NZ738469B2

NZ738469B2 - New hydroxyacid derivatives, a process for their preparation and pharmaceutical compositions containing them

Info

Publication number: NZ738469B2
Application number: NZ738469A
Authority: NZ
Inventors: Balazs Balint; Maia Chanrion; James Edward Paul Davidson; Olivier Geneste; Andras Kotschy; James Brooke Murray; Attila Paczal; Agnes Proszenyak; Szabolcs Sipos; Zoltan Szlavik
Original assignee: Les Laboratoires Servier; Vernalis (R&D) Limited
Filing date: 2016-06-22
Publication date: 2024-12-03

Abstract

Compounds of formula (I): wherein R1, R2, R3, R4, R5, R6, R7, R8, R14, A and n are as defined in the description as B-cell lymphoma 2 (Bcl-2) inhibitors, pharmaceutical compositions thereof, and their use as pro-apoptotic agents and in the treatment of cancers.

Claims

1. Compound of formula (I): wherein: ? A represents the group in which 1 is linked to the oxygen atom and 2 is linked to the phenyl ring, ? R represents a linear or branched (C -C )alkyl group, or a halogen atom, 1 1 6 ? R represents a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched (C -C )alkoxy group, 10 ? R represents -O-alkyl(C -C )-NR R ’, 3 1 6 10 10 ? R represents a hydrogen atom or a halogen atom, ? R represents a hydrogen atom or a linear or branched (C -C )alkyl group, 5 1 6 or the substituents of one of the pair (R , R ) are identical and represent a (C - 1 5 1 C )alkyl group whereas the substituents of the pair (R , R ) are identical and 6 2 4 15 represent a halogen atom or a hydrogen atom ? R represents a hydrogen atom, a linear or branched (C -C )alkyl group, a -CHR R 8 1 8 a b group, an aryl group, a heteroaryl group, an arylalkyl(C -C ) group, or a heteroarylalkyl(C -C ) group, ? R represents a linear or branched (C -C )alkynyl group, an aryl group, or a 9 2 6 heteroaryl group, ? R and R ’ independently of one another represent a linear or branched (C - 10 10 1 5 C )alkyl group, or the substituents of the pair (R , R ’) form together with the nitrogen atom 10 10 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, sulphur and nitrogen, it being understood that the nitrogen in question may 10 be substituted by a group representing a hydrogen atom, or a linear or branched (C -C )alkyl group, ? R represents -Cy -Cy , 11 5 6 ? R represents a hydrogen atom, a hydroxy group, or a hydroxy(C -C )alkyl group, 14 1 6 ? R represents a hydrogen atom or a linear or branched (C -C )alkyl group, a 1 6 15 ? 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 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 20 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 substituted by a group representing a linear or branched (C -C )alkyl group, 25 ? Cy represents a heteroaryl group, ? Cy represents or Cy represents 5-(hydroxymethyl)pyridinyl group, a 2- (hydroxymethyl)pyrimidinyl group, a 2-(hydroxymethyl)pyridinyl group, a 6- (hydroxymethyl)pyridazinyl group, a 6-(hydroxymethyl)pyrazinyl group ? R represents a hydrogen atom; a -(CH ) -O-CH -CH(CHOH)-OH group; 15 2 p 2 2 a -(CH ) -O-(CH -CH -O)-H group; a -(CH ) -O-(CH -CH -O) -CH group; 2 p 2 2 q 2 p 2 2 q 3 a methoxymethyl group; a (2,2-dimethyl-1,3-dioxolanyl)methoxy group; a 5 (2,2-dimethyl-1,3-dioxolanyl)methoxymethyl group; or a -Y-(CH2)q-N(CH2- CH -OH) group ? R represents a hydrogen atom; a hydroxy group; a hydroxymethyl group; a (2,2- dimethyl-1,3-dioxolanyl)methoxy group; a -O-P(O)(OH)2 group; a -(CH2)p-O- CH -CH(CHOH)-OH group; a -(CH ) -O-(CH -CH -O)-H group; 2 2 2 p 2 2 q 10 a -(CH ) -O-(CH -CH -O) -CH group; a -O-CH(CH -OCH ) group; a -CH -O- 2 p 2 2 q 3 2 3 2 2 C(O)-NR R group; a -O-(CH ) -NR R ’ group; a -CH -NR R ’ group; a 22 23 2 2 21 21 2 21 21 (CH ) -O-X-O-P(O)(OR ) group; or a -(CH ) -Y-(CH ) -heterocycloalkyl group, 2 r 20 2 2 r 2 s in which Y is a bond, r and s are integers equal to 0 and the heterocycloalkyl group represents an aldohexose of formula: in which each R is independent, ? R represents a hydrogen atom; a hydroxy group; a hydroxymethyl group; a hydroxyethyl group; a -O-(CH -CH -O) -CH group; a -O-CH -CH(CH OH)-OH 2 2 q 3 2 2 group; a -(CH ) -O-(CH -CH -O) -H group; a -O-P(O)(OH) group; a -O-P(O)(O ) 2 p 2 2 q 2 2 20 group; a -O-CH(CH -OCH ) group; a -O-(CH ) -NR R ’ group; a -CH - 2 3 2 2 2 21 21 2 NR R ’ group; a (2,2-dimethyl-1,3-dioxolanyl)methoxy group; D-mannonic 21 21 acid; a -(CH ) -Y-(CH ) -heterocycloalkyl group in which Y is an oxygen atom, s is 2 r 2 s an integer equal to 0, r is an integer equal to 1 and the heterocycloalkyl group represents a 1,2-O-ethylidene- ß-D-mannopyranose; or a -(CH ) -Y-(CH ) - 2 r 2 s 25 heterocycloalkyl group in which Y is a bond, s is an integer equal to 0 and the heterocycloalkyl group represents an aldohexose of formula: OR OR 20 20 R O OR R O OR 20 20 20 20 R O O O O in which each R is independent, ? X represents a -(CH ) - group or a -C(O)- group, 5 ? Y represents a bond or an oxygen atom, ? R represents a hydrogen atom or a (C -C )alkoxy(C -C )alkyl group, 18 1 6 1 6 ? R represents a hydrogen atom or a hydroxy(C -C )alkyl group, 19 1 6 ? R represents a hydrogen atom or a linear or branched (C -C )alkyl group, 20 1 6 ? R and R ’ independently of one another represent a hydrogen atom, a linear or 21 21 10 branched (C -C )alkyl group, or a hydroxy(C -C )alkyl group, 1 6 1 6 or the substituents of the pair (R , R ’) form together with the nitrogen atom 21 21 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 15 the resulting ring may be substituted by a group representing a hydrogen atom or a linear or branched (C -C )alkyl group, ? R represents a (C -C )alkoxy(C -C )alkyl group, a -(CH ) -NR R ’ group, or 22 1 6 1 6 2 p 24 24 a -(CH ) -O-(CHR -CHR -O) -R group and R represents a hydrogen atom, 2 p 18 19 q 20 23 or R and R represents a (C -C )alkoxy(C -C )alkyl group, 22 23 1 6 1 6 20 or the substituents of the pair (R , R ) form together with the nitrogen atom 22 23 carrying them an aromatic or non-aromatic ring composed of from 5 to 18 ring members, which may contain in addition to the nitrogen atom from 1 to 5 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a linear or branched 25 (C -C )alkyl group or a heterocycloalkyl group, ? R and R ’ independently of one another represent a hydrogen atom or a linear or 24 24 branched (C -C )alkyl group, or the substituents of the pair (R , R ’) form together with the nitrogen atom 24 24 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 one to 3 heteroatoms selected from oxygen, sulphur and nitrogen, it being understood that the resulting ring may be substituted by a group representing a hydrogen atom or a 5 linear or branched (C -C )alkyl group, ? n is an integer equal to 1, ? p is an integer equal to 0, 1 or 2, ? q is an integer equal to 1, 2, 3 or 4, ? r and s are independently an integer equal to 0 or 1, 10 with the proviso that R , R and R cannot represent together a hydrogen atom and, 15 16 17 when R represents a methyl group, R cannot represent a methoxyethoxy group, it being understood that: - "aryl" means a phenyl, naphthyl, biphenyl, indanyl or indenyl group, - "heteroaryl" means any mono- or bi-cyclic group composed of from 5 to 10 ring 15 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 20 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, to be substituted by from 1 to 5 25 groups selected from linear or branched (C -C )alkyl; linear or branched (C - 1 6 2 C )alkenyl group; linear or branched (C -C )alkynyl group; linear or branched (C - 6 2 6 1 C )alkoxy; (C -C )alkyl-S-; hydroxy; oxo (or N-oxide where appropriate); nitro; 6 1 6 cyano; -C(O)-OR’; -O-C(O)-R’; -C(O)-NR’R’’; -NR’R’’; -(C=NR’)-OR’’; linear or branched (C -C )polyhaloalkyl; trifluoromethoxy; or halogen, 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 it being understood that one or more of the carbon atoms of the preceding possible substituents, may be deuterated, their enantiomers, diastereoisomers and atropisomers, and addition salts thereof with a 5 pharmaceutically acceptable acid or base.

2. Compounds according to claim 1, wherein R represents a hydrogen atom, a hydroxy group, a hydroxymethyl group or a hydroxyethyl group.

3. Compound according to claim 1, wherein R and R represent a hydrogen atom

4. Compounds according to claim 1, wherein represents , wherein R , R and R ’ are as defined in claim 1. 1 10 10

5. Compounds according to claim 1, wherein represents , wherein R and R ’ are as defined in claim 1. 10 10

6. Compounds according to claim 1, wherein R represents a hydrogen atom, a -CHR R 8 a b group, a linear or branched (C -C )alkyl group, or a heteroarylalkyl(C -C ) group. 1 8 1 6

7. Compounds according to claim 1, wherein Cy represents a pyrimidinyl group, a 5 pyrazolyl group, a triazolyl group, a pyrazinyl group or a pyridinyl group.

8. Compounds according to claim 1, wherein Cy represents 15 17 wherein R , R and R are as defined in claim 1. 15 16 17

9. Compounds according to claim 1, wherein R and R represent a hydrogen atom and 16 17 10 R represents a -(CH ) -O-CH -CH(CH OH)-OH group; a -(CH ) -O-(CH -CH -O) - 15 2 p 2 2 2 p 2 2 q H group; a -(CH ) -O-(CH -CH -O) -CH group; a methoxymethyl group; a (2,2- 2 p 2 2 q 3 dimethyl-1,3-dioxolanyl)methoxy group; a (2,2-dimethyl-1,3-dioxolan yl)methoxymethyl group; or a -Y-(CH ) -N(CH -CH -OH) group. 2 q 2 2 2

10. Compounds according to claim 1, wherein R and R represent a hydrogen atom 15 17 15 and R represents a hydroxy group; a hydroxymethyl group; a (2,2-dimethyl-1,3- dioxolanyl)methoxy group; a -O-P(O)(OH) group; a -(CH ) -O-CH -CH(CH OH)- 2 2 p 2 2 OH group; a -(CH ) -O-(CH -CH -O) -H group; a -(CH ) -O-(CH -CH -O) -CH 2 p 2 2 q 2 p 2 2 q 3 group; a -O-CH(CH -OCH ) group; a -CH -O-C(O)-NR R group; a -O-(CH ) - 2 3 2 2 22 23 2 2 NR R ’ group; a -CH -NR R ’ group; a (CH ) -O-X-O-P(O)(OR ) group; or a 21 21 2 21 21 2 r 20 2 20 -(CH ) -Y-(CH ) -heterocycloalkyl group, in which Y is a bond, r and s are integers 2 r 2 s equal to 0 and the heterocycloalkyl group represents an aldohexose of formula: in which each R is independent.

11. Compounds according to claim 1, wherein R and R represent a hydrogen atom 15 16 and R represents a hydroxy group; a hydroxymethyl group; a hydroxyethyl group; a - 5 O-(CH -CH -O) -CH group; a -O-CH -CH(CH OH)-OH group; a -(CH ) -O-(CH - 2 2 q 3 2 2 2 p 2 CH -O) -H group; a -O-P(O)(OH) group; a -O-P(O)(O ) group; a -O-CH(CH - 2 q 2 2 2 OCH ) group; a -O-(CH ) -NR R ’ group; a -CH -NR R ’ group; a (2,2-dimethyl- 3 2 2 2 21 21 2 21 21 1,3-dioxolanyl)methoxy group; D-mannonic acid; a -(CH ) -Y-(CH ) - 2 r 2 s heterocycloalkyl group in which Y is an oxygen atom, s is an integer equal to 0, r is an 10 integer equal to 1 and the heterocycloalkyl group represents a 1,2-O-ethylidene- ß-D- mannopyranose; or a -(CH ) -Y-(CH ) -heterocycloalkyl group in which Y is a bond, s 2 r 2 s is an integer equal to 0, r is as defined for formula (I) and the heterocycloalkyl group represents an aldohexose of formula: OR OR 20 20 R O OR R O OR 20 20 20 20 R O O O O 15 in which each R is independent.

12. Compounds according to claim 1, which are: - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3- hydroxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; 20 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4- hydroxyphenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[3- (hydroxymethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 5 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[4- (hydroxymethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{2-[(2,2-dimethyl- 1,3-dioxolanyl)methoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic 10 acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{2-[2-(2- methoxyethoxy)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 15 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-{2-[2-(2- methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2- 20 (methoxymethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{2-[(2- methoxyethoxy)methyl]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 25 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{2-[(2- hydroxyethoxy)methyl]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(2-{[(2,2-dimethyl- 1,3-dioxolanyl)methoxy]methyl}phenyl)pyrimidin 30 yl]methoxy}phenyl)propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[(2- hydroxyethoxy)methyl]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 5 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[(1,3- dimethoxypropanyl)oxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{4-[(1,3- 10 dimethoxypropanyl)oxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[4-(2,3- dihydroxypropoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; 15 - methyl 6-O-{3-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] pyrimidinyl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]phenyl}- a-D- mannopyranoside; - methyl 6-O-{3-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4- 20 methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] pyrimidinyl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]phenyl}-2,3,4-tri-O- methyl- a-D-mannopyranoside; - methyl 6-O-{4-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] 25 pyrimidinyl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]phenyl}- a-D- mannopyranoside; - methyl 6-O-{4-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] pyrimidinyl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]phenyl}-2,3,4-tri-O- 30 methyl- a-D-mannopyranoside; - 6-O-{4-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]phenyl}-D-mannopyranose; - 6-O-{2-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4- 5 methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]phenyl}-D-mannonic acid; - 1,2-O-[(1R)({4-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d] pyrimidinyl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]benzyl}oxy)ethylidene]- 10 ß-D-mannopyranose; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{4-[( a-D- mannopyranosyloxy)methyl]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; 15 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[4-(2- hydroxyethyl)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2,3- 20 dihydroxypropoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[2-(2- hydroxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 25 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{2-[(2,3- dihydroxypropoxy)methyl]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[3- (phosphonooxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; 30 - 4-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4-methyl piperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]phenyl phosphate; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[3-(2- hydroxyethoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 5 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{4-[2-(2- methoxyethoxy)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{4-[2-(2- hydroxyethoxy)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; 10 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-{2-[2-(2- methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 15 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{4-[2- (dimethylamino)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[(2,2-dimethyl- 1,3-dioxolanyl)methoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic 20 acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[3-(15- hydroxyoxo-2,7,10,13-tetraoxaazapentadecyl)phenyl]pyrimidin yl}methoxy)phenyl]propanoic acid; 25 - (2R)(2-{[2-(3-{[(1,4'-bipiperidin-1'-ylcarbonyl)oxy]methyl}phenyl) pyrimidinyl]methoxy}phenyl){[(5S ){3-chloromethyl[2-(4- methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 30 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[2-(2- hydroxyethoxy)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 5 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[2-(2- methoxyethoxy)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[({[2-(4- methylpiperazinyl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin 10 yl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[({[2- (morpholinyl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidinyl)methoxy] phenyl}propanoic acid; 15 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[({[2- (dimethylamino)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidinyl)methoxy] phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 20 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[({[2- (pyrrolidinyl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidinyl)methoxy] phenyl}propanoic acid; - (2R)[2-({2-[3-({[bis(2-methoxyethyl)carbamoyl]oxy}methyl)phenyl] pyrimidinyl}methoxy)phenyl]{[(5S ){3-chloromethyl[2-(4- 25 methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3- {[(1,4,7,10,13-pentaoxaazacyclooctadecan 30 ylcarbonyl)oxy]methyl}phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[3-(2,3- dihydroxypropoxy)phenyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 5 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(3-{2-[2-(2- methoxyethoxy)ethoxy]ethoxy}phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; - (2R)(2-{[2-(3-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin yl]methoxy}phenyl){[(5S ){3-chloromethyl[2-(4-methylpiperazin 10 yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic acid; - (2R){[(5Sa){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy]phenyl}- 6-(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[({[2-(piperidin- 1-yl)ethyl]carbamoyl}oxy)methyl]phenyl}pyrimidin 15 yl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[2- (morpholinyl)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] 20 phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{3-[2- (dimethylamino)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - (2R)(2-{[2-(4-{2-[bis(2-hydroxyethyl)amino]ethoxy}phenyl)pyrimidin yl]methoxy}phenyl){[(5S ){3-chloromethyl[2-(4-methylpiperazin yl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}propanoic 25 acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2-(4-{2-[2-(2- hydroxyethoxy)ethoxy]ethoxy}phenyl)pyrimidinyl]methoxy}phenyl)propanoic acid; 30 - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{4-[(2,2- dimethyl-1,3-dioxolanyl)methoxy]phenyl}pyrimidinyl)methoxy]phenyl} propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}{2-[(2-{4-[2- 5 (morpholinyl)ethoxy]phenyl}pyrimidinyl)methoxy]phenyl}propanoic acid; - 4-[4-({2-[(2R)carboxy{[(5S ){3-chloromethyl[2-(4-methyl piperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}ethyl]phenoxy}methyl)pyrimidinyl]phenyl phosphate disodium salt; - 1-[(ethoxycarbonyl)oxy]ethyl (2R){[(5S ){3-chloromethyl[2-(4- 10 methylpiperazinyl)ethoxy]phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidin yl]oxy}{2-[(2-{3-[(1,3-dimethoxypropanyl)oxy]phenyl}pyrimidin yl)methoxy]phenyl}propanoate; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}[2-({2-[5-(hydroxy 15 methyl)pyridinyl]pyrimidinyl}methoxy)phenyl]propanoic acid; - (2R){[(5S ){3-chloromethyl[2-(4-methylpiperazinyl)ethoxy] phenyl}(4-fluorophenyl)thieno[2,3-d]pyrimidinyl]oxy}(2-{[2'-(hydroxy methyl)-2,5'-bipyrimidinyl]methoxy}phenyl)propanoic acid.

13. Process for the preparation of a compound of formula (I) according to claim 1, 20 wherein there is used as starting material the compound of formula (II): wherein A is as defined for formula (I) in which 1 is linked to the chlorine atom and 2 is linked to the bromine atom, which compound of formula (II) is subjected to coupling with a compound of 25 formula (III): (III) wherein R , R and n are as defined for formula (I), and Alk represents a linear or 11 14 branched (C -C )alkyl group, to yield the compound of formula (IV): wherein R , R , A and n are as defined for formula (I) and Alk is as defined before, 11 14 compound of formula (IV) which is further subjected to coupling with compound of formula (V): 10 wherein R , R , R , R and R are as defined for formula (I), and R and R represent 1 2 3 4 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, to yield the compound of formula (VI): wherein R , R , R , R , R , R , R , A and n are as defined for formula (I) and Alk is 1 2 3 4 5 11 14 as defined before, 5 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 8 8 8 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 10 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, 15 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.

14. Pharmaceutical composition comprising a compound of formula (I) according to any 20 one of claims 1 to 12 or an addition salt thereof with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

15. Use of a compound of formula (I) according to any one of claims 1 to 12 or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament useful as a pro-apoptotic agent. 5

16. Use of a compound of formula (I) according to any one of claims 1 to 12 or an addition salt thereof with a pharmaceutically acceptable acid or base in the manufacture of a medicament for the treatment of cancers and of auto-immune and immune system diseases.

17. Use of a compound of formula (I) according to any one of claims 1 to 12 or an 10 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, lymphoblastic leukaemias, acute myeloid leukaemias, lymphomas, melanomas, malignant haemopathies, myelomas, ovarian cancer, non-small-cell lung cancer, 15 prostate cancer, pancreatic cancer and small-cell lung cancer.

18. Combination of a compound of formula (I) according to any one of claims 1 to 12 with an anti-cancer agent selected from genotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors, kinase inhibitors and antibodies. 20

19. Pharmaceutical composition comprising a combination according to claim 18 in combination with one or more pharmaceutically acceptable excipients.

20. Combination according to claim 18 for use in the treatment of cancers.

21. Use of a combination according to claim 18 in the manufacture of a medicament for the treatment of cancers.

22. Use of a compound of formula (I) according to any one of claims 1 to 12 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.

23. Compound according to any one of claims 1 to 12, substantially as herein described with reference to any example thereof.

24. Process according to claim 13, substantially as herein described with reference to any 10 example thereof.

25. Pharmaceutical composition according to claim 14, or claim 19, substantially as herein described with reference to any example thereof. 15

26. Use according to any one of claims 15 to 17, 21, or 22, substantially as herein described with reference to any example thereof.

27. Combination according to claim 18 or claim 20, substantially as herein described with reference to any example thereof.