^■ N- [4- (4-cyclopropylcarbamoyl-3-isopropyl-pyrazol-1-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 32)

^■ N- [4- (5-Cyclopropylcarbamoyl-l-isopropyl-lH-pyrrol-3-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 33)

^■ N- {4- [1-isopropyl-5- (2-piperidin-1-yl-ethylcarbamoyl) - lH-pyrazol-3-yl] -phenyl} - thieno [2,3-b] pyridine-2-carboxamide (compound no. 34)

^■ N- {4- [5- (2-diisopropylamino-ethylcarbamoyl) -furan-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 35)

N- (4- {5- [2- (4-Methoxy-piperidin-1-yl) ethylcarbamoyl] -furan-2-yl} -phenyl) -thieno [2,3-b] pyridine-2-carboxamide (Compound No. 36)

^■ N- (4- {5- [2- (3-hydroxy-piperidin-1-yl) -ethylcarbamoyl] -furan-2-yl} -phenyl) - thieno [2,3-b] pyridine-2-carboxamide (Compound No. 37)

^■ N- {4- [5- (4-piperidin-1-yl-butylcarbamoyl) -furan-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 38)

^■ N- (4- {5- [2- (4-hydroxy-piperidin-1-yl) -ethylcarbamoyl] -furan-2-yl} -phenyl) - thieno [2,3-b] pyridine-2-carboxamide (Compound No. 39)

^■ N- [4- (5-methylcarbamoyl-4-trifluoromethyl-thiazol-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 40)

N- {4- [5- (2-cyclohexyl-ethylcarbamoyl) -4-trifluoromethyl-thiazol-2-yl] -phenyl} -thieno [2,3-b] pyridine-2-carboxamide (Compound No. 41)

^■ N- [4- (5-cyclopropylcarbamoyl-4-trifluoromethyl-thiazol-2-yl) -phenyl] -6-amino-thieno [2,3-b] pyridine-2-carboxamide (Compound No. 42)

^■ N- {4- [5- (3-methyl-butylcarbamoyl) -furan-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 43)

^■ N- {4- [5- (2-cyclohexyl-ethylcarbamoyl) -furan-2-yl] -phenyl} thieno [2,3-b] pyridine-2-carboxamide (Compound No. 44)

^■ N- [4- (5-isopropylcarbamoyl-furan-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 45)

N- [4- (5-Cyclopropylcarbamoyl-furan-2-yl) -phenyl] -thieno [2,3-b] pyridine-2-carboxamide (Compound No. 46)

^■ N- {4- [1-ethyl-5- (2-piperidin-1-yl-ethylcarbamoyl) - lH-pyrazol-3-yl] -phenyl} - Thieno [2,3-b] pyridine-2-carboxamide (Compound No. 47)

^■ N- {4- [4-pentafluoroethyl-5- (2-piperidin-1-yl-ethylcarbamoyl) -thiazol-2-yl] -phenyl} - thieno [2,3-b] pyridine-2-carboxamide (compound # 48)

^■ N- [4- (5-cyclopropylcarbamoyl-4-pentafluoroethyl-thiazol-2-yl) -phenyl] thieno [2,3-b] pyridine-2-carboxamide (Compound No. 49)

The compounds described in Tables I and II have been the subject of pharmacological tests for determining anticancer activity. They were tested in vitro on the tumor line HCT116 (ATCC-CCL247). Proliferation and cell viability were determined in a test using 3- (4,5-dimethylthiazol-2-yl) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium (MTS) according to Fujishita T. et al. Oncology 2003, 64 (4), 399-406. In this test, the mitochondrial capacity of living cells is measured to transform MTS into a colored compound after 72 hours of incubation of the test compound. The concentration of compound which leads to 50% loss of proliferation and cell viability is noted as IC ₅₀ .

For the compounds of Tables I and II, an IC _{50 of} less than or equal to 1000 nM (1 μl), preferably a ₅ ο <500 nM, and still more preferably a Cl ₅ o <100 nM, on the line HCT116.

The following Table III illustrates the individual value of IC ₅₀ for certain specific compounds of general formula (I) according to the invention. In this Table II, the numbers of the compounds indicated correspond to the compound numbers specified in Tables I and II. Table III

Compound No. IC ₅₀ (in nM) on the HCT116 line

1 24.4

2 2

3,473

4 6.9

5 18 Compound No. IC ₅₀ (in nM) on the HCT116 line

7 16.2

8 22.4

41.4

10,335

11,296

12 27.1

13 43

14 47

15,996

16 31

17,201

18 85

19,146

20,524

21 115

22,597

28 2.4

29 12.4

0.25

31 0.58

32 17

33 23

34 0.06

35 4.85

36 15.2

37 49.3

38 0.96

39 52.1

40 4.7

41 42 Compound No. IC ₅₀ (in nM) on the HCT116 line

42 4.85

43 42.9

44,248

45 1000

46 38.3

47 1, 87

50 12

51 68

52 6.56

Claims

Compound of general formula (I):

in which :

D represents a 5- or 6-membered aromatic or heteroaromatic ring;

Ri and R ₂ represent, independently of one another:

o a hydrogen atom,

a (C 1 -C 6) alkyl group, optionally substituted by one or more hydroxyl or (C 1 -C 4) alkoxy groups,

o a -CF _3i group

o a -CF ₂ CF _{3 group} ,

o a group -NRaR,

o a -CO-NRaRb group,

. one or more hydroxy, (C 1 -C 4) alkoxy, (C ₃ -C ₆ ) cycloalkyl groups, or

. a group -NRcRd in which R _c and Rd independently of one another represent a hydrogen atom or a (C 1 -C ₆ ) alkyl group or form together with the nitrogen atom to which they are attached a group (C4-C6) heterocycloalkyl optionally comprising in the ring the group -S (O) _q with q = 0, 1 or 2, said group (C ₄ - C6) heterocycloalkyl optionally substituted with hydroxyl, (Ci-C ₆₎ alkyl or (Ci-C ₆₎ alkoxy,

It being understood that at least one of R 1 or R ₂ is different from a hydrogen atom;

R ₃ represents at least one substituent of the thieno [2,3-b] pyridine ring chosen from a hydrogen or fluorine atom, a (C ₁ -C ₄ ) alkyl group and a group -NR _e R _f in which R _e and R _f represent a hydrogen atom or a (C 1 -C ₄ ) alkyl group;

N is an integer of 0, 1 or 2, representing the number of fluorine atoms attached to the central phenyl ring;

• L represents a simple covalent bond;

in the form of a base or an addition salt with an acid or in the form of a hydrate or a solvate.

The compound of claim 1 wherein D (R 1) (R ₂ ) is:

a 5-membered heteroaromatic ring of formula (A) which follows:

In which :

R 1 and R ₂ are as defined above for the compound of general formula (I), and

Or

a 6-membered aromatic or heteroaromatic ring of formula (B) which follows

In which :

R 1 and R ₂ are as defined above for the compound of general formula (I), and

Z and Z 'represent, independently of one another, a nitrogen atom or a radical -CH-, more particularly Z' represents -CH- and Z represents a nitrogen atom;

3. Compound according to one of the preceding claims wherein R ₃ is in position 5 and / or 6 on the thieno [2,3-b] pyridine ring;

4. Compound according to one of the preceding claims wherein the number of substituents R ₃ is 1 and / or R ₃ is in position 5 or 6 on the thieno [2,3-b] pyridine ring;

5. Compound according to one of the preceding claims wherein R ₃ is a hydrogen atom or a group -NH ₂ ;

6. Compound according to one of the preceding claims of formula (IA) which follows:

in which R 1, R ₂ , R ₃ , L and n are as defined for the compound of formula general (I) and X, Y, Z ₁ , Z ₂ and Z ₃ are as defined for group (A) according to claim 2;

A compound of formula (IA) according to claim 6 wherein the 5-membered heteroaromatic ring represents a thiazolyl, pyrrolyl, pyrazolyl or furanyl ring;

8. Compound of formula (IA) according to any one of claims 6 to 7 wherein n is 0;

9. Compound of formula (IA) according to any one of claims 6 to 8 wherein R ₃ represents a hydrogen atom;

10. Compound of formula (IA) according to claim 6 wherein:

R ₃ represents a hydrogen atom;

L represents a single covalent bond;

n represents 0; and

Ri and R ₂ represent independently of one another:

o a hydrogen atom,

a (Ci-Ce) alkyl group,

o a -CF _3i group

o a -CO-NRaRb group,

with R _a and R _b independently of one another a hydrogen atom or a (C ₁ -C ₆ ) alkyl group, said (C ₁ -C ₆ ) alkyl group being substituted by a group

-NRcRd wherein R _c and Rd together with the nitrogen atom to which they are attached form a (C4-C6) heterocycloalkyl group; it being understood that at least one of Ri or R ₂ is different from a hydrogen atom;

11. Compound according to one of claims 1 to 6 of formula (IB) which follows:

Wherein R ₁ , R ₂ , R 3, L and n are as defined for the compound of formula (I) and Z 'and Z are as defined for group (B) in claim 2;

12. Compound according to the preceding claim, of formula (ΓΒ) which follows:

in which

• R'i represents:

a (Ci-C ₆ ) alkyl group, optionally substituted with:

one or more hydroxyl or (C ₁ -C ₄ ) alkoxy groups;

a (C3-Ce) cycloalkyl group;

a group -NR _c R _d in which R _c and R _d form together with the nitrogen atom to which they are attached a (C ₄ -C ₆ ) heterocycloalkyl group optionally comprising in the ring the group -S (0) _q with q = 1 or 2, said group (C ₄ - C6) heterocycloalkyl optionally substituted by hydroxy or (Ci-C ₆₎ alkoxy;

R '2 representing a (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl group, or a phenyl; and

• R " ₂ representing a hydrogen atom;

13. Compound according to the preceding claim wherein Z 'represents a group -CH- and Z represents N.

A process for preparing a compound of formula (I) according to claim 1, comprising reacting a compound Pi with a compound P ₂ via a Suzuki coupling as follows:

Where Hal represents a halogen atom such as chlorine, bromine or iodine, K and K 'represent a hydrogen atom, an alkyl or aryl group, optionally linked together to form together with the boron atom and both oxygen atoms form a 5- to 7-membered optionally substituted by at least one group (Ci-C4) alkyl or in which optionally is attached on two consecutive carbon atoms of said ring is phenyl, and R _ls R _2, R 3, L , D and n are as defined in claim 1 for the compound of general formula (I), in the presence of a complex of palladium in basic medium, at a temperature between 50 and 120 ° C.

15. Medicinal product characterized in that it comprises a compound according to one of claims 1 to 13.

16. Pharmaceutical composition characterized in that it comprises a compound according to one of claims 1 to 13 and at least one pharmaceutically acceptable excipient.

17. Compound according to one of claims 1 to 13 for its use for the treatment or prevention of cancer.