NZ738459B2

NZ738459B2 - New aminoacid derivatives, a process for their preparation and pharmaceutical compositions containing them

Info

Publication number: NZ738459B2
Application number: NZ738459A
Authority: NZ
Inventors: Balazs Balint; Alain Bruno; I Jen Chen; Marton Csekei; James Edward Paul Davidson; Olivier Geneste; Andras Kotschy; James Brooke Murray; Levente Ondi; Attila Paczal
Original assignee: Les Laboratoires Servier; Vernalis (R&D) Limited
Filing date: 2016-06-22
Publication date: 2024-09-03

Abstract

Compounds of formula (I): wherein R1, R2, R5, R6, R7, R12, X, Y, A, E and n are as defined in the description and their use as medicaments for the treatment of cancer and immune/auto-immune diseases.

Claims

1. Compounds of formula (I): wherein: ? A represents the group in which 1 is linked to the -NH- group and 2 is linked to the aromatic ring, ? E represents a cycloalkyl group, a heterocycloalkyl group, an aryl group or a heteroaryl group, ? X represents a nitrogen atom or a C-R group, 10 ? Y represents a nitrogen atom or a C-R group, ? R represents a halogen atom, a linear or branched (C -C )alkyl group, a linear or 1 1 6 branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear 2 6 2 6 or branched (C -C )polyhaloalkyl group, a hydroxy group, a hydroxy(C -C )alkyl 1 6 1 6 group, a linear or branched (C -C )alkoxy group, -S-(C -C )alkyl, a cyano group, a 1 6 1 6 15 nitro group, -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, -O-alkyl(C -C )-R , 0 6 9 9 1 6 9 9 1 6 10 -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, -NR -C(O)-OR ’, 9 9 9 9 9 9 9 9 -alkyl(C1-C6)-NR9-C(O)-R9’, -SO2-NR9R9’, -SO2-alkyl(C1-C6), ? R , R , R and R independently of one another represent a hydrogen atom, a 2 3 4 5 halogen atom, a linear or branched (C -C )alkyl group, a linear or branched (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, a linear or 2 6 2 6 branched (C -C )polyhaloalkyl group, a hydroxy group, a hydroxy(C -C )alkyl 1 6 1 6 group, a linear or branched (C -C )alkoxy group, -S-(C -C )alkyl, a cyano group, a 1 6 1 6 nitro group, -alkyl(C -C )-NR R ’, -O-alkyl(C -C )-NR R ’, -O-alkyl(C -C )-R , 0 6 9 9 1 6 9 9 1 6 10 5 -C(O)-OR , -O-C(O)-R , -C(O)-NR R ’, -NR -C(O)-R ’, -NR -C(O)-OR ’, 9 9 9 9 9 9 9 9 -alkyl(C -C )-NR -C(O)-R ’, -SO -NR R ’, or -SO -alkyl(C -C ), 1 6 9 9 2 9 9 2 1 6 or the substituents of the pair (R , R ) form together with the carbon atoms carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 heteroatoms selected from oxygen, sulphur and 10 nitrogen, it being understood that resulting ring may be substituted by from 1 to 2 groups selected from halogen, linear or branched (C -C )alkyl, -alkyl(C -C )-NR R ’, -NR R ’, -alkyl(C -C )-Cy , or oxo, 0 6 9 9 11 11 0 6 1 ? R represents a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl 6 1 6 group, a linear or branched (C -C )alkenyl group, a linear or branched 15 (C -C )alkynyl group, a linear or branched (C -C )polyhaloalkyl group, a hydroxy 2 6 1 6 group, a linear or branched (C -C )alkoxy group, -S-(C -C )alkyl, a cyano group, a 1 6 1 6 nitro group, -alkyl(C -C )-NR R ’, -O-Cy , -alkyl(C -C )-Cy , -alkenyl(C -C )-Cy , 0 6 9 9 1 0 6 1 2 6 1 -alkynyl(C -C )-Cy , -O-alkyl(C -C )-R , -C(O)-OR , -O-C(O)-R , 2 6 1 1 6 10 9 9 -C(O)-NR R ’, -NR -C(O)-R ’, -NR -C(O)-OR ’, -alkyl(C -C )-NR -C(O)-R ’, 9 9 9 9 9 9 1 6 9 9 20 -SO -NR R ’, or -SO -alkyl(C -C ), 2 9 9 2 1 6 ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a 7 1 8 -CHR R group, an aryl group, a heteroaryl group, an arylalkyl(C -C ) group, or a a b 1 6 heteroarylalkyl(C -C ) group, ? R represents a linear or branched (C -C )alkyl group, a linear or branched 8 1 6 25 (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, -Cy , a halogen 2 6 2 6 2 atom, a cyano group, -C(O)-R , or -C(O)-NR R ’, 11 11 11 ? R and R ’ independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group, or the substituents of the pair (R , R ’) form together with the nitrogen atom 30 carrying them an aromatic or non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a hydrogen atom, or a linear or branched (C -C )alkyl group, ? R represents -Cy , -Cy -alkyl(C -C )-Cy , -C(O)-NR R ’, -NR R ’, -OR , 10 3 3 0 6 4 9 9 9 9 9 -NR -C(O)-R ’, -O-alkyl(C -C )-OR , -SO -R , -C(O)-OR ,or -NH-C(O)-NH-R , 9 9 1 6 9 2 9 9 9 5 ? R and R ’ independently of one another represent a hydrogen atom or a linear or 11 11 branched (C -C )alkyl group, ? R represents a hydrogen atom, a hydroxy group, or a hydroxy(C -C )alkyl group, 12 1 6 ? R represents a hydrogen atom or a linear or branched (C -C )alkyl group, a 1 6 ? R represents a -O-C(O)-O-R group, a -O-C(O)-NR R ’ group, or a -O-P(O)(OR ) b c c c c 2 10 group, ? R and R ’ independently of one another represent a hydrogen atom, a linear or branched (C -C )alkyl group, a cycloalkyl group, a (C -C )alkoxy(C -C )alkyl 1 8 1 6 1 6 group, a (C -C )alkoxycarbonyl(C -C )alkyl group, 1 6 1 6 or the substituents of the pair (R , R ’) form together with the nitrogen atom 15 carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a group representing a linear or branched (C -C )alkyl group, ? Cy , Cy , Cy and Cy independently of one another, represent a cycloalkyl group, 1 2 3 4 20 a heterocycloalkyl group, an aryl group or a heteroaryl group, ? n is an integer equal to 0, 1 or 2, it being understood that: - “aryl” means a phenyl, naphthyl, biphenyl group, - “heteroaryl” means any mono- or bi-cyclic group composed of from 5 to 10 ring 25 members, having at least one aromatic moiety and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, - “cycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group containing from 3 to 10 ring members, - “heterocycloalkyl” means any mono- or bi-cyclic non-aromatic carbocyclic group 30 containing from 3 to 10 ring members, and containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen, which may include fused, bridged or spiro ring systems, it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may be substituted by from 1 to 4 groups selected from linear or branched (C -C )alkyl which may be substituted by a 5 group representing a linear or branched (C -C )alkoxy; linear or branched (C - 1 6 2 C )alkenyl; linear or branched (C -C )alkynyl; linear or branched (C -C )alkoxy which 6 2 6 1 6 may be substituted by a group representing halogen or a linear or branched (C - C )alkoxy; (C -C )alkyl-S-; hydroxy; hydroxy(C -C )alkyl; oxo (or N-oxide where 6 1 6 1 6 appropriate); nitro; cyano; -C(O)-OR’; -O-C(O)-R’; -C(O)-NR’R’’; -O-C(O)-NR’R’’; 10 -NR’R’’; -(C=NR’)-OR’’; -O-P(O)(OR’) ; -O-P(O)(O M ) ; linear or branched (C -C )polyhaloalkyl; trifluoromethoxy; halogen; or an aldohexose of formula: in which each R’ is independent; it being understood that R’ and R’’ independently of one another represent a hydrogen 15 atom or a linear or branched (C -C )alkyl group and M represents a pharmaceutically acceptable monovalent cation, their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a pharmaceutically acceptable acid or base.

2. Compound of formula (I) according to claim 1, wherein: 20 ? R and R independently of one another represent a halogen atom, a linear or branched (C -C )alkyl group, a hydroxy group, a hydroxy(C -C )alkyl group, a 1 6 1 6 linear or branched (C -C )alkoxy group, or the substituents of the pair (R , R ) form together with the carbon atoms carrying them an aromatic ring composed of from 5 to 7 ring members, which may contain from 1 to 3 nitrogen atoms, it being understood that resulting ring may be substituted by from 1 to 2 groups selected from halogen, linear or branched (C -C )alkyl, or -alkyl(C -C )-NR R ’, 1 6 0 6 9 9 ? R represents a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl 3 1 6 5 group, a hydroxy group, a linear or branched (C -C )alkoxy group, or -O-alkyl(C -C )-NR R ’, 1 6 9 9 ? R and R independently of one another represent a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl group, a hydroxy group, a linear or branched (C -C )alkoxy group, 10 ? R represents a hydrogen atom, a halogen atom, a linear or branched (C -C )alkyl 6 1 6 group, a linear or branched (C -C )polyhaloalkyl group, a hydroxy group, a linear or branched (C -C )alkoxy group, a cyano group, a nitro group, -alkyl(C -C )-NR R ’, -alkyl(C -C )-Cy , -O-alkyl(C -C )-R , or -C(O)-NR R ’, 0 6 9 9 0 6 1 1 6 10 9 9 ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a -CHR R 7 1 8 a b 15 group, or a heteroarylalkyl(C -C ) group, ? R represents a linear or branched (C -C )alkyl group, a linear or branched 8 1 6 (C -C )alkenyl group, a linear or branched (C -C )alkynyl group, -Cy , a halogen 2 6 2 6 2 atom, or -C(O)-R , ? R and R ’ independently of one another represent a hydrogen atom, or a linear or 20 branched (C -C )alkyl group, or the substituents of the pair (R , R ’) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be 25 substituted by a group representing a linear or branched (C -C )alkyl group, ? R represents -Cy or -Cy -alkyl(C -C )-Cy , 10 3 3 0 6 4 ? R represents a linear or branched (C -C )alkyl group, 11 1 6 it being possible for the aryl, heteroaryl, cycloalkyl and heterocycloalkyl groups so defined and the alkyl, alkenyl, alkynyl, alkoxy groups, may be substituted by from 1 to 30 4 groups selected from linear or branched (C -C )alkyl which may be substituted by a group representing a linear or branched (C -C )alkoxy; linear or branched (C - 1 6 1 C )alkoxy which may be substituted by a group representing halogen, or a linear or branched (C -C )alkoxy; hydroxy; oxo (or N-oxide where appropriate); -C(O)-OR’; - C(O)-NR’R’’; -O-C(O)-NR’R’’; -NR’R’’; -O-P(O)(OR’) ;-O-P(O)(O M ) ; linear or branched (C -C )polyhaloalkyl; halogen; or an aldohexose of formula: in which each R’ is independent; it being understood that R’ and R’’ independently of one another represent a hydrogen atom or a linear or branched (C -C )alkyl group and M represents a pharmaceutically acceptable monovalent cation.

3. Compounds according to claim 1, wherein n is an integer equal to 1. 10 4. Compounds according to claim 1, wherein at least one the groups selected from R ,

4.R , R and R does not represent a hydrogen atom. 3 4 5

5. Compounds according to claim 1, wherein R represents a hydrogen atom.

6. Compounds according to claim 1, wherein R represents a linear or branched (C -C )alkyl group or a halogen atom. 15

7. Compounds according to claim 1, wherein R represents a linear or branched (C -C )alkoxy group, a hydroxy group or a halogen atom.

8. Compounds according to claim 1, wherein X represents a C-R group.

9. Compounds according to claim 1, wherein Y represents a C-R group.

10. Compounds according to claim 1, wherein R and R represent a hydrogen atom.

11. Compound according to claim 1, wherein the substituents of the pair (R , R ) are identical and the substituents of the pair (R , R ) are identical.

12. Compounds according to claim 1, wherein: represents , 5 wherein R , R , R and R ’ are as defined in claim 1. 1 2 9 9

13. Compounds according to claim 1, wherein: represents , wherein R and R ’ are as defined in claim 1.

14. Compounds according to claim 1, wherein E represents a phenyl group, a pyridinyl, 10 a cyclohexyl group, a pyrazolyl group, a cyclopentyl group, an indolyl group, a cyclopropyl group, a pyridinyl group, an indolyl group, a naphthyl group, an imidazolyl group or a pyridinyl group.

15. Compounds according to claim 1, which are compounds of formula (I-b): (I-b) wherein R , R , R , R , R , R , X, Y, A and n are as defined for formula (I). 1 2 5 6 7 12

16. Compounds according to claim 1, wherein R represents a hydrogen atom; a fluorine atom; a chlorine atom; a bromine atom; a methyl group; a trifluoromethyl group; a 5 hydroxy group; a methoxy group; a linear (C -C )alkoxy group substituted by halogen atoms, a -C(O)-NR’R’’ group or a -NR’R’’ group; a cyano; a nitro group; an aminomethyl group; a benzyl group; -O-alkyl(C1-C6)-R10; -C(O)-NR9R9’.

17. Compounds according to claim 1, wherein R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a -CHR R group, or a heteroarylalkyl(C -C ) 1 6 a b 1 6 10 group.

18. Compounds according to claim 1, wherein R represents a linear or branched (C -C )alkynyl group, an aryl group or a heteroaryl group.

19. Compounds according to claim 1, wherein R and R ’ independently of one another represent a linear or branched (C -C )alkyl group, or the substituents of the pair 15 (R , R ’) form together with the nitrogen atom carrying them a non-aromatic ring composed of from 5 to 7 ring members, which may contain in addition to the nitrogen atom from 1 to 3 heteroatoms selected from oxygen and nitrogen, it being understood that the nitrogen in question may be substituted by a linear or branched (C -C )alkyl group.

20.20. Compounds according to claim 1, wherein R10 represents -Cy3 or -Cy -alkyl(C -C )-Cy . 3 0 6 4

21. Compounds according to claim 20, wherein Cy represents a cycloalkyl group, an aryl group or a heteroaryl group.

22. Compounds according to claim 20, wherein Cy represents phenyl group or a 5 morpholinyl group.

23. Compounds according to claim 20, wherein R represents in which p is an integer equal to 0 or 1 and R represents a hydrogen atom, a hydroxy group, a linear or branched (C -C )alkyl group which may be substituted by a group 10 representing a linear or branched (C -C )alkoxy; a linear or branched (C1-C6)alkoxy group; a -O-(CHR16-CHR17-O)q-R’ group; a -O-P(O)(OR’) group; a -O-P(O)(O M ) group; a -O-C(O)-NR R group; 2 2 18 19 a di(C -C )alkylamino(C -C )alkoxy group; a halogen atom; or an aldohexose of 1 6 1 6 formula: in which each R’ is independent; it being understood that: ? R’ represents a hydrogen atom or a linear or branched (C -C )alkyl group, ? R represents a hydrogen atom or a (C -C )alkoxy(C -C )alkyl group, 16 1 6 1 6 ? R represents a hydrogen atom or a hydroxy(C -C )alkyl group, 17 1 6 ? R represents a hydrogen atom or a (C -C )alkoxy(C -C )alkyl group, 18 1 6 1 6 ? R represents a (C -C )alkoxy(C -C )alkyl group, a -(CH ) -NR R ’ group or 19 1 6 1 6 2 r 9 9 5 a -(CH ) -O-(CHR -CHR -O) -R’ group, 2 r 16 17 q ? q is an integer equal to 1, 2 or 3 and r is an integer equal to 0 or 1, ? M represents a pharmaceutically acceptable monovalent cation.

24. Compounds according to claim 23, wherein the aldohexose is D-mannose.

25. Compounds according to claim 1, which are: 10 - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- fluorophenyl)thieno[2,3-d]pyrimidinyl][(1-methyl-1H-pyrazolyl) methoxy]-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- fluorophenyl)thieno[2,3-d]pyrimidinyl][(2-ethoxypyrimidinyl)methoxy]- 15 D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(4- fluorophenyl)thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl)pyrimidin yl]methoxy}-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(furan- 20 2-yl)thieno[2,3-d]pyrimidinyl]methoxy-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5- fluorofuranyl)thieno[2,3-d]pyrimidinyl]methoxy-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5- fluorofuranyl)thieno[2,3-d]pyrimidinyl](2,2,2-trifluoroethoxy)-D- 25 phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5- fluorofuranyl)thieno[2,3-d]pyrimidinyl](pyridinylmethoxy)-D- phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5- 30 fluorofuranyl)thieno[2,3-d]pyrimidinyl][(1-methyl-1H-pyrazolyl) methoxy]-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5- fluorofuranyl)thieno[2,3-d]pyrimidinyl][(1-ethyl-1H-pyrazolyl) methoxy]-D-phenylalanine, 5 - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5- fluorofuranyl)thieno[2,3-d]pyrimidinyl][(2-ethoxypyrimidinyl) methoxy]-D-phenylalanine, - 2-[(1-butyl-1H-pyrazolyl)methoxy]-N-[5-{3-chloromethyl[2-(4-methyl piperazinyl)ethoxy]phenyl}(5-fluorofuranyl)thieno[2,3-d]pyrimidinyl]- 10 D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5- fluorofuranyl)thieno[2,3-d]pyrimidinyl]{[2-(2,2,2-trifluoroethoxy) pyrimidinyl]methoxy}-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(5- 15 fluorofuranyl)thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(prop ynyl)thieno[2,3-d]pyrimidinyl]methoxy-D-phenylalanine, - 2-[(1-tert-butyl-1H-pyrazolyl)methoxy]-N-[5-{3-chloromethyl[2-(4- 20 methylpiperazinyl)ethoxy]phenyl}(propynyl)thieno[2,3-d]pyrimidin yl]-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(prop ynyl)thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyethyl)pyrimidinyl] methoxy}-D-phenylalanine, 25 - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(prop ynyl)thieno[2,3-d]pyrimidinyl]{[1-(2,2,2-trifluoroethyl)-1H-pyrazolyl] methoxy}-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(prop ynyl)thieno[2,3-d]pyrimidinyl]{[2-(morpholinyl)pyrimidinyl] 30 methoxy}-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(prop ynyl)thieno[2,3-d]pyrimidinyl]{[2-(2,2,2-trifluoroethoxy)pyrimidinyl] methoxy}-D-phenylalanine, - N-[5-{3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}(prop ynyl)thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl)pyrimidinyl] methoxy}-D-phenylalanine, 5 - N-[5-{3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(propynyl) thieno[2,3-d]pyrimidinyl]{[1-(2,2,2-trifluoroethyl)-1H-pyrazolyl] methoxy}-D-phenylalanine, - N-[5-{3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(propynyl) thieno[2,3-d]pyrimidinyl]{[2-(morpholinyl)pyrimidinyl]methoxy}-D- 10 phenylalanine, - N-[5-{3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(propynyl) thieno[2,3-d]pyrimidinyl]{[2-(2,2,2-trifluoroethoxy)pyrimidinyl] methoxy}-D-phenylalanine, - N-[5-{3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(propynyl) 15 thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl)pyrimidinyl]methoxy}-D- phenylalanine, - N-[5-{3-chloro[2-(dimethylamino)ethoxy]methylphenyl}(4-fluoro phenyl)thieno[2,3-d]pyrimidinyl]({2-[2-(2-methoxyethoxy)phenyl]pyrimidin- 4-yl}methoxy)-D-phenylalanine; 20 - ethyl N-[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl) pyrimidinyl]methoxy}-D-phenylalaninate; - ethyl N-[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(propynyl)thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl) 25 pyrimidinyl]methoxy}-D-phenylalaninate; - ethyl N-[(5Sa){3-chloro[2-(dimethylamino)ethoxy]methylphenyl} (propynyl)thieno[2,3-d]pyrimidinyl]{[2-(2-methoxyphenyl)pyrimidin- 4-yl]methoxy}-D-phenylalaninate; - N-[5-{3,5-dichloro-2,6-dimethyl[2-(4-methylpiperazinyl) 30 ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]{[2-(2- methoxyphenyl)pyrimidinyl]methoxy}-D-phenylalanine.

26. Process for the preparation of a compound of formula (I) according to claim 1, wherein the starting material is the compound of formula (II-a): (II-a) wherein Z represents bromine or iodine and A is as defined for formula (I) in which 1 5 is linked to the chlorine atom and 2 is linked to the Z group, which compound of formula (II-a) is subjected to coupling with a compound of formula (III): (III) wherein R , R , E and n are as defined for formula (I), and Alk represents a linear or 10 branched (C -C )alkyl group, to yield the compound of formula (IV): wherein R , R , A, E and n are as defined for formula (I) and, Z and Alk is as defined before, 15 compound of formula (IV) which is further subjected to coupling with compound of formula (V): wherein R , R , R , X and Y are as defined for formula (I), and R and R represent 1 2 5 B1 B2 a hydrogen atom, a linear or branched (C -C ) alkyl group, or R and R form with 1 6 B1 B2 the oxygen carrying them an optionally methylated ring, 5 to yield the compound of formula (VI): wherein R , R , R , R , R , X, Y, A, E and n are as defined for formula (I) and Alk is 1 2 5 6 12 as defined before, the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to 10 yield the carboxylic acid, which may optionally be reacted with an alcohol of formula R ’-OH or a chlorinated compound of formula R ’-Cl wherein R ’ represents a linear 7 7 7 or branched (C -C )alkyl group, a -CHR R group, an aryl group, a heteroaryl group, 1 8 a b an arylalkyl(C -C ) group, or a heteroarylalkyl(C -C ) group, R and R are as defined 1 6 1 6 a b for formula (I), 15 to yield the compound of formula (I), which may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique, it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino…) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and 5 functionalized, as required by the synthesis.

27. Process for the preparation of a compound of formula (I) according to claim 1, wherein the starting material is the compound of formula (II-b): (II-b) wherein A is as defined in formula (I) in which 1 is linked to the chlorine atom and 2 10 is linked to the iodine atom, which compound of formula (II-b) is subjected to coupling with a compound of formula (V): wherein R , R , R , X and Y are as defined for formula (I), and R and R represent 1 2 5 B1 B2 15 a hydrogen atom, a linear or branched (C -C ) alkyl group, or R and R form with 1 6 B1 B2 the oxygen carrying them an optionally methylated ring, to yield the compound of formula (VII): (VII) wherein R , R , R , A, X and Y are as defined in formula (I), 1 2 5 which compound of formula (VII) is further subjected to coupling with a compound of formula (III): (III) 5 wherein R , R , E and n are as defined for formula (I), and Alk represents a linear or branched (C1-C6)alkyl group, to yield the compound of formula (VI): wherein R , R , R , R , R , X, Y, A, E and n are as defined for formula (I) and Alk is 1 2 5 6 12 10 as defined before, the Alk-O-C(O)- ester function of which compound of formula (VI) is hydrolysed to yield the carboxylic acid, which may optionally be reacted with an alcohol of formula R ’-OH or a chlorinated compound of formula R ’-Cl wherein R ’ represents a linear 7 7 7 or branched (C -C )alkyl group, a -CHR R group, an aryl group, a heteroaryl group, 1 8 a b 15 an arylalkyl(C -C ) group, or a heteroarylalkyl(C -C ) group, R and R are as defined 1 6 1 6 a b for formula (I), to yield the compound of formula (I), which may be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and which is optionally separated into its isomers according to a conventional separation technique, 5 it being understood that at any moment considered appropriate during the course of the process described above, some groups (hydroxy, amino…) of the starting reagents or of the synthesis intermediates can be protected, subsequently deprotected and functionalized, as required by the synthesis.

28. Pharmaceutical composition comprising a compound of formula (I) according to any 10 one of claims 1 to 25 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

29. Pharmaceutical composition according to claim 28 for use as pro-apoptotic agents.

30. Pharmaceutical composition according to claim 29 for use in the treatment of cancers and of auto-immune and immune system diseases. 15

31. Pharmaceutical composition according to claim 30 for use in the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non- small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer. 20

32. Use of a compound of formula (I) according to any one of claims 1 to 25 or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament useful as a pro-apoptotic agent.

33. Use of a compound of formula (I) according to any one of claims 1 to 25 or an addition salt thereof with a pharmaceutically acceptable acid or base in the 25 manufacture of a medicament for the treatment of cancers and of auto-immune and immune system diseases.

34. Use of a compound of formula (I) according to any one of claims 1 to 25 or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament for the treatment of cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, 5 lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer.

35. Compound of formula (I) according to any one of claims 1 to 25, or an addition salt thereof with a pharmaceutically acceptable acid or base, for use in the treatment of 10 cancers of the bladder, brain, breast and uterus, chronic lymphoid leukaemias, cancer of the colon, œsophagus and liver, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, prostate cancer, pancreatic cancer and small-cell lung cancer. 15

36. Combination of a compound of formula (I) according to any one of claims 1 to 25 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies.

37. Pharmaceutical composition comprising a combination according to claim 36 in combination with one or more pharmaceutically acceptable excipients. 20

38. Combination according to claim 36 for use in the treatment of cancers.

39. Use of a combination according to claim 36 in the manufacture of a medicament for the treatment of cancers.

40. Compound of formula (I) according to any one of claims 1 to 25 for use in the treatment of cancers requiring radiotherapy.

41. Use of a compound of formula (I) according to any one of claims 1 to 25 or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament for the treatment of cancers requiring radiotherapy.

42. A compound according to any one of claims 1 to 25, 35, or 40; process according to 5 claim 26 or claim 27; pharmaceutical composition according to any one of claims 28 to 31, or 37; use according to any one of claims 32 to 34, 39, or 41; or combination according to claim 36 or claim 38, substantially as herein described with reference to any example thereof.